Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX-2

Prostanoids generated by COX-2 are involved in the regulation of inflammation but their exact role in the innate immune response has not been defined. We investigated whether COX-2 is involved in host defense against Pseudomonas aeruginosa pneumonia. In vitro studies, in a macrophage cell line, showed that cytotoxic strain of P aeruginosa (PA103) induced significant COX-2 protein expression and enzymatic function. In vivo data showed that infection with PA103 increased COX-2 protein production in whole lung tissue compared to mice that were infected with mutant bacteria that lack ExoU (DeltaU) or ExoU and ExoT (DeltaUT). COX-2(-/-) mice had accentuated clearance of cytotoxic P. aeruginosa from the lungs. We further tested the effects of COX-2 products such as prostaglandin E(2) on the function of phagocytic cells. Our studies indicate that prostaglandin E(2) may be involved through interacting with the EP2 receptors in modulating the host response because treatment of macrophages with prostaglandin E(2) suppressed production of reactive oxygen species. Furthermore there was enhanced bacterial clearance in EP2 receptor(-/-) mice compared to the wild-type controls. Thus it is possible that inhibition of COX-2 or EP2 receptors could be an effective adjunctive treatment for severe or resistant P. aeruginosa pneumonia.     

Ethnography in Nutrition and Dietetics Research: A Systematic Review

Ethnography is a qualitative research approach used to learn about people and their culture. There is a need to explore the application and use of ethnographic methodology in nutrition and dietetics research to inform future research and practice. Our aim was to examine the extent, range, nature, and contribution of ethnographic methodology in nutrition and dietetics research. Eight electronic databases were searched using a defined search strategy until November 2017. No restrictions were placed on language, date, or study design of original research. Two authors independently assessed titles and abstracts, then full-text records, against inclusion criteria. Hand-searching of reviews identified in the database search was undertaken. Quality assessment was conducted using the Critical Appraisal Skills Programme checklist. Data were described narratively. A total of 2,185 records were identified, with 92 studies from public health nutrition (n=72), clinical nutrition (n=13), and foodservice (n=7) practice areas meeting inclusion criteria. Common research areas included infant/child feeding, food choice, diabetes, nutrition in schools and food insecurity. In addition to observation, frequently reported data collection techniques were interview (n=85), focus groups (n=17), and document analysis (n=10). Ethnographic research was most often reported from North America (n=31), Europe (n=16), and Australia/Oceania (n=13). This research approach was shown to inform dietetic research and practice by illuminating sociocultural factors that influence dietary beliefs and practices, practitioner training opportunities, evaluating nutrition education methods, informing programs and interventions, identifying nutrition policy and guideline focus areas, and the need for new approaches and communication strategies. Ethnography can increase understanding of complex food and nutrition–related health issues and their contributing factors across public health nutrition, foodservice, and clinical dietetic practice. It can be used to explain health inequalities, direct policy, and inform more effective intervention design and delivery. Wider uptake of this research approach as a stand-alone or complementary study design will advance efforts to improve health and wellbeing through food and nutrition.     

Design,synthesis and evaluation of alkylphosphocholine-gefitinib conjugates as multitarget anticancer agents

The evolving resistance to the currently used chemotherapeutic agents requires continuous efforts to develop new anticancer agents overcoming resistance and with lower side effects. Polypharmacology via designing a single molecule intercepting multiple signaling pathways is more effective than targeting a single one. Several alkylphosphocholines show anticancer activity via inhibition of Akt phosphorylation. On the other hand, several molecules having quinazoline scaffold elicit anticancer activity through inhibition of epidermal growth factor receptor (EGFR) tyrosine kinases. We report our efforts to develop alkylphosphocholines-gefitinib conjugates as multitarget anticancer agents. The antiproliferative activities of the newly synthesized compounds were evaluated against cell lines representing lung, breast, liver and skin cancers. In addition, the capability of the newly synthesized compounds to inhibit Akt phosphorylation and EGFR tyrosine kinases were determined. The results emphasized the influence of the linkers’ length on the elicited bioactivity. The long chain linkers possessing conjugates were more active regarding both of the elicited antiproliferative effect and inhibition of Akt phosphorylation, while maintained the ability to inhibit EGFR tyrosine kinases. Their cytotoxic activities were superior or comparable to erlotinib and miltefosine.     

Xanthohumol ameliorates 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin–induced cellular toxicity in cultured MC3T3‐E1 osteoblastic cells

2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) is an environmental contaminant. Xanthohumol is a prenylated flavonoid found in hops (Humulus lupulus) and beer. The aim of the current study was to explore the role of xanthohumol in modulating the toxicity of TCDD in MC3T3‐E1 osteoblastic cells. In cells treated with TCDD alone, intracellular Ca²⁺ concentrations, mitochondrial membrane potential disruption, reactive oxygen species production, cardiolipin peroxidation, nitric oxide release and cytochrome P450 1A1 expression were significantly increased. TCDD treatment increased the mRNA levels of extracellular signal‐regulated kinase 1 and nuclear factor kappa B, and significantly decreased the level of protein kinase B (AKT) in MC3T3‐E1 osteoblastic cells. However, the presence of xanthohumol alleviated the pathological effects of TCDD. In addition, xanthohumol treatment significantly increased the expression of genes associated with osteoblast differentiation (alkaline phosphatase, osteocalcin, osteoprotegerin and osterix). We conclude that xanthohumol has a beneficial influence and may antagonize TCDD toxicity in osteoblastic cells.     

Enhancing excitability of dopamine neurons promotes motivational behaviour through increased action initiation

Motivational deficits are a key symptom in multiple psychiatric disorders, including major depressive disorder, schizophrenia and addiction. A likely neural substrate for these motivational deficits is the brain dopamine (DA) system. In particular, DA signalling in the nucleus accumbens, which originates from DA neurons in the ventral tegmental area (VTA), has been identified as a crucial substrate for effort-related and activational aspects of motivation. Unravelling how VTA DA neuronal activity relates to motivational behaviours is required to understand how motivational deficits in psychiatry can be specifically targeted. In this study, we therefore used designer receptors exclusively activated by designer drugs (DREADD) in TH:Cre rats, in order to determine the effects of chemogenetic DA neuron activation on different aspects of motivational behaviour. We found that chemogenetic activation of DA neurons in the VTA, but not substantia nigra, significantly increased responding for sucrose under a progressive ratio schedule of reinforcement. More specifically, high effort exertion was characterized by increased initiations of reward-seeking actions. This effect was dependent on effort requirements and instrumental contingencies, but was not affected by sucrose pre-feeding. Together, these findings indicate that VTA DA neuronal activation drives motivational behaviour by facilitating action initiation. With this study, we show that enhancing excitability of VTA DA neurons is a viable strategy to improve motivational behaviour.     

Insulin Resistance is Associated with Chronic Laryngitis in Korean Women

Objectives

The aim of this study was to investigate the association between chronic laryngitis (CL) and insulin resistance (IR) in South Korea using data from the 2010 Korea National Health and Nutrition Examination Surveys (KNHANES).

Design, setting and participants

Cross-sectional data of 4,261 adults who completed KNHANES were analyzed. CL was considered when participants experienced a voice change and demonstrated flexible laryngoscopic findings of diffuse laryngeal inflammation. All participants were assessed for IR using the homeostasis model assessment of insulin resistance (HOMA-IR).

Results

Among the Korean population older than 19 years, the prevalence of chronic laryngitis was 3.8±0.7%. Univariate analysis demonstrated that CL was significantly associated with smoking and systolic and diastolic blood pressure in men and with age, diastolic blood pressure, HDL cholesterol, insulin, and HOMA-IR in women. Multiple regression analysis demonstrated that the mean value of HOMA-IR was significantly associated with CL in women only. In addition, CL was more prevalent in the highest compared with the lowest HOMA-IR quartile (OR [95% CI]: 2.268 [1.053-4.884] after adjusting for age, OR [95% CI]: 2.235 [1.040-6.181] after adjusting for confounding factors of age, body mass index, smoking status, alcohol intake, regular exercise, education, and income).

Conclusions

These findings indicate that IR characterized by HOMA-IR is significantly associated with CL in Korean women only. Our results suggest that HOMA-IR could be an early predictive factor of increased risk of CL in Korean women.

     

Residents feel unprepared and unsupervised as leaders of cardiac arrest teams in teaching hospitals: a survey of internal medicine residents

OBJECTIVE: We aimed to determine internal medicine residents' perceptions of the adequacy of their training to serve as in-hospital cardiac arrest team leaders, given the responsibility of managing acutely critically ill patients and with recent evidence suggesting that the quality of cardiopulmonary resuscitation provided in teaching hospitals is suboptimal. DESIGN: Cross-sectional postal survey. SETTING: Canadian internal medicine training programs. PARTICIPANTS: Internal medicine residents attending Canadian English-speaking medical schools. INTERVENTIONS: A survey was mailed to internal medicine residents asking questions relating to four domains: adequacy of training, perception of preparedness, adequacy of supervision and feedback, and effectiveness of additional training tools. MEASUREMENTS AND MAIN RESULTS: Of the 654 residents who were sent the survey, 289 residents (44.2%) responded. Almost half of the respondents (49.3%) felt inadequately trained to lead cardiac arrest teams. Many (50.9%) felt that the advanced cardiac life support course did not provide the necessary training for team leadership. A substantial number of respondents (40%) reported receiving no additional cardiac arrest training beyond the advanced cardiac life support course. Only 52.1% of respondents felt prepared to lead a cardiac arrest team, with 55.3% worrying that they made errors. Few respondents reported receiving supervision during weekdays (14.2%) or evenings and weekends (1.4%). Very few respondents reported receiving postevent debriefing (5.9%) or any performance feedback (1.3%). Level of training and receiving performance feedback were associated with perception of adequacy of training (r(2) = .085, p < .001). Respondents felt that additional training involving full-scale simulation, leadership skills training, and postevent debriefing would be most effective in increasing their skills and confidence. CONCLUSIONS: The results suggest that residents perceive deficits in their training and supervision to care for critically ill patients as cardiac arrest team leaders. This raises sufficient concern to prompt teaching hospitals and medical schools to consider including more appropriate supervision, feedback, and further education for residents in their role as cardiac arrest team leaders.     

The RANTES -403G>A promoter polymorphism in Korean men: association with serum RANTES concentration and coronary artery disease

In the present study we investigated the association of the RANTES (regulated upon activation, normal T-cell expressed and secreted) -28C>G and -403G>A promoter polymorphisms with the concentration of serum RANTES and CAD (coronary artery disease) in Korean men. We included 553 male CAD patients with (n=176) or without (n=377) Type 2 diabetes, aged 40-65 years with previous myocardial infarction ( approximately 50%) or angiographically confirmed CAD ( approximately 50%), and 416 aged-matched healthy male controls. The main outcome measures were the OR (odds ratio) of CAD risk and the serum RANTES concentration evaluated by sandwich ELISA. Although the RANTES -28C>G genotype had no significant association with CAD risk, the presence of the minor allele of the RANTES -403G>A single nucleotide polymorphism was associated with a lower risk of CAD {OR 0.70 [95% CI (confidence interval) 0.54-0.92], P=0.011} after adjusting for age, BMI (body mass index), cigarette smoking and alcohol consumption. Serum RANTES concentrations were significantly associated with the -403G>A genotype in controls (G/G: 44.7+/-3.3 ng/ml, G/A: 36.5+/-2.0 ng/ml, A/A: 28.7+/-2.5 ng/ml; P<0.001), non-diabetic CAD patients (G/G: 50.9+/-3.0 ng/ml, G/A: 42.2+/-2.6 ng/ml, A/A: 41.3+/-4.4 ng/ml; P<0.05) and diabetic CAD patients (G/G: 58.5+/-3.5 ng/ml, G/A: 49.6+/-4.1 ng/ml, A/A: 42.2+/-4.3 ng/ml; P<0.05); however, such associations were not observed in the subgroup of CAD patients taking lipid-lowering medication. Moreover, serum RANTES was positively correlated with C-reactive protein (r=0.289, P<0.001) and platelet counts (r=0.253, P<0.001). The results of the present study demonstrate that the RANTES -403A allele is associated with lower serum RANTES concentrations and consequently with reduced CAD risk.