tbuckley/cabot-search huggingface dataset:
Atelocollagen-mediated Systemic Delivery Prevents Immunostimulatory Adverse Effects of siRNA in Mammals
Authors: Shinichiro Inaba, Shunji Nagahara, Naoki Makita, Yuzo Tarumi, Takuji Ishimoto, Seiichi Matsuo, Kenji Kadomatsu, Yoshifumi Takei
Journal: Molecular Therapy (2011)

Short interfering RNA (siRNA) is a potent activator of the mammalian innate immune system. When considering possible clinical applications of siRNA for humans, the adverse immunostimulatory effects must also be taken into account. Here, we show that atelocollagen-mediated systemic delivery of siRNA without chemical modifications did not cause any immunostimulation in both animals and human peripheral blood mononuclear cells (PBMCs), even if the siRNA harbored an interferon (IFN)-inducible sequence. In contrast, systemic delivery of immunostimulatory RNA (isRNA)-mediated by a cationic lipid (such as Invivofectamine) induced potent type-I IFNs and inflammatory cytokines. Regarding the mechanism by which the isRNA/atelocollagen complex avoided adverse effects on immunostimulation, we revealed that this complex was not incorporated into PBMCs. On the other hand, Invivofectamine delivered isRNA into PBMCs. The use of either atelocollagen or Invivofectamine as a vehicle elicited significant and undistinguishable therapeutic effects in a contact hypersensitivity (CHS) inflammatory model mouse, when we intravenously injected the siRNA targeting monocyte chemoattractant protein-1 as the complex. For the goal of realizing siRNA-based medicines for humans, atelocollagen is an excellent and promising delivery vehicle, and it has the useful advantage of evading detection by the "radar" of innate immunity. Short interfering RNA (siRNA) is a potent activator of the mammalian innate immune system. When considering possible clinical applications of siRNA for humans, the adverse immunostimulatory effects must also be taken into account. Here, we show that atelocollagen-mediated systemic delivery of siRNA without chemical modifications did not cause any immunostimulation in both animals and human peripheral blood mononuclear cells (PBMCs), even if the siRNA harbored an interferon (IFN)-inducible sequence. In contrast, systemic delivery of immunostimulatory RNA (isRNA)-mediated by a cationic lipid (such as Invivofectamine) induced potent type-I IFNs and inflammatory cytokines. Regarding the mechanism by which the isRNA/atelocollagen complex avoided adverse effects on immunostimulation, we revealed that this complex was not incorporated into PBMCs. On the other hand, Invivofectamine delivered isRNA into PBMCs. The use of either atelocollagen or Invivofectamine as a vehicle elicited significant and undistinguishable therapeutic effects in a contact hypersensitivity (CHS) inflammatory model mouse, when we intravenously injected the siRNA targeting monocyte chemoattractant protein-1 as the complex. For the goal of realizing siRNA-based medicines for humans, atelocollagen is an excellent and promising delivery vehicle, and it has the useful advantage of evading detection by the "radar" of innate immunity.
The Pharmaceutical Price Regulation Scheme
Authors: Joe Collier
Journal: BMJ (2007)

Early last week, the Office of Fair Trading (OFT) published its report on the Pharmaceutical Price Regulation Scheme,1 a uniquely British mechanism for determining the prices the National Health Service pays for brand name drugs (currently costing around £8bn (€12bn; $15.6bn) a year). For 18 months the enquiry team had analysed the scheme, heard evidence, looked at arrangements in other countries, and modelled alternatives in an NHS context. Early on Tuesday 20 February it delivered its verdict: the scheme was no longer fit for purpose and needed to change.
Care of the Child Facing Death
Authors: Grace S. Wolff
Journal: JAMA (1975)

This book is a compilation of writings concerning the dying child. The discussions are concentrated upon those children whose deterioration before death will extend from months to years. The primary focus is upon the psychological, social, physical and economic aspects of the child facing death and of those who face the death of the child. The book is divided into four sections: the first gives an overview of the general problem; the second provides a discussion of specific problems, such as relief of pain and multiple childhood deaths in the same family; the third section deals with direct aid to the child; the fourth with aid to the family. While there are fragments of helpful information in each section, there is a monotonous replication that might have been avoided if some of the chapters had been consolidated. However, several meritorious chapters deserve the perusal of those who deal with children
Multifactorial Inheritance Hypothesis for the Etiology of Congenital Heart Diseases
Authors: JAMES J. NORA
Journal: Circulation (1968)

A systematic investigation into the etiology of congenital heart diseases (CHD) has been undertaken through the testing of four alternative hypotheses. Data was obtained for six common congenital heart lesions from the investigation of familial aggregates, twin studies, and chromosomal evaluations. Animal homologies were also considered in the evaluation of the hypotheses. Hypothesis 1—no genetic basis for the etiology of congenital heart diseases—was tested and rejected. Then in an effort to define the possible genetic basis of congenital cardiovascular malformations hypothesis 2—the genetic basis of CHD is determined by gross chromosomal aberrations—was evaluated by reviewing karyotypes of nonsyndrome CHD patients in the literature as as well as 104 personal cases. Rejection of hypothesis 2 is required by all available evidence. Hypothesis 3—the genetic basis of common isolated congenital heart lesions is determined by single mutant genes—was also tested and rejected. Hypothesis 4—congenital heart diseases are a heterogeneous category of developmental anomalies, representing in most cases the multifactorial inheritance of threshold characters, the expression of which is the product of a genetic-environmental interaction—was tested by the same criteria. On the basis of these criteria this hypothesis could not be rejected. Therefore the multifactorial hypothesis is proposed as a working hypothesis which encompasses both the genetic and environmental factors known to participate in the etiology of congenital heart diseases. It is hoped that through the testing of this hypothesis investigation into new areas will be stimulated, which ultimately will lead to active methods of prevention.
Association of Maternal Exposure to Childhood Abuse With Elevated Risk for Autism in Offspring
Authors: Andrea L. Roberts, Kristen Lyall, Janet W. Rich-Edwards, Alberto Ascherio, Marc G. Weisskopf
Journal: JAMA Psychiatry (2013)

<h3>Importance</h3>Adverse perinatal circumstances have been associated with increased risk for autism in offspring. Women exposed to childhood abuse experience more adverse perinatal circumstances than women unexposed, but whether maternal abuse is associated with autism in offspring is unknown.<h3>Objectives</h3>To determine whether maternal exposure to childhood abuse is associated with risk for autism in offspring and whether possible increased risk is accounted for by a higher prevalence of adverse perinatal circumstances among abused women, including toxemia, low birth weight, gestational diabetes, previous induced abortion, intimate partner abuse, pregnancy length shorter than 37 weeks, selective serotonin reuptake inhibitor use, and alcohol use and smoking during pregnancy.<h3>Design and Setting</h3>Nurses' Health Study II, a population-based longitudinal cohort of 116 430 women.<h3>Participants</h3>Nurses with data on maternal childhood abuse and child's autism status (97.0% were of white race/ethnicity). Controls were randomly selected from among children of women who did not report autism in offspring (participants included 451 mothers of children with autism and 52 498 mothers of children without autism).<h3>Main Outcome Measures</h3>Autism spectrum disorder in offspring, assessed by maternal report and validated with the Autism Diagnostic Interview–Revised in a subsample.<h3>Results</h3>Exposure to abuse was associated with increased risk for autism in children in a monotonically increasing fashion. The highest level of abuse was associated with the greatest prevalence of autism (1.8% vs 0.7% among women not abused, P = .005) and with the greatest risk for autism adjusted for demographic factors (risk ratio, 3.7; 95% CI, 2.3-5.8). All adverse perinatal circumstances except low birth weight were more prevalent among women abused in childhood. Adjusted for perinatal factors, the association of maternal childhood abuse with autism in offspring was slightly attenuated (risk ratio for highest level of abuse, 3.0; 95% CI, 1.9-4.8).<h3>Conclusions and Relevance</h3>We identify an intergenerational association between maternal exposure to childhood abuse and risk for autism in the subsequent generation. Adverse perinatal circumstances accounted for only a small portion of this increased risk.
Idiopathic Tropical Splenomegaly Syndrome in Ibadan
Authors: E. J. Watson-Williams, N. C. Allan
Journal: BMJ (1968)

Follow-up of 33 patients with idiopathic splenomegaly, 25 for a period ranging from 14 to 80 months after starting treatment with proguanil 100 mg. daily, showed that there was an excellent response of the splenomegaly, anaemia, and hepatomegaly, together with a definite gain in weight. Every patient improved, though a maximum result was not attained until after at least one year's treatment.Therapy with proguanil is considered superior to and safer than splenectomy. Malaria seems unlikely to have a causal role in the aetiology of the disease, which is probably a manifestation of a disorder of the normal immune mechanism. Idiopathic splenomegaly has a close relation with the type of chronic lymphatic leukaemia seen in Nigeria, and it is possible that the two diseases have a similar aetiological factor.
Uric acid effects on in vitro models of rheumatoid inflammatory and autoimmune processes.
Authors: R.A Turner, E.J Pisko, C.A Agudelo, G.B Counts, S.L Foster, W.J Treadway
Journal: Annals of the Rheumatic Diseases (1983)

A neutrophil monolayer system was used to study the effects of uric acid on neutrophil-aggregate interactions important in rheumatoid inflammation. No effect on immunoglobulin G aggregate phagocytosis was seen, but hyperuricaemic levels of uric acid were associated with an enhancement of phagocytosis-induced release of the azurophilic granular enzyme beta-glucuronidase. A trinitrophenyl-coupled mononuclear leucocyte rheumatoid factor plaque-forming assay was utilised to study uric acid effects on polyclonal activation of immunocompetent cells. Low levels of uric acid enhanced and high levels suppressed this system. Hyperuricaemia may enhance some aspects of rheumatoid inflammation, while uric acid may modulate an important component of rheumatoid autoimmunity.
Investigation of QT interval in adult coeliac disease.
Authors: G. R. Corazza, M. Frisoni, C. Filipponi, L. Gullo, V. M. Poggi, G. Gasbarrini
Journal: BMJ (1992)

Delayed heart repolarisation is marked by prolonged QT interval on electrocardiography and may be complicated by ventricular arrhythmias, syncope, and sudden death.'Such events have recently been associated with severe malnutrition, as occurs in anorexia nervosa2 and after ileojejunal bypass.3These reports have prompted us to measure QT interval in adult patients with coeliac disease, a condition which often presents with nutritional impairment.
Increased calcium-channel currents of pancreatic β cells in neonatally streptozocin-induced diabetic rats
Authors: Seika Kato, Hitoshi Ishida, Yoshiyuki Tsuura, Yoshimasa Okamoto, Kazuo Tsuji, Minoru Horie, Yasunobu Okada, Yutaka Seino
Journal: Metabolism (1994)
Leukemia Cutis
Authors: William H. Robey, G. Gardiner Russell
Journal: New England Journal of Medicine (1947)

LEUKEMIA is characterized by hyperplasia of the leukopoietic tissues throughout the body and is usually associated with qualitative and quantitative variations in the circulating leukocytes. Urticaria, pruritus and prurigo, hematomas and actual tumor formations may occur. In the case reported below, the intense skin involvement began early; the leonine appearance of the face and general leukemic infiltration of the skin led to the diagnosis of leukemia cutis — a rare manifestation, only 4 cases having been seen at the Boston City Hospital in twenty years. In association with these skin lesions the blood may remain normal for years or may . . .
Mitochondrial oxidative injury and energy metabolism alteration in rat fatty liver: Effect of the nutritional status
Authors: Gianluigi Vendemiale, Ignazio Grattagliano, Paolo Caraceni, Giovanni Caraccio, Marco Domenicali, Monia Dall'Agata, Franco Trevisani, Ferruccio Guerrieri, Mauro Bernardi, Emanuele Altomare
Journal: Hepatology (2001)

Hepatic steatosis is associated with mitochondrial oxidative alterations. This study aimed to characterize in a choline-deficient model of rat fatty liver whether this oxidative imbalance is related to an impairment of the capacity of ATP synthesis both under fed conditions and after starvation, which may sensitize mitochondria to oxidative injury. Mitochondria were isolated from normal and fatty livers of fed or 18-hour fasted rats. Oxidative injury was evaluated by measuring the mitochondrial content of thiobarbituric reactive substances, protein carbonyls, glutathione, and protein sulfhydryls. The mitochondrial F(0)F(1)-ATP synthase content, tissue ATP concentration, and liver histology were also determined. Compared with normal liver, under fed conditions, fatty livers showed a greater mitochondrial content of oxidized lipids and proteins together with a low concentration of sulfhydryls and glutathione. The mitochondrial catalytic beta-F(1) subunit of the F(0)F(1)-ATP synthase was about 35% lower in fatty livers. Hepatic ATP was also significantly reduced in fatty liver. Starvation exacerbated mitochondrial oxidative injury in both groups but to a greater extent in fatty livers. In the steatotic group, fasting induced a significant decrease of the ATP levels, which was accompanied by a 70% fall of the catalytic beta-F(1) subunit. These data indicate that the mitochondrial oxidative alterations in fatty livers are associated with an important reduction of the F(0)F(1)-ATP synthase. These changes, which are greatly exacerbated after starvation, may account for the reduced synthesis of the hepatic ATP observed in the presence of fatty infiltration.
Tethered spinal cord syndrome
Authors: John Payne
Journal: BMJ (2007)

<h3>Background and importance</h3> Adherence is one of the most important variables for achieving the benefits of antiretroviral treatment (ART) since effectiveness and safety of current treatments are optimal. Adherence can be measured by direct methods, which consist of measuring the substances in biological samples, or by indirect methods based on patient interviews and dispensing records. Indirect methods have the advantages of simplicity, an easier application in daily clinical practice and lower costs. <h3>Aim and objectives</h3> The objectives of this study were to describe ART adherence in people living with human inmunodeficency virus (HIV) and to analyse the correlation and the concordance between two indirect methods used to measure adherence: a simple single item rating scale answered with a visual analogue scale (SIRS-VAS) and the medication possession rate (MPR). <h3>Material and methods</h3> Multicentre (5 centres), observational, prospective and cross-sectional study. We enrolled adult people living with HIV (PLHIV) on ART. The adherence was measured using two indirect methods. One was a SIRS-VAS about the percentage of ART taken in the previous month. The other method was the MPR, calculated over the previous 6 months from dispensing records. MPR (%) = (days covered with dispensed medication/time interval)*100. For studing the adherence as a qualitative variable, different cut-off points were established on the SIRS-VAS and the MPR (95%, 90%, 85% and 80%), classifying participants as ‘adherent’ or ‘non-adherent’. Spearman correlation coefficient (r) was studied between quantitative variables. Cohen’s kappa concordance coefficient (κ) was studied between qualitative variables. P values under 5% were considered statistically significant. <h3>Results</h3> We enrolled 128 participants, aged 20–81 years (&amp;xbar;=46.9±11.7); 112 men, 14 women, and 2 non-binary people. The mean±SD MPR was 96.8±7.0%. The mean±SD SIRS-VAS score was 96.9±5.8%. There was a modest correlation between both measures (r= 0.31, p&lt;0.001). We observed the following qualitative concordance results between both measures: <h3>Conclusion and relevance</h3> According to the results of both the SIRS-VAS and the MPR the adherence to ART in our population is optimal. The correlation between the SIRS-VAS and the MPR was only modest. The concordance between both measures was higher for people with high adherence results. <h3>References and/or acknowledgements</h3> <h3>Conflict of interest</h3> No conflict of interest
Kinetics of Early T Cell Receptor Signaling Regulate the Pathway of Lytic Granule Delivery to the Secretory Domain
Authors: Allison M. Beal, Nadia Anikeeva, Rajat Varma, Thomas O. Cameron, Gaia Vasiliver-Shamis, Philip J. Norris, Michael L. Dustin, Yuri Sykulev
Journal: Immunity (2009)
Counseling services at the University of California, Davis: helping medical students cope
Authors: E. Rodolfa
Journal: JAMA (1995)

Our on-site counseling for medical students at UCD School of Medicine has provided easily accessible services by psychologists who understand the rules, values, and traditions of the medical training experience. We also have had the benefit of a close working relationship with the faculty, staff, and administration of the School of Medicine. Counseling can facilitate exploration of personal issues that have been exposed during medical training, and it offers medical students an opportunity to learn new coping skills and enhance their understanding of themselves and their training environment, which in turn contributes to their professional growth. On-site psychological services also provide faculty and staff with a referral resource when they encounter students who present with specific psychological challenges and concerns. We encourage students who are experiencing the stress of their arduous training experience to seek counseling when their usual coping strategies are exhausted. We encourage other medical schools to provide effective, accessible counseling services to their students. These services will assist in the development of a training atmosphere in which students can learn that medical education involves their whole person.
[212] BRAIN SWELLING AND COMA IN CIRRHOTIC RATS ADMINISTERED ENDOTOXIN IS ASSOCIATED WITH INCREASED PROTEIN NITROSATION
Authors: G. Wright, N.A. Davies, D.L. Shawcross, S.J. Hodges, C. Zwingmann, A. Mani, K.P. Moore, D. Harry, V. Stadlbauer, D.C. Davies, H.F. Brooks, Z. Zou, R. Williams, R. Jalan
Journal: Journal of Hepatology (2007)
Differences in endogenous peptides presented by HLA-B*2705 and B*2703 allelic variants. Implications for susceptibility to spondylarthropathies.
Authors: F Boisgérault, V Tieng, M C Stolzenberg, N Dulphy, I Khalil, R Tamouza, D Charron, A Toubert
Journal: Journal of Clinical Investigation (1996)

The association between HLA-B27 and spondylarthropathies is currently being reinvestigated in the light of HLA-B27 subtyping. At least 11 different subtypes have been described among which B*2703, B*2706, and B*2709 could be less closely associated with disease at the population level. Differences in the presentation of antigenic peptides by these subtypes could be related to differences in disease susceptibility. We focused our work on the comparison of B*2705 and B*2703 which differ at a single position at residue 59 in pocket A of the peptide binding groove. Endogenous peptides from the human C1R line transfected by B*2705 or B*2703 were acid-eluted and separated by HPLC. Major individual fractions were sequenced by Edman NH2-terminal degradation. Differences observed between B*2705 versus B*2703 individual ligands were confirmed in an in vitro stabilization assay with T2-B*2705 or B*2703 transfected cells in the presence of synthetic peptides. One B*2705 associated peptide is derived from the sequence 169-179 in the second extracellular domain of several HLA class I molecules including HLA-B27. This sequence (RRYLENGKETL) is highly homologous to a previously reported sequence (LRRYLENGK) sharing similarities with proteins from enteric bacteria. We show here that it is naturally presented as a major endogenous peptide by B*2705 and B*2702 disease-associated subtypes and not by B*2703.
Refractive and Aberrometric Outcomes of Intracorneal Ring Segments for Keratoconus: Mechanical versus Femtosecond-assisted Procedures
Authors: David P. Piñero, Jorge L. Alio, Bassam El Kady, Efekan Coskunseven, Hector Morbelli, Antonio Uceda-Montanes, Miguel J. Maldonado, Diego Cuevas, Inmaculada Pascual
Journal: Ophthalmology (2009)
MUC1-Induced Transcriptional Programs Associated with Tumorigenesis Predict Outcome in Breast and Lung Cancer
Authors: Nikolai N. Khodarev, Sean P. Pitroda, Michael A. Beckett, Dhara M. MacDermed, Lei Huang, Donald W. Kufe, Ralph R. Weichselbaum
Journal: Cancer Research (2009)

The Mucin 1 (MUC1) oncoprotein is aberrantly overexpressed in diverse human malignancies including breast and lung cancer. Although MUC1 modulates the activity of several transcription factors, there is no information regarding the effects of MUC1 on global gene expression patterns and the potential role of MUC1-induced genes in predicting outcome for cancer patients. We have developed an experimental model of MUC1-induced transformation that has identified the activation of gene families involved in oncogenesis, angiogenesis, and extracellular matrix remodeling. A set of experimentally derived MUC1-induced genes associated with tumorigenesis was applied to the analysis of breast and lung adenocarcinoma cancer databases. A 35-gene MUC1-induced tumorigenesis signature predicts significant decreases in both disease-free and overall survival in patients with breast (n=295) and lung (n=442) cancers. The data show that the MUC1 oncoprotein contributes to the regulation of genes that are highly predictive of clinical outcome in breast and lung cancer patients.
Comprehensive Primary Care for Older Patients With Multiple Chronic Conditions
Authors: Chad Boult, G. Darryl Wieland
Journal: JAMA (2010)

Older patients with multiple chronic health conditions and complex health care needs often receive care that is fragmented, incomplete, inefficient, and ineffective. This article describes the case of an older woman whose case cannot be managed effectively through the customary approach of simply diagnosing and treating her individual diseases. Based on expert consensus about the available evidence, this article identifies 4 proactive, continuous processes that can substantially improve the primary care of community-dwelling older patients who have multiple chronic conditions: comprehensive assessment, evidence-based care planning and monitoring, promotion of patients' and (family caregivers') active engagement in care, and coordination of professionals in care of the patient--all tailored to the patient's goals and preferences. Three models of chronic care that include these processes and that appear to improve some aspects of the effectiveness and the efficiency of complex primary care--the Geriatric Resources for Assessment and Care of Elders (GRACE) model, Guided Care, and the Program of All-inclusive Care for the Elderly (PACE)--are described briefly, and steps toward their implementation are discussed.