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.

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.

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.

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.

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.

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.

Human red blood cells: prostaglandin E2, epinephrine, and isoproterenol alter deformability.

The human red blood cell responds to prostaglandin E(2), epinephrine, and isoproterenol with a decrease in deformability. The maximum decrease is brought about by 10(-10)M prostaglandin E(2), 10(-9)M epinephrine, or 10(-7)M isoproterenol. The dose response curve is biphasic. The sensitivity of the red cell to prostaglandin suggests that this cell may be a primary target for prostaglandin action. These changes in response to vasoactive substances indicate that the red cell must be considered an active element in circulatory control.

Evolution and immunology. The economics of immunity.

Our vigilant immune systems are ready to mount an attack as soon as an invading pathogen is spotted. But what is the cost of keeping this sophisticated defense system on red alert? In a provocative Perspective, Read and Allen discuss new findings showing that the cost of immune defense in animals is very high (Moret and Schmid-Hempel), and the claim that, in some circumstances, the cost may be worth the benefit gained (Nunn et al.).

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.

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.

The effect of catecholamines and prostaglandins upon human and rat erythrocytes.

Both human and rat erythrocytes respond to low doses (10(-11)--10(-9) M) of L-isoproterenol and L-epinephrine with an increased degree of hypotonic hemolysis and a decreased rate of filtration through standardized paper filters. The receptors in both cell types have many of the characteristics of beta-receptors for catecholamines. However, hormone-receptor interaction in the human cell does not lead to an increase in intracellular cyclic AMP concentration, but in the rat cell, hormone-receptor interaction does lead to a significant increase in cyclic AMP content. Thus, catecholamine-beta-receptor interaction, at least in the human red cell, leads to a change in red cell properties which are not mediated by adenylate cyclase activation. Likewise, prostaglandin E2, at 10(-12)--10(-10) M, causes are increased degree of hypotonic hemolysis and a decreased rate of filtration through standardized paper filters, but it also does not increase the cycliC AMP content of the human erythrocyte but does increase that of the rat erythrocyte. Nevertheless, exogenous cyclic AMP, when added at a concentration of 10(-8) M to washed human erythrocytes, increases the degree of hypotonic hemolysis. Conversely, prostaglandin E1, at 10(-12)--10(-10) M, causes a decreased degree of hypotonic hemolysis and an increased rate of filtration through a standard filter. Both prostaglandin E2 and the catecholamines decrease the size of a rapidly exchangeable calcium pool, and prostaglandin E1 increases it.

The use of different induction and maintenance chemotherapy regimens for the treatment of advanced yolk sac tumors.

Four children with yolk sac tumor were treated with an aggressive combination chemotherapy program. Three children had presacral primary tumors, one having pulmonary metastases, and one had a testicular primary tumor with pulmonary metastases. Three children were treated when they had measurable disease, and one had no measurable disease. The chemotherapy program consisted of a 6-wk induction period with vincristine (VCR), cis-diamminedichloroplatinum (DDP), and bleomycin. Maintenance therapy consisted of VCR, actinomycin D, and cyclophosphamide (cytoxan) every 3-4 wk as tolerated. Treatment was discontinued after 12 mo of complete remission. All three patients with evaluable disease had a partial response (PR) to induction therapy. Two underwent surgical exploration following induction therapy, one a laparotomy and the other a thoracotomy, and were found to have only scar tissue at the sites of presumed residual disease. The third child with measurable disease progressed to a clinical complete response (CR) during maintenance therapy. Two patients have had no evidence of disease (NED) for 42+ and 41+ mo since starting therapy (28+ and 27+ mo since completing treatment). Two patients are NED 11+ and 7+ mo since starting therapy and remain on treatment. We have encountered no significant renal or pulmonary toxicity, and there have been only two hospitalizations during maintenance therapy for fever and neutropenia. These preliminary results employing different induction and maintenance chemotherapy programs and planned second-look surgical intervention appear encouraging.

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.

The gp15/400 polyprotein antigen of Brugia malayi binds fatty acids and retinoids.

Gp15/400 is a surface-proximal antigen of the filarial nematode Brugia malayi, produced as a large polyprotein precursor comprising an array of polypeptide units of approx. 14.5 kDa. Here we describe a biochemical function for gp15/400. A single 14.5-kDa unit of gp15/400 has been expressed in Escherichia coli, and found to dimerise spontaneously. This protein (designated P-RUNG) has high-affinity fatty acid and retinoid binding activity, suggesting that the parent polypeptide itself has these properties. Fluorescent fatty acid probes show significant enhancement of fluorescence intensity and shifts in emission wavelength in the presence of P-RUNG, which can be reversed by competing non-fluorescent fatty acids (oleic, palmitic, steric, arachidonic), retinoids (retinol and retinoic acid) and oleoyl Coenzyme A, but not by tryptophan, cholesterol, caproic acid, squalene, tocopherol, tocopherol acetate, succinyl CoA, 2-methylbutyric acid and 2-methylvaleric acid. Changes in intrinsic fluorescence of retinol or retinoic acid confirmed the retinoid binding function. The results of fluorescence titration experiments are consistent with stoichiometric binding to a single protein site per monomer unit with affinities (Kd) in the range 2 x 10(-6) M (for the fluorescent probe 11-((5-dansyl)amino)undecanoic acid) and 2 x 10(-7) M (for oleic acid). The extreme blue shift of the fluorescent fatty acid-protein complex suggests an unusually low polarity for the protein binding site. The intrinsic fluorescence of the single tryptophan residue of P-RUNG indicates that it also is deeply buried in a non-polar environment, but is probably not involved in ligand binding. Gp15/400, therefore, represents a new class of lipid binding protein which is possibly restricted to nematodes.

Value of the American College of Cardiology/American Heart Association stenosis morphology classification for coronary interventions in the late 1990s.

The goal of this study was to reassess the accuracy of the American College of Cardiology/American Heart Association (ACC/AHA) stenosis morphology classification for predicting coronary intervention success and complications in the era of new devices. Previous studies performed in the early part of this decade for percutaneous transluminal coronary angioplasty in patients with multivessel coronary artery disease found that these criteria were predictive of success rates but not complication rates. Data for 957 consecutive coronary interventions in 1,404 lesions from June 1994 to October 1996 were prospectively classified according to ACC/AHA guidelines and entered into a database. Ninety-one and 9/10 of coronary interventions were successful, defined as <50% residual stenosis of each vessel attempted in the absence of major in-hospital complications, including Q-wave myocardial infarction, ventricular arrhythmia, need for emergency coronary artery bypass surgery, or death. Success rates did not differ between A (186 of 193, 96.3%), B1 (211 of 221, 95.5%), and B2 (676 of 711, 95.1%) lesions, but each was more successful than C (246 of 279, 88.2%) lesions (p <0.003, p < 0.004, and p = 0.0001, respectively). The class of lesion (A, B, or C) did not predict device (atherectomy, rotablator, and stent) use but specific morphologic characteristics of lesions within these classes were predictive of which device was used. Multiple regression analysis revealed that total occlusion and vessel tortuosity were predictive of procedure failure. Lesion type (A, B, or C) was not predictive of complications, but bifurcation lesions (p = 0.0045), presence of thrombus (p = 0.0001), inability to protect a major side branch (p = 0.0468), and degenerated vein graft lesions (p = 0.0283) were predictive. Thus, the ACC/AHA grading system is predictive of successful coronary intervention outcome, particularly of C-type characteristics, but not of complications or device success rate and selection. Although lesion type (A, B, or C) was not predictive of complications, specific lesion morphologies were predictive of adverse events and device use.

TASTRAK spectroscopy of polonium-210 alpha-particle activity at bone surfaces: evidence for a concentrated surface deposit less than 3 microns deep.

The technique of alpha-particle spectroscopy by CR-39 type TASTRAK plastic has been used to study the depth distribution of natural alpha-particle emitters at the surface of human bone. The predominant component of this alpha-particle activity was 210Po supported by 210Pb, although a smaller activity of 226Ra was also detected. Autopsy samples of human femur and cranium were obtained from subjects age 63 to 86. Both cortical and trabecular surfaces were analyzed. The results indicate that 210Pb-supported 210Po is concentrated at the surfaces of human bone from elderly subjects, in a narrow band 3 microns deep or less, by a factor of about four. As a result, the alpha-particle dose to the nuclei of cells lining bone surfaces is around 1.8 times greater than that calculated for a uniform volume distribution. Polonium-210 activity indicates the distribution of 210Pb, and of stable lead, received by continuous intake throughout life at a very low level. A persistent bone surface concentration of lead and other osteotropic metals may be associated with the hypermineralized layer about 1 micron thick which occurs at the surface of resting bone mineral.

Fetal dosimetry from natural alpha-particle emitters.

The alpha-particle dose to human fetal bone marrow from natural exposure was investigated. The rate of calcification and the (210)Pb activity levels in fetal vertebrae showed that (210)Pb follows the uptake of calcium into the skeleton. Lead-210-supported (210)Po activity concentrations of up to 0.18 Bq kg(-1) were found in fetal lumbar vertebra. The mean chord length of the trabecular spaces in lumbar vertebra were 110-320 micrometer at 20- 40 weeks, in rib 130-180 micrometer at 20-35 weeks, and in sternum 190 micrometer at 35 weeks of gestation. In lumbar vertebra, up to 80% of marrow was within alpha-particle range (37 micrometer) of a bone surface. This resulted in a gestational equivalent dose to marrow from (210)Pb-supported (210)Po in bone of 8 and 24 micrometerSv when the contribution from all major natural alpha-particle-emitting radionuclides was considered. The mean distance of CD34(+) cells from the nearest bone surfaces in lumbar vertebra was 61 and 46 micrometer at mid- and late gestation, respectively. The mean cellular and nuclear diameters of CD34(+) cells were 5.5 and 3.8 micrometer respectively, and remained constant with gestational age. Few stem cells were hit by alpha particles at natural exposure; however, those that were hit received doses of up to 1.3 Gy.