Burden of Norovirus and Rotavirus in Children after Rotavirus Vaccine Introduction,Cochabamba, Bolivia

The effectiveness of rotavirus vaccine in the field may set the stage for a changing landscape of diarrheal illness affecting children worldwide. Norovirus and rotavirus are the two major viral enteropathogens of childhood. This study describes the prevalence of norovirus and rotavirus 2 years after widespread rotavirus vaccination in Cochabamba, Bolivia. Stool samples from hospitalized children with acute gastroenteritis (AGE) and outpatients aged 5–24 months without AGE were recruited from an urban hospital serving Bolivia''s third largest city. Both viruses were genotyped, and norovirus GII.4 was further sequenced. Norovirus was found much more frequently than rotavirus. Norovirus was detected in 69/201 (34.3%) of specimens from children with AGE and 13/71 (18.3%) of those without diarrhea. Rotavirus was detected in 38/201 (18.9%) of diarrheal specimens and 3/71 (4.2%) of non-diarrheal specimens. Norovirus GII was identified in 97.8% of norovirus-positive samples; GII.4 was the most common genotype (71.4% of typed specimens). Rotavirus G3P[8] was the most prevalent rotavirus genotype (44.0% of typed specimens) and G2P[4] was second most prevalent (16.0% of typed specimens). This community is likely part of a trend toward norovirus predominance over rotavirus in children after widespread vaccination against rotavirus.     

The effect of neighborhood-level socioeconomic status on racial differences in ovarian cancer treatment in a population-based analysis in Chicago

Background

Less than half of women with ovarian cancer and blacks specifically receive therapy adherent to National Comprehensive Cancer Network (NCCN) guidelines. The purpose is to assess the effect of neighborhood-level socioeconomic status (SES) on black-white treatment differences in a population-based analysis in a highly-segregated community.

Methods

Illinois State Cancer Registry data for invasive epithelial ovarian cancer cases diagnosed in Cook County, IL in non-Hispanic white (NHW) or black (NHB) women from 1998 to 2009 was analyzed. As few women receive NCCN-adherent care, variables were constructed to assess extent of treatment, including receipt of: 1) debulking surgery; 2) any surgery; 3) multi-agent chemotherapy; and 4) any chemotherapy. Two measures (concentrated affluence and disadvantage) were used to estimate neighborhood-level SES. Multivariable logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (95% CI), with generalized linear mixed models to account for hierarchical data.

Results

2766 (81.0%) NHW and 647 (19.0%) NHB women were diagnosed. Adjusting for covariates, NHB were less likely to receive debulking surgery (OR: 0.39; 95% CI: 0.30–0.50), any surgery (OR: 0.38; 95%CI: 0.29–0.49), multi-agent chemotherapy (OR: 0.56; 95% CI: 0.45–0.71) and any chemotherapy (OR: 0.58; 95% CI: 0.45–0.74). Concentrated affluence but not disadvantage was significant in final models for multi-agent and any chemotherapy, but not debulking or any surgery.

Conclusions

Results identify black-white differences consistent across treatments that persist despite adjustment for neighborhood-level SES.

Impact

Results advance inequality awareness beyond “ideal” NCCN-adherent care, indicating inequality exists in delivery of even the most basic oncologic care.     

Progressive Cellular Senescence Mediates Renal Dysfunction in Ischemic Nephropathy

BackgroundPeripheral vascular diseases may induce chronic ischemia and cellular injury distal to the arterial obstruction. Cellular senescence involves proliferation arrest in response to stress, which can damage neighboring cells. Renal artery stenosis (RAS) induces stenotic-kidney dysfunction and injury, but whether these arise from cellular senescenceand their temporal pattern remain unknown.MethodsChronic renal ischemia was induced in transgenic INK-ATTAC and wild type C57BL/6 mice by unilateral RAS, and kidney function (in vivo micro-MRI) and tissue damage were assessed. Mouse healthy and stenotic kidneys were analyzed using unbiased single-cell RNA-sequencing. To demonstrate translational relevance, cellular senescence was studied in human stenotic kidneys.ResultsUsing intraperitoneal AP20187 injections starting 1, 2, or 4 weeks after RAS, selective clearance of cells highly expressing p16^Ink4a attenuated cellular senescence and improved stenotic-kidney function; however, starting treatment immediately after RAS induction was unsuccessful. Broader clearance of senescent cells, using the oral senolytic combination dasatinib and quercetin, in C57BL/6 RAS mice was more effective in clearing cells positive for p21 (Cdkn1a) and alleviating renal dysfunction and damage. Unbiased, single-cell RNA sequencing in freshly dissociated cells from healthy and stenotic mouse kidneys identified stenotic-kidney epithelial cells undergoing both mesenchymal transition and senescence. As in mice, injured human stenotic kidneys exhibited cellular senescence, suggesting this process is conserved.ConclusionsMaladaptive tubular cell senescence, involving upregulated p16 (Cdkn2a), p19 (Cdkn2d), and p21 (Cdkn1a) expression, is associated with renal dysfunction and injury in chronic ischemia. These findings support development of senolytic strategies to delay chronic ischemic renal injury.     

Effects of atomoxetine on subjective and neurocognitive symptoms of nicotine abstinence

Nicotine dependence has been linked to attention-deficit hyperactivity disorder (ADHD) symptoms in both clinical and general populations. This behavioural pharmacology study used a within-subject, double-blind, crossover design to test the effects of atomoxetine, a medication for ADHD, on nicotine abstinence symptoms. Fifty non treatment-seeking smokers (>/=15 cigarettes/day) completed a baseline session when they were smoking as usual and then two laboratory testing sessions after overnight abstinence and treatment with 7 days of either atomoxetine (1.2 mg/kg) or placebo. During each laboratory session, participants completed subjective measures of abstinence symptoms and performed neurocognitive tasks. In mixed effects models, atomoxetine, compared with placebo, was found to be associated with a reduction in abstinence-induced subjective withdrawal symptoms. Atomoxetine was also associated with significant reductions in self-reported smoking urges amongst smokers who scored high on a baseline measure of smoking for stimulation. However, atomoxetine had no effect on any of the cognitive tasks employed in the study. Thus, atomoxetine may reduce cravings to smoke among smokers who use nicotine to increase arousal.     

A naturally chimeric type IIA topoisomerase in Aquifex aeolicus highlights an evolutionary path for the emergence of functional paralogs

Bacteria frequently possess two type IIA DNA topoisomerases, gyrase and topo IV, which maintain chromosome topology by variously supercoiling, relaxing, and disentangling DNA. DNA recognition and functional output is thought to be controlled by the C-terminal domain (CTD) of the topoisomerase DNA binding subunit (GyrA/ParC). The deeply rooted organism Aquifex aeolicus encodes one type IIA topoisomerase conflictingly categorized as either DNA gyrase or topo IV. To resolve this enzyme's catalytic properties and heritage, we conducted a series of structural and biochemical studies on the isolated GyrA/ParC CTD and the holoenzyme. Whereas the CTD displays a global structure similar to that seen in bone fide GyrA and ParC paralogs, it lacks a key functional motif (the "GyrA-box") and fails to wrap DNA. Biochemical assays show that the A. aeolicus topoisomerase cannot supercoil DNA, but robustly removes supercoils and decatenates DNA, two hallmark activities of topo IV. Despite these properties, phylogenetic analyses place all functional domains except the CTD squarely within a gyrase lineage, and the A. aeolicus GyrB subunit is capable of supporting supercoiling with Escherichia coli GyrA, but not DNA relaxation with E. coli ParC. Moreover, swapping the A. aeolicus GyrA/ParC CTD with the GyrA CTD from Thermotoga maritima creates an enzyme that negatively supercoils DNA. These findings identify A. aeolicus as the first bacterial species yet found to exist without a functional gyrase, and suggest an evolutionary path for generation of bacterial type IIA paralogs.     

A novel recruitment message to increase enrollment into a smoking cessation treatment program: preliminary results from a randomized trial

Most smokers do not utilize approved interventions for nicotine dependence, reducing the probability of cessation. Smoking cessation programs typically use recruitment messages emphasizing the health threats of smoking. Augmenting this threat message by describing the genetic aspects of nicotine addiction may enhance enrollment into a cessation program. During telephone recruitment, 125 treatment-seeking smokers were randomized to receive by phone either a standard threat message or a threat plus genetic prime message and were offered open-label varenicline and counseling. There was a greater rate of enrollment into the cessation program for the threat plus genetic prime participants (51.7%) versus the threat-only participants (37.7%; p = .03). Smokers who self-identified from racial/ethnic minority groups were less likely to enroll in the cessation program (p = .01) versus smokers who self-identified as Caucasian. These preliminary data suggest that a simple, affordable, and transportable communication approach enhances enrollment of smokers into a smoking cessation program. A larger clinical trial to evaluate a genetic prime message for improving recruitment into smoking cessation programs is warranted.     

The use of lightly embalmed (fresh tissue) cadavers for resident laparoscopic training

STUDY OBJECTIVE: The value of a cadaver training program in laparoscopic surgery has rarely been studied. As there is a dearth of cadaver training programs, it is important to evaluate them. The goal of this study was to estimate if our cadaver training program significantly and relatively rapidly taught residents laparoscopic surgical skills. DESIGN: Observational, timed comparative study (Canadian Task Force classification II-3). SETTING: University of Louisville School of Medicine, Fresh Tissue Laboratory, Louisville, KY. PARTICIPANTS: Twenty-nine obstetric/gynecology residents (15 postgraduate year PGY 2 and 14 PGY 3) participated in the study. INTERVENTION: During 5 half days, we compared the performance of each postgraduate year (PGY) 2 and PGY 3 obstetric/gynecology resident to his or her own results on five outcome skills before and after training in lightly embalmed cadavers. The testing was performed at the beginning and at the end of the week so that all improvement was secondary only to the training experience with the cadaver. Residents were assessed using laparoscopic techniques in a physical-reality simulator for three outcomes: bead transfer time, number of beads transferred, and suturing time on a stuffed vinyl glove and in two specific areas of the cadaver pelvis, with one slightly more difficult than the other. Assessment of suturing time was made on the two distinct tasks using the embalmed cadavers. Although the number of residents was relatively small, it covered two levels for one year. MEASUREMENTS AND MAIN RESULTS: The residents were assessed on a simulator before and after laparoscopic surgical training on the cadaver. The median decrease in bead transfer time (task I, simulator) was 38.5 seconds (p=.02); 69% of the residents showed some reduction in time to complete this task. The median increase in the number of beads transferred (task II, simulator) was 2.5 beads (p=.0001); 72.4% of the residents transferred at least one more bead after training. The median decrease in suture time (task III, simulator) was 63.5 seconds (p=.001); 79.3% of the residents performed this task more quickly after training. The median decrease in suture time (task IV, cadaver) was 54.5 seconds (p=.001); 72.4% of the residents showed improved performance on this task after training. The median reduction in suture time (task V, cadaver) was 53.5 seconds (p<.001); 82.8% of the residents completed this task more quickly after training. CONCLUSIONS: This cadaver surgical training program appeared to significantly improve laparoscopic surgical techniques in PGY 2 and PGY 3 obstetric/gynecology residents in a relatively short time. This model teaches residents specific training in the handling and manipulation of tissue as well as practice in surgical techniques for adnexal surgery, pelvic dissection, laparoscopic hysterectomy, and dissection within the space of Retzius that is not possible with mechanical trainers.     

Bosentan preserves endothelial function in mice overexpressing APP

This study was designed to test the hypothesis that Alzheimer's disease (AD) is associated with endothelial dysfunction and that chronic endothelin-1 antagonism preserves endothelial function in mice overexpressing the AD amyloid precursor protein (APP). Three groups of mice were studied: C57BL/6 (normal control, n = 6), transgenic mice overexpressing APP (Tg2576, n = 5), and Tg2576 mice fed Bosentan (100 mg/(kg day)(-1)), a combined endothelin A and B receptor antagonist, for 4 months (Tg2576+Bosentan, n = 5). Mice were sacrificed at the age of 7 months. In vitro, the endothelium-dependent aortic vasorelaxation was significantly attenuated in Tg2576 mice as compared to C57BL/6 and Tg2576+Bosentan mice. In contrast, Tg2576+Bosentan and C57BL/6 mice showed similar endothelium-dependent aortic vasorelaxation. Similarly, endothelium-dependent carotid vasorelaxation was significantly attenuated in Tg2576 mice compared to C57BL/6 and Tg2576+Bosentan mice. There was no difference between the three groups in the response to nitroprusside. The current study demonstrates the presence of endothelial dysfunction in both carotid and aortic arteries in mice overexpressing APP and suggests a pathophysiological role for the endogenous endothelin system in AD.