Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility.

Intestinal peristalsis is a dynamic physiologic process influenced by dietary and microbial changes. It is tightly regulated by complex cellular interactions; however, our understanding of these controls is incomplete. A distinct population of macrophages is distributed in the intestinal muscularis externa. We demonstrate that, in the steady state, muscularis macrophages regulate peristaltic activity of the colon. They change the pattern of smooth muscle contractions by secreting bone morphogenetic protein 2 (BMP2), which activates BMP receptor (BMPR) expressed by enteric neurons. Enteric neurons, in turn, secrete colony stimulatory factor 1 (CSF1), a growth factor required for macrophage development. Finally, stimuli from microbial commensals regulate BMP2 expression by macrophages and CSF1 expression by enteric neurons. Our findings identify a plastic, microbiota-driven crosstalk between muscularis macrophages and enteric neurons that controls gastrointestinal motility. PAPERFLICK:

Effects of in ovo injection of bacterial peptides and CpG-ODN on Salmonella enterica serovar Heidelberg infection in specific pathogen-free (SPF) chicks.

RESEARCH HIGHLIGHTS: Peptides + CpG-ODN reduced SH in caeca at the first week post-infection.Administered formulations did not reduce SH-faecal excretion.Levels of intestinal IgA were similar between all groups.CpG-ODN improved some parameters associated with chick intestinal health.

AB569, a nontoxic chemical tandem that kills major human pathogenic bacteria.

Antibiotic-resistant superbug bacteria represent a global health problem with no imminent solutions. Here we demonstrate that the combination (termed AB569) of acidified nitrite (A-NO2-) and Na2-EDTA (disodium ethylenediaminetetraacetic acid) inhibited all Gram-negative and Gram-positive bacteria tested. AB569 was also efficacious at killing the model organism Pseudomonas aeruginosa in biofilms and in a murine chronic lung infection model. AB569 was not toxic to human cell lines at bactericidal concentrations using a basic viability assay. RNA-Seq analyses upon treatment of P. aeruginosa with AB569 revealed a catastrophic loss of the ability to support core pathways encompassing DNA, RNA, protein, ATP biosynthesis, and iron metabolism. Electrochemical analyses elucidated that AB569 produced more stable SNO proteins, potentially explaining one mechanism of bacterial killing. Our data implicate that AB569 is a safe and effective means to kill pathogenic bacteria, suggesting that simple strategies could be applied with highly advantageous therapeutic/toxicity index ratios to pathogens associated with a myriad of periepithelial infections and related disease scenarios.

Acute Kidney Injury within an Enhanced Recovery after Surgery (ERAS) Program for Colorectal Surgery.

BACKGROUND: We aimed to determine the prevalence, risk factors, and outcomes of acute kidney injury (AKI) within an ERAS program for colorectal surgery (CRS). METHODS: This is a retrospective case-control study conducted from March 2016 to September 2018 at a single tertiary hospital in Singapore. All adult patients requiring CRS within our ERAS program were considered eligible. Exclusions were stage 5 chronic kidney disease or patients requiring a synchronous liver resection. The primary outcome was AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. Secondary outcomes included mortality, major complications, and hospital length of stay. Patient, surgical, and anaesthesia-related data were analysed to determine factors associated with AKI. RESULTS: A total of 575 patients were eligible for the study. Twenty patients were excluded from the study leaving 555 patients for analysis. Mean age was 67.8 (SD 11.4) years. Seventy-four patients met the criteria for AKI (13.4%: stage 1-11.2%, stage 2-2.0%, stage 3-0.2%). One patient required renal replacement therapy (RRT). Patients with AKI had a longer length of stay (median [IQR], 11.0 [5.0-17.0] days vs 6.0 [4.0-8.0] days; P < .001), more major complications (OR, 6.55; 95% CI, 3.00-14.35, P < .001), and a trend towards higher mortality at one year (OR, 1.44; 95% CI 0.48-4.30; p = 0.511. After multivariable regression analysis, factors associated with AKI were preoperative creatinine (OR, 1.01 per 10 µmol/l; 95% CI, 1.03-1.22; P = 0.01), robotic surgery vs open surgery (OR, 0.15; 95% CI, 0.06-0.39; P < 0.001), anaesthesia duration (OR, 1.38 per hour; 95% CI, 1.22-1.55; P < 0.001), and major complications (OR, 5.55; 95% CI, 2.63-11.70; P < 0.001). CONCLUSIONS: Within the present cohort, the implementation of an ERAS program for CRS was associated with a low prevalence of moderate to severe AKI despite a balanced intravenous fluid regimen. Patients having open surgery, longer procedures, and major complications are at increased risk of AKI.

Temporal changes in blood pressure following prehospital rapid sequence intubation.

BACKGROUND: Rapid Sequence intubation (RSI) is an airway procedure that uses sedative and paralytic drugs to facilitate endotracheal intubation. It is known that RSI could impact blood pressure in the peri-intubation period. However, little is known about blood pressure changes in longer time frames. Therefore, this analysis aims to describe the changes in systolic blood pressure in a large cohort of paramedic-led RSI cases over the whole prehospital timespan. METHODS: Intensive Care Paramedics in Victoria, Australia, are authorised to use RSI in medical or trauma patients with a Glasgow Coma Scale <10. This retrospective cohort study analysed data from patientcare records for patients aged 12 years and above that had received RSI, from 1 January 2008 to 31 December 2019. This study quantifies the systolic blood pressure changes using regression with fractional polynomial terms. The analysis is further stratified by high versus Low Shock Index (LSI). The shock index is calculated by dividing pulse rate by systolic blood pressure. RESULTS: During the study period RSI was used in 8613 patients. The median number of blood pressure measurements was 5 (IQR 3-8). Systolic blood pressure rose significantly by 3.4 mm Hg (p<0.001) and then returned to baseline in the first 5 min after intubation for LSI cases. No initial rise in blood pressure is apparent in High Shock Index (HSI) cases. Across the whole cohort, systolic blood pressure decreased by 7.1 mm Hg (95% CI 7.9 to 6.3 mm Hg; p<0.001) from the first to the last blood pressure measured. CONCLUSIONS: Our study shows that in RSI patients a small transient elevation in systolic blood pressure in the immediate postintubation period is found in LSI, but this elevation is not apparent in HSI. Blood pressure decreased over the prehospital phase in RSI patients with LSI, but increased for HSI cases.

Primary Corrosion Processes for Polymer-Embedded Free-Standing or Substrate-Supported Silicon Microwire Arrays in Aqueous Alkaline Electrolytes.

Solar fuel devices have shown promise as a sustainable source of chemical fuels. However, long-term stability of light absorbing materials remains a substantial barrier to practical devices. Herein, multiple corrosion pathways in 1 M KOH(aq) have been defined for TiO2-protected Si microwire arrays in a polymer membrane either attached to a substrate or free-standing. Top-down corrosion was observed in both morphologies through defects in the TiO2 coating. For the substrate-based samples, bottom-up corrosion was observed through the substrate and up the adjacent wires. In the free-standing samples, uniform bottom-up corrosion was observed through the membrane with all wire material corroded within 10 days of immersion in the dark in 1 M KOH(aq).

Gravity assisted reduction of ankle (GARA) fractures: Results of a novel technique for relocating displaced ankle fractures in the emergency setting in comparison to traditional manipulation and reduction (TMR) technique.

BACKGROUND: Ankle fracture displacements cause significant discomfort to the patient and can compromise soft tissues including the neurovascular structures. Prompt reduction and plaster splint application are vital in the early management of these potentially limb-threatening conditions. The process can be distressing for the patient often requiring additional personnel or equipment. We have used a novel technique of Gravity Assisted Reduction of Ankle (GARA) fractures and compared the results with the Traditional Manipulation and Reduction (TMR) technique. MATERIAL AND METHODS: With adequate analgesia, the patient turns to lay either in lateral or prone position depending on fracture pattern, thus permitting gravity to gradually aid in reduction and hold the fracture in place while Plaster Of Paris (POP) is applied. We performed a retrospective comparative study of GARA vs TMR using validated radiological parameters to assess the quality of reduction with both techniques. RESULTS: 21 patients had GARA technique, in comparison with 19 patients in TMR group. All measured radiological parameters showed similar improvement in both the groups, despite the fact that the pronation-external rotation injury pattern was more often seen in the GARA group. Intravenous sedation and monitoring were needed in 10 patients of TMR group, none in GARA group. On an average 4 personnel needed for TMR, but only 2 personnel needed for GARA technique. CONCLUSION: Gravity assisted ankle fracture reduction is a simple, effective and reproducible alternative technique to TMR, with no need of intravenous sedation along with fewer people needed to perform the procedure. LEVEL OF EVIDENCE: 3b.

Heat stress impairs egg production in commercial laying hens infected by fowl typhoid.

Salmonella Gallinarum (SG) is an avian-restricted pathogen that causes fowl typhoid in poultry. Although it has been reported frequently over many decades in poultry flocks worldwide, the microorganism is more commonly associated with poultry in developing countries, particularly those with high ambient temperatures, where the acute form of the disease results in considerable economic losses. A more detailed investigation of environmental factors that affect the course of disease may assist in identifying effective prevention and control measures. Heat stress is known to impair the immunological response to a variety of pathogens and clearly may be an important contributory factor in the prevalence of disease in countries with warm or hot climates. Thus, the objective of the present study was to evaluate the effects of heat stress on chickens infected with SG. For this, light and semi-heavy commercial laying hens were distributed randomly within four groups as follows: infected and non-infected groups in rooms held at ambient temperature, and infected and non-infected groups under heat stress. Clinical signs, egg production, and mortality were recorded daily. Bacteriological counts in liver and spleen samples were estimated at 2, 5, 7, and 14 days post-infection. The results showed that both SG infection and heat stress had similar effects on egg production and a synergistic effect of the two stressors was observed. The data show an interaction between disease and heat stress which could point towards environmental and biosecurity approaches to resolving the possible 30% fall in production observed in such countries.

Predictors of endometrial carcinoma in patients with atypical endometrial hyperplasia at a tertiary gynaecological cancer centre in Western Australia.

AIM: Our objective was to assess clinical and pathological factors associated with a final diagnosis of endometrial carcinoma in patients with atypical endometrial hyperplasia with a particular emphasis on the grading of atypia. MATERIALS AND METHODS: A retrospective review over five years on patients (N = 97) who underwent hysterectomy for a diagnosis of atypical endometrial hyperplasia at a statewide public tertiary gynaecologic oncology centre. Clinical and pathological characteristics were obtained. RESULTS: The rate of concurrent endometrial carcinoma was 34% (n = 33) with most being stage 1A endometrioid. A significant group difference was reported for age at diagnosis (t = -2.20 P = 0.031 d = 0.43) with carcinoma patients on average older (Mage  = 60.2 (8.9) years) than patients without carcinoma (Mage  = 55.5 (12.3) years). No significant group differences were found for body mass index, endometrial thickness or time between diagnosis and treatment. Significantly higher rates of carcinoma were reported in patients with moderate atypical hyperplasia (27.6%) and severe atypical hyperplasia (66.7%), compared to mild atypical hyperplasia (7.1%). Only severe atypical hyperplasia (odds ratio (OR) = 21.5, 95% CI 2.8-163.1, P = 0.003) and postmenopausal status (OR = 13.2, 95% CI 1.3-139.0, P = 0.032) significantly increased the risk of carcinoma in a multivariate model. CONCLUSION: Severe atypical hyperplasia and postmenopausal status were significant predictors of concurrent endometrial carcinoma in patients with atypical endometrial hyperplasia. The grading of atypical hyperplasia may be utilised by gynaecologic oncologists in the triage and referral process of managing these patients; however, the grading system requires external validation in larger prospective studies.

Determining the prognostic significance of IKKα in prostate cancer.

BACKGROUND: As the survival of castration-resistant prostate cancer (CRPC) remains poor, and the nuclear factor-κB (NF-κB) pathways play key roles in prostate cancer (PC) progression, several studies have focused on inhibiting the NF-κB pathway through generating inhibitory κB kinase subunit α (IKKα) small molecule inhibitors. However, the identification of prognostic markers able to discriminate which patients could benefit from IKKα inhibitors is urgently required. The present study investigated the prognostic value of IKKα, IKKα phosphorylated at serine 180 (p-IKKα S180) and threonine 23 (p-IKKα T23), and their relationship with the androgen receptor (AR) and Ki67 proliferation index to predict patient outcome. METHODS: A cohort of 115 patients with hormone-naïve PC (HNPC) and CRPC specimens available were used to assess tumor cell expression of proteins within both the cytoplasm and the nucleus by immunohistochemistry. The expression levels were dichotomized (low vs high) to determine the associations between IKKα, AR, Ki67, and patients'Isurvival. In addition, an analysis was performed to assess potential IKKα associations with clinicopathological and inflammatory features, and potential IKKα correlations with other cancer pathways essential for CRPC growth. RESULTS: High levels of cytoplasmic IKKα were associated with a higher cancer-specific survival in HNPC patients with low AR expression (hazards ratio [HR], 0.33; 95% confidence interval [CI] log-rank, 0.11-0.98; P = .04). Furthermore, nuclear IKKα (HR, 2.60; 95% CI, 1.27-5.33; P = .01) and cytoplasmic p-IKKα S180 (HR, 2.10; 95% CI, 1.17-3.76; P = .01) were associated with a lower time to death from recurrence in patients with CRPC. In addition, high IKKα expression was associated with high levels of T-cells (CD3+ P = .01 and CD8+ P = .03) in HNPC; however, under castration conditions, high IKKα expression was associated with high levels of CD68+ macrophages (P = .04), higher Gleason score (P = .01) and more prostate-specific antigen concentration (P = .03). Finally, we identified crosstalk between IKKα and members of the canonical NF-κB pathway in the nucleus of HNPC. Otherwise, IKKα phosphorylated by noncanonical NF-κB and Akt pathways correlated with members of the canonical NF-κB pathway in CRPC. CONCLUSION: The present study reports that patients with CRPC expressing high levels of nuclear IKKα or cytoplasmic p-IKKα S180, which associated with a lower time to death from recurrence, may benefit from IKKα inhibitors.

Reduction of Salmonella contamination on the surface of chicken skin using bacteriophage.

BACKGROUND: Enteric infections caused by Salmonella spp. remain a major public health burden worldwide. Chickens are known to be a major reservoir for this zoonotic pathogen. The presence of Salmonella in poultry farms and abattoirs is associated with financial costs of treatment and a serious risk to human health. The use of bacteriophages as a biocontrol is one possible intervention by which Salmonella colonization of chickens could be reduced. In a prior study, phages Eϕ151 and Tϕ7 significantly reduced broiler chicken caecal colonization by S. Enteritidis and S. Typhimurium respectively. METHODS: Salmonella-free Ross broiler chickens were orally infected with S. Enteritidis P125109 or S. Typhimurium 4/74. After 7 days of infection, the animals were euthanased, and 25cm2 sections of skin were collected. The skin samples were sprayed with a phage suspension of either Eϕ151 (S. Enteritidis), Tϕ7 phage suspension (S. Typhimurium) or SM buffer (Control). After incubation, the number of surviving Salmonellas was determined by direct plating and Most Probable Number (MPN). To determine the rate of reduction of Salmonella numbers on the skin surface, a bioluminescent S. Typhimurium DT104 strain was cultured, spread on sections of chicken breast skin, and after spraying with a Tϕ11 phage suspension, skin samples were monitored using photon counting for up to 24 h. RESULTS: The median levels of Salmonella reduction following phage treatment were 1.38 log10 MPN (Enteritidis) and 1.83 log10 MPN (Typhimurium) per skin section. Treatment reductions were significant when compared with Salmonella recovery from control skin sections treated with buffer (p < 0.0001). Additionally, significant reduction in light intensity was observed within 1 min of phage Tϕ11 spraying onto the skin contaminated with a bioluminescent Salmonella recombinant strain, compared with buffer-treated controls (p < 0.01), implying that some lysis of Salmonella was occurring on the skin surface. CONCLUSIONS: The results of this study suggest that phages may be used on the surface of chicken skin as biocontrol agents against Salmonella infected broiler chicken carcasses. The rate of bioluminescence reduction shown by the recombinant Salmonella strain used supported the hypothesis that at least some of the reduction observed was due to lysis occurred on the skin surface.

PD-L1-Independent Mechanisms Control the Resistance of Melanoma to CD4+ T Cell Adoptive Immunotherapy.

Immunotherapy is becoming the standard of care for melanoma. However, resistance to therapy is a major problem. Previously, we showed that tumor-specific, cytotoxic CD4+ T cells from tyrosinase-related protein 1 transgenic mice could overcome secondary resistance to recurring melanoma when anti-programmed cell death 1 ligand (PD-L1) checkpoint blockade was combined with either anti-lymphocyte-activated gene 3 (LAG-3) Abs or depletion of tumor-specific regulatory T (Treg) cells. In this study, we show that PD-L1 expressed by the host, not B16 melanoma, plays a major role in the early stages of exhaustion or primary resistance. We observed durable regression of melanoma in tumor-bearing PD-L1-/-RAG-/- mice with transfer of naive tumor-specific CD4+ T cells. However, exhausted tumor-specific CD4+ T cells, which included tumor-specific Treg cells, failed to maintain durable regression of tumors in PD-L1-/-RAG-/- mice unless tumor-specific Treg cells were eliminated, showing nonredundant pathways of resistance to immunotherapy were present. Translating these findings to a clinically relevant model of cancer immunotherapy, we unexpectedly showed that anti-PD-L1 checkpoint blockade mildly improved immunotherapy with tumor-specific CD4+ T cells and irradiation in wild-type mice. Instead, anti-LAG-3 checkpoint blockade, in combination with tumor-specific CD4+ T cells and irradiation, overcame primary resistance and treated established tumors resulting in fewer recurrences. Because LAG-3 negatively regulates effector T cell function and activates Treg cells, LAG-3 blockade may be more beneficial in overcoming primary resistance in combination immunotherapies using adoptive cellular therapy and irradiation than blockade of PD-L1.

The utility of the brain trauma evidence to inform paramedic rapid sequence intubation in out-of-hospital stroke.

BACKGROUND: Rapid sequence intubation (RSI) is used to secure the airway of stroke patients. Randomized controlled trial evidence exists to support the use of paramedic RSI for traumatic brain injury (TBI), but cannot necessarily be applied to stroke RSI because of differences between the stroke and TBI patient. To understand if the TBI evidence can be used for stroke RSI, we analysed a retrospective cohort of TBI and strokes to compare how survival is impacted differently by RSI when comparing strokes and TBI. METHODS: This study was a retrospective analysis of 10 years of in-hospital and out-of-hospital data for all stroke and TBI patients attended by Ambulance Victoria, Australia. Logistic regression predicted the survival for ischemic and haemorrhagic strokes as well as TBI. The constituents of RSI, such a medications, intubation success and time intervals were analysed against survival using interactions to asses if RSI impacts survival differently for strokes compared to TBI. RESULTS: This analysis found significant interactions in the RSI-only group for age, number of intubation attempts, atropine, fentanyl, pulse rate and perhaps scene time and time- to-RSI. Such interactions imply that RSI impact survival differently for TBI versus strokes. Additionally, no significant difference in survival for TBI was found, with a - 0.7% lesser survival for RSI compared to no-RSI; OR 0.86 (95% CI 0.67 to 1.11; p = 0.25). Survival for haemorrhagic stroke was - 14.1% less for RSI versus no-RSI; OR 0.44 (95% CI 0.33 to 0.58; p = 0.01) and was - 4.3%; OR 0.67 (95% CI 0.49 to 0.91; p = 0.01) lesser for ischemic strokes. CONCLUSIONS: Rapid sequence intubation and related factors interact with stroke and TBI, which suggests that RSI effects stroke survival in a different way from TBI. If RSI impact survival differently for strokes compared to TBI, then perhaps the TBI evidence cannot be used for stroke RSI.

The association of paramedic rapid sequence intubation and survival in out-of-hospital stroke.

INTRODUCTION: Ambulance transport of patients with stroke is common, with rapid sequence intubation (RSI) to secure the airway used regularly. Randomised controlled trial evidence exists to support the use of RSI in traumatic brain injuries (TBIs), but it is not clear whether the RSI evidence from TBI can be applied to the patient with stroke. To this end, we analysed a retrospective stroke dataset to compare survival of patients with RSI compared with patients that did not receive RSI. METHODS: This study was a retrospective analysis of 10 years of in-hospital and out-of-hospital data for all patients with stroke attended by Ambulance Victoria, in Victoria Australia. Generalised boosted logistic regression was used to predict propensity scores, with initial vital signs, age and demographic variables as well as measures of illness severity and comorbidity included in the prediction model. This analysis employed a 1:1 nearest-neighbour matching which was applied to generate a dataset from which we calculated the OR of survival to hospital discharge of patients receiving RSI versus no-RSI. The sensitivity of these results to unmeasured confounding was assessed with deterministic sensitivity analysis. RESULTS: The propensity score-matched cohort showed a decreased survival for RSI in strokes with an OR 0.61 (95% CI 0.45 to 0.82; p=0.001) when compared with no-RSI. A subgroup analysis showed no significant survival difference for ischaemic strokes: OR 0.66 (95% CI 40 to 1.07; p=0.09). The survival for haemorrhagic stroke was OR 0.60 (95% CI 0.41 to 0.90; p=0.01) lesser for RSI. Results were likely robust to unmeasured confounding and missing data. CONCLUSIONS: Our retrospective analysis shows a decrease in survival when RSI is utilised by paramedics for stroke. Since RSI is commonly used for strokes, controlled trial evidence to support this practice is urgently needed.

Suitability of the Cyclic Voltammetry Measurements and DPPH• Spectrophotometric Assay to Determine the Antioxidant Capacity of Food-Grade Oenological Tannins.

Twenty commercially available oenological tannins (including hydrolysable and condensed) were assessed for their antiradical/reducing activity, comparing two analytical approaches: The 2,2-diphenyl-1-picrylhydrazyl (DPPH•) radical scavenging spectrophotometric assay and the cyclic voltammetry (CV) electrochemical method. Electrochemical measurements were performed over a -200 mV-500 mV scan range, and integrated anodic currents to 500 mV were used to build a calibration graph with (+)-catechin as a reference standard (linear range: From 0.0078 to 1 mM, R2 = 0.9887). The CV results were compared with the DPPH• assay (expressed as % of radical scavenged in time), showing high correlation due to the similarity of the chemical mechanisms underlying both methods involving polyphenolic compounds as reductants. Improved correlation was observed by increasing the incubation time with DPPH• to 24 h (R2 = 0.925), demonstrating that the spectrophotometric method requires a long-term incubation to complete the scavenging reaction when high-molecular weight tannins are involved; this constraint has been overcome by using instant CV measurements. We concluded that the CV represents a valid alternative to the DPPH• colorimetric assay, taking advantage of fast analysis and control on the experimental conditions and, because of these properties, it can assist the quality control along the supply chain.

Reported analgesic and anaesthetic administration to non-human primates undergoing experimental surgical procedure: 2010-2015.

BACKGROUND: The use of non-human primates (NHPs) in research remains a major societal concern with public expectations that appropriate anaesthetics and analgesics are used to minimize any pain or distress caused to animals undergoing invasive procedures. A literature review was conducted to examine the reporting of anaesthesia and analgesia methods used in non-human primates undergoing surgical procedures, with recovery from anaesthesia. METHODS: A total of 397 papers from peer-review journals published between 2010 and 2015 were examined. RESULTS: Only 25.9% of papers reported the analgesic regimen used, with carprofen and buprenorphine the 2 most widely used agents. Reporting of the anaesthetic regimens was included in 49.9% of papers. Ketamine and isoflurane were the most frequently used anaesthetic agents. CONCLUSIONS: Anaesthetic and analgesic regimens administered to NHPs remain poorly reported. This lack of detailed descriptions of protocols does little to reassure the public or regulatory authorities that appropriate high standards of perioperative care are employed.

Parental psychopathology and expectations for the futures of children with autism spectrum disorder.

BACKGROUND: The influence of parental psychopathology and parental expectations on child well-being is well documented among typically developing populations. However, to date little research has examined the relationship among these factors in families of children with autism spectrum disorder (ASD). This study examines an observed relationship between parental psychopathology and expectations in families with children with ASD in the light of research in other populations. METHOD: Twenty-four parents of children diagnosed with ASD were assessed for symptoms of psychopathology. Parents completed measures of child ASD severity as well as their expectations for possible outcomes of their child. RESULTS: Two main effects were found: higher parental psychopathology and ASD severity were both related to lower expectations. Interaction of ASD severity and parental psychopathology in relation to parent expectations was not observed. CONCLUSION: These results emphasize the necessity of providing services not only to individuals diagnosed with ASD, but to caregivers as well.

High IKKα expression is associated with reduced time to recurrence and cancer specific survival in oestrogen receptor (ER)-positive breast cancer.

The aim of our study was to examine the relationship between tumour IKKα expression and breast cancer recurrence and survival. Immunohistochemistry was employed in a discovery and a validation tissue microarray to assess the association of tumour IKKα expression and clinico-pathological characteristics. After siRNA-mediated silencing of IKKα, cell viability and apoptosis were assessed in MCF7 and MDA-MB-231 breast cancer cells. In both the discovery and validation cohorts, associations observed between IKKα and clinical outcome measures were potentiated in oestrogen receptor (ER) positive Luminal A tumours. In the discovery cohort, cytoplasmic IKKα was associated with disease-free survival (p = 0.029) and recurrence-free survival on tamoxifen (p < 0.001) in Luminal A tumours. Nuclear IKKα and a combination of cytoplasmic and nuclear IKKα (total tumour cell IKKα) were associated with cancer-specific survival (p = 0.012 and p = 0.007, respectively) and recurrence-free survival on tamoxifen (p = 0.013 and p < 0.001, respectively) in Luminal A tumours. In the validation cohort, cytoplasmic IKKα was associated with cancer-specific survival (p = 0.023), disease-free survival (p = 0.002) and recurrence-free survival on tamoxifen (p = 0.009) in Luminal A tumours. Parallel experiment with breast cancer cells in vitro demonstrated the non-canonical NF-κB pathway was inducible by exposure to lymphotoxin in ER-positive MCF7 cells and not in ER-negative MDA-MB-231 cells. Reduction in IKKα expression by siRNA transfection increased levels of apoptosis and reduced cell viability in MCF7 but not in MDA-MB-231 cells. IKKα is an important determinant of poor outcome in patients with ER-positive invasive ductal breast cancer and thus may represent a potential therapeutic target.

Further investigations on the epidemiology of fowl typhoid in Brazil.

Salmonella Gallinarum (SG) causes fowl typhoid (FT), a disease responsible for economic losses to the poultry industry worldwide. FT has been considered to be under control in Brazil; nevertheless, since 2012 it has frequently been identified in poultry farming of several Brazilian states. The present study was aimed at assessing (i) the pathogenicity of a SG strain recently isolated from an FT outbreak affecting chickens of both white and brown layers; (ii) the transmission of SG through eggs and hatching; (iii) the effects of antibiotic therapy on SG persistence in poultry tissues and on its vertical transmission and (iv) the genetic profiles of strains isolated over 27 years by Pulsed Field Gel Electrophoresis. Clinical signs, mortality and gross pathologies were very marked amongst brown-egg layers. In contrast, clinical manifestation of FT and mortality were barely present amongst the white-egg layers, although bacteria could be re-isolated from their tissues up to 35 days after infection. No bacteria were re-isolated from the laid eggs, so vertical transmission was not achieved, although newly hatched uninfected chicks became infected spontaneously after hatching. Antibiotic therapy was shown to be effective at reducing mortality, but was not able to clear infection or to favour SG transmission via eggs. Our pulsed field gel electrophoresis results revealed an endemic SG clone that may have been circulating in the Brazilian poultry flocks in the south and southeast regions for more than 20 years. The results suggest that the industrial incubation of SG-contaminated eggs could be one of the factors responsible for the spread of FT in Brazil.