Chlorogenic acid depresses cellular bioenergetics to suppress pancreatic carcinoma through modulating c-Myc-TFR1 axis.

Pancreatic ductal adenocarcinoma (PDAC) is severe malignant tumor in human, the outcomes of PDAC is extremely poor. Here, we evaluated the potential anti-tumor activity of chlorogenic Acid (CA) in PDAC. Here, we found CA was effective to suppress PDAC cell growth in vitro and in vivo. Importantly, we found overall oxygen consumption rate was significantly decreased in CA dose-dependent manner. We also found glycolysis reverse was decreased in CA-treated cells, while basal glycolysis and glycolytic capacity were not significantly changed. Mechanistically, we demonstrated TFR1 could be a novel downstream target of CA, which is essential for PDAC cell growth and cellular bioenergetics maintenance. Furthermore, we validated that CA-reduced c-Myc resulted to down-regulation of TFR1, which contributes to mitochondrial respiration dysfunction and cell growth delay. Together, this study indicates that CA suppresses PDAC cell growth through targeting c-Myc-TFR1 axis and suggests CA could be considered as a promising compound for PDAC treatment.

Providing Anesthesia Care in Resource-limited Settings: A 6-year Analysis of Anesthesia Services Provided at Médecins Sans Frontières Facilities.

BACKGROUND: Anesthesia is integral to improving surgical care in low-resource settings. Anesthesia providers who work in these areas should be familiar with the particularities associated with providing care in these settings, including the types and outcomes of commonly performed anesthetic procedures. METHODS: The authors conducted a retrospective analysis of anesthetic procedures performed at Médecins Sans Frontières facilities from July 2008 to June 2014. The authors collected data on patient demographics, procedural characteristics, and patient outcome. The factors associated with perioperative mortality were analyzed. RESULTS: Over the 6-yr period, 75,536 anesthetics were provided to adult patients. The most common anesthesia techniques were spinal anesthesia (45.56%) and general anesthesia without intubation (33.85%). Overall perioperative mortality was 0.25%. Emergent procedures (0.41%; adjusted odds ratio [AOR], 15.86; 95% CI, 2.14 to 115.58), specialized surgeries (2.74%; AOR, 3.82; 95% CI, 1.27 to 11.47), and surgical duration more than 6 h (9.76%; AOR, 4.02; 95% CI, 1.09 to 14.88) were associated with higher odds of mortality than elective surgeries, minor surgeries, and surgical duration less than 1 h, respectively. Compared with general anesthesia with intubation, spinal anesthesia, regional anesthesia, and general anesthesia without intubation were associated with lower perioperative mortality rates of 0.04% (AOR, 0.10; 95% CI, 0.05 to 0.18), 0.06% (AOR, 0.26; 95% CI, 0.08 to 0.92), and 0.14% (AOR, 0.29; 95% CI, 0.18 to 0.45), respectively. CONCLUSIONS: A wide range of anesthetics can be carried out safely in resource-limited settings. Providers need to be aware of the potential risks and the outcomes associated with anesthesia administration in these settings.

A Rare Case of Apixaban-Induced Subdural Hematoma in Elderly Heart Failure Patient.

New oral anticoagulants (NOACs) have become more popular in the last few decades. Although apixaban has been proven to be safer than warfarin and causes less hemorrhage in comparison to other NOACs, it still poses a risk of spontaneous bleeding. We present here an 81-year-old male known case of heart failure with reduced ejection fraction (HFrEF) associated with an apical thrombus of 0.93×1.29 cm who presents with cognitive decline, slurred speech, and right side weakness following apixaban use for his apical thrombus. On further evaluation of non-contrast brain computerized tomography (CT), there was a large extra-axial subacute subdural hematoma with thick septations in the left parietal region, measuring 2.6 cm in thickness, causing an a mass effect, and an a midline shift of 1 mm. Following neurosurgery, cardiology, and anesthesiology discussions, the surgery was deferred due to his age and coexisting conditions with regular follow-ups. The patient has now gained full consciousness and is currently undergoing physiotherapy. This case highlights an elderly patient with apixaban-induced subdural hemorrhage, which is a rare entity in the medical literature. Although apixaban is safer than other NOACs, it may cause subdural hemorrhage.

Urinary RBP as an Independent Predictor of Renal Outcome in Diabetic Nephropathy.

Background: Renal tubular impairment is prevalent in diabetic nephropathy (DN) and the histological severity predicted renal outcome. Biomarkers of tubular injury also increased in the urine of DN patients. The retrospective study aimed to assess the prognostic value of clinically widely applied urinary tubular injury markers, retinol-binding protein (RBP), ß2-microglobulin (ß2-MG) and N-acetyl-ß-D-glucosaminidase (NAG) in DN. Method: A total of 305 patients with biopsy-proven DN were enrolled. The baseline urine total protein and components including albumin, IgG, RBP, ß2-MG and NAG were retrieved from medical records. The primary outcome was end stage renal disease (ESRD). Cox proportional hazard analysis and restricted cubic splines were performed to evaluate the association of parameters with ESRD. Nomograms were constructed and concordance index (C-index) was used to measure the prediction ability. Result: The levels of urinary RBP, ß2-MG and NAG were positively correlated with the severity of interstitial fibrosis and tubular atrophy (IFTA). Positive correlations were also observed among ß2-MG, NAG and mesangial expansion. Urinary RBP was not correlated with any glomerular lesions. Urinary RBP, ß2-MG and NAG were risk factors for ESRD in hazard analysis with adjustment for age, gender and body mass index (BMI). The hazard ratios increased with the increment of baseline levels. In the multivariate Cox model including serum creatinine (SCr), total urinary protein, urinary albumin, urinary IgG and the tubular injury biomarkers, urinary RBP (with every g/mol.Cr increase: HR 1.06, 95% CI 1.03-1.10, p =0.001) remained as an independent risk factor for ESRD in DN patients. Patients were divided by the medium value of urinary RBP into the low RBP and high RBP groups. Survival analysis showed that significantly more patients in the high RBP progressed to ESRD compared to those in the low RBP group (p =0.02) when urinary total protein was less than 3.5 g/g. The C-index of the nomogram incorporating age, gender, BMI, SCr and total urine protein was 0.757. The value increased to 0.777 after adding urinary RBP to the model. Conclusions: Urinary RBP excretion was only correlated with the severity of IFTA and independently predicted ESRD in DN patients.

Coagulation factors IX and X enhance binding and infection of adenovirus types 5 and 31 in human epithelial cells.

Most adenoviruses bind directly to the coxsackie and adenovirus receptor (CAR) on target cells in vitro, but recent research has shown that adenoviruses can also use soluble components in body fluids for indirect binding to target cells. These mechanisms have been identified upon addressing the questions of how to de- and retarget adenovirus-based vectors for human gene and cancer therapy, but the newly identified mechanisms also suggest that the role of body fluids and their components may also be of importance for natural, primary infections. Here we demonstrate that plasma, saliva, and tear fluid promote binding and infection of adenovirus type 5 (Ad5) in respiratory and ocular epithelial cells, which corresponds to the natural tropism of most adenoviruses, and that plasma promotes infection by Ad31. By using a set of binding and infection experiments, we also found that Ad5 and Ad31 require coagulation factors IX (FIX) or X (FX) or just FIX, respectively, for efficient binding and infection. The concentrations of these factors that were required for maximum binding were 1/100th of the physiological concentrations. Preincubation of virions with heparin or pretreatment of cells with heparinase I indicated that the role of cell surface heparan sulfate during FIX- and FX-mediated adenovirus binding and infection is mechanistically serotype specific. We conclude that the use of coagulation factors by adenoviruses may be of importance not only for the liver tropism seen when administering adenovirus vectors to the circulation but also during primary infections by wild-type viruses of their natural target cell types.

Factors contributing to the uptake of childhood vaccination in Galkayo District, Puntland, Somalia.

BACKGROUND: As in many Sub-Saharan African countries, the health system in Somalia is not operating at the capacity needed to lift childhood vaccination coverage to ninety percent or above, as recommended by United Nations Children's Fund. Current national estimates of coverage for the six major vaccine preventable childhood diseases range from thirty to sixty percent. Infectious disease outbreaks continue to pose significant challenges for the country's health authorities. OBJECTIVE: This important qualitative study, conducted in Galkayo District, Somalia, investigates limiting factors associated with childhood vaccination uptake from the perspective of both communities and health care workers. METHODS: Qualitative information was collected through six focus group discussions with parents (n = 48) and five one-to-one interviews with health workers (n = 15) between March and May 2017, in three settings in the Galkayo District - Galkayo city, Bayra and Bacadwayn. RESULTS: From a health system perspective, the factors are: awareness raising, hard to reach areas, negative attitudes and perceived knowledge of health workers, inadequate supplies and infrastructure, and missed vaccination opportunities. From the perspective of individuals and communities the factors are: low trust in vaccines, misinterpretation of religious beliefs, vaccine refusals, Somalia's patriarchal system and rumours and misinformation. Parents mostly received immunization information from social mobilizers and health facilities. Fathers, who are typically family decision-makers, were poorly informed. The findings highlight the need for in-service training to enable health workers to improve communication with parents, particularly fathers, peripheral communities and local religious leaders. CONCLUSIONS: Enhancing knowledge and awareness of vaccination among parents is crucial. Fathers' involvement is lacking. This may be boosted by highlighting fathers' obligation to protect their children's health through vaccination. It is also important that men engage with the wider community in decision-making and advance towards the global vaccination targets.

Health Status and Health Care Needs of Drought-Related Migrants in the Horn of Africa-A Qualitative Investigation.

Somalia, Kenya and Ethiopia, situated in the Horn of Africa, are highly vulnerable to climate change, which manifests itself through increasing temperatures, erratic rains and prolonged droughts. Millions of people have to flee from droughts or floods either as cross-border refugees or as internally displaced persons (IDPs). The aim of this study was to identify knowledge status and gaps regarding public health consequences of large-scale displacement in these countries. After a scoping review, we conducted qualitative in-depth interviews during 2018 with 39 stakeholders from different disciplines and agencies in these three countries. A validation workshop was held with a selection of 13 interviewees and four project partners. Malnutrition and a lack of vaccination of displaced people are well-known challenges, while mental health problems and gender-based violence (GBV) are less visible to stakeholders. In particular, the needs of IDPs are not well understood. The treatment of mental health and GBV is insufficient, and IDPs have inadequate access to essential health services in refugee camps. Needs assessment and program evaluations with a patients' perspective are either lacking or inadequate in most situations. The Horn of Africa is facing chronic food insecurity, poor population health and mass displacement. IDPs are an underserved group, and mental health services are lacking. A development approach is necessary that moves beyond emergency responses to the building of long-term resilience, the provision of livelihood support and protection to reduce displacement by droughts.

RvD1 ameliorates LPS-induced acute lung injury via the suppression of neutrophil infiltration by reducing CXCL2 expression and release from resident alveolar macrophages.

Acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS) are life-threatening critical syndromes characterized by the infiltration of a large number of inflammatory cells that lead to an excessive inflammatory response. Resolvin D1 (RvD1), an endogenous lipid mediator, is believed to have anti-inflammatory and proresolving effects. In the present study, we examined the impact of RvD1 on the pulmonary inflammatory response, neutrophil influx, and lung damage in a murine model of lipopolysaccharide (LPS)-induced ALI. Treatment with RvD1 protected mice against LPS-induced ALI, and compared to untreated mice, RvD1-treated mice exhibited significantly ameliorated lung pathological changes, decreased tumor necrosis factor-α (TNF-α) concentrations and attenuated neutrophil infiltration. In addition, treatment with RvD1 attenuated LPS-induced neutrophil infiltration via the downregulation of CXCL2 expression on resident alveolar macrophages. Finally, BOC-2, which inhibits the RvD1 receptor lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2), reversed the protective effects of RvD1. These data demonstrate that RvD1 ameliorates LPS-induced ALI via the suppression of neutrophil infiltration by an ALX/FPR2-dependent reduction in CXCL2 expression on resident alveolar macrophages.

The eradication of Helicobacter pylori is affected by body mass index (BMI).

BACKGROUND: Bariatric surgeons often advocate preoperative Helicobacter pylori (H. pylori) testing and eradication because of the increased risk of postoperative ulcers and foregut symptoms in H. pylori-positive patients. The aim of this pilot study was to evaluate whether body mass index (BMI) might influence the success rate of eradication. METHODS: Eighty one nondiabetic naïve H. pylori-positive patients were divided into two groups according to their BMI, with 41 in the control group (normal BMI) and 40 in the overweight/obese group (BMI > or = 25). Gastroscopy was performed and multiple biopsies were obtained from the antrum and corpus. Both groups were given a triple therapy consisting of pantoprazole 40 mg for 2 weeks plus amoxicillin 1 g tris in die (t.i.d), and clarithromycin 250 mg t.i.d, for the first week of treatment. Eradication was confirmed by the (13)C-urea breath test at 3 months. RESULTS: Successful eradication was observed in 55.0% of the overweight/obese group compared with 85.4% [p < 0.005; odds ratio (OR): 4.77; 95% confidence interval (CI): 1.64-13.87]. The distribution of age, gender, and smoking, as well as the proportion with corpus predominant gastritis (41.4% and 35.0% in control and overweight/obese groups, respectively), did not differ significantly between the two groups. Regression analysis showed that risk factors for treatment failure were BMI (p < 0.02) with an OR of 1.06 (95% CI: 1.01-1.11) and corpus-predominant gastritis (p < 0.001) with an OR of 8.74 (95% CI: 2.48-30.8). CONCLUSION: Overweight/obese nondiabetic patients showed a significantly lower rate of eradication rate of H. pylori infection than controls. BMI and corpus-predominant gastritis appear to be independent risk factors for eradication failure.

Synthesis of a pseudo-disaccharide library and its application to the characterisation of the heparanase catalytic site.

A novel methodology is described for the efficient and divergent synthesis of pseudodisaccharides, molecules comprising of amino carbasugar analogues linked to natural sugars. The methodology is general and enables the introduction of diversity both at the carbasugar and the natural sugar components of the pseudodisaccharides. Using this approach, a series of pseudodisaccharides are synthesised that mimic the repeating backbone unit of heparan sulfate, and are tested for inhibition of heparanase, a disease-relevant enzyme that hydrolyses heparan sulfate. A new homology model of human heparanase is described based on a family 79 ß-glucuronidase. This model is used to postulate a computational rationale for the observed activity of the different pseudodisaccharides and provide valuable information that informs the design of potential inhibitors of this enzyme.

A synthesis of carbasugar-sugar pseudodisaccharides via a cycloaddition-cycloreversion reaction of 2H-pyran-2-ones.

Cycloaddition of 3-carbomethoxy-2H-pyran-2-one to a vinylated sugar followed by the loss of bridging CO(2) from the cycloadduct affords a cyclohexadiene which can be manipulated to a carbasugar-sugar pseudodisaccharide.

A new, general method for the synthesis of carbasugar-sugar pseudodisaccharides.

A general synthetic methodology for the synthesis of sugar-carbasugar pseudodisaccharides is described. The methodology is based on the cycloaddition of pyran-2-ones to vinylated sugars and the subsequent manipulation of the cycloadducts to construct the carbasugar component of the pseudodisaccharide.

Efficacy of monotherapies and artesunate-based combination therapies in children with uncomplicated malaria in Somalia.

In order to guide the antimalarial treatment policy of Somalia, we conducted therapeutic efficacy studies of routinely used antimalarial monotherapies as well as artemisinin-based combination therapies (ACTs) for uncomplicated malaria in three sentinel sites during 2003-2006. Therapeutic efficacy of chloroquine (CQ), amodiaquine (AQ) and sulfadoxine/pyrimetahmine (SP) monotherapies, and artesunate plus SP (AS+SP) or AQ (AS+AQ) were evaluated in children 6 months to 10 years old with uncomplicated malaria. For the assessment of the monotherapies, 2003 WHO protocol with 14-day follow-up was used while the 2005 WHO protocol with 28-day follow-up was used for testing the ACTs. Of the monotherapies, CQ performed very poorly with treatment failures varying from 76.5% to 88% between the sites. AQ treatment failure was low except for Janale site with treatment failure of 23.4% compared to 2.8% and 8% in Jamame and Jowhar, respectively. For SP, treatment failures from 7.8% to 12.2% were observed. A 28-day test of artemisinin-based combinations, AS+SP and AS+AQ, proved to be highly efficacious with cure rates of 98-100% supporting the choice of AS+SP combination as first line treatment for uncomplicated malaria for Somalia.