Initial adherence of EPEC, EHEC and VTEC to host cells

Initial adherence to host cells is the first step of the infection of enteropathogenic Escherichia coli (EPEC), enterohaemorrhagic Escherichia coli (EHEC) and verotoxigenic Escherichia coli (VTEC) strains. The importance of this step in the infection resides in the fact that (1) adherence is the first contact between bacteria and intestinal cells without which the other steps cannot occur and (2) adherence is the basis of host specificity for a lot of pathogens. This review describes the initial adhesins of the EPEC, EHEC and VTEC strains. During the last few years, several new adhesins and putative colonisation factors have been described, especially in EHEC strains. Only a few adhesins (BfpA, AF/R1, AF/R2, Ral, F18 adhesins) appear to be host and pathotype specific. The others are found in more than one species and/or pathotype (EPEC, EHEC, VTEC). Initial adherence of EPEC, EHEC and VTEC strains to host cells is probably mediated by multiple mechanisms

Galectin-3C Inhibits Tumor Growth and Increases the Anticancer Activity of Bortezomib in a Murine Model of Human Multiple Myeloma

Galectin-3 is a human lectin involved in many cellular processes including differentiation, apoptosis, angiogenesis, neoplastic transformation, and metastasis. We evaluated galectin-3C, an N-terminally truncated form of galectin-3 that is thought to act as a dominant negative inhibitor, as a potential treatment for multiple myeloma (MM). Galectin-3 was expressed at varying levels by all 9 human MM cell lines tested. In vitro galectin-3C exhibited modest anti-proliferative effects on MM cells and inhibited chemotaxis and invasion of U266 MM cells induced by stromal cell-derived factor (SDF)-1α. Galectin-3C facilitated the anticancer activity of bortezomib, a proteasome inhibitor approved by the FDA for MM treatment. Galectin-3C and bortezomib also synergistically inhibited MM-induced angiogenesis activity in vitro. Delivery of galectin-3C intravenously via an osmotic pump in a subcutaneous U266 cell NOD/SCID mouse model of MM significantly inhibited tumor growth. The average tumor volume of bortezomib-treated animals was 19.6% and of galectin-3C treated animals was 13.5% of the average volume of the untreated controls at day 35. The maximal effect was obtained with the combination of galectin-3C with bortezomib that afforded a reduction of 94% in the mean tumor volume compared to the untreated controls at day 35. In conclusion, this is the first study to show that inhibition of galectin-3 is efficacious in a murine model of human MM. Our results demonstrated that galectin-3C alone was efficacious in a xenograft mouse model of human MM, and that it enhanced the anti-tumor activity of bortezomib in vitro and in vivo. These data provide the rationale for continued testing of galectin-3C towards initiation of clinical trials for treatment of MM

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Induction of thioltransferase and thioredoxin/thioredoxin reductase systems in cultured pig lenses under oxidative stress. Invest Ophthalmol Vis Sci.

PURPOSE. In view of the important antioxidant roles of thioltransferase (TTase), thioredoxin (Trx), and thioredoxin reductase (TR) in the lens, the present study was conducted to investigate the induction of these cytosolic enzymes in response to H 2 O 2 stress in cultured lenses. METHODS. Porcine lenses were cultured, exposed to H 2 O 2 for various lengths of time between 0 and 24 hours, and photographed to detect morphologic changes. The lenses were then harvested; dissected into epithelial layer, cortex, and nucleus; and homogenized for the determination of the glutathione (GSH) level. Pooled epithelial layers were used to examine TTase, Trx, and TR protein or mRNA levels. RESULTS. Treatment of lenses with H 2 O 2 caused distinct morphologic changes. Lower concentrations of H 2 O 2 (0.2 mM) caused the lens to be hazy after 6 hours and to worsen progressively between 12 and 24 hours. Higher levels of H 2 O 2 (0.5 mM) induced similar morphologic changes, but sooner (within 1 hour) and more severe. Both H 2 O 2 -treated groups showed a dramatic and gradual GSH depletion during the 24-hour incubation, but the GSH level at 50% or above appeared to be essential in maintaining lens clarity. However, TTase, Trx, and TR activities, protein expressions, and mRNA transcriptions in the epithelial layers of these lenses were increased, but each enzyme had a distinct pattern. Under mild H 2 O 2 stress, a slow and transient activation of TTase, Trx, and TR was observed. However, under stronger H 2 O 2 stress, all three enzymes showed a very rapid increase and then a steady decline in activity. Western blot and RT-PCR analyses revealed that this increase in activity in all three enzymes was due to the induction of protein and mRNA expression. In the control group (no oxidative stress) all three enzyme activities and their respective expressions remained constant throughout the experimental period. ROS molecules are generated endogenously by enzyme systems in the lens, as by-products of normal metabolic processes, or exogenously from the environment. The main ROS molecules that generate in the lens include superoxide anion, hydroxyl radical, and H 2 O 2 . CONCLUSIONS. The data show that 2 Endogenous systems that can generate ROS in the lens include NADPH oxidase, mitochondria, and peroxisomes (Rao PV et al. IOVS 1999;40 Two main sources that produce exogenous ROS are UV light and ionic radiation. ROS molecules produced through these processes in the lens are neutralized by antioxidants and oxidation defense systems. 2,3 Even in the presence of these powerful antioxidants and ROS-neutralizing enzyme systems, some ROS molecules get through these defense systems and oxidatively damage cellular molecules such as proteins, lipids, and DNA

Cancer statistics for Asian Americans, Native Hawaiians, and Pacific Islanders, 2016: Converging incidence in males and females.

Cancer is the leading cause of death among Asian Americans, Native Hawaiians, and Pacific Islanders (AANHPIs). In this report, the American Cancer Society presents AANHPI cancer incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Among AANHPIs in 2016, there will be an estimated 57,740 new cancer cases and 16,910 cancer deaths. While AANHPIs have 30% to 40% lower incidence and mortality rates than non-Hispanic whites for all cancers combined, risk of stomach and liver cancers is double. The male-to-female incidence rate ratio among AANHPIs declined from 1.43 (95% confidence interval, 1.36-1.49) in 1992 to 1.04 (95% confidence interval, 1.01-1.07) in 2012 because of declining prostate and lung cancer rates in males and increasing breast cancer rates in females. The diversity within the AANHPI population is reflected in the disparate cancer risk by subgroup. For example, the overall incidence rate in Samoan men (526.5 per 100,000) is more than twice that in Asian Indian/Pakistani men (216.8). Variations in cancer rates in AANHPIs are related to differences in behavioral risk factors, use of screening and preventive services, and exposure to cancer-causing infections. Cancer-control strategies include improved use of vaccination and screening; interventions to increase physical activity and reduce excess body weight, tobacco use, and alcohol consumption; and subgroup-level research on burden and risk factors. CA Cancer J Clin 2016;66:182-202. © 2016 American Cancer Society

NAFTNet retrospective report on the treatment of anti-Ro/SSA mediated fetal heart block with dexamethasone

BACKGROUND: Complete atrioventricular block (CAVB) is a complication of maternal antibody positivity and treatment of fetal disease is controversial in terms of efficacy and safety. We hypothesized that dexamethasone treatment for fetal anti-Ro/SSA antibody-mediated cardiac disease leads to better pregnancy outcomes than expectant management. METHODS: A retrospective multi-center cohort study of anti-Ro/SSA antibody positive pregnancies with fetal conduction disease reported by participating North American Fetal Therapy Network (NAFTNet) centers between January 2010 and December 2018. The primary outcomes included: fetal death, oligohydramnios, growth restriction, preterm delivery, and new maternal comorbidities. Secondary outcomes included: pacemaker prior to 28 days, transplantation, and neonatal death in maternal/fetal dyads treated with dexamethasone versus not. RESULTS: In 127 anti-Ro/SSA positive pregnancies, 98 were treated with dexamethasone and 29 were not. Of those treated, 61/96 (63.5%) met the primary outcome including 45/91 (49.4%) premature deliveries; 20 mothers developed comorbidities during treatment (fetal death 5, 10 growth restriction, 14 oligohydramnios, two new/worsening gestational diabetes). In the untreated group, 15/25 (60%) met the primary outcome including 11/22 (50%) premature deliveries and four mothers developing comorbidities during their pregnancy (fetal death 3, one growth restriction, one new onset maternal hypertension). Regarding secondary outcomes, 37/96 (43%) treated fetuses required a pacemaker or died by 28 days, while untreated 13/25 (52%) required pacemaker placement, died prior to 28 days or required listing for transplantation. Excluding terminations, survival without transplant was 17 (68%) in untreated and 85 (89%) in treated patients (\u3c.01). CONCLUSIONS: While the use of dexamethasone in anti-Ro/SSA positive pregnancies is associated with a high rate of poor pregnancy outcomes, there was an unexpected similarly high rate in untreated positive pregnancies. This suggests that the maternal disease itself is influencing pregnancy complications independent of dexamethasone. Our data, which show that treatment decreases neonatal morbidity and overall mortality without increasing overall pregnancy complications, warrant further study

Lay health educators and print materials for the promotion of colorectal cancer screening among Korean Americans: A randomized comparative effectiveness study.

BackgroundColorectal cancer (CRC) is the second most commonly diagnosed cancer among Korean American men and women. Although CRC screening is effective in reducing the burden of this disease, studies have shown that Korean Americans have low screening rates.MethodsThe authors conducted a 2-arm cluster randomized controlled trial comparing a brochure (print) with a brochure and lay health educator (LHE) outreach (print + LHE) in increasing CRC screening rates among Korean American individuals. Self-administered written surveys at baseline and at 6 months assessed knowledge of CRC and its screening, ever screening, and being up to date with screening.ResultsA total of 28 LHEs recruited 348 participants aged 50 to 75 years from their social networks. Significant percentages of participants reported not having health insurance (29.3%) or a usual source of care (35.6%). At 6 months postintervention, the print + LHE participants had a greater increase in knowledge compared with those in the print arm (P = .0013). In multivariable analyses, both groups had significant increases in ever screening (print plus LHE: odds ratio [OR], 1.60 [95% confidence interval (95% CI), 1.26-2.03] and print: OR, 1.42 [95% CI, 1.10-1.82]) and being up to date with screening (print plus LHE: OR, 1.63 [95% CI, 1.23-2.16] and print: OR, 1.40 [95% CI, 1.04-1.89]). However, these increases did not differ significantly between the study arms. Having insurance and having seen a provider within the past year were found to be positively associated with screening.ConclusionsCompared with a brochure, LHE outreach yielded greater increases in knowledge but resulted in similar increases in CRC screening in a Korean American population with barriers to health care access. More work is needed to appropriately address logistical and system barriers in this community. Cancer 2017;123:2705-15. © 2017 American Cancer Society

North American Fetal Therapy Network: timing of and indications for delivery following laser ablation for twin-twin transfusion syndrome

BackgroundDespite improvements in fetal survival for pregnancies affected by twin-twin transfusion syndrome since the introduction of laser photocoagulation, prematurity remains a major source of neonatal morbidity and mortality.ObjectiveTo investigate the indications and factors influencing the timing of delivery following laser treatment, we collected delivery information regarding twin-twin transfusion syndrome cases in a large multicenter cohort.Study designEleven North American Fetal Therapy Network (NAFTNet) centers conducted a retrospective review of twin-twin transfusion syndrome patients who underwent laser photocoagulation. Clinical, demographic and ultrasound variables including twin-twin transfusion syndrome stage, and gestational age at treatment and delivery were recorded. Primary and secondary maternal and fetal indications for delivery were identified. Univariate analysis was used to select candidate variables with significant correlation with latency and GA at delivery. Multivariable Cox regression with competing risk analysis was utilized to determine the independent associations.ResultsA total of 847 pregnancies were analyzed. After laser, the average latency to delivery was 10.11 ± 4.8 weeks and the mean gestational age at delivery was 30.7 ± 4.5 weeks. Primary maternal indications for delivery comprised 79% of cases. The leading indications included spontaneous labor (46.8%), premature rupture of membranes (17.1%), and placental abruption (8.4%). Primary fetal indications accounted for 21% of cases and the most frequent indications included donor non-reassuring status (20.5%), abnormal donor Dopplers (15.1%), and donor growth restriction (14.5%). The most common secondary indications for delivery were premature rupture of membranes, spontaneous labor and donor growth restriction. Multivariate modeling found gestational age at diagnosis, stage, history of prior amnioreduction, cerclage, interwin membrane disruption, procedure complications and chorioamniotic membrane separation as predictors for both gestational age at delivery and latency.ConclusionPremature delivery after laser therapy for twin-twin transfusion syndrome is primarily due to spontaneous labor, preterm premature rupture of membranes and non-reassuring status of the donor fetus. Placental abruption was found to be a frequent complication resulting in early delivery. Future research should be directed toward the goal of prolonging gestation after laser photocoagulation to further reduce morbidity and mortality associated with twin-twin transfusion syndrome

Lay health educators increase colorectal cancer screening among Hmong Americans: A cluster randomized controlled trial.

BackgroundAsian Americans have lower colorectal cancer (CRC) screening rates than non-Hispanic white individuals. Hmong Americans have limited socioeconomic resources and literacy. The current randomized controlled trial was conducted to determine whether bilingual/bicultural lay health educator (LHE) education could increase CRC screening among Hmong Americans.MethodsA cluster randomized controlled trial was conducted among Hmong Americans in Sacramento, California. LHEs and recruited participants were randomized to intervention or control groups. The intervention group received CRC education over 3 months delivered by an LHE. The control group received education regarding nutrition and physical activity delivered by a health educator. The outcomes were changes in self-reported ever-screening and up-to-date CRC screening after 6 months.ResultsAll 329 participants were foreign-born with mostly no formal education, limited English proficiency, and no employment. The majority of the participants were insured and had a regular source of health care. The intervention group experienced greater changes after the intervention than the control group for ever-screening (P = .068) and being up-to-date with screening (P&lt;.0001). In multivariable regression analyses, the intervention group demonstrated a greater increase than the control group in reporting ever-screening (adjusted odds ratio, 1.73; 95% confidence interval, 1.07-2.79) and being up-to-date with screening (adjusted odds ratio, 1.71; 95% confidence interval, 1.26-2.32). Individuals who had health insurance were found to have &gt;4 times the odds of receiving screening, both ever-screening and up-to-date screening. A higher CRC knowledge score mediated the intervention effect for both screening outcomes.ConclusionsA culturally and linguistically appropriate educational intervention delivered by trained LHEs was found to increase CRC screening in an immigrant population with low levels of education, employment, English proficiency, and literacy. Cancer 2017;98-106. © 2016 American Cancer Society