Miracle-dz/UniFAR-FTUs huggingface dataset:
Physicians encouraging colorectal screening: a randomized controlled trial of enhanced office and patient management on compliance with colorectal cancer screening.

BACKGROUND Colorectal cancer screening is underused. Our objective was to evaluate methods for promoting colorectal cancer screening in primary care practice. METHODS A 2 x 2 factorial randomized clinical trial measured the effects of a tailored vs nontailored physician recommendation letter and an enhanced vs nonenhanced physician office and patient management intervention on colorectal cancer screening adherence. The enhanced and nonenhanced physician office and patient management interventions varied the amount of external support to help physician offices develop and implement colorectal cancer screening programs. The study included 10 primary care physician office practices and 599 screen-eligible patients aged 50 to 79 years. The primary end point was medical-record-verified flexible sigmoidoscopy or colonoscopy. Statistical end-point analysis (according to randomization intent) used generalized estimating equations to account for correlated outcomes according to physician group. RESULTS During a 1-year period, endoscopy in the lower gastrointestinal tract (lower endoscopy) occurred in 289 of 599 patients (48.2%). This finding included the following rates of lower endoscopy: 81 of 152 patients (53.3%) in the group that received the tailored letter and enhanced management; 103 of 190 (54.2%) in the group that received the nontailored letter and enhanced management; 58 of 133 (43.6%) in the group that received the tailored letter and nonenhanced management; and 47 of 124 (37.9%) in the group that received the nontailored letter and nonenhanced management. Enhanced office and patient management increased the odds of completing a colonoscopy or flexible sigmoidoscopy by 1.63-fold (95% confidence interval, 1.11-2.41; P = .01). However, the tailored letter increased the odds of completion by only 1.08-fold (95% confidence interval, 0.72-1.62; P = .71). CONCLUSIONS Approximately one-half of the screen-eligible primary medical care patients aged 50 to 79 years obtained lower endoscopic colorectal cancer screening within 1 year of recommendation. An enhanced office and patient management system significantly improved colorectal cancer screening adherence. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00327457.
The natural history of insomnia: a population-based 3-year longitudinal study.

BACKGROUND Despite its high prevalence, little information is available about the natural history of insomnia. The extent to which episodes of insomnia will persist or remit over time is difficult to predict. We examined the natural history of insomnia and describe the most common trajectories over 3 years. METHODS Three hundred eighty-eight adults (mean [SD] age, 44.8 [13.9] years; 61% women) were selected from a larger population-based sample on the basis of the presence of insomnia at baseline. They completed standardized sleep/insomnia questionnaires at 3 annual follow-up assessments. For each follow-up assessment, participants were classified into 1 of 3 groups (individuals with an insomnia syndrome, individuals with insomnia symptoms, and individuals with good sleep) on the basis of algorithms using standard diagnostic criteria for insomnia. Rates of persistent insomnia, remission, and relapse were computed for each group. RESULTS Of the study sample, 74% reported insomnia for at least 1 year (2 consecutive assessments) and 46% reported insomnia persisting over the entire 3-year study. The course of insomnia was more likely to be persistent in those with more severe insomnia at baseline (ie, insomnia syndrome) and in women and older adults. Remission rate was 54%; however, 27% of those with remission of insomnia eventually experienced relapse. Individuals with subsyndromal insomnia at baseline were 3 times more likely to remit than worsen to syndrome status, although persistence was the most frequent course in that group as well. CONCLUSION These findings indicate that insomnia is often a persistent condition, in particular when it reaches the diagnostic threshold for an insomnia disorder.
Attenuated store-operated Ca2+ entry underpins the dual inhibition of nitric oxide and EDHF-type relaxations by iodinated contrast media.

AIMS Our objective was to investigate whether alterations in endothelial Ca(2+) homeostasis contribute to the clinical toxicity of iodinated radiographic contrast media (IRCM) by modulating nitric oxide (NO) production and the endothelium-derived hyperpolarizing factor (EDHF) phenomenon. METHODS AND RESULTS The triiodinated monomer iohexol caused concentration-dependent reductions in store-operated Ca(2+) entry (SOCE) in rabbit aortic valve endothelium incubated in Ca(2+)-free buffer with cyclopiazonic acid (CPA, 30 microM) to deplete endoplasmic reticulum Ca(2+) stores. This action was mimicked by Gd(3+) ions and 2-aminoethoxydiphenyl borate, two established inhibitors of SOCE, whereas Ca(2+) entry was unaffected by the osmotic agent mannitol. Immunohistochemistry demonstrated that iohexol did not prevent CPA-evoked membrane clustering of Orai1, the key pore element of the store-operated Ca(2+) channel (SOC) apparatus. In myograph studies with rabbit iliac artery rings, iohexol, and the hexaiodinated dimer iodixanol (both at 90 mg I/mL) attenuated NO-mediated and EDHF-type arterial relaxations evoked by CPA, but did not affect EDHF-type relaxations to acetylcholine, whose principal mode of action is to mobilize Ca(2+) via inositol 1,4,5-trisphosphate (InsP(3))-induced Ca(2+) release. Iohexol also exerted inhibitory effects on NO-mediated relaxation and smooth muscle contraction that were not evident with iodixanol. CONCLUSIONS The data support the hypothesis that IRCM induce generalized endothelial dysfunction by inhibiting Ca(2+) influx via SOCs rather than their assembly. The presence of organically bound iodine, rather than osmolar effects, may underpin this previously unrecognized phenomenon. In contrast, direct effects of IRCM on smooth muscle function may correlate with osmolarity rather than iodine concentration.
Matrix metalloproteinase-2 and -9 exacerbate arterial stiffening and angiogenesis in diabetes and chronic kidney disease.

AIMS Chronic kidney disease (CKD) and diabetes are the prominent risk factors of cardiovascular disease (CVD). Matrix metalloproteinase (MMP)-2 and -9 regulate vascular structure by degrading elastic fibre and inhibit angiogenesis by generating angiostatin. We hypothesized that MMP-2 and -9 were up-regulated in the arterial vasculature from CKD patients with diabetes, compared with those without diabetes. METHODS AND RESULTS During living donor transplantation procedures, arteries from donors (n = 8) and recipients (non-diabetic, n = 8; diabetic, n = 8; matched in age, gender, and dialysis treatments) were harvested. Diabetic arteries had increased MMP-2 and -9 activities by 42 and 116% compared with non-diabetic ones. Diabetic arteries were the stiffest, and the stiffness measurement was highly correlated with the summation of MMP-2 + MMP-9 activities (r = 0.738, P = 0.0002). Pulse wave velocity measurements correlated with MMP activity (r = 0.683, P = 0.005). Elastic fibre degradation and calcification were worst in diabetic vessels. The phosphate level, which was 25% higher in diabetic patients, correlated with MMP activity (r = 0.513, P = 0.04) and in vitro stiffness (r = 0.545, P = 0.03), respectively. Angiostatin expression was doubled, whereas vascular endothelial growth factor was 50% reduced in diabetic compared with non-diabetic vessels. Microvascular density in diabetic vessels was 48% of that in non-diabetic ones, and it was strongly associated with MMP activity (r = -0.792, P < 0.0001) and vasorelaxation (r = 0.685, P = 0.0009). CONCLUSION Using a matched case-control design, we report up-regulation of MMP-2 and -9 in diabetic CKD arteries and correlate those with stiffening, impaired angiogenesis, and endothelial dysfunction. These findings may help to explain the high susceptibility of CVD in diabetic and non-diabetic CKD patients.
Case Study: We Have a Voice. Experiences of Students With Special Needs and Typical Students in a Model Primary School in the St. George East District

This qualitative study examined the experiences of inclusion within a model school of both students with special education needs and their peers within the general education classroom. Data were collected using focus group and individual interviews. The researcher made contact three times with each of the participants. Each pupil participated in one focus group interview and one classroom observation and met once to resolve field issues. The following research question was the basis for the interview and questions: What are students’ experiences of inclusion in a model school? As researcher and observer, I used a constant comparison analysis to ensure that the themes, as they occurred in its natural setting, emerged from the data itself. Major themes that emerged are the physical, academic and social aspects of inclusion. Social justice also emerged as an entrenched belief of the students. The students also provided insight into what will make their school more inclusive.
An empirical model to estimate the potential impact of medication safety alerts on patient safety, health care utilization, and cost in ambulatory care.

BACKGROUND Because ambulatory care clinicians override as many as 91% of drug interaction alerts, the potential benefit of electronic prescribing (e-prescribing) with decision support is uncertain. METHODS We studied 279 476 alerted prescriptions written by 2321 Massachusetts ambulatory care clinicians using a single commercial e-prescribing system from January 1 through June 30, 2006. An expert panel reviewed a sample of common drug interaction alerts, estimating the likelihood and severity of adverse drug events (ADEs) associated with each alert, the likely injury to the patient, and the health care utilization required to address each ADE. We estimated the cost savings due to e-prescribing by using third-party-payer and publicly available information. RESULTS Based on the expert panel's estimates, electronic drug alerts likely prevented 402 (interquartile range [IQR], 133-846) ADEs in 2006, including 49 (14-130) potentially serious, 125 (34-307) significant, and 228 (85-409) minor ADEs. Accepted alerts may have prevented a death in 3 (IQR, 2-13) cases, permanent disability in 14 (3-18), and temporary disability in 31 (10-97). Alerts potentially resulted in 39 (IQR, 14-100) fewer hospitalizations, 34 (6-74) fewer emergency department visits, and 267 (105-541) fewer office visits, for a cost savings of 402,619 USD (IQR, 141,012-1,012,386 USD). Based on the panel's estimates, 331 alerts were required to prevent 1 ADE, and a few alerts (10%) likely accounted for 60% of ADEs and 78% of cost savings. CONCLUSIONS Electronic prescribing alerts in ambulatory care may prevent a substantial number of injuries and reduce health care costs in Massachusetts. Because a few alerts account for most of the benefit, e-prescribing systems should suppress low-value alerts.
Influence of heart failure on nucleocytoplasmic transport in human cardiomyocytes.

AIMS The role of the cell nucleus in the development of heart failure (HF) is unknown, so the objectives of this study were to analyse the effect of HF on nucleocytoplasmic transport and density of the nuclear pore complex (NPC). METHODS AND RESULTS A total of 51 human heart samples from ischaemic (ICM, n = 30) and dilated (DCM, n = 16) patients undergoing heart transplantation and control donors (CNT, n = 5) were analysed by western blotting. Subcellular distribution of proteins and NPC were analysed by fluorescence and electron microscopy, respectively. When we compared nucleocytoplasmic machinery protein levels according to aetiology of HF, ICM showed higher levels of importins [(IMP-beta3) (150%, P < 0.0001), IMP-alpha2 (69%, P = 0.001)] and exportins [EXP-1 (178%, P < 0.0001), EXP-4 (81%, P = 0.006)] than those of the CNT group. Furthermore, DCM also showed significant differences for IMP-beta3 (192%, P < 0.0001), IMP-alpha2 (52%, P = 0.025), and EXP-1 (228%, P < 0.0001). RanGTPase-activating proteins (RanGAP1 and RaGAP1u) were increased in ICM (76%, P = 0.005; 51%, P = 0.012) and DCM (41%, P = 0.042; 50%, P = 0.029). Furthermore, subcellular distribution of nucleocytoplasmic machinery was not altered in pathological hearts. Finally, nucleoporin (Nup) p62 was increased in ICM (80%) and DCM (109%) (P < 0.001 and P = 0.024). Nuclear pore density was comparable in pathological and CNT hearts, and ICM showed a low diameter (P = 0.005) and different structural configuration of NPC. CONCLUSION This study shows the effect of HF on nucleocytoplasmic trafficking machinery, evidenced by higher levels of importins, exportins, Ran regulators and Nup p62 in ischaemic and dilated human hearts than those in the controls, with NPCs acquiring a different configuration and morphology in ICM.
Muramyl dipeptide mediated activation of human bronchial epithelial cells interacting with basophils: a novel mechanism of airway inflammation

Respiratory tract bacterial infection can amplify and sustain airway inflammation. Intracytosolic nucleotide‐binding oligomerization domain‐containing protein 2 (NOD2) is one member of the nucleotide binding and oligomerization domain (NOD)‐like receptor (NLR) family, which senses the conserved structural peptidoglycan component muramyl dipeptide (MDP) in almost all bacteria. In the present study, activation of the NOD2 ligand MDP on primary human bronchial epithelial cells (HBE) co‐cultured with human basophils was investigated. Cytokines, NOD2, adhesion molecules and intracellular signalling molecules were assayed by enzyme‐linked immunosorbent assay or flow cytometry. The protein expression of NOD2 was confirmed in basophils/KU812 cells and HBE/human bronchial epithelial cell line (BEAS‐2B) cells. MDP was found to up‐regulate significantly the cell surface expression of intercellular adhesion molecule (ICAM)‐1 and vascular cell adhesion molecule (VCAM)‐1 on basophils and HBE in the co‐culture system with or without basophil priming by interleukin (IL)‐33 (all P < 0·05). MDP could further enhance the release of inflammatory cytokine IL‐6 and chemokine CXCL8, and epithelium‐derived anti‐microbial peptide β‐defensin 2 in the co‐culture. HBE cells were the major source for the release of IL‐6, CXCL8 and β‐defensin2 upon stimulation by MDP in the co‐culture system. The expression of ICAM‐1 and VCAM‐1 and release of IL‐6 and CXCL8 were suppressed by various signalling molecule inhibitors, implying that the interaction between basophils and primary human bronchial epithelial cells could be regulated differentially by the mitogen‐activated protein kinase pathways and nuclear transcription factors. The results therefore provide a new insight into the functional role of basophils in innate immunity, and the link between respiratory bacteria‐mediated innate immunity and subsequent amplification of allergic inflammation in the airway.
Protecting against plague: towards a next‐generation vaccine

The causative organism of plague is the bacterium Yersinia pestis. Advances in understanding the complex pathogenesis of plague infection have led to the identification of the F1‐ and V‐antigens as key components of a next‐generation vaccine for plague, which have the potential to be effective against all forms of the disease. Here we review the roles of F1‐ and V‐antigens in the context of the range of virulence mechanisms deployed by Y. pestis, in order to develop a greater understanding of the protective immune responses required to protect against plague.
Promoting transplantation tolerance; adoptive regulatory T cell therapy

Transplantation is a successful treatment for end‐stage organ failure. Despite improvements in short‐term outcome, long‐term survival remains suboptimal because of the morbidity and mortality associated with long‐term use of immunosuppression. There is, therefore, a pressing need to devise protocols that induce tolerance in order to minimize or completely withdraw immunosuppression in transplant recipients. In this review we will discuss how regulatory T cells (Tregs) came to be recognized as an attractive way to promote transplantation tolerance. We will summarize the preclinical data, supporting the importance of these cells in the induction and maintenance of immune tolerance and that provide the rationale for the isolation and expansion of these cells for cellular therapy. We will also describe the data from the first clinical trials, using Tregs to inhibit graft‐versus‐host disease (GVHD) after haematopoietic stem cell transplantation and will address both the challenges and opportunities in human Treg cell therapy.
Red blood cell distribution width and mortality risk in a community-based prospective cohort.

BACKGROUND Red blood cell distribution width (RDW), an automated measure of red blood cell size heterogeneity (eg, anisocytosis) that is largely overlooked, is a newly recognized risk marker in patients with established cardiovascular disease (CVD). It is unknown whether RDW is associated with mortality in the general population or whether this association is specific to CVD. METHODS We examined the association of RDW with all-cause mortality and with CVD, cancer, and chronic lower respiratory tract disease mortality in 15 852 adult participants in the Third National Health and Nutrition Examination Survey (1988-1994), a nationally representative sample of the US population. Mortality status was obtained by matching to the National Death Index, with follow-up through December 31, 2000. RESULTS Estimated mortality rates increased 5-fold from the lowest to the highest quintile of RDW after accounting for age and 2-fold after multivariable adjustment (P(trend) < . 001 for each). A 1-SD increment in RDW (0.98%) was associated with a 23% greater risk of all-cause mortality (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.18-1.28) after multivariable adjustment. The RDW was also associated with risk of death due to CVD (HR, 1.22; 95% CI, 1.14-1.31), cancer (1.28; 1.21-1.36), and chronic lower respiratory tract disease (1.32; 1.17-1.49). CONCLUSIONS Higher RDW is associated with increased mortality risk in this large, community-based sample, an association not specific to CVD. Study of anisocytosis may, therefore, yield novel pathophysiologic insights, and measurement of RDW may contribute to risk assessment.
The Last Dance: Encountering Death and Dying

Physicians are dedicated to countering death. The new technologies of medicine focus on this end. Therefore, heart transplants, intrauterine surgery, and possible tissue transplants from fetal brains to injured brains are among issues at the frontier of medicine. The focus on finding a cure is so pervasive that the physician comes to regard death as a medical failure rather than a natural event. When Barney Clark died, his mechanical heart went on beating. This book does not focus on medicine's treatment approaches to counter death but on attitudes and social customs prevalent in regarding death. Many physicians in emphasizing technical issues are less prepared to deal with these facets. It is pointed out in the book that until the beginning of this century, death took place in the home with all family members present and participating, at times even building the coffin. The physician was almost peripheral. Today, the role
Matrix metalloproteinases inhibition promotes the polyfunctionality of human natural killer cells in therapeutic antibody‐based anti‐tumour immunotherapy

Activation of human natural killer (NK) cells is associated with the cleavage of CD16 from the cell surface, a process mediated by matrix metalloproteinases (MMPs). In this report, we examined whether inhibition of MMPs would lead to improved NK cell antibody‐dependent cell‐mediated cytotoxicity (ADCC) function. Using an in‐vitro ADCC assay, we tested the anti‐tumour function of NK cells with three different therapeutic monoclonal antibodies (mAbs) in the presence of MMPs inhibitor GM6001 or its control. Loss of CD16 was observed when NK cells were co‐cultured with tumour targets in the presence of specific anti‐tumour antibodies, and was found particularly on the majority of degranulating NK responding cells. Treatment with MMPs inhibitors not only prevented CD16 down‐regulation, but improved the quality of the responding cells significantly, as shown by an increase in the percentage of polyfunctional NK cells that are capable of both producing cytokines and degranulation. Furthermore, MMPs inhibition resulted in augmented and sustained CD16‐mediated signalling, as shown by increased tyrosine phosphorylation of CD3ζ and other downstream signalling intermediates, which may account for the improved NK cell function. Collectively, our results provide a foundation for combining MMPs inhibitors and therapeutic mAbs in new clinical trials for cancer treatment.
Neuroinflammation of the central and peripheral nervous system: an update

Inflammatory disorders of the peripheral nervous system (PNS) and central nervous system (CNS) are common, and contribute substantially to physical and emotional disability of affected individuals. Often, the afflicted are young and in their active years. In the past, physicians and scientists often had very little to offer in terms of diagnostic precision and therapeutic effectiveness. During the past two decades, both of these relative shortcomings have clearly improved. Some of the recent developments in clinical neuroimmunology are illustrated in this special edition of Clinical and Experimental Immunology.
Immune modulation in MS models by peptidoglycan, CD97 and CD44

The clinical expression of an autoimmune disease depends on the activation of resident antigen presenting cells (APC) in the target organ(s), being in this study brain and spinal cord. Most evidence comes from rodent models, and it is unclear whether this principle holds in primates (including humans) and which potential APC stimuli reach the brain. We previously demonstrated that APC containing peptidoglycan (PG) are present in post-mortem multiple sclerosis (MS) brain. PG is a major cell wall component of Gram-positive bacteria exerting proinflammatory signals via TLR2 and Nod1/2 ligation. In the brain, PG may thus activate both infiltrating and resident APC. To assess how PG is brought into the brain and to investigate its functional relevance in demyelination, we systematically compared MS to non-human primates, which are genetically and immunologically closely related to humans and are therefore valuable models to analyze the regulation of chronic inflammation in MS. Localization of APC subsets containing PG, as well as their expression of enzymes degrading PG (lysozyme and NAMLAA) were determined in the two main primate EAE models for MS, with acute (rhesus monkey) versus chronic disease (marmoset). Distinct phagocytic subsets in MS and EAE brain carried PG, including granulocytes, macrophages and dendritic cells. The number of PG-containing cells in brain tissue during both acute and chronic disease was significantly higher compared to control animals, and acute EAE was accompanied by higher numbers of PG-containing cells in brain compared with chronic EAE. PG-degrading enzymes were scarcely expressed in monkey brain, spleen and in MS brain, favouring persistence of intracellular PG in the periphery as well as the CNS. Peripheral blood leukocytes from all three primate species produced IL-12p70 upon stimulation with PG purified from Staphylococcus aureus. The presence of a TLR/Nod ligand in the inflamed brain has major implications, since TLR are widely expressed in the CNS and their ligation potentially promotes inflammation and progression of demyelinating disease.