Campylobacteriosis Outbreak Linked to Municipal Water, Nebraska, USA, 20211.

In September 2021, eight campylobacteriosis cases were identified in a town in Nebraska, USA. We assessed potential exposures for a case-control analysis. We conducted whole-genome sequencing on Campylobacter isolates from patients' stool specimens. We collected large-volume dead-end ultrafiltration water samples for Campylobacter and microbial source tracking testing at the Centers for Disease Control and Prevention. We identified 64 cases in 2 waves of illnesses. Untreated municipal tap water consumption was strongly associated with illness (wave 1 odds ratio 15.36; wave 2 odds ratio 16.11). Whole-genome sequencing of 12 isolates identified 2 distinct Campylobacter jejuni subtypes (1 subtype/wave). The town began water chlorination, after which water testing detected coliforms. One dead-end ultrafiltration sample yielded nonculturable Campylobacter and avian-specific fecal rRNA genomic material. Our investigation implicated contaminated, untreated, municipal water as the source. Results of microbial source tracking supported mitigation with continued water chlorination. No further campylobacteriosis cases attributable to water were reported.

Risk for Infection in Humans after Exposure to Birds Infected with Highly Pathogenic Avian Influenza A(H5N1) Virus, United States, 2022.

During February 7─September 3, 2022, a total of 39 US states experienced outbreaks of highly pathogenic avian influenza A(H5N1) virus in birds from commercial poultry farms and backyard flocks. Among persons exposed to infected birds, highly pathogenic avian influenza A(H5) viral RNA was detected in 1 respiratory specimen from 1 person.

Elucidation of the GSK3α Structure Informs the Design of Novel, Paralog-Selective Inhibitors.

Glycogen synthase kinase 3 (GSK3) remains a therapeutic target of interest for diverse clinical indications. However, one hurdle in the development of small molecule GSK3 inhibitors has been safety concerns related to pan-inhibition of both GSK3 paralogs, leading to activation of the Wnt/ß-catenin pathway and potential for aberrant cell proliferation. Development of GSK3α or GSK3ß paralog-selective inhibitors that could offer an improved safety profile has been reported but further advancement has been hampered by the lack of structural information for GSK3α. Here we report for the first time the crystal structure for GSK3α, both in apo form and bound to a paralog-selective inhibitor. Taking advantage of this new structural information, we describe the design and in vitro testing of novel compounds with up to ∼37-fold selectivity for GSK3α over GSK3ß with favorable drug-like properties. Furthermore, using chemoproteomics, we confirm that acute inhibition of GSK3α can lower tau phosphorylation at disease-relevant sites in vivo, with a high degree of selectivity over GSK3ß and other kinases. Altogether, our studies advance prior efforts to develop GSK3 inhibitors by describing GSK3α structure and novel GSK3α inhibitors with improved selectivity, potency, and activity in disease-relevant systems.

Longitudinal EEG model detects antisense oligonucleotide treatment effect and increased UBE3A in Angelman syndrome.

Angelman syndrome is a neurodevelopmental disorder caused by deficiency of the maternally inherited UBE3A gene in neurons. Antisense oligonucleotide therapies are under development to reinstate UBE3A protein production. Non-invasive biomarkers to detect target engagement and treatment response are needed to support clinical trials. Delta power measured in the scalp EEG is a reliable biomarker for Angelman syndrome but varies widely across individuals and throughout development, making detection of a treatment effect using single measurements challenging. We utilized a longitudinal dataset of 204 EEG recordings from 56 subjects with Angelman syndrome to develop a natural history model of delta (2-4 Hz) power, with predictors of age, elapsed time, and relative delta power at an initial recording. Using this model, we computed the sample and effect sizes needed to detect a treatment effect in a human clinical trial with 80% power. We applied the same model structure to a mouse model of Angelman syndrome (n = 41) to detect antisense oligonucleotide-mediated treatment effects on absolute delta activity and Ube3a expression. In humans, delta power at a second time point can be reliably predicted using the natural history model. In mice, a treatment effect can be detected after antisense oligonucleotide treatment targeting the Ube3a-antisense transcript through at least 8 weeks post-treatment (P < 1e-15). Deviations in delta power from the expected natural history correlated with Ube3a expression in the mouse model (P < 0.001). Deviations in delta power from a human natural history model in Angelman syndrome can detect antisense oligonucleotide-mediated improvement in Ube3a expression in Angelman syndrome mice and may be relevant for human clinical trials.

Aedes aegypti Identified in York, Nebraska, Through Routine Arboviral Surveillance-August-October 2019.

On August 27, 2019, Aedes aegypti mosquitoes were identified in a neighborhood located in York, NE, through routine arboviral surveillance. Expanded surveillance using traps and morphologic identification revealed 118 adult Ae. aegypti throughout the adjacent neighborhood, including identification from larval sampling. Our findings describe the first recorded Ae. aegypti introduction in Nebraska and provide evidence of a breeding mosquito population, which suggests suitable habitat and the risk of potential establishment, raising concerns about prevention of arboviral diseases in Nebraska.

Multistate Mumps Outbreak Originating from Asymptomatic Transmission at a Nebraska Wedding - Six States, August-October 2019.

In August 2019, 30 attendees at a Nebraska wedding developed mumps after being exposed to one asymptomatic index patient who was fully vaccinated according to Advisory Committee on Immunization Practices (ACIP) recommendations (1), resulting in a multistate outbreak. A public health investigation and response revealed epidemiologic links that extended from the index patient through secondary, tertiary, and quaternary patients and culminated in a measles-mumps-rubella (MMR) booster vaccination campaign in the local community where approximately half of the patients resided.

Successive Norovirus Outbreaks at an Event Center - Nebraska, October-November, 2017.

In October 2017, the Nebraska Department of Health and Human Services (NDHHS) was notified by a local health department of a gastrointestinal illness outbreak among attendees of a wedding reception at facility A, an event center. Shortly thereafter, state and local public health officials began receiving reports of similar gastrointestinal illness among attendees of subsequent facility A events. An investigation was initiated to identify cases, establish the cause, assess possible transmission routes, and provide control recommendations. Overall, 159 cases consistent with norovirus infection (three confirmed and 156 probable) were identified among employees of facility A and attendees of nine facility A events during October 27-November 18, 2017. The investigation revealed a public vomiting episode at the facility on October 27 and at least one employee involved with preparing and serving food who returned to work <24 hours after symptom resolution, suggesting that a combination of contaminated environmental surfaces and infected food handlers likely sustained the outbreak. Recommendations regarding sanitation and excluding ill employees were communicated to facility A management. However, facility A performed minimal environmental cleaning and did not exclude ill employees. Consequently, transmission continued. To prevent persistent norovirus outbreaks in similar settings, public health officials should ensure that involved facilities implement a comprehensive prevention strategy as early as possible that includes extensive sanitation and strict exclusion of ill food handlers for at least 48 hours after symptom resolution (1).

Centers for Disease Control and Prevention's Temporary Epidemiology Field Assignee program: Supporting state and local preparedness in the wake of Ebola.

OBJECTIVES: The Centers for Disease Control and Prevention launched the Temporary Epidemiology Field Assignee (TEFA) Program to help state and local jurisdictions respond to the risk of Ebola virus importation during the 2014-2016 Ebola Outbreak in West Africa. We describe steps taken to launch the 2-year program, its outcomes and lessons learned. METHODS: State and local health departments submitted proposals for a TEFA to strengthen local capacity in four key public health preparedness areas: 1) epidemiology and surveillance, 2) health systems preparedness, 3) health communications, and 4) incident management. TEFAs and jurisdictions were selected through a competitive process. Descriptions of TEFA activities in their quarterly reports were reviewed to select illustrative examples for each preparedness area. RESULTS: Eleven TEFAs began in the fall of 2015, assigned to 7 states, 2 cities, 1 county and the District of Columbia. TEFAs strengthened epidemiologic capacity, investigating routine and major outbreaks in addition to implementing event-based and syndromic surveillance systems. They supported improvements in health communications, strengthened healthcare coalitions, and enhanced collaboration between local epidemiology and emergency preparedness units. Several TEFAs deployed to United States territories for the 2016 Zika Outbreak response. CONCLUSION: TEFAs made important contributions to their jurisdictions' preparedness. We believe the TEFA model can be a significant component of a national strategy for surging state and local capacity in future high-consequence events.

Campylobacteriosis Outbreak Associated with Contaminated Municipal Water Supply - Nebraska, 2017.

In March 2017, the Nebraska Department of Health and Human Services (NDHHS) and the Southwest Nebraska Public Health Department were notified of an apparent cluster of Campylobacter jejuni infections in city A and initiated an investigation. Overall, 39 cases were investigated, including six confirmed and 33 probable. Untreated, unboiled city A tap water (i.e., well water) was the only exposure significantly associated with illness (odds ratio [OR] = 7.84; 95% confidence interval [CI] = 1.69-36.36). City A is served by four untreated wells and an interconnected distribution system. Onsite investigations identified that a center pivot irrigation system intended to pump livestock wastewater from a nearby concentrated animal feeding operation onto adjacent farmland had malfunctioned, allowing excessive runoff to collect in a road ditch near two wells that supplied water to the city. These wells were promptly removed from service, after which no subsequent cases occurred. This coordinated response rapidly identified an important risk to city A's municipal water supply and provided the evidence needed to decommission the affected wells, with plans to build a new well to safely serve this community.

REDCap for Biocontainment Worker Symptom Monitoring.

The Ebola epidemic of 2014 demonstrated that outbreaks of high-consequence infectious diseases, even in remote parts of the world, can affect communities anywhere in the developed world and that every healthcare facility must be prepared to identify, isolate, and provide care for infected patients. The Nebraska Biocontainment Unit (NBU), located at Nebraska Medicine in Omaha, Nebraska, cared for 3 American citizens exposed in West Africa and confirmed with Ebola virus disease (EVD). Symptom monitoring of healthcare workers caring for these patients was implemented, which included twice daily contact to document the absence or presence of signs of fever or illness. This article describes the symptom monitoring experience of the NBU and local and state public health agencies. Based on lessons learned from that experience, we sought a more efficient solution to meet the needs of both the healthcare facility and public health authorities. REDCap, an open-source application used commonly by academic health centers, was used to develop an inexpensive symptom monitoring application that could reduce the burden of managing these activities, thus freeing up valuable time. Our pilot activities demonstrated that this novel use of REDCap holds promise for minimizing costs and resource demands associated with symptom monitoring while offering a more user-friendly experience for people being monitored and the officials managing the response.

Changing Antimicrobial Resistance Trends in Kathmandu, Nepal: A 23-Year Retrospective Analysis of Bacteraemia.

A comprehensive longitudinal understanding of the changing epidemiology of the agents causing bacteraemia and their AMR profiles in key locations is crucial for assessing the progression and magnitude of the global AMR crisis. We performed a retrospective analysis of routine microbiological data from April 1992 to December 2014, studying the time trends of non-Salmonella associated bacteraemia at a single Kathmandu healthcare facility. The distribution of aetiological agents, their antimicrobial susceptibility profiles, and the hospital ward of isolation were assessed. Two hundred twenty-four thousand seven hundred forty-one blood cultures were performed over the study period, of which, 30,353 (13.5%) exhibited growth for non-contaminant bacteria. We observed a significant increasing trend in the proportion of MDR non-Salmonella Enterobacteriaceae (p < 0.001), other Gram-negative organisms (p = 0.006), and Gram-positive organisms (p = 0.006) over time. Additionally, there was an annual increasing trend in the proportion of MDR organisms in bacteria-positive blood cultures originating from patients attending the emergency ward (p = 0.006) and the outpatient department (p = 0.006). This unique dataset demonstrates that community acquired non-Salmonella bacteraemia has become an increasingly important cause of hospital admission in Kathmandu. An increasing burden of bacteraemia associated with MDR organisms in the community underscores the need for preventing the circulation of MDR bacteria within the local population.

TREM2-activating antibodies abrogate the negative pleiotropic effects of the Alzheimer's disease variant Trem2R47H on murine myeloid cell function.

Triggering receptor expressed on myeloid cells 2 (TREM2) is an orphan immune receptor expressed on cells of myeloid lineage such as macrophages and microglia. The rare variant R47H TREM2 is associated with an increased risk for Alzheimer's disease, supporting the hypothesis that TREM2 loss of function may exacerbate disease progression. However, a complete knockout of the TREM2 gene in different genetic models of neurodegenerative diseases has been reported to result in both protective and deleterious effects on disease-related end points and myeloid cell function. Here, we describe a Trem2R47H transgenic mouse model and report that even in the absence of additional genetic perturbations, this variant clearly confers a loss of function on myeloid cells. The Trem2R47H variant-containing myeloid cells exhibited subtle defects in survival and migration and displayed an unexpected dysregulation of cytokine responses in a lipopolysaccharide challenge environment. These subtle phenotypic defects with a gradation in severity across genotypes were confirmed in whole-genome RNA-Seq analyses of WT, Trem2-/-, and Trem2R47H myeloid cells under challenge conditions. Of note, TREM2-activating antibodies that boost proximal signaling abrogated survival defects conferred by the variant and also modulated migration and cytokine responses in an antibody-, ligand-, and challenge-dependent manner. In some instances, these antibodies also boosted WT myeloid cell function. Our studies provide a first glimpse into the boost in myeloid cell function that can be achieved by pharmacological modulation of TREM2 activity that can potentially be ameliorative in neurodegenerative diseases such as Alzheimer's disease.

A 23-year retrospective investigation of Salmonella Typhi and Salmonella Paratyphi isolated in a tertiary Kathmandu hospital.

BACKGROUND: Salmonella serovars Typhi (S. Typhi) and Paratyphi A (S. Paratyphi A), the causative agents of enteric fever, have been routinely isolated organisms from the blood of febrile patients in the Kathmandu Valley since the early 1990s. Susceptibility against commonly used antimicrobials for treating enteric fever has gradually changed throughout South Asia since this time, posing serious treatment challenges. Here, we aimed to longitudinally describe trends in the isolation of Salmonella enterica and assess changes in their antimicrobial susceptibility in Kathmandu over a 23-year period. METHODS: We conducted a retrospective analysis of standardised microbiological data from April 1992 to December 2014 at a single healthcare facility in Kathmandu, examining time trends of Salmonella-associated bacteraemia and the corresponding antimicrobial susceptibility profiles of the isolated organisms. RESULTS: Over 23 years there were 30,353 positive blood cultures. Salmonella enterica accounted for 65.4% (19,857/30,353) of all the bacteria positive blood cultures. S. Typhi and S. Paratyphi A were the dominant serovars, constituting 68.5% (13,592/19,857) and 30.5% (6,057/19,857) of all isolated Salmonellae. We observed (i) a peak in the number of Salmonella-positive cultures in 2002, a year of heavy rainfall and flooding in the Kathmandu Valley, followed by a decline toward pre-flood baseline by 2014, (ii) an increase in the proportion of S. Paratyphi in all Salmonella-positive cultures between 1992 and 2014, (iii) a decrease in the prevalence of MDR for both S. Typhi and S. Paratyphi, and (iv) a recent increase in fluoroquinolone non-susceptibility in both S. Typhi and S. Paratyphi isolates. CONCLUSIONS: Our work describes significant changes in the epidemiology of Salmonella enterica in the Kathmandu Valley during the last quarter of a century. We highlight the need to examine current treatment protocols for enteric fever and suggest a change from fluoroquinolone monotherapy to combination therapies of macrolides or cephalosporins along with older first-line antimicrobials that have regained their efficacy.

Pseudomonas aeruginosa Outbreak in a Neonatal Intensive Care Unit Attributed to Hospital Tap Water.

OBJECTIVE To investigate an outbreak of Pseudomonas aeruginosa infections and colonization in a neonatal intensive care unit. DESIGN Infection control assessment, environmental evaluation, and case-control study. SETTING Newly built community-based hospital, 28-bed neonatal intensive care unit. PATIENTS Neonatal intensive care unit patients receiving care between June 1, 2013, and September 30, 2014. METHODS Case finding was performed through microbiology record review. Infection control observations, interviews, and environmental assessment were performed. A matched case-control study was conducted to identify risk factors for P. aeruginosa infection. Patient and environmental isolates were collected for pulsed-field gel electrophoresis to determine strain relatedness. RESULTS In total, 31 cases were identified. Case clusters were temporally associated with absence of point-of-use filters on faucets in patient rooms. After adjusting for gestational age, case patients were more likely to have been in a room without a point-of-use filter (odds ratio [OR], 37.55; 95% confidence interval [CI], 7.16-∞). Case patients had higher odds of exposure to peripherally inserted central catheters (OR, 7.20; 95% CI, 1.75-37.30) and invasive ventilation (OR, 5.79; 95% CI, 1.39-30.62). Of 42 environmental samples, 28 (67%) grew P. aeruginosa. Isolates from the 2 most recent case patients were indistinguishable by pulsed-field gel electrophoresis from water-related samples obtained from these case-patient rooms. CONCLUSIONS This outbreak was attributed to contaminated water. Interruption of the outbreak with point-of-use filters provided a short-term solution; however, eradication of P. aeruginosa in water and fixtures was necessary to protect patients. This outbreak highlights the importance of understanding the risks of stagnant water in healthcare facilities. Infect Control Hosp Epidemiol 2017;38:801-808.

Gatifloxacin versus ceftriaxone for uncomplicated enteric fever in Nepal: an open-label, two-centre, randomised controlled trial.

BACKGROUND: Because treatment with third-generation cephalosporins is associated with slow clinical improvement and high relapse burden for enteric fever, whereas the fluoroquinolone gatifloxacin is associated with rapid fever clearance and low relapse burden, we postulated that gatifloxacin would be superior to the cephalosporin ceftriaxone in treating enteric fever. METHODS: We did an open-label, randomised, controlled, superiority trial at two hospitals in the Kathmandu valley, Nepal. Eligible participants were children (aged 2-13 years) and adult (aged 14-45 years) with criteria for suspected enteric fever (body temperature ≥38·0°C for ≥4 days without a focus of infection). We randomly assigned eligible patients (1:1) without stratification to 7 days of either oral gatifloxacin (10 mg/kg per day) or intravenous ceftriaxone (60 mg/kg up to 2 g per day for patients aged 2-13 years, or 2 g per day for patients aged ≥14 years). The randomisation list was computer-generated using blocks of four and six. The primary outcome was a composite of treatment failure, defined as the occurrence of at least one of the following: fever clearance time of more than 7 days after treatment initiation; the need for rescue treatment on day 8; microbiological failure (ie, blood cultures positive for Salmonella enterica serotype Typhi, or Paratyphi A, B, or C) on day 8; or relapse or disease-related complications within 28 days of treatment initiation. We did the analyses in the modified intention-to-treat population, and subpopulations with either confirmed blood-culture positivity, or blood-culture negativity. The trial was powered to detect an increase of 20% in the risk of failure. This trial was registered at ClinicalTrials.gov, number NCT01421693, and is now closed. FINDINGS: Between Sept 18, 2011, and July 14, 2014, we screened 725 patients for eligibility. On July 14, 2014, the trial was stopped early by the data safety and monitoring board because S Typhi strains with high-level resistance to ciprofloxacin and gatifloxacin had emerged. At this point, 239 were in the modified intention-to-treat population (120 assigned to gatifloxacin, 119 to ceftriaxone). 18 (15%) patients who received gatifloxacin had treatment failure, compared with 19 (16%) who received ceftriaxone (hazard ratio [HR] 1·04 [95% CI 0·55-1·98]; p=0·91). In the culture-confirmed population, 16 (26%) of 62 patients who received gatifloxacin failed treatment, compared with four (7%) of 54 who received ceftriaxone (HR 0·24 [95% CI 0·08-0·73]; p=0·01). Treatment failure was associated with the emergence of S Typhi exhibiting resistance against fluoroquinolones, requiring the trial to be stopped. By contrast, in patients with a negative blood culture, only two (3%) of 58 who received gatifloxacin failed treatment versus 15 (23%) of 65 who received ceftriaxone (HR 7·50 [95% CI 1·71-32·80]; p=0·01). A similar number of non-serious adverse events occurred in each treatment group, and no serious events were reported. INTERPRETATION: Our results suggest that fluoroquinolones should no longer be used for treatment of enteric fever in Nepal. Additionally, under our study conditions, ceftriaxone was suboptimum in a high proportion of patients with culture-negative enteric fever. Since antimicrobials, specifically fluoroquinolones, are one of the only routinely used control measures for enteric fever, the assessment of novel diagnostics, new treatment options, and use of existing vaccines and development of next-generation vaccines are now a high priority. FUNDING: Wellcome Trust and Li Ka Shing Foundation.

Notes from the Field: Acute Mercury Poisoning After Home Gold and Silver Smelting--Iowa, 2014.

In March 2014, a man, aged 59 years, who lived alone and had been using different smelting techniques viewed on the Internet to recover gold and silver from computer components, was evaluated at a local emergency department for shortness of breath, tremors, anorexia, and generalized weakness. During the smelting processes, he had used hydrogen peroxide, nitric acid, muriatic acid, and sulfuric acid purchased from local stores or Internet retailers. For protection, he wore a military gas mask of unknown type. The mask was used with filter cartridges, but their effectiveness against chemical fumes was not known.

Variation at HLA-DRB1 is associated with resistance to enteric fever.

Enteric fever affects more than 25 million people annually and results from systemic infection with Salmonella enterica serovar Typhi or Paratyphi pathovars A, B or C(1). We conducted a genome-wide association study of 432 individuals with blood culture-confirmed enteric fever and 2,011 controls from Vietnam. We observed strong association at rs7765379 (odds ratio (OR) for the minor allele = 0.18, P = 4.5 × 10(-10)), a marker mapping to the HLA class II region, in proximity to HLA-DQB1 and HLA-DRB1. We replicated this association in 595 enteric fever cases and 386 controls from Nepal and also in a second independent collection of 151 cases and 668 controls from Vietnam. Imputation-based fine-mapping across the extended MHC region showed that the classical HLA-DRB1*04:05 allele (OR = 0.14, P = 2.60 × 10(-11)) could entirely explain the association at rs7765379, thus implicating HLA-DRB1 as a major contributor to resistance against enteric fever, presumably through antigen presentation.

Prolactin/Stat5 and androgen R1881 coactivate carboxypeptidase-D gene in breast cancer cells.

Plasma membrane-bound carboxypeptidase-D (CPD) cleaves C-terminal arginine from extracellular substrates. In the cell, arginine is converted to nitric oxide (NO). We have reported that up-regulation of CPD mRNA/protein levels by 17ß-estradiol and prolactin (PRL) in breast cancer cells, and by testosterone in prostate cancer cells, increased NO production and cell survival. The CPD promoter contains a consensus γ-interferon-activated sequence (GAS) and 3 putative androgen response elements (ARE.1, ARE.2, ARE.3) that could potentially bind PRL-activated transcription factor Stat5 (signal transducer and activator of transcription 5) and the liganded androgen receptor (AR), respectively. This study showed that synthetic androgen R1881 and PRL elevated CPD mRNA/protein levels in human MCF-7 and T47D breast cancer cells in a time-/dose-dependent manner. PRL/R1881-elevated CPD expression was blocked by actinomycin-D, and a CPD promoter construct containing these GAS and AREs was stimulated by PRL or R1881, indicating transcriptional regulation by both hormones. Luciferase reporter assays showed that GAS and the adjacent ARE.1 only were active. Mutation of GAS in the ΔGAS-CPD construct (ARE.1 intact) abolished CPD promoter activity in response to PRL and, surprisingly, to R1881 as well. ΔGAS-CPD promoter activity was restored by PRL+R1881 in combination, and enhanced by ectopic Stat5, but abolished by Stat5 gene knockdown. Chromatin immunoprecipitation analysis confirmed binding of activated Stat5 and liganded AR to GAS and ARE.1, respectively. Activated Stat5 also induced binding of unliganded AR to ARE.1, and liganded AR induced binding of unactivated Stat5 to GAS. In summary, PRL and R1881, acting through Stat5 and AR, act cooperatively to stimulate CPD gene transcription in breast cancer cells.

Progestin-inducible EDD E3 ubiquitin ligase binds to α4 phosphoprotein to regulate ubiquitination and degradation of protein phosphatase PP2Ac.

Mammalian α4 phosphoprotein binds to the protein phosphatase 2A catalytic subunit (PP2Ac) to regulate PP2A activity, and to poly(A)-binding protein (PABP) and progestin-inducible EDD E3 ubiquitin ligase. This study showed induction of the EDD protein by progesterone, 17ß-estradiol and prolactin in breast cancer cells. Co-immunoprecipitation analyses, using lysates of COS-1 cells transfected with α4-deletion constructs, showed the α4 N-terminus binding to endogenous PP2Ac and PABP, and the C-terminus to EDD. Monoubiquitinated α4 in MCF-7 cells was unaffected by EDD-targeting siRNA (siEDD) nor by non-targetting siNT, thus, EDD does not ubiquitinate α4. PP2Ac is polyubiquitinated, and 36-kDa PP2Ac only was detected in siEDD- or siNT-transfected cells. However, treatment with proteasomal inhibitor MG132 showed polyubiquitinated-PP2Ac molecules (∼65-250kDa) abundantly in siNT controls but low in siEDD-transfectants, implicating PP2Ac as an EDD substrate. Finally, progesterone induction of EDD in MCF-7 cells correlated with decreased PP2Ac levels, further implicating hormone-inducible EDD in PP2Ac turnover.

Gatifloxacin versus ofloxacin for the treatment of uncomplicated enteric fever in Nepal: an open-label, randomized, controlled trial.

BACKGROUND: Fluoroquinolones are the most commonly used group of antimicrobials for the treatment of enteric fever, but no direct comparison between two fluoroquinolones has been performed in a large randomised trial. An open-label randomized trial was conducted to investigate whether gatifloxacin is more effective than ofloxacin in the treatment of uncomplicated enteric fever caused by nalidixic acid-resistant Salmonella enterica serovars Typhi and Paratyphi A. METHODOLOGY AND PRINCIPAL FINDINGS: Adults and children clinically diagnosed with uncomplicated enteric fever were enrolled in the study to receive gatifloxacin (10 mg/kg/day) in a single dose or ofloxacin (20 mg/kg/day) in two divided doses for 7 days. Patients were followed for six months. The primary outcome was treatment failure in patients infected with nalidixic acid resistant isolates. 627 patients with a median age of 17 (IQR 9-23) years were randomised. Of the 218 patients with culture confirmed enteric fever, 170 patients were infected with nalidixic acid-resistant isolates. In the ofloxacin group, 6 out of 83 patients had treatment failure compared to 5 out of 87 in the gatifloxacin group (hazard ratio [HR] of time to failure 0.81, 95% CI 0.25 to 2.65, p = 0.73). The median time to fever clearance was 4.70 days (IQR 2.98-5.90) in the ofloxacin group versus 3.31 days (IQR 2.29-4.75) in the gatifloxacin group (HR = 1.59, 95% CI 1.16 to 2.18, p = 0.004). The results in all blood culture-confirmed patients and all randomized patients were comparable. CONCLUSION: Gatifloxacin was not superior to ofloxacin in preventing failure, but use of gatifloxacin did result in more prompt fever clearance time compared to ofloxacin. TRIAL REGISTRATION: ISRCTN 63006567 (www.controlled-trials.com).