Meprin-β regulates production of pro-inflammatory factors via a disintegrin and metalloproteinase-10 (ADAM-10) dependent pathway in macrophages

Inflammatory response plays an important role not only in the normal physiology but also in the pathology such as atherosclerosis. Meprin, an astacin metalloproteinase, has exhibited proinflammatory effects in vivo and in vitro studies. Here, we tried to further investigate the proinflammatory potential of meprin-β and the possible underlying mechanisms in primary human peripheral blood macrophages. In our current study, ELISA assay revealed that meprin-β increased the production of pro-inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-18 and interleukin-6 (IL-6) in macrophages. However, meprin-β shows no effects on the level of ligands of epidermal growth factor receptor (EGFR), and the activation of EGFR. The molecular mechanism was associated with activation of a disintegrin and metalloproteinase 10 (ADAM10) and the phosphorylation of IκB. Further analysis of upstream mechanisms showed that activation of NF-κB by meprin-β was mediated by inhibiting ADAM10-downstream extracellular signal regulated kinase (ERK1/2) pathway. Taken together, these results indicated that meprin-β exhibited pro-inflammatory effects by targeting activating ADAM10, leading to ERK1/2-mediated activation of NF-κB in macrophages, and this would make meprin-β a strong candidate for further study as proinflammatory target.     

The Impact of a Longitudinal Curriculum on Medical Student Obstetrics and Gynecology Clinical Training

Clinical training in most medical schools consists of separate rotations, based out of tertiary-care facilities, across the core medical disciplines. In addition to a traditional clinical curriculum, the University of Hawai‘i offers a longitudinal clinical curriculum as an option to medical students. The longitudinal curriculum provides students with an innovative, alternative educational track to achieve their educational goals in clinical medicine. The objective of this study was to describe the obstetrics and gynecology procedural experiences of third-year medical students who participated in a longitudinal curriculum versus a traditional block clerkship. The number of procedures reported by third-year medical students who participated in a non-traditional, longitudinal clerkship was compared with the number of procedures reported by students who participated in the traditional block third-year curriculum between July 2007 and June 2009. National Board of Medical Examiners (NBME) subject scores, clerkship grade and chosen residency specialty were also compared. The mean number of pelvic exams (longitudinally-trained 36 [SD 33] versus block-trained 8 [SD 6], [t=4.3, P<.01]) and pap smears (longitudinally-trained 28 [SD 26] versus block-trained 7 [SD 3] [t=4.4, P<.01]) was significantly higher for longitudinally-trained students compared to block-trained students. No significant differences in overall clerkship grades or NBME shelf scores emerged.     

The “Latina Epidemiologic Paradox”: Contrasting Patterns of Adverse Birth Outcomes in U.S.-Born and Foreign-Born Latinas

BackgroundThe “Latina epidemiologic paradox” postulates that despite socioeconomic disadvantages, Latina mothers have a lower risk for delivering low birth weight (LBW) babies than non-Latina Whites. However, these patterns may be changing over time and may differ depending on the mother's birthplace and legal status in the United States. This study investigates differences in risk for three birth outcomes among Whites, U.S.-born Latinas, and foreign-born Latinas.MethodsWe undertook a cross-sectional study of rates of LBW, preterm, and small-for-gestational-age (SGA) births among 196,617 women delivering live, singleton births in Utah from 2004 to 2007. Each group was compared using logistic regression.ResultsU.S.-born Latinas had a similar or greater risk for all three outcomes when compared with Whites. Foreign-born Latinas had lower risk for preterm birth (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.80–0.90) compared with Whites, but not for LBW and SGA; foreign-born Latinas had a lower risk for LBW (OR, 0.82; 95% CI, 0.74–0.92), preterm birth (OR, 0.81; 95% CI, 0.74–0.89), and SGA (OR, 0.91; 95% CI, 0.83–0.99) compared with U.S.-born Latinas. Among foreign-born Latinas only, there was no difference in risk between documented (i.e., those who had a legal social security number) and undocumented women for LBW, preterm birth, or SGA.ConclusionsThese data support the existence of a variation of the “Latina paradox” among Latinas according to birthplace, where U.S.-born Latinas do not experience better birth outcomes than Whites, but foreign-born Latinas experience better birth outcomes for several endpoints compared with U.S.-born Latinas. Prevention efforts may prove more effective by considering the different composition of risk factors among foreign- and U.S.-born Latina populations.     

Usefulness of a Visual Analog Scale for Measuring Anxiety in Hospitalized Patients Experiencing Pain: A Multicenter Cross-Sectional Study

BackgroundAnxiety is common in hospitalized patients and can worsen pain or lead to unsuccessful pain relief.AimsThe purpose of this study was to evaluate the usefulness of measuring anxiety with a visual analog scale (VAS) in the hospitalized patient experiencing pain.DesignWe conducted a multiple-center cross-sectional study.Participants/SubjectsAdult inpatients experiencing moderate to severe pain defined by a pain VAS score ≥40 of 100 were included.MethodsPain and anxiety data were collected using the following instruments: pain VAS, anxiety VAS, State Anxiety Scale of the Spielberger State-Trait Anxiety Inventory (STAI-YA) and Anxiety Subscale of the Hospital Anxiety and Depression Scale (HAD-A).ResultsData were collected from 394 patients. Of those patients, 43.6% (171 of 392) and 36.6% (143 of 391) had significant anxiety according to STAI-Ya and HAD-A, respectively. Correlation was good between anxiety-VAS and STAI-YA (ρ = 0.67 [95% confidence interval 0.61-0.72]) and moderate between anxiety VAS and HAD-D (ρ = 0.48 [0.39-0.56]). The main factor predictive of situational anxiety was history of anxiety-depression symptoms (odds ratio = 2.95 [1.93-4.56]). For anxiety VAS score ≥ 40 of 100, the sensitivity for detecting anxiety was 81% with 70% specificity.ConclusionThis study confirmed the high prevalence of anxiety among inpatients experiencing pain, demonstrated the capacity of a VAS to assess this anxiety, determined an anxiety VAS cutoff level to screen for significant anxiety, and identified risk factors of anxiety in this population. Anxiety VAS has been found to be an easy-to-use method familiar to caregivers, with all the advantages needed for an effective screening instrument. An anxiety VAS score ≥40 of 100 would thus warrant particular attention to adapt care to the patient's anxiety-related pain and initiate specific therapeutic interventions.     

Simultaneous identification and typing of Candida species by MSP-PCR and AFLP: Study of clinical isolates from a Portuguese pediatric hospital

ObjectivesTo compare the advantages of two methods for Candida species identification, strain differentiation, and epidemiological analysis. Discrimination power, ease of use, and cost are analyzed to determine the clinical practicality and utility of these molecular tools.MethodsFifty-one Candida isolates (26 Candida albicans, 18 Candida parapsilosis, and seven Candida tropicalis), collected from 42 different patients and seven healthcare workers in a Portuguese pediatric hospital over a three-year-period, were characterized by microsatellite-PCR (MSP-PCR) and amplified fragment length polymorphism (AFLP).ResultsBoth MSP-PCR fingerprints and AFLPs with two distinct primer sets (E-AC/M-CAA and E-AC/M-CAC) showed good identification and typing ability, since the isolates were grouped in well-separated clusters for each species and high values were observed for Simpson's discrimination indices (DI, 0.964–0.987) and Shannon–Weaver (J′, 0.930–0.972). Among the combined analyses of MSP-PCR and AFLP data, composite MSP-PCR/AFLP-CAC fingerprinting was seen to be the most discriminating (DI, 0.999; J′, 0.976) and in agreement with the separate analyses (over 95% cophenetic correlation). The MSP-PCR/AFLP-CAC typing was thus selected as a simultaneous identification and typing method for Candida isolates.ConclusionsUsing this approach, 38 types were defined among clinical isolates (21 for C. albicans, 12 for C. parapsilosis and five for C. tropicalis), and clonal and epidemiological relationships could be inferred for some groups of isolates.     

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

PurposeWe assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.MethodsRetrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)–negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort.ResultsThe ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25–1.33], P = 3×10⁻⁷²). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27–1.36], P = 7×10⁻⁵⁰). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25–1.40], P = 3×10⁻²²) and BRCA2 (HR = 1.44 [95% CI 1.30–1.60], P = 4×10⁻¹²) carriers. The associations in the prospective cohort were similar.ConclusionPopulation-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.     

18F-sodium fluoride positron emission tomography (NaF-18-PET/CT) radiomic signatures to evaluate responses to alpha-particle Radium-223 dichloride therapy in osteosarcoma metastases

Patients with osteoblastic metastases from high risk osteosarcoma continue to have a poor prognosis after progression from standard-of-care multi-agent chemotherapy. In a first-in-human dose escalation trial of bone targeted Radium 223 dichloride alpha-particle therapy in 18 patients with advanced osteosarcoma only 1 patient responded based on conventional Response Evaluation Criteria in Solid Tumors (RECIST). Na¹⁸F PET response Criteria in Solid Tumors(NAFCIST), based on Sodium fluoride-18 (Na¹⁸F) positron emission tomography (PET)-CT was developed to better evaluate bone specific response. To further appreciate the spatial and temporal heterogeneity of the partial or mixed responses, a radiomics method was developed. Analyses were performed with ¹⁸F-sodium fluoride positron emission tomography imaging studies before and after alpha-particle therapy. Radioactive ¹⁸F⁻ -atom concentrations were measured in soft-tissues, in approximately 1000 concentration data points for ¹⁸F⁻ per 1 cm³ metastatic tumor. Data was analyzed from the SUV intensity values, the histogram of intensities and entropy values. Radiomics may inform intra-tumoral and inter-tumoral heterogeneity in response of bone forming osteosarcoma to alpha particle therapy. Each patient (and each tumor) represents an “N of 1” case and warrants in depth analysis individually.