IL-13 protects from C. difficile colitis.

OBJECTIVES: Clostridioides difficile infection (CDI) is the leading hospital-acquired infection in North America. We have previously discovered that antibiotic disruption of the gut microbiota decreases intestinal IL-33 and IL-25 and increases susceptibility to CDI. We further found that IL-33 promotes protection through type 2 Innate Lymphoid Cells (ILC2s), which produce IL-13. However, the contribution of IL-13 to disease has never been explored. METHODS: We used a validated model of CDI in mice, in which we neutralized via blocking antibodies, or administered recombinant protein, IL-13 to assess the role of this cytokine during infection using weight and clinical scores. Fluorescent activated cell sorting (FACS) was used to characterize myeloid cell population changes in response to IL-13 manipulation. RESULTS: We found that administration of IL-13 protected, and anti-IL-13 exacerbated CDI. Additionally, we observed alterations to the monocyte/macrophage cells following neutralization of IL-13 as early as day three post infection. We also observed elevated accumulation of myeloid cells by day four post-infection following IL-13 neutralization. Neutralization of the decoy receptor, IL-13Rα2, resulted in protection from disease, likely through increased available endogenous IL-13. CONCLUSIONS: Our data highlight the protective role of IL-13 in protecting from more severe CDI and the association of poor responses with a dysregulated monocyte-macrophage compartment. These results increase our understanding of type 2 immunity in CDI and may have implications for treating disease in patients.

Solitary and periodic waves in collisionless plasmas: The Adlam-Allen model revisited.

We consider the Adlam-Allen (AA) system of partial differential equations, which, arguably, is the first model that was introduced to describe solitary waves in the context of propagation of hydrodynamic disturbances in collisionless plasmas. Here, we identify the solitary waves of the model by implementing a dynamical systems approach. The latter suggests that the model also possesses periodic wave solutions-which reduce to the solitary wave in the limiting case of an infinite period-as well as rational solutions that are obtained herein. In addition, employing a long-wave approximation via a relevant multiscale expansion method, we establish the asymptotic reduction of the AA system to the Korteweg-de Vries equation. Such a reduction is not only another justification for the above solitary wave dynamics, but may also offer additional insights for the emergence of other possible plasma waves. Direct numerical simulations are performed for the study of multiple solitary waves and their pairwise interactions. The stability of solitary waves is discussed in terms of potentially relevant criteria, while the robustness of spatially periodic wave solutions is touched upon via numerical experiments.

Enhanced monocyte recruitment and delayed alternative macrophage polarization accompanies impaired repair following myocardial infarction in C57BL/6 compared to BALB/c mice.

Activation of the innate immune response following myocardial infarction (MI) is essential for infarct repair. Preclinical models of MI commonly use C57BL/6 mice, which have a type 1-dominant immune response, whereas other mouse strains such as BALB/c mice have a type 2-dominant immune response. We compared C57BL/6 and BALB/c mice to investigate whether predisposition towards a proinflammatory phenotype influences the dynamics of the innate immune response to MI and associated infarct healing and the risk of cardiac rupture. MI was induced by permanent coronary artery ligation in 12-15-week-old male wild-type BALB/c and C57BL/6 mice. Prior to MI, C57BL/6 mice had a lower proportion of CD206+ anti-inflammatory macrophages in the heart and an expanded blood pool of proinflammatory Ly6Chigh monocytes in comparison to BALB/c mice. The systemic inflammatory response in C57BL/6 mice following MI was more pronounced, with greater peripheral blood Ly6Chigh monocytosis, splenic Ly6Chigh monocyte mobilization and myeloid cell infiltration of pericardial adipose tissue. This led to an increased and prolonged macrophage accumulation, as well as delayed transition towards anti-inflammatory macrophage polarization in the infarct zone and surrounding tissues of C57BL/6 mice. These findings accompanied a higher rate of mortality due to cardiac rupture in C57BL/6 mice compared with BALB/c mice. We conclude that lower post-MI survival of C57BL/6 mice over BALB/c mice is mediated in part by a more pronounced and prolonged inflammatory response. Outcomes in BALB/c mice highlight the therapeutic potential of modulating resolution of the innate immune response following MI for the benefit of successful infarct healing.

Management of Barrett's esophagus with low-grade dysplasia.

Barrett's esophagus progresses to esophageal adenocarcinoma in a stepwise histological fashion of no dysplasia, low grade dysplasia, high grade dysplasia and cancer. Hence the progression to cancer from various histological stages is different. Progression to cancer from low grade dysplasia is highly variable in the literature due to high inter-observer variability between pathologists in diagnosing it. Studies have shown the utility of having confirmation of low grade dysplasia by expert pathologists or documenting its persistence on two subsequent endoscopies in order to unify the diagnosis. The treatment of low grade dysplasia is variable. In this article we summarize the diagnosis, evaluation and management of low grade dysplasia in Barrett's Esophagus.

Detection of antimicrobial resistance genes associated with the International Space Station environmental surfaces.

Antimicrobial resistance (AMR) is a global health issue. In an effort to minimize this threat to astronauts, who may be immunocompromised and thus at a greater risk of infection from antimicrobial resistant pathogens, a comprehensive study of the ISS "resistome' was conducted. Using whole genome sequencing (WGS) and disc diffusion antibiotic resistance assays, 9 biosafety level 2 organisms isolated from the ISS were assessed for their antibiotic resistance. Molecular analysis of AMR genes from 24 surface samples collected from the ISS during 3 different sampling events over a span of a year were analyzed with Ion AmpliSeq™ and metagenomics. Disc diffusion assays showed that Enterobacter bugandensis strains were resistant to all 9 antibiotics tested and Staphylococcus haemolyticus being resistant to none. Ion AmpliSeq™ revealed that 123 AMR genes were found, with those responsible for beta-lactam and trimethoprim resistance being the most abundant and widespread. Using a variety of methods, the genes involved in antimicrobial resistance have been examined for the first time from the ISS. This information could lead to mitigation strategies to maintain astronaut health during long duration space missions when return to Earth for treatment is not possible.

Scheduling terminology for oral and maxillofacial surgery. Are we speaking a universal language?

Use of a universal vocabulary to assist with the scheduling of operations has been shown to considerably reduce delays and improve the use of theatre resources. Within the UK the National Confidential Enquiry into Patient Outcome and Death (NCEPOD) has established a classification to assist with the triage of both emergency and non-emergency operating lists. We completed a survey to assess the uptake and understanding of this classification when scheduling maxillofacial operations. From a list of eight scheduling terms, respondents had to choose one each for 20 different clinical situations (that represented equally) immediate, urgent, expedited, and elective operations as defined by them. A total of 50 surveys were collated. Only 65% of answers selected represented NCPOD terms. 25% of answers represented a term higher and 18% a term lower, on the scale of intervention for the same category of situation. Current NCEPOD terms do not seem to be used universally and are poorly understood. Considerable variation in terminology exists when scheduling maxillofacial operations.

Utility of sentinel node biopsy in patients with high-risk cutaneous squamous cell carcinoma.

BACKGROUND: Currently there is no consensual agreement on the standard use of Sentinel Lymph Node Biopsy (SLNB) in staging of high-risk patients. OBJECTIVE: The objective was to define the predictive value and role of SLNB combined with the different high-risk factors to determine which patients could benefit from SLNB. METHOD: We conducted a review of the literature on cutaneous squamous cell carcinoma (SCC) and SLNB published in the year 2000 until May 2012. 173 patients with SCC tumors and SLNB were found. Risk factors were listed along with lymph node status. Sensitivity, specificity and negative predictive value (NPV) were calculated for the cumulative results for each risk factor. RESULTS: Sensitivity for the total cohort was 79%, specificity was 100% and negative predictive value was 96%. The sensitivity, specificity and NPV were 78.26%, 100% and 95.14%, respectively, for tumor size >2 cm. Sensitivity, specificity and NPV for a tumor localized at a high-risk area were 72.63%, 100% and 96.74%, respectively. Specificity was 100% as was NPV for immunosuppression. CONCLUSION: SLNB has a high NPV and low false negative rate and carries a low risk of complications. SLNB may prove to enhance the survival or aid the prognosis of high-risk cSCC. Further, detailed investigations and longer follow-up times are needed to define the right group of patients that could benefit from this procedure.

Floating potential of large dust grains in a collisionless flowing plasma.

Dust immersed in plasma quickly charges to a potential where the ion and electron currents to its surface balance; this is the floating potential. In order to accurately determine dust behavior, the floating potential must be known. The charging of dust grains that are small with respect to electron Debye length (λ(D)) may be adequately approximated using the orbital-motion-limited (OML) approach. A modified version of OML is presented for large dust grains in both stationary and flowing plasmas. This modified OML is compared with simulation and found to be in good agreement. The modified OML is applied to large grains charging under tokamak conditions and found to have an appreciable effect on the drag force.

Future prospects and challenges of vaccines against filariasis.

Filarial infections remain a major public health and socio-economic problem across the tropics, despite considerable effort to reduce disease burden or regionally eliminate the infection with mass drug administration programmes. The sustainability of these programmes is now open to question owing to a range of issues, not least of which is emerging evidence for drug resistance. Vaccination, if developed appropriately, remains the most cost-effective means of long-term disease control. The rationale for the feasibility of vaccination against filarial parasites including onchocerciasis (river blindness, Onchocerca volvulus) and lymphatic filariasis (Wuchereria bancrofti or Brugia malayi) is founded on evidence from both humans and animal models for the development of protective immunity. Nonetheless, enormous challenges need to be faced in terms of overcoming parasite-induced suppression without inducing pathology as well as the need to both recognize and tackle evolutionary and ecological obstacles to successful vaccine development. Nonetheless, new technological advances in addition to systems biology approaches offer hope that optimal immune responses can be induced that will prevent infection, disease and/or transmission.

Wakes formed by dust grains in supersonically flowing plasmas.

Interesting wake effects are found in simulations of dust grains in supersonically flowing plasma. A Mach cone is formed at an angle to the flow determined by the ratio of flow to Bohm speed. The latter is well approximated by [k(T(e)+γT(i))/m(i)](1/2) with γ=3. For ion temperatures significantly lower than the electron temperature, a second (inner) cone forms due to flow convergence. An "ion vacuum" and stagnation point occur downstream. These latter effects cannot be described by conventional (cold-ion) gas dynamics. Critically, none of the cones observed are shocks but are more akin to weak discontinuities.

Cold machine perfusion versus static cold storage of kidneys donated after cardiac death: a UK multicenter randomized controlled trial.

One third of deceased donor kidneys for transplantation in the UK are donated following cardiac death (DCD). Such kidneys have a high rate of delayed graft function (DGF) following transplantation. We conducted a multicenter, randomized controlled trial to determine whether kidney preservation using cold, pulsatile machine perfusion (MP) was superior to simple cold storage (CS) for DCD kidneys. One kidney from each DCD donor was randomly allocated to CS, the other to MP. A sequential trial design was used with the primary endpoint being DGF, defined as the necessity for dialysis within the first 7 days following transplant. The trial was stopped when data were available for 45 pairs of kidneys. There was no difference in the incidence of DGF between kidneys assigned to MP or CS (58% vs. 56%, respectively), in the context of an asystolic period of 15 min and median cold ischemic times of 13.9 h for MP and 14.3 h for CS kidneys. Renal function at 3 and 12 months was similar between groups, as was graft and patient survival. For kidneys from controlled DCD donors (with mean cold ischemic times around 14 h), MP offers no advantage over CS, which is cheaper and more straightforward.

Chitinases and chitinase-like proteins: potential therapeutic targets for the treatment of T-helper type 2 allergies.

Mammalian chitinase and chitinase-like proteins (CLPs) are a family of mediators increasingly associated with infection, T cell-mediated inflammation, wound healing, allergy and asthma. Although our current knowledge of the function of mammalian chitinases and CLPs is very limited, important information can be deduced from research carried out in lower organisms, and in different immunopathological conditions. Enzymatically active mammalian chitinase proteins may have evolved to degrade the copious amounts of chitin mammals are exposed to on a daily basis, and to form an innate barrier to chitin-containing organisms. CLPs are homologous to chitinases but lack the ability to degrade chitin. It is most striking that both chitinases and CLPs are up-regulated in T-helper type 2 (Th2)-driven conditions, and the first evidence is now emerging that these proteins may accentuate Th2 reactivity, and possibly contribute to the repair process that follows inflammation. Following studies demonstrating that chitinase inhibition leads to an attenuated allergic response, several strategies are being used to develop enzyme inhibitors for therapeutic use in human diseases. In this review, we will summarize recent insights into the effects of chitinases and CLPs in the context of Th2-dominated pathology with particular focus on allergy and asthma, discussing whether chitinase enzyme inhibitors may be of therapeutic value.

Prolonged recovery of consciousness in children following symptomatic epileptic seizures.

INTRODUCTION: There is little published data on the duration of depressed consciousness following epileptic seizures. A prolonged recovery time may be a symptom of underlying brain pathology. This prospective paediatric cohort study investigates whether recovery is prolonged following symptomatic seizures. METHODS: Children aged 1-16 years, who had a witnessed seizure in which consciousness was impaired, were recruited. One hundred and twenty eight children (158 seizures) were studied. Seizure aetiology was classified as febrile, idiopathic, remote symptomatic, acute symptomatic and acute on remote symptomatic. At least hourly Paediatric Coma Scale recordings were used to assess recovery time. RESULTS: Recovery time was longest for children with acute on remote symptomatic seizures (4.0 h, range 0.89-10.5), followed by those with acute symptomatic seizures (1.94 h, range 0-35.27), remote symptomatic seizures (1.5h, range 0.07-85.5) and idiopathic seizures (0.83 h, range 0.07-13.13). Children with febrile seizures recovered the quickest (0.3h, range 0.05-9). Recovery time was significantly longer (p<0.001, CI 1.96-5.38) following seizures for which rescue antiepileptic drugs were administered compared to those for which it was not. Age, sex, type and duration of seizure did not independently affect recovery time. DISCUSSION: Symptomatic seizures take longer to recover than seizures of other aetiologies. It is recommended that a febrile child who presents with a seizure, who has not fully recovered within 30 min, should be investigated for an acute symptomatic aetiology. A high index of suspicion is also needed if children with apparent idiopathic seizures have not fully recovered within 1.5h.

Does Litomosoides sigmodontis synthesize dimethylethanolamine from choline?

Juvenile female Litomosoides sigmodontis secrete a protein (Juv-p120) highly modified with dimethylethanolamine (DMAE). In an attempt to establish the source of this decoration worms were pulsed with [3H]-choline and [3H]-ethanolamine and the radio-isotope labelled products analysed. Both isotope labels were successfully taken up by the worms, as demonstrated by labelling of phospholipids with [3H]-choline, being predominantly incorporated into phosphatidylcholine and [3H]-ethanolamine into phosphatidylethanolamine. Isotope labelling of phosphatidylethanolamine was particularly striking with the worms taking up approximately 30 times as much labelled ethanolamine as choline. It was possible to detect faint labelling of Juv-p120 with [3H]-ethanolamine after prolonged exposure periods but, unlike the situation with the phospholipids, it was much more readily labelled with [3H]-choline. When pulsing with [3H]-ethanolamine it was also possible to detect isotope-labelled phosphatidylcholine, which may ultimately account for the low levels of labelling of Juv-p120. Overall our results raise the previously unconsidered but intriguing possibility that in L. sigmodontis, choline may be the precursor of DMAE.

Recovery of consciousness after epileptic seizures in children.

OBJECTIVE: To investigate the duration of postictal impairment of consciousness and the factors that affect it. PATIENTS AND METHODS: 90 children aged 1-16 years (37 male, 53 female, median age 6 years), attending the accident and emergency department, and inpatients of Leeds General Infirmary, Leeds, UK, who had experienced seizures involving impairment of consciousness. Interventions-hourly modified paediatric coma scores were determined, until a coma score of 15 was obtained. Linear regression analysis was used to determine the factors influencing recovery time. RESULTS: 49 children were excluded owing to incomplete coma scoring, lost notes and refusal of consent. Median time for full recovery of consciousness was 38 min (0.63 h, range 0.05-17 h). Median recovery time was 18 min (0.3 h, range 0.05-9 h) from febrile seizures, which was significantly shorter than for seizures of other aetiologies (p<0.05), 1.35 h (range 0.07-13.13 h) from idiopathic seizures, 1.25 h (0.07-12.1 h) from remote symptomatic seizures and 4.57 h (0.25-17 h) from acute symptomatic seizures. Median recovery time after the use of benzodiazepines was 3.46 h (range 0.08-14.25 h), and was significantly longer (p<0.05) than for seizures not treated with benzodiazepines (median 0.47 h, range 0.05-17 h). Age, sex, seizure type and duration did not significantly affect recovery time. CONCLUSIONS: Most children experiencing febrile seizures recover within 30 min. An acute symptomatic aetiology should be considered if recovery takes >1 h.

Parasite genetic diversity does not influence TNF-mediated effects on the virulence of primary rodent malaria infections.

The pro-inflammatory cytokine tumour necrosis factor alpha (TNF-alpha) is associated with malaria virulence (disease severity) in both rodents and humans. We are interested in whether parasite genetic diversity influences TNF-mediated effects on malaria virulence. Here, primary infections with genetically distinct Plasmodium chabaudi chabaudi (P.c.c.) clones varied in the virulence and cytokine responses induced in female C57BL/6 mice. Even when parasitaemia was controlled for, a greater day 7 TNF-alpha response was induced by infection with more virulent P.c.c. clones. Since many functions of TNF-alpha are exerted through TNF receptor 1 (TNFR1), a TNFR-1 fusion protein (TNFR-Ig) was used to investigate whether TNFR1 blockade eliminated clone virulence differences. We found that TNFR-1 blockade ameliorated the weight loss but not the anaemia induced by malaria infection, regardless of P.c.c. clone. We show that distinct P.c.c. infections induced significantly different plasma interferon gamma (IFN-gamma), interleukin 6 (IL-6) and interleukin 10 (IL-10) levels. Our results demonstrate that regardless of P.c.c. genotype, blocking TNFR1 signalling protected against weight loss, but had negligible effects on both anaemia and asexual parasite kinetics. Thus, during P.c.c. infection, TNF-alpha is a key mediator of weight loss, independent of parasite load and across parasite genotypes.

Co-infected C57BL/6 mice mount appropriately polarized and compartmentalized cytokine responses to Litomosoides sigmodontis and Leishmania major but disease progression is altered.

This study examines the capacity of the mammalian host to fully compartmentalize the response to infection with type 1 vs. type 2 inducing organisms that infect different sites in the body. For this purpose, C57BL/6 mice were infected with the rodent filarial nematode Litomosoides sigmodontis followed by footpad infection with the protozoan parasite Leishmania major. In this host, nematode infection is established in the thoracic cavity but no microfilariae circulate in the bloodstream. We utilized quantitative ELISPOT analysis of IL-4 and IFN-gamma producing cells to assess cytokine bias and response magnitude in the lymph nodes draining the sites of infection as well as more systemic responses in the spleen and serum. Contrary to other systems where co-infection has a major impact on bias, cytokine ratios were unaltered in either local lymph node. The most notable effect of co-infection was an unexpected increase in the magnitude of the IFN-gamma response to L. major in mice previously infected with L. sigmodontis. Further, lesion development was significantly delayed in these mice. Thus, despite the ability of the immune system to appropriately compartmentalize the immune response, interactions between responses at distinct infection sites can alter disease progression.

The transcriptional landscape of the mammalian genome.

This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.