Surveillance for norovirus and enteric bacterial pathogens as etiologies of acute gastroenteritis at U.S. military recruit training centers, 2011-2016.

An estimated 179 million cases of acute gastroenteritis (AGE) occur each year in the U.S. and AGE is commonly reported within both training and deployed U.S. military populations. Beginning in 2011, the Operational Infectious Diseases laboratory at Naval Health Research Center (NHRC) has undertaken routine surveillance of four U.S. military training facilities to systematically track the prevalence of AGE and to establish its etiologies among U.S. military recruits. Employing both molecular and standard microbiological techniques, NHRC routinely assays for pathogens of direct military relevance, including norovirus genogroups I and II, Salmonella, Shigella, and Campylobacter. During its initial surveillance efforts (2011-2016), NHRC identified norovirus as the primary etiology of both sporadic cases and outbreaks of AGE among trainees.

Incidence, Etiology and Risk Factors for Travelers' Diarrhea during a Hospital Ship-Based Military Humanitarian Mission: Continuing Promise 2011.

Travelers' diarrhea (TD) is the most common ailment affecting travelers, including deployed U.S. military. Continuing Promise 2011 was a 5-month humanitarian assistance/disaster response (HA/DR) military and non-governmental organization training mission aboard the hospital ship USNS Comfort, which deployed to Central and South America and the Caribbean between April and September 2011. Enhanced TD surveillance was undertaken during this mission for public health purposes. Passive surveillance (clinic visits), active surveillance (self-reported questionnaires), and stool samples were collected weekly from shipboard personnel. Descriptive statistics and multivariate-logistic regression methods were used to estimate disease burden and risk factor identification. Two polymerase chain reaction methods on frozen stool were used for microbiological identification. TD was the primary complaint for all clinic visits (20%) and the leading cause of lost duties days due to bed rest confinement (62%), though underreported, as the active self-reported incidence was 3.5 times higher than the passive clinic-reported incidence. Vomiting (p = 0.002), feeling lightheaded or weak (p = 0.005), and being a food handler (p = 0.017) were associated with increased odds of lost duty days. Thirty-eight percent of self-reported cases reported some amount of performance impact. Based on the epidemiological curve, country of exercise and liberty appeared to be temporally associated with increased risk. From the weekly self-reported questionnaire risk factor analysis, eating off ship in the prior week was strongly associated (adjusted odds ratio [OR] 2.4, p<0.001). Consumption of seafood increased risk (aOR 1.7, p = 0.03), though consumption of ice appeared protective (aOR 0.3, p = 0.01). Etiology was bacterial (48%), with enterotoxigenic Escherichia coli as the predominant pathogen (35%). Norovirus was identified as a sole pathogen in 12%, though found as a copathogen in an additional 6%. Despite employment of current and targeted preventive interventions, ship-board HA/DR missions may experience a significant risk for TD among deployed US military personnel and potentially impact mission success.

Gabapentin therapy of hiccups.

OBJECTIVE: To determine whether gabapentin is effective in the treatment of persistent or intractable hiccups. DATA SOURCES: A search of MEDLINE (1966-March 2013) using the MeSH search terms gabapentin, hiccups, and hiccups/drug therapy was performed. Additional databases searched included Web of Science (1945-March 2013) and International Pharmaceutical Abstracts (1970-March 2013) using the text words gabapentin and hiccups. Bibliographies of relevant articles were reviewed for additional citations. STUDY SELECTION AND DATA EXTRACTION: All data sources were considered for inclusion. Preference was given for articles written in English, although one abstract in German was used. DATA SYNTHESIS: Because of the low incidence of persistent or intractable hiccups, few if any controlled clinical trials are conducted on the efficacy of drug treatment. Therefore, most of the data involve case reports or case series. We evaluated 17 case reports and 2 case series involving gabapentin therapy for persistent or intractable hiccups. Therapeutic outcomes with gabapentin were positive in all cases, with temporal evidence suggesting an effect, but outcomes often were obscured by combination therapy and comorbidities in some cases. Case reports suggest that gabapentin might be useful as a second-line agent in patients undergoing stroke rehabilitation or in the palliative care setting where chlorpromazine adverse effects are undesirable. Gabapentin was very well tolerated, with only a few minor adverse effects. CONCLUSIONS: Gabapentin has a similar body of evidence as other pharmacotherapeutic agents used to treat hiccups. Gabapentin is well tolerated and should be considered as a second-line agent in selected patients.

A review and assessment of drug-induced parotitis.

OBJECTIVE: To review the current literature on drug-induced parotitis. DATA SOURCES: Literature was accessed through MEDLINE/PubMed (1980-May 2012), using the search terms sialadenitis/chemically induced and parotitis/chemically induced. EMBASE (1980-May 2012) was searched using the terms parotitis/diagnosis, sialadenitis/side effect, and parotitis/side effect. International Pharmaceutical Abstracts (1970-May 2012) was searched using the search terms parotitis and sialadenitis. All searches were limited to articles on humans written in English. Inclusion criteria were published letters, case reports, reviews, and clinical trials involving drugs that may be associated with parotitis. Articles pertaining to parotitis induced by iodine-containing drugs were excluded. References of all relevant articles were reviewed for additional citations. STUDY SELECTION AND DATA EXTRACTION: Review articles, clinical trials, background data, and case reports of drug-induced parotitis were collected and case reports were assessed for causality. DATA SYNTHESIS: Parotitis is an uncommon adverse effect; however, signs and symptoms of parotitis have been noted in case reports as an adverse drug reaction related to various medications. Assessing causality of an adverse drug reaction such as parotitis is challenging. To help determine the probability of causality for these events, algorithms such as the Naranjo probability scale have been developed. Eighty-four case reports of drug-induced parotitis from 40 different drugs were reviewed using a modified Naranjo probability scale that included criteria specific for parotitis. Medications that met the criteria for establishing causality included l-asparaginase with 7 case reports, clozapine with 13 case reports, and phenylbutazone with 13 case reports. CONCLUSIONS: Drug-induced parotitis is a rare adverse drug reaction. Based on the quantitative and qualitative evidence collected from the case reports, medications that are associated with drug-induced parotitis include l-asparaginase, clozapine, and phenylbutazone. Many other drugs have been implicated in the development of parotitis; however, the evidence supporting this association is insufficient to determine causality at this time.

Rapid steps in the glmS ribozyme catalytic pathway: cation and ligand requirements.

The glmS ribozyme is a conserved riboswitch found in numerous Gram-positive bacteria and responds to the cellular concentrations of glucosamine 6-phosphate (GlcN6P). GlcN6P binding promotes site-specific self-cleavage in the 5' UTR of the glmS mRNA, resulting in downregulation of gene expression. The glmS ribozyme has previously been shown to lack strong cation specificity when the rate-limiting folding step of the cleavage reaction pathway is measured. This does not provide data regarding cation and ligand specificities of the glmS ribozyme during the rapid ligand binding chemical catalysis events. Prefolding of the ribozyme in Mg(2+)-containing buffers effectively isolates the rapid ligand binding and catalytic events (k(obs) > 60 min(-1)) from rate-limiting folding (k(obs) < 4 min(-1)). Here we employ this experimental design to assay the cations and ligand requirements for rapid ligand binding and catalysis. We show that molar concentrations of monovalent cations are also capable of inducing the formation of the native GlcN6P binding structure but are unable to promote ligand binding and catalysis rates of >4 min(-1). Our data show that the sole obligatory role for divalent cations, for which there is crystallographic evidence, is coordination of the phosphate moiety of GlcN6P in the ligand-binding pocket. In further support of this hypothesis, our data show that a nonphosphorylated analogue of GlcN6P, glucosamine, is unable to promote rapid ligand binding and catalysis in the presence of divalent cations. Folding of the ribozyme is, therefore, relatively independent of cation identity, but the rapid initiation of catalysis upon the addition of ligand is stricter.

A rate-limiting conformational step in the catalytic pathway of the glmS ribozyme.

The glmS ribozyme is a conserved riboswitch in numerous Gram-positive bacteria and is located upstream of the glucosamine-6-phosphate (GlcN6P) synthetase reading frame. Binding of GlcN6P activates site-specific self-cleavage of the glmS mRNA, resulting in the downregulation of glmS gene expression. Unlike other riboswitches, the glmS ribozyme does not undergo structural rearrangement upon metabolite binding, indicating that the metabolite binding pocket is preformed in the absence of ligand. This observation led us to test if individual steps in the reaction pathway could be dissected by initiating the cleavage reaction before or after Mg(2+)-dependent folding. Here we show that self-cleavage reactions initiated with simultaneous addition of Mg(2+) and GlcN6P are slow (3 min(-1)) compared to reactions initiated by addition of GlcN6P to glmS RNA that has been prefolded in Mg(2+)-containing buffer (72 min(-1)). These data indicate that some level of Mg(2+)-dependent folding is rate-limiting for catalysis. Reactions initiated by addition of GlcN6P to the prefolded ribozyme also resulted in a 30-fold increase in the apparent ligand K(d) compared to those of reactions initiated by a global folding step. Time-resolved hydroxyl-radical footprinting was employed to determine if global tertiary structure formation is the rate-limiting step. The results of these experiments provided evidence for fast and largely concerted folding of the global tertiary structure (>13 min(-1)). This indicates that the rate-limiting step that we have identified either is a slow folding step between the fast initial folding and ligand binding events or represents the rate of escape from a nativelike folding trap.

Inhibitors of cellular signalling are cytotoxic or block the budded-to-hyphal transition in the pathogenic yeast Candida albicans.

The pathogenic yeast Candida albicans can grow in multiple morphological states including budded, pseudohyphal and true hyphal forms. The ability to interconvert between budded and hyphal forms, herein termed the budded-to-hyphal transition (BHT), is important for C. albicans virulence, and is regulated by multiple environmental and cellular signals. To identify small-molecule inhibitors of known cellular processes that can also block the BHT, a microplate-based morphological assay was used to screen the BIOMOL-Institute of Chemistry and Cell Biology (ICCB) Known Bioactives collection from the ICCB-Longwood Screening Facility (Harvard Medical School, Boston, MA, USA). Of 480 molecules tested, 53 were cytotoxic to C. albicans and 16 were able to block the BHT without inhibiting budded growth. These 16 BHT inhibitors affected protein kinases, protein phosphatases, Ras signalling pathways, G protein-coupled receptors, calcium homeostasis, nitric oxide and guanylate cyclase signalling, and apoptosis in mammalian cells. Several of these molecules were also able to inhibit filamentous growth in other Candida species, as well as the pathogenic filamentous fungus Aspergillus fumigatus, suggesting a broad fungal host range for these inhibitory molecules. Results from secondary assays, including hyphal-specific transcription and septin localization analysis, were consistent with the inhibitors affecting known BHT signalling pathways in C. albicans. Therefore, these molecules will not only be invaluable in deciphering the signalling pathways regulating the BHT, but also may serve as starting points for potential new antifungal therapeutics.

Increased male-male courtship in ecdysone receptor deficient adult flies.

Male-male courtship is infrequent among mature adult Drosophila melanogaster. After pairs of mature adult males expressing a temperature-sensitive allele of the ecdysone receptor (EcR) gene were treated at a restrictive temperature, however, they engaged in elevated levels of male-male courtship. EcR-deficient males courted wildtype males and females, but were not courted by wildtype males. These results suggest that the ecdysone steroid hormone system may have a role in courtship initiation by adult male fruit flies.