tbuckley/cabot-search huggingface dataset:
The Complement Factor H R1210C Mutation Is Associated With Atypical Hemolytic Uremic Syndrome
Authors: Ruben Martinez-Barricarte, Gaia Pianetti, Ruxandra Gautard, Joachim Misselwitz, Lisa Strain, Veronique Fremeaux-Bacchi, Christine Skerka, Peter F. Zipfel, Tim Goodship, Marina Noris, Giuseppe Remuzzi, Santiago Rodriguez de Cordoba
Journal: Journal of the American Society of Nephrology (2008)

Mutations in the gene encoding complement factor H (CFH) that alter the C3b/polyanions-binding site in the C-terminal region impair the capacity of factor H to protect host cells. These mutations are also strongly associated with atypical hemolytic uremic syndrome (aHUS). Although most of the aHUS-associated CFH mutations seem "unique" to an individual patient or family, the R1210C mutation has been reported in several unrelated aHUS patients from distinct geographic origins. Five aHUS pedigrees and 7 individual aHUS patients were analyzed to identify potential correlations between the R1210C mutation and clinical phenotype and to characterize the origins of this mutation. The clinical phenotype of aHUS patients carrying the R1210C mutation was heterogeneous. Interestingly, 12 of the 13 affected patients carried at least one additional known genetic risk factor for aHUS. These data are in accord with the 30% penetrance of aHUS in R1210C mutation carriers, as it seems that the presence of other genetic or environmental risk factors significantly contribute to the manifestation and severity of aHUS in these subjects. Genotype analysis of CFH and CFHR3 polymorphisms in the 12 unrelated carriers suggested that the R1210C mutation has a single origin. In conclusion, the R1210C mutation of complement factor H is a prototypical aHUS mutation that is present as a rare polymorphism in geographically separated human populations.
Hypoxia and proinflammatory factors upregulate apelin receptor expression in human stellate cells and hepatocytes
Authors: P. Melgar-Lesmes, M. Pauta, V. Reichenbach, G. Casals, J. Ros, R. Bataller, M. Morales-Ruiz, W. Jimenez
Journal: Gut (2011)

The activation of the apelin receptor (APJ) plays a major role in both angiogenic and fibrogenic response to chronic liver injury. However, the mechanisms that govern the induction of APJ expression have not been clarified so far.The regulation and the role of APJ in cultured human liver cells were investigated. Tissular expression of APJ and α-smooth muscle actin was analysed by immunocolocalisation in human cirrhotic liver and in control samples. mRNA and protein expression of APJ were analysed in two cell lines, LX-2 (as hepatic stellate cells, HSCs) and HepG2 (as hepatocytes), under hypoxic conditions or after exposure to proinflammatory or profibrogenic factors. Additionally, both hepatic cell lines were stimulated with apelin to assess cell survival and the expression of angiogenic factors.The APJ-positive signal was negligible in control livers. In contrast, APJ was highly expressed in HSCs and slightly expressed in hepatocytes of human cirrhotic liver. Sustained hypoxia and lipopolysaccharide stimulated the expression of APJ in LX-2 cells. Moreover, hypoxia, tumour necrosis factor α and angiotensin II induced the expression of APJ in HepG2 cells. Activation of APJ stimulated angiopoietin-1 expression and cell survival in LX-2 cells and, in turn, triggered the synthesis of vascular endothelial growth factor type A and platelet-derived growth factor-BB in HepG2 cells.These results suggest that hypoxia and inflammatory factors could play a major role in the activation of the hepatic apelin system leading to angiogenic and fibroproliferative response occurring in chronic liver disease.
Amine containing phenylboronic acid gel for glucose-responsive insulin release under physiological pH
Authors: Daijiro Shiino, Yoshishige Murata, Akira Kubo, Yong Joo Kim, Kazunori Kataoka, Yoshiyuki Koyama, Akihiko Kikuchi, Masayuki Yokoyama, Yasuhisa Sakurai, Teruo Okano
Journal: Journal of Controlled Release (1995)
Disruption of NAD(P)H:Quinone Oxidoreductase 1 Gene in Mice Leads to Radiation-Induced Myeloproliferative Disease
Authors: Karim Iskander, Roberto J. Barrios, Anil K. Jaiswal
Journal: Cancer Research (2008)

Abstract NAD(P)H:quinone oxidoreductase 1 null (NQO1−/−) mice exposed to 3 Gy of γ-radiation showed an increase in neutrophils, bone marrow hypercellularity, and enlarged lymph nodes and spleen. The spleen showed disrupted follicular structure, loss of red pulp, and granulocyte and megakarocyte invasion. Blood and histologic analysis did not show any sign of infection in mice. These results suggested that exposure of NQO1−/− mice to γ-radiation led to myeloproliferative disease. Radiation-induced myeloproliferative disease was observed in 74% of NQO1−/− mice as compared with none in wild-type (WT) mice. NQO1−/− mice exposed to γ-radiation also showed lymphoma tissues (32%) and lung adenocarcinoma (84%). In contrast, only 11% WT mice showed lymphoma and none showed lung adenocarcinoma. Exposure of NQO1−/− mice to γ-radiation resulted in reduced apoptosis in granulocytes and lack of induction of p53, p21, and Bax. NQO1−/− mice also showed increased expression of myeloid differentiation factors CCAAT/enhancer binding protein α (C/EBPα) and Pu.1. Intriguingly, exposure of NQO1−/− mice to γ-radiation failed to induce C/EBPα and Pu.1, as was observed in WT mice. These results suggest that decreased p53/apoptosis and increased Pu.1 and C/EBPα led to myeloid hyperplasia in NQO1−/− mice. The lack of induction of apoptosis and differentiation contributed to radiation-induced myeloproliferative disease in NQO1−/− mice. [Cancer Res 2008;68(19):7915–22]
Evidence for an increase in adrenergic nerve function in blood vessels from experimental hypertensive rabbits.
Authors: R D Bevan, R E Purdy, C Su, J A Bevan
Journal: Circulation Research (1975)

The possibility of changes in the adrenergic innervation of blood vessels in experimental hypertension was investigated by measuring arterial norepinephrine content, neuronal uptake of norepinephrine, and the neurogenic contractile response in rabbits made hypertensive by partial constriction of the abdominal aorta proximal to the kidneys. Two to 3 weeks after surgery, norepinephrine content was increased in the arteries above the ligature, where arterial blood pressure was increased, but not in the arteries below the ligature, where arterial blood pressure was normal, in the heart, or in the veins. Neuronal norepinephrine uptake per unit length of vessel and the neurogenic contractile response increased with the rise in arterial blood pressure. The neurogenic contractile response can be taken as an indication of an increase in transmitter release. The results taken together suggest an increase in the function and possibly the amount of the adrenergic neuroneal terminal in hypertension. Since the distributions of the changes in the adrenergic innervation and the increases in smooth muscle cell proliferation in hypertension are similar, these two processes may be interrelated.
A Randomized Trial of Protocol-Based Care for Early Septic Shock
Authors: Donald M. Yealy, John A. Kellum, David T. Huang, Lisa A. Weissfeld, Francis Pike, Thomas Terndrup, Peter C. Hou, Frank LoVecchio, Michael R. Fil, Nathan I. Shapiro, Beth, Derek C. Angus
Journal: New England Journal of Medicine (2014)

In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary.
Determination of mortality risk in obstructive pulmonary syndromes: physical examination compared with measurement of forced expired volume in one second.
Authors: N E Pardee, R H Winterbauer, E H Morgan, J D Allen
Journal: Thorax (1981)

A standardised physical examination based on four clinical signs was compared with the FEV1 with regard to ability to determine five-year mortality risk in subjects with varying degrees of obstructive airway disease. Both evaluation methods identified low, intermediate, and high risk groups within the population studied. Individuals with no positive physical signs, or with an FEV1 of 70% of predicted or more had mortality not significantly greater than that predicted on the basis of standard mortality tables. There was no difference between the FEV1 and the physical examination in ability to predict mortality.
Circadian Metabolism in the Light of Evolution
Authors: Zachary Gerhart-Hines, Mitchell A. Lazar
Journal: Endocrine Reviews (2015)

Circadian rhythm, or daily oscillation, of behaviors and biological processes is a fundamental feature of mammalian physiology that has developed over hundreds of thousands of years under the continuous evolutionary pressure of energy conservation and efficiency. Evolution has fine-tuned the body's clock to anticipate and respond to numerous environmental cues in order to maintain homeostatic balance and promote survival. However, we now live in a society in which these classic circadian entrainment stimuli have been dramatically altered from the conditions under which the clock machinery was originally set. A bombardment of artificial lighting, heating, and cooling systems that maintain constant ambient temperature; sedentary lifestyle; and the availability of inexpensive, high-calorie foods has threatened even the most powerful and ancient circadian programming mechanisms. Such environmental changes have contributed to the recent staggering elevation in lifestyle-influenced pathologies, including cancer, cardiovascular disease, depression, obesity, and diabetes. This review scrutinizes the role of the body's internal clocks in the hard-wiring of circadian networks that have evolved to achieve energetic balance and adaptability, and it discusses potential therapeutic strategies to reset clock metabolic control to modern time for the benefit of human health.
A 7 month old presenting with respiratory distress
Authors: S. Chakraborty, A.V. Sridhar, K.N. Rao, R. Shannon
Journal: European Respiratory Journal (2004)

A 5 month old south Asian male presented to his general practitioner (GP) with a history of recurrent wheeze and noisy breathing of 2 months duration. He had been born at term and his growth and development were normal. There were no significant medical problems in the family, apart from his grandmother's hypothyroidism. He was diagnosed by his GP to have viral wheeze and was started on inhaled salbutamol via a metered dose inhaler plus spacer with no apparent benefit. At this stage, a chest radiograph did not show any abnormality. At 6 months old, the patient was admitted to the local hospital with a history of cough, respiratory distress and stridor, which improved after receiving oral dexamethasone for 2 days.

At 7 months old, he presented at the current authors' hospital with a 2‐day history of cough, wheeze and breathlessness. On examination, the patient was afebrile with moderate respiratory distress and had widespread crepitations and rhonchi. Otherwise, clinical examination was normal. A clinical diagnosis of acute bronchiolitis was made. He needed supplemental oxygen to maintain normal oxygen saturations and was also given a trial of nebulised salbutamol with no apparent benefit.

He was noted to have intermittent noisy breathing, although no obvious upper airway obstructive pathology could be identified. He was making a very slow, but gradual, recovery; however, on day 8, there was clinical deterioration with worsening cough, breathlessness, and noisy breathing. He was found to be tachypnoeic with subcostal and intercostal recession, but his chest was clinically clear on auscultation.

The chest radiograph (fig. 1⇓) showed significant radiological changes compared to the chest radiograph taken at 5 months old.



Fig. 1.— 
Chest radiograph of the patient.



The patient was extensively investigated. Table 1⇓ shows a summary of the investigations performed.

View this table:

Table 1— 
Summary of investigations



Biopsies were …
Cancer-Associated Stromal Fibroblasts Promote Pancreatic Tumor Progression
Authors: Rosa F. Hwang, Todd Moore, Thiruvengadam Arumugam, Vijaya Ramachandran, Keith D. Amos, Armando Rivera, Baoan Ji, Douglas B. Evans, Craig D. Logsdon
Journal: Cancer Research (2008)

Abstract Pancreatic adenocarcinoma is characterized by a dense background of tumor associated stroma originating from abundant pancreatic stellate cells. The aim of this study was to determine the effect of human pancreatic stellate cells (HPSC) on pancreatic tumor progression. HPSCs were isolated from resected pancreatic adenocarcinoma samples and immortalized with telomerase and SV40 large T antigen. Effects of HPSC conditioned medium (HPSC-CM) on in vitro proliferation, migration, invasion, soft-agar colony formation, and survival in the presence of gemcitabine or radiation therapy were measured in two pancreatic cancer cell lines. The effects of HPSCs on tumors were examined in an orthotopic murine model of pancreatic cancer by co-injecting them with cancer cells and analyzing growth and metastasis. HPSC-CM dose-dependently increased BxPC3 and Panc1 tumor cell proliferation, migration, invasion, and colony formation. Furthermore, gemcitabine and radiation therapy were less effective in tumor cells treated with HPSC-CM. HPSC-CM activated the mitogen-activated protein kinase and Akt pathways in tumor cells. Co-injection of tumor cells with HPSCs in an orthotopic model resulted in increased primary tumor incidence, size, and metastasis, which corresponded with the proportion of HPSCs. HPSCs produce soluble factors that stimulate signaling pathways related to proliferation and survival of pancreatic cancer cells, and the presence of HPSCs in tumors increases the growth and metastasis of these cells. These data indicate that stellate cells have an important role in supporting and promoting pancreatic cancer. Identification of HPSC-derived factors may lead to novel stroma-targeted therapies for pancreatic cancer. [Cancer Res 2008;68(3):918–26]
Formation of a novel phagosome by the Legionnaires' disease bacterium (Legionella pneumophila) in human monocytes.
Authors: M A Horwitz
Journal: The Journal of Experimental Medicine (1983)

Previous studies have shown that L. pneumophila multiplies intracellularly in human monocytes and alveolar macrophages within a membrane-bound cytoplasmic vacuole studded with ribosomes. In this paper, the formation of this novel vacuole is examined. After entry into monocytes, L. pneumophila resides in a membrane-bound vacuole. During the first hour after entry, vacuoles containing L. pneumophila are found surrounded by smooth vesicles fusing with or budding off from the vacuolar membrane and by mitochondria closely apposed to the vacuolar membrane. By 4 h, vacuoles are found less frequently surrounded by these cytoplasmic organelles, but now ribosomes and rough vesicles are found gathered about the vacuole. By 8 h, the ribosome-lined vacuole has formed. Erythromycin, at concentrations that completely inhibit the intracellular multiplication of L. pneumophila, has no effect on vacuole formation. Formalin-killed L. pneumophila also reside in a membrane-bound vacuole after entry into monocytes. In contrast to the situation with live L. pneumophila, cytoplasmic organelles are not found surrounding vacuoles containing formalin-killed L. pneumophila at any time after entry. Formalin-killed bacteria are rapidly digested, and by 4 h, few remain intact. The L. pneumophila-containing vacuole has certain features in common with other intracellular organisms that inhibit phagosome-lysosome fusion; these organisms may share a common mechanism for vacuole formation and inhibition of phagosome-lysosome fusion.
Epidemiology of Anemia Associated with Chronic Renal Insufficiency among Adults in the United States
Authors: Chi-yuan Hsu, Charles E. McCulloch, Gary C. Curhan
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Anemia associated with chronic renal insufficiency (CRI) may have substantial clinical and public health importance, but little is known about its epidemiology. This study aims to quantify the relationship between reduced renal function and hemoglobin level, to assess the iron status of subjects with CRI, and to estimate the burden of anemia associated with CRI. The Third National Health and Nutrition Examination Survey (NHANES III) (1988 to 1994) data on 15,971 adults aged >18 yr with measurements of serum creatinine, hemoglobin, and iron profile were analyzed. General linear models were used to determine the relationship between hemoglobin level and Cockcroft-Gault creatinine clearance (CrCl) and to estimate the likelihood of anemia at different levels of renal function in different demographic subgroups. Sample weights were used to produce weighted regression parameters and population estimates. A statistically significant decrease in hemoglobin was apparent among men starting at CrCl ≤70 ml/min and among women starting at CrCl ≤50 ml/min. At any given level of CrCl, men had a larger decrease in hemoglobin than women. For example, compared with subjects with CrCl >80 ml/min, the decrease in hemoglobin for subjects with CrCl 20 to 30 ml/min was 1.0 g/dl in women and 1.4 g/dl in men. A substantial number of subjects with CRI might not have sufficient iron stores to support erythropoiesis as judged by the NKF-K/DOQI transferrin saturation or serum ferritin targets. Among those with CrCl 20 to 30 ml/min, 46% of women and 19% of men had transferrin saturation <20%, and 47% of women and 44% of men had serum ferritin <100 ng/ml. Results estimate that 13.5 million US adults had CrCl ≤50 ml/min. The overall burden of CRI associated anemia, defined as hemoglobin <11 g/dl, was 800,000 adults. The public health burden of anemia associated with CRI may be substantial, given the large number of people with CRI; and that even a modest reduction in renal function is associated with decreased hemoglobin level.
A short-term comparison of two methods of sputum expectoration in cystic fibrosis
Authors: K. Chatham, A.A. Ionescu, L.S. Nixon, D.J. Shale
Journal: European Respiratory Journal (2004)

The aim of this study was to determine whether repeated maximum inspiratory vital capacity manoeuvres against a fixed resistance increased effective short-term sputum clearance in adults with cystic fibrosis (CF). Twenty adults with CF were randomised to receive, on alternate days, either standardised physiotherapy (SP) for 30 min, comprising postural drainage and the active cycle of breathing technique, or a series of resistive inspiratory manoeuvres (RIM) at 80% of their maximum sustained inspiratory pressure developed between residual volume and total lung capacity during the first 4 days of the treatment of an exacerbation of respiratory symptoms. Expectorated sputum was collected during and for 30 min after each treatment and weighed. Total protein, immunoreactive interleukin (IL)‐8 and human neutrophil elastase (HNE) concentrations, and the amount of each component expectorated, were determined. Compared with SP, RIM increased sputum weight two-fold, independent of treatment order or day. The concentrations of protein, IL-8 and HNE in sputum were similar for both treatments, while the quantity expectorated was greater with RIM treatment. In conclusion, short-term resistive inspiratory manoeuvres treatment was more effective at clearing sputum and inflammatory mediators than standardised physiotherapy.
Compromised LCAT Function Is Associated With Increased Atherosclerosis
Authors: G. Kees Hovingh, Barbara A. Hutten, Adriaan G. Holleboom, Wilma Petersen, Patrick Rol, Anton Stalenhoef, Aeilko H. Zwinderman, Eric de Groot, John J.P. Kastelein MD, Jan Albert Kuivenhoven
Journal: Circulation (2005)

Background— Prospective epidemiological studies have shown that low plasma levels of HDL cholesterol (HDL-C) are associated with an increased risk for cardiovascular disease (CVD). Despite nearly 40 years of research, however, it is unclear whether this also holds true for individuals with severely reduced levels of HDL-C due to mutations in the lecithin:cholesterol acyltransferase ( LCAT ) gene. Better insight into CVD risk in these individuals may provide clues toward the potential of LCAT as a pharmaceutical target to raise HDL-C levels. Methods and Results— Lipids, lipoproteins, high-sensitivity C-reactive protein (CRP), and carotid artery intima-media thickness (IMT) were assessed in 47 heterozygotes for LCAT gene mutations and 58 family controls. Compared with controls, heterozygotes presented with a mean 36% decrease in HDL-C levels ( P &lt;0.0001), a 23% increase in triglyceride levels ( P &lt;0.0001), and a 2.1-fold increase in CRP levels ( P &lt;0.0001). Mean carotid IMT was significantly increased in heterozygotes compared with family controls (0.623±0.13 versus 0.591±0.08 mm). After adjustment for age, gender, and alcohol use, this difference proved statistically significant ( P &lt;0.0015). Conclusions— The data show that heterozygosity for LCAT gene defects is associated with low HDL-C levels and elevated concentration of triglycerides and CRP in plasma. This phenotype underlies increased IMT in carriers versus controls, which suggests that LCAT protects against atherosclerosis. This in turn indicates that targeting LCAT to raise HDL-C may reduce CVD risk.
The Case for Biennial Retinopathy Screening in Children and Adolescents
Authors: Rakesh Amin
Journal: Diabetes Care (2005)

I have read the article by Maguire et al. (1) with interest. In a large, longitudinal cohort of type 1 diabetic children and adolescents, the study describes the natural history and prevalence of retinopathy. Although not the main focus of the article, their data also highlight two important points. First, Maguire et al. highlight the relationship between puberty and microvascular complications, as evidenced by the significantly increased incidence of retinopathy after 2 years’ follow-up in subjects aged …
Response of resting human peripheral blood natural killer cells to interleukin 2.
Authors: G Trinchieri, M Matsumoto-Kobayashi, S C Clark, J Seehra, L London, B Perussia
Journal: The Journal of Experimental Medicine (1984)

The present study shows that recombinant interleukin 2 (IL-2) purified to homogeneity induces a rapid and potent enhancement of spontaneous cytotoxicity of human peripheral blood lymphocytes. The cells mediating cytotoxicity after 18-h treatment with IL-2 have surface markers of natural killer (NK) cells and are generated from the peripheral blood subset containing spontaneous cytotoxic cells. A parallel production of gamma interferon (IFN-gamma) is induced by recombinant IL-2 (rIL-2), and NK cells appear to be the major producer cells, whereas T cells are unable to produce IFN-gamma under these experimental conditions. However, the kinetics of the enhancement of cytotoxicity are faster than those of IFN-gamma production, and monoclonal anti-IFN-gamma antibodies do not suppress this effect, making it unlikely that the IFN-gamma produced is responsible for the enhancement. The enhancement of NK cell activity induced by rIL-2 precedes any proliferative response of the lymphocytes, which is instead observed in longer-term cultures of both NK and T cells.