tbuckley/cabot-search huggingface dataset:
THE GLOMERULUS IN EXPERIMENTAL RENAL DISEASE IN RATS AS OBSERVED BY LIGHT AND ELECTRON MICROSCOPY
Authors: Carolyn F. Piel, Luther Dong, F.W.S. Modern, Joseph R. Goodman, Roger Moore
Journal: The Journal of Experimental Medicine (1955)

Nephrotoxic serum disease in rats has been studied by light and electron microscopy from 1 hour to 10 weeks after production of the disease. By light microscopy leucocytic infiltration of the glomerular capillary was observed between the 3rd and 6th hour. At 6 hours an increase in colloidal iron-positive material was observed coating the extraluminal surface of the capillaries. Also at this time swelling of the endothelial cells becomes prominent. By 72 hours, thickening of the basement membrane was observed. Glomerular capillary thrombi were observed in approximately half the tissue examined in the first 2 weeks of disease. 50 per cent of the animals showed severe chronic lesions, exudation into the capsular space, crescent formation, and obliteration of glomeruli. At 1 hour electron microscopic pictures showed that osmophilic material may line the foot processes of the epithelial cells and obliterate all but narrow channels of the space between the feet. By 6 hours thickening of the basement membrane was prominent. This change persisted throughout 10 weeks of observation. The tissue from animals which had severe chronic alterations by light microscopy revealed changes which could not be interpreted at this time.
Neuropeptide tyrosine (NPY): a newly discovered peptide is present in the mammalian respiratory tract.
Authors: M N Sheppard, J M Polak, J M Allen, S R Bloom
Journal: Thorax (1984)

Neuropeptide tyrosine (NPY), a newly discovered peptide known to modulate blood vessel diameter and smooth muscle tone, has been found in many mammalian organs. Its distribution is similar to that of sympathetic nerve fibres and NPY immunoreactivity has been found in noradrenergic ganglion cells. In a study of the respiratory tract of four mammalian species--man, cat, guinea pig, and rat--NPY immunoreactivity has been localised to nerve fibres. NPY immunoreactive nerve fibres were found in the adventitia of blood vessels and in the airway smooth muscle. Its distribution was strikingly similar to that of sympathetic nerve fibres as demonstrated by dopamine-beta-hydroxylase antibodies. The mean (SD) concentrations of NPY in the guinea pig respiratory tract, as determined by radioimmunoassay of tissue extracts, were: upper trachea 3.3 (0.7), lower trachea 2.0 (0.5), and major bronchus 3.5 (1.1) pmol/g. During developmental studies in man NPY immunoreactive nerve fibres were first observed at 20 weeks9 gestation in the trachea, and fibres gradually extended down into the intrapulmonary airways after birth. NPY immunoreactive nerve fibres have a distribution and developmental pattern similar to that of sympathetic nerve fibres in the respiratory tract. The finding of NPY immunoreactivity in nerve fibres in the mammalian respiratory tract adds to the growing number of peptides having potent biological actions found in this organ, and shows that the lung possesses a rich peptidergic system, which may influence pulmonary function.
Complement-Mediated Vasoconstriction and Graft Rejection
Authors: JOERG A. JENSEN, DANA DAVIES, BERNARD S. LINN, RALPH SNYDERMAN, LINDA FRANKLIN
Journal: Circulation Research (1972)

The hyperacute rejection of renal allografts has much in common with pig-to-dog renal xenograft rejections. An analysis of the xenograft model revealed new functional aspects of graft rejection that appear to be an integral part of the humoral immune injury. Anaphylatoxin or C5a, a cleavage product of the fifth complement component was shown to play a major role in the rejection of isolated kidneys; it was generated in pig and dog serum by activation of the complement system and caused severe Vasoconstriction in the renal vasculature. It is suggested that histocompatibility antibodies and complement may affect allograft survival via this potent mediator.
Genetic Diversity of the Allodeterminant alr2 in Hydractinia symbiolongicarpus
Authors: R. D. Rosengarten, M. A. Moreno, F. G. Lakkis, L. W. Buss, S. L. Dellaporta
Journal: Molecular Biology and Evolution (2010)

Hydractinia symbiolongicarpus, a colonial cnidarian (class Hydrozoa) epibiont on hermit crab shells, is well established as a model for genetic studies of allorecognition. Recently, two linked loci, allorecognition (alr) 1 and alr2, were identified by positional cloning and shown to be major determinants of histocompatibility. Both genes encode putative transmembrane proteins with hypervariable extracellular domains similar to immunoglobulin (Ig)-like domains. We sought to characterize the naturally occurring variation at the alr2 locus and to understand the origins of this molecular diversity. We examined full-length cDNA coding sequences derived from a sample of 21 field-collected colonies, including 18 chosen haphazardly and two laboratory reference strains. Of the 35 alleles recovered from the 18 unbiased samples, 34 encoded unique gene products. We identified two distinct structural classes of alleles that varied over a large central region of the gene but both possessed highly polymorphic extracellular domains I, similar to an Ig-like V-set domain. The discovery of structurally chimeric alleles provided evidence that interallelic recombination may contribute to alr2 variation. Comparisons of the genomic region encompassing alr2 from two field-derived haplotypes and one laboratory reference sequence revealed a history of structural variation at the haplotype level as well. Maintenance of large numbers of equally rare alleles in a natural population is a hallmark of negative frequency–dependent selection and is expected to produce high levels of heterozygosity. The observed alr2 allelic diversity is comparable with that found in immune recognition molecules such as human leukocyte antigens, B cell Igs, or natural killer cell Ig-like receptors.
A Novel Role for Type 1 Angiotensin Receptors on T Lymphocytes to Limit Target Organ Damage in Hypertension
Authors: Jian-dong Zhang, Mehul B. Patel, Young-Soo Song, Robert Griffiths, James Burchette, Phillip Ruiz, Matthew A. Sparks, Ming Yan, David N. Howell, Jose A. Gomez, Robert F. Spurney, Thomas M. Coffman, Steven D. Crowley
Journal: Circulation Research (2012)

Human clinical trials using type 1 angiotensin (AT(1)) receptor antagonists indicate that angiotensin II is a critical mediator of cardiovascular and renal disease. However, recent studies have suggested that individual tissue pools of AT(1) receptors may have divergent effects on target organ damage in hypertension.We examined the role of AT(1) receptors on T lymphocytes in the pathogenesis of hypertension and its complications.Deficiency of AT(1) receptors on T cells potentiated kidney injury during hypertension with exaggerated renal expression of chemokines and enhanced accumulation of T cells in the kidney. Kidneys and purified CD4(+) T cells from "T cell knockout" mice lacking AT(1) receptors on T lymphocytes had augmented expression of Th1-associated cytokines including interferon-γ and tumor necrosis factor-α. Within T lymphocytes, the transcription factors T-bet and GATA-3 promote differentiation toward the Th1 and Th2 lineages, respectively, and AT(1) receptor-deficient CD4(+) T cells had enhanced T-bet/GATA-3 expression ratios favoring induction of the Th1 response. Inversely, mice that were unable to mount a Th1 response due to T-bet deficiency were protected from kidney injury in our hypertension model.The current studies identify an unexpected role for AT(1) receptors on T lymphocytes to protect the kidney in the setting of hypertension by favorably modulating CD4(+) T helper cell differentiation.
Evolutionary relationships of class II major-histocompatibility-complex genes in mammals.
Authors: A L Hughes, M Nei
Journal: Molecular Biology and Evolution (1990)

The major histocompatibility complex (MHC) class II molecule consists of noncovalently associated alpha and beta chains. In mammals studied so far, the class II MHC can be divided into a number of regions, each containing one or more alpha-chain genes (A genes) and beta-chain genes (B genes), and it has been known for some time that orthologous relationships exist between genes in corresponding regions from different mammalian species. A phylogenetic analysis of DNA sequences of class II A and B genes confirmed these relationships; but no such orthologous relationship was observed between the B genes of mammals and those of birds. Thus, the class II regions have diverged since the separation of birds and mammals (approximately 300 Mya) but before the radiation of the placental mammalian orders (60-80 Mya). Comparison of the phylogenetic trees for A and B genes revealed an unexpected characteristic of DP-region genes: DPB genes are most closely related to DQB genes, whereas DPA chain genes are most closely related to DRA-chain genes. Thus, the DP region seems to have originated through a recombinational event which brought together a DQB gene and a DRA gene (perhaps approximately 120 Mya). The 5' untranslated region of all class II genes includes sequences which are believed to be important in regulating class II gene expression but which are not conserved in known pseudogenes. These sequences are conserved to an extraordinary degree in the human DQB1 gene and its mouse homologue A beta 1, suggesting that regulation of expression of this locus may play a key role in expression of the entire class II MHC.
Benefit from earlier thrombolytic therapy is certain, but what is the magnitude of benefit?
Authors: A. Leizorovicz
Journal: BMJ (1996)

Abundant evidence exists to confirm that fibrinolytic treatment saves lives in patients with acute myocardial infarction and that the earlier the treatment the higher the benefit obtained.1 There is also evidence to suggest that administration of fibrinolytic treatment, under certain conditions, before hospital admission may lead to further improvement in patients' prognosis with no significant additional risk.2 3 4

John Rawles attempts to quantify the benefit of earlier fibrinolytic treatment using the data from the 311 patients included in the GREAT trial, which evaluated the feasibility, safety, and efficacy of domiciliary fibrinolysis by general practitioners.5 Such quantification is essential if providers of health care are to make an informed decision on whether to allocate resources to domiciliary fibrinolysis. The …
Modest Improvements of Survival for Patients with Small Cell Lung Cancer Aged 45 to 59 Years Only, Diagnosed in the Netherlands, 1989 to 2008
Authors: Maryska L.G. Janssen-Heijnen, Henrike E. Karim-Kos, Miep A. van der Drift, Harry J.M. Groen, Vincent K.Y. Ho, Caro Koning, Esther de Vries
Journal: Journal of Thoracic Oncology (2011)
In Vivo Delivery of RNAi with Lipid-Based Nanoparticles
Authors: Leaf Huang, Yang Liu
Journal: Annual Review of Biomedical Engineering (2011)

RNA interference (RNAi) technology represents a fundamentally new category of treatments for human disease by addressing targets that are traditionally considered undruggable with existing medicines. The major challenge for RNAi-based therapy is the delivery system that meets human therapeutic needs. Therefore, engineering vectors with good delivery efficiency and safety profile is an intense area of research. Lipid-based nanoparticles for RNAi have yielded successful advances in vivo and to an extent in clinical trials. In this review, we discuss the barriers in developing lipid-based nanoparticles for in vivo RNAi and different strategies to overcome them. Rational designs that address safety concerns and ensure effective delivery will aid the translation of engineered lipid-based nanoparticles toward the clinic in the foreseeable future.
Antiangiogenic and Antimetastatic Activity of JAK Inhibitor AZD1480
Authors: Hong Xin, Andreas Herrmann, Karen Reckamp, Wang Zhang, Sumanta Pal, Michael Hedvat, Chunyan Zhang, Wei Liang, Anna Scuto, Shaobu Weng, Deborah Morosini, Zhu A. Cao, Michael Zinda, Robert Figlin, Dennis Huszar, Richard Jove, Hua Yu
Journal: Cancer Research (2011)

STAT3 has important functions in both tumor cells and the tumor microenvironment to facilitate cancer progression. The STAT regulatory kinase Janus-activated kinase (JAK) has been strongly implicated in promoting oncogenesis of various solid tumors, including the use of JAK kinase inhibitors such as AZD1480. However, direct evidence that JAK drives STAT3 function and cancer pathogenesis at the level of the tumor microenvironment is yet to be established clearly. In this study, we show that AZD1480 inhibits STAT3 in tumor-associated myeloid cells, reducing their number and inhibiting tumor metastasis. Myeloid cell-mediated angiogenesis was also diminished by AZD1480, with additional direct inhibition of endothelial cell function in vitro and in vivo. AZD1480 blocked lung infiltration of myeloid cells and formation of pulmonary metastases in both mouse syngeneic experimental and spontaneous metastatic models. Furthermore, AZD1480 reduced angiogenesis and metastasis in a human xenograft tumor model. Although the effects of AZD1480 on the tumor microenvironment were important for the observed antiangiogenic activity, constitutive activation of STAT3 in tumor cells themselves could block these antiangiogenic effects, showing the complexity of the JAK/STAT signaling network in tumor progression. Together, our results indicated that AZD1480 can effectively inhibit tumor angiogenesis and metastasis mediated by STAT3 in stromal cells as well as tumor cells.
A Study of Dapagliflozin in Patients With Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin Sensitizers
Authors: John P.H. Wilding, Paul Norwood, Caroline T'joen, Arnaud Bastien, James F. List, Fred T. Fiedorek
Journal: Diabetes Care (2009)

OBJECTIVE To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs). RESEARCH DESIGN AND METHODS This was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort (n = 4), patients in the treatment cohort (n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]). RESULTS At week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated −0.70 and −0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C ≥0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and −9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were −1.9, −4.5, and −4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group. CONCLUSIONS In patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo.
Viral Vectors for Gene Therapy: Translational and Clinical Outlook
Authors: Melissa A. Kotterman, Thomas W. Chalberg, David V. Schaffer
Journal: Annual Review of Biomedical Engineering (2015)

In a range of human trials, viral vectors have emerged as safe and effective delivery vehicles for clinical gene therapy, particularly for monogenic recessive disorders, but there has also been early work on some idiopathic diseases. These successes have been enabled by research and development efforts focusing on vectors that combine low genotoxicity and immunogenicity with highly efficient delivery, including vehicles based on adeno-associated virus and lentivirus, which are increasingly enabling clinical success. However, numerous delivery challenges must be overcome to extend this success to many diseases; these challenges include developing techniques to evade preexisting immunity, to ensure more efficient transduction of therapeutically relevant cell types, to target delivery, and to ensure genomic maintenance. Fortunately, vector-engineering efforts are demonstrating promise in the development of next-generation gene therapy vectors that can overcome these barriers. This review highlights key historical trends in clinical gene therapy, the recent clinical successes of viral-based gene therapy, and current research that may enable future clinical application.
Prevalence of Eating Disorder Symptoms in Preadolescent and Adolescent Girls With IDDM
Authors: Ruth H Striegel-Moore, Timothy J Nicholson, William V Tamborlane
Journal: Diabetes Care (1992)

OBJECTIVE To assess attitudinal and behavioral symptoms of eating disorders in preadolescent and adolescent girls with IDDM and a matched sample of nondiabetic subjects, and to explore the relationship between the perceived impact of IDDM and eating disorder symptoms. RESEARCH DESIGN AND METHODS All eligible IDDM patients (girls, age 8–18 yr) from the case register of the Yale Children's Diabetes Clinic were recruited for this study. Of 49 eligible patients, 46 participated in the study. Control subjects were recruited among students in several local schools; 46 girls, individually age and race-matched with IDDM patients, and group-matched by father's socioeconomic status, were included in this study. All subjects participated in an investigator-based clinical interview (EDE) and completed a self-report measure of eating-related psychopathology (EDI). IDDM subjects completed the DQOL measure to determine the perceived impact of diabetes on patients' lives. RESULTS IDDM patients reported significantly more regular consumption of meals and snacks than did nondiabetic subjects. No group differences were found on measures of symptoms of eating disorders: both groups reported minimal levels of symptoms. Among adolescent IDDM patients, eating disorder symptoms were related significantly to patients' dissatisfaction with the illness and its impact on their lives. CONCLUSIONS It appears that when applying stringent diagnostic procedures and matching criteria, IDDM girls do not evidence an elevated prevalence of eating disorder symptoms. However, those IDDM patients who did report symptoms may be a high-risk group for the development of an eating disorder and should be followed prospectively.
Brodalumab, an Anti–Interleukin-17–Receptor Antibody for Psoriasis
Authors: Kim A. Papp, Craig Leonardi, Alan Menter, Jean-Paul Ortonne, James G. Krueger, Gregory Kricorian, Girish Aras, Juan Li, Chris B. Russell, Elizabeth H.Z. Thompson, Scott Baumgartner
Journal: New England Journal of Medicine (2012)

In this phase 2, randomized, double-blind, placebo-controlled, dose-ranging study, we assessed the efficacy and safety of brodalumab (AMG 827), a human anti-interleukin-17-receptor monoclonal antibody, for the treatment of moderate-to-severe plaque psoriasis.We randomly assigned patients with a score of 12 or higher on the psoriasis area-and-severity index (PASI, on which scores range from 0 to 72, with higher scores indicating more severe disease) and with 10% or more of their body-surface area affected by psoriasis to receive brodalumab (70 mg, 140 mg, or 210 mg at day 1 and weeks 1, 2, 4, 6, 8, and 10 or 280 mg monthly) or placebo. The primary end point was the percentage improvement from baseline in the PASI score at week 12. Secondary end points included improvement of at least 75% and at least 90% in the PASI score and the score on the static physician's global assessment at week 12.A total of 198 patients underwent randomization. At week 12, the mean percentage improvements in the PASI score were 45.0% among patients receiving 70 mg of brodalumab, 85.9% among those receiving 140 mg, 86.3% among those receiving 210 mg, 76.0% among those receiving 280 mg, and 16.0% among those receiving placebo (P<0.001 for all comparisons with placebo). An improvement of at least 75% and at least 90% in the PASI score at week 12 was seen in 77% and 72%, respectively, of the patients in the 140-mg brodalumab group and in 82% and 75%, respectively, of the patients in the 210-mg group, as compared with 0% in the placebo group (P<0.001 for all comparisons). The percentage of patients with a static physician's global assessment of clear or minimal disease was 26%, 85%, 80%, and 69% with the 70-mg, 140-mg, 210-mg, and 280-mg doses, respectively, of brodalumab, as compared with 3% with placebo (P<0.01 for all comparisons with placebo). Two cases of grade 3 neutropenia were reported in the 210-mg brodalumab group. The most commonly reported adverse events in the combined brodalumab groups were nasopharyngitis (8%), upper respiratory tract infection (8%), and injection-site erythema (6%).Brodalumab significantly improved plaque psoriasis in this 12-week, phase 2 study. (Funded by Amgen; ClinicalTrials.gov number, NCT00975637.).
Hostility, Race, and Glucose Metabolism in Nondiabetic Individuals
Authors: Richard S. Surwit, Redford B. Williams, Ilene C. Siegler, James D. Lane, Michael Helms, Katherine L. Applegate, Nancy Zucker, Mark N. Feinglos, Cynthia M. McCaskill, John C. Barefoot
Journal: Diabetes Care (2002)

The present study was designed to determine whether hostility is differentially related to measures of glucose metabolism in African-Americans and Caucasians.The relationship of hostility, as measured by a subset of the Cook-Medley hostility scale (CMHOST) inventory items, to various parameters of glucose metabolism were examined in a young, healthy sample of male and female African-American and Caucasian volunteers. Fasting blood samples were collected during an inpatient admission, at which time the CMHOST was also administered.In the entire sample, the CMHOST was found to be significantly correlated with fasting glucose and insulin sensitivity, as measured by the homeostatic model assessment (HOMA). However, the relationship of hostility to these parameters of glucose metabolism was different in African-American and Caucasian subjects. Hostility was significantly related to fasting glucose in African-Americans and to insulin sensitivity and fasting insulin in Caucasian subjects. The relationship of hostility to insulin sensitivity and fasting insulin was partially dependent on BMI in Caucasians, but the relationship of hostility to fasting glucose was unrelated to BMI in African-Americans.Our data suggest that the relationship of hostility to measures of glucose metabolism is mediated differently in these two ethnic groups. Therefore, hostility seems to be part of a constellation of risk-related behaviors related to BMI in Caucasians but independently related to fasting glucose in African-Americans.
A VIRUS RECOVERED FROM THE FECES OF "POLIOMYELITIS" PATIENTS PATHOGENIC FOR SUCKLING MICE
Authors: Gilbert Dalldorf, Grace M. Sickles, Hildegard Plager, Rebecca Gifford
Journal: The Journal of Experimental Medicine (1949)

A virus has been recovered from the feces of two children having symptoms similar to those of poliomyelitis. The virus is pathogenic for suckling mice and hamsters but not for rhesus monkeys. It induces striking lesions in the skeletal muscles of the experimental animal but not in the central nervous system. Other viruses inducing similar signs and lesions in suckling mice have been isolated from several other outbreaks of a poliomyelitis-like disease, including one large urban epidemic.