Symptoms-Based Phenotypes Among Women With Dysmenorrhea: A Latent Class Analysis

Dysmenorrhea is highly prevalent and may increase women’s risk for developing other chronic pain conditions. Although it is highly variable, symptom-based dysmenorrhea phenotypes have not been identified. The study aims were to identify symptom-based dysmenorrhea phenotypes and examine their relationships with demographic and clinical characteristics. In a cross-sectional study, 762 women with dysmenorrhea rated severity of 14 dysmenorrhea-related symptoms. Using latent class analysis, we identified three distinctive phenotypes. Women in the “mild localized pain” phenotype (n=202, 26.51%) had mild abdominal cramps and dull abdominal pain/discomfort. Women in the “severe localized pain” phenotype (n=412 54.07%) had severe abdominal cramps. Women in the “multiple severe symptoms” phenotype (n=148, 19.42%) had severe pain at multiple locations and multiple gastrointestinal symptoms. Race, ethnicity, age, and comorbid chronic pain conditions were significantly associated with phenotypes. Identification of these symptom-based phenotypes provides a foundation for research examining genotype-phenotype associations, etiologic mechanisms, and/or variability in treatment responses

Examining whether the information-motivation-behavioral skills model predicts medication adherence for patients with a rare disease.

The information-motivation-behavioral skills (IMB) model has been used to explain and promote medication adherence among patients with diabetes and HIV. The objective of this study was to examine whether the IMB model predicted medication adherence among vasculitis patients. Adult vasculitis patients (n=228) completed online questionnaires at baseline and 3-month follow-up. Linear regressions were calculated to determine the direct effects of information and motivation on medication adherence (P<0.05). A mediation analysis using a bootstrapping approach was used to test whether behavioral skills significantly mediated the effect of information and motivation on medication adherence. Participants reported high levels of information (M=4.0; standard deviation [SD]=0.68), moderate levels of motivation (M=2.7; SD=1.00), and high levels of behavioral skills (M=4.1; SD=0.74). In the regression model, only behavioral skills (B=0.38; P<0.001) were significantly associated with medication adherence; however, mediation analysis revealed that behavioral skills significantly mediated the effects of information and motivation on medication adherence. The results support the IMB-hypothesized relationships between information, motivation, behavioral skills, and medication adherence in our sample. Findings suggest that providers should work with vasculitis patients to increase their medication-related skills to improve medication adherence

Identifying Interaction Sites in Recalcitrant Proteins: Predicted Protein and RNA Binding Sites in Rev Proteins of HIV-1 and EIAV Agree with Experimental Data

Protein-protein and protein nucleic acid interactions are vitally important for a wide range of biological processes, including regulation of gene expression, protein synthesis, and replication and assembly of many viruses. We have developed machine learning approaches for predicting which amino acids of a protein participate in its interactions with other proteins and/or nucleic acids, using only the protein sequence as input. In this paper, we describe an application of classifiers trained on datasets of well-characterized protein-protein and protein-RNA complexes for which experimental structures are available. We apply these classifiers to the problem of predicting protein and RNA binding sites in the sequence of a clinically important protein for which the structure is not known: the regulatory protein Rev, essential for the replication of HIV-1 and other lentiviruses. We compare our predictions with published biochemical, genetic and partial structural information for HIV-1 and EIAV Rev and with our own published experimental mapping of RNA binding sites in EIAV Rev. The predicted and experimentally determined binding sites are in very good agreement. The ability to predict reliably the residues of a protein that directly contribute to specific binding events - without the requirement for structural information regarding either the protein or complexes in which it participates - can potentially generate new disease intervention strategies

Integrin α6β4 Promotes Autocrine Epidermal Growth Factor Receptor (EGFR) Signaling to Stimulate Migration and Invasion toward Hepatocyte Growth Factor (HGF)

Integrin α6β4 is up-regulated in pancreatic adenocarcinomas where it contributes to carcinoma cell invasion by altering the transcriptome. In this study, we found that integrin α6β4 up-regulates several genes in the epidermal growth factor receptor (EGFR) pathway, including amphiregulin (AREG), epiregulin (EREG), and ectodomain cleavage protease MMP1, which is mediated by promoter demethylation and NFAT5. The correlation of these genes with integrin α6β4 was confirmed in The Cancer Genome Atlas Pancreatic Cancer Database. Based on previous observations that integrin α6β4 cooperates with c-Met in pancreatic cancers, we examined the impact of EGFR signaling on hepatocyte growth factor (HGF)-stimulated migration and invasion. We found that AREG and EREG were required for autocrine EGFR signaling, as knocking down either ligand inhibited HGF-mediated migration and invasion. We further determined that HGF induced secretion of AREG, which is dependent on integrin-growth factor signaling pathways, including MAPK, PI3K, and PKC. Moreover, matrix metalloproteinase activity and integrin α6β4 signaling were required for AREG secretion. Blocking EGFR signaling with EGFR-specific antibodies or an EGFR tyrosine kinase inhibitor hindered HGF-stimulated pancreatic carcinoma cell chemotaxis and invasive growth in three-dimensional culture. Finally, we found that EGFR was phosphorylated in response to HGF stimulation that is dependent on EGFR kinase activity; however, c-Met phosphorylation in response to HGF was unaffected by EGFR signaling. Taken together, these data illustrate that integrin α6β4 stimulates invasion by promoting autocrine EGFR signaling through transcriptional up-regulation of key EGFR family members and by facilitating HGF-stimulated EGFR ligand secretion. These signaling events, in turn, promote pancreatic carcinoma migration and invasion

Predictors of medication non-adherence for vasculitis patients

The primary purpose of this article is to document whether demographic, clinical, regimen-related, intrapersonal, and interpersonal factors predict medication non-adherence for vasculitis patients. A secondary purpose is to explore whether adherence varies by medication type and whether patients experienced drug-related side effects. Vasculitis patients (n=228) completed online baseline and 3-month follow-up surveys. Demographic (age, gender, education, race, marital status, and insurance status), clinical (perceived vasculitis severity, disease duration, vasculitis type, and relapse/remission status), regimen-related (experience of side effects), intrapersonal (depressive symptoms), and interpersonal (adherence-related support from family and friends) factors were measured at baseline. Medication non-adherence was assessed at follow-up using the Vasculitis Self-Management Survey medication adherence sub-scale (α=0.89). Variables that significantly correlated (p<0.05) with non-adherence were included in a linear regression model to predict non-adherence. Younger age (r=−0.23, p<0.001), female sex (r=0.16, p<0.05), experience of side effects (r=0.15, p<0.05), and more depressive symptoms (r=0.22, p< 0.001) were associated with more medication non-adherence, In the regression model, younger age (β=−0.01, p=0.01) and more depressive symptoms (β=0.01 p=0.02) predicted worse adherence. For six out of eight vasculitis medication types, patients who experienced side effects were less adherent than patients who did not experience side effects. Multiple factors are associated with medication non-adherence for vasculitis patients. Providers should discuss medication adherence and drug-related side effects with vasculitis patients. Providers may want to particularly target younger patients and patients with clinical signs of depression

Factors Associated with Neutralizing Antibody Response in Piglets Experimentally Infected with Porcine Reproductive and Respiratory Virus

Host genetic differences and other factors associated with neutralizing antibody (NAb) response were examined in 464 Large White-Landrace piglets that were experimentally challenged with porcine reproductive and respiratory virus (PRRSv) isolate NVSL-97-7895. Serum samples and viremia data were collected on piglets periodically for 42 days post infection (dpi). NAb response was defined as the inverse of the highest 1:2 serial dilution of serum without cytopathic effects. Heritability and other factors associated with NAb response were estimated using an animal model in ASReml. These analyses identified two aspects of viremia that were associated with NAb response: viral load (area under the curve from 0-21 dpi) and virus rebound (a two Log increase in viremia after the virus had started to clear). These results also suggested that NAb response may be lowly heritable and provided the groundwork for further characterization of NAb response

Extracellular N-Acetylaspartate in Human Traumatic Brain Injury.

N-acetylaspartate (NAA) is an amino acid derivative primarily located in the neurons of the adult brain. The function of NAA is incompletely understood. Decrease in brain tissue NAA is presently considered symptomatic and a potential biomarker of acute and chronic neuropathological conditions. The aim of this study was to use microdialysis to investigate the behavior of extracellular NAA (eNAA) levels after traumatic brain injury (TBI). Sampling for this study was performed using cerebral microdialysis catheters (M Dialysis 71) perfused at 0.3 μL/min. Extracellular NAA was measured in microdialysates by high-performance liquid chromatography in 30 patients with severe TBI and for comparison, in radiographically "normal" areas of brain in six non-TBI neurosurgical patients. We established a detailed temporal eNAA profile in eight of the severe TBI patients. Microdialysate concentrations of glucose, lactate, pyruvate, glutamate, and glycerol were measured on an ISCUS clinical microdialysis analyzer. Here, we show that the temporal profile of microdialysate eNAA was characterized by highest levels in the earliest time-points post-injury, followed by a steady decline; beyond 70 h post-injury, average levels were 40% lower than those measured in non-TBI patients. There was a significant inverse correlation between concentrations of eNAA and pyruvate; eNAA showed significant positive correlations with glycerol and the lactate/pyruvate (L/P) ratio measured in microdialysates. The results of this on-going study suggest that changes in eNAA after TBI relate to the release of intracellular components, possibly due to neuronal death or injury, as well as to adverse brain energy metabolism.We gratefully acknowledge financial support as follows. Research support: the Medical Research Council (MRC, Grant Nos. G0600986 ID79068 and G1002277 ID98489) and the National Institute for Health Research Biomedical Research Centre (NIHR BRC) Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). Authors’ support: R.J.S. - NIHR BRC (Neuroscience Theme; Brain Injury and Repair Theme); SV - NIHR BRC (Neuroscience Theme; Brain Injury and Repair Theme); I.J. – MRC (Grant no. G1002277 ID 98489) and NIHR BRC Cambridge; D.K.M. - NIHR Senior Investigator Award; P.J.H. – NIHR Research Professorship, Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship; K.L.H.C. – NIHR BRC Cambridge (Neuroscience Theme; Brain Injury and Repair Theme).This is the final version of the article. It first appeared from Mary Ann Liebert via http://dx.doi.org/10.1089/neu.2015.395

Exploring youth and caregiver preferences for asthma education video content

This study examines: 1) whether youth and their caregivers have different preferences for asthma education video topics and 2) if education topic preferences vary by youth and caregiver sociodemographic characteristics