tbuckley/cabot-search huggingface dataset:
Endothelin-1 stimulates contraction of rat glomerular mesangial cells and potentiates beta-adrenergic-mediated cyclic adenosine monophosphate accumulation.
Authors: M S Simonson, M J Dunn
Journal: Journal of Clinical Investigation (1990)

The newly isolated peptide, endothelin-1 (ET-1), is a potent pressor agent that reduces GFR and the glomerular ultrafiltration coefficient. Recent evidence demonstrates that ET-1 mobilizes intracellular Ca2+ [( Ca2+]i) in glomerular mesangial cells by activating the phosphoinositide cascade. The present experiments were designed to examine whether ET-1 stimulates mesangial cell contraction and regulates the synthesis of PGE2 and cAMP, which dampen vasoconstrictor-induced mesangial contraction. ET-1 (greater than or equal to 1 nM) reduced the cross-sectional area of rat mesangial cells cultured on three-dimensional gels of collagen type I. ET-1 also caused complex rearrangements of F-actin microfilaments consistent with a motile response. Contraction in response to ET-1 occurred only at concentrations that activate phospholipase C, and contraction was unaffected by blockade of dihydropyridine-sensitive Ca2+ channels. Elevation of [Ca2+]i with ionomycin, to equivalent concentrations of [Ca2+]i achieved with ET-1, also reduced mesangial cell cross-sectional area. ET-1 (0.1 microM) also evoked [3H]arachidonate release and a fivefold increase in PGE2 synthesis as well as increased synthesis of PGF2 alpha and small changes of TXB2. ET-1 caused a minor increase in intracellular cAMP accumulation only in the presence of 3-isobutyl-1-methylxanthine. ET-1 also amplified cAMP production in response to isoproterenol. TPA and ionomycin, alone and in combination, failed to mimic the potentiating effect of ET-1; however, indomethacin blocked ET-1-induced potentiation of isoproterenol-stimulated cAMP, which was restored by addition of exogenous 10 nM PGE2. Thus the present data demonstrate that ET-1 stimulates mesangial cell contraction via pharmacomechanical coupling and activates phospholipase A2 to produce PGE2, PGF2 alpha, and TXB2. ET-1 also amplified beta adrenergic-stimulated cAMP accumulation by a PGE2-dependent mechanism.
Prostaglandin synthetase activity from human rheumatoid synovial microsomes. Effect of 'aspirin-like' drug therapy.
Authors: D Crook, A J Collins, P A Bacon, R Chan
Journal: Annals of the Rheumatic Diseases (1976)

Using a radiometric technique, prostaglandin synthetase activity was measured in vitro in the microsomal fraction of 19 synovial tissues taken from 17 rheumatoid arthritis patients. The enzyme was inhibited in vitro by low concentrations of several 'aspirin-like' drugs, though paracetamol and salicylic acid were virtually inactive. While the synthetase preparations from patients receiving indomethacin, ibuprofen, or naproxen therapy exhibited considerable activity in vitro, we were unable to show any activity in preparations from patients taking aspirin, even in low doses. These findings suggest that in vivo aspirin may be unique in being an irreversible inhibitor of the enzyme, compared with other 'aspirin-like' drugs.
Focal segmental glomerular sclerosis, a type of intractable chronic glomerulonephritis, is a stem cell disorder.
Authors: M Nishimura, J Toki, K Sugiura, F Hashimoto, T Tomita, H Fujishima, Y Hiramatsu, N Nishioka, N Nagata, Y Takahashi
Journal: The Journal of Experimental Medicine (1994)

The etiopathogenesis of focal and segmental glomerular sclerosis (FGS) remains unknown. Using a new animal model for FGS (FGS mouse), we demonstrate here that bone marrow transplantation from normal mice to FGS mice with a high grade of proteinuria (+ + +) ameliorates FGS, and that the transplantation of bone marrow cells or purified hemopoietic stem cells (HSCs) from FGS mice induces FGS in normal mice. These findings strongly suggest that FGS is a stem cell disorder; the abnormalities may be genetically programmed at the level of HSCs.
Improvement in Preventive Care of Young Adults After the Affordable Care Act
Authors: Josephine S. Lau, Sally H. Adams, M. Jane Park, W. John Boscardin, Charles E. Irwin
Journal: JAMA Pediatrics (2014)

The 2010 Affordable Care Act (ACA) included expansion of insurance coverage for young adults and improved access to preventive care.To examine the ACA's initial effects on young adults' receipt of preventive care.Secondary data analysis using a pre-post design that compared health care use by young adults (aged 18 to 25 years) from 2009 and 2011 Medical Expenditure Panel Surveys. Data were collected through computer-assisted personal interviews of a nationally representative sample of the noninstitutionalized US population.Differences by year in rates of receiving a routine examination in the past year, blood pressure screening, cholesterol screening, influenza vaccination, and annual dental visit. Three logistic regression models were developed to (1) compare pre-ACA (2009) and post-ACA (2011) rates of receiving preventive care and (2) determine if post-ACA increases in insurance coverage accounted for changes in preventive care rates. Model 1 was a bivariate model to determine differences in preventive care rates by year; model 2, a multivariable model adding insurance status (full-year private, full-year public, partial-year uninsured, and full-year uninsured) to determine whether insurance accounted for survey year differences; and model 3, a multivariable model adding covariates (usual source of care and sociodemographic variables) to determine whether they further accounted for differences by survey year or insurance status.After ACA, young adults had significantly higher rates of receiving a routine examination (47.8% vs. 44.1%; P < .05), blood pressure screening (68.3% vs. 65.2%; P < .05), cholesterol screening (29.1% vs. 24.3%; P < .001), and annual dental visit (60.9% vs. 55.2%; P < .001) but not an influenza vaccination (22.1% vs. 21.5%; P = .70). Full-year private insurance coverage increased (50.1% vs. 43.4%; P < .001), and rates of lacking insurance decreased (partial-year uninsured, 18.4% vs. 20.7%; P = .03; and full-year uninsured, 22.2% vs. 27.1%; P < .001). Full-year public insurance rates remained stable (9.4% vs. 8.8%; P = .53). Insurance status fully accounted for the pre- and post-ACA differences in routine examination and blood pressure screening and partially accounted for year differences for cholesterol screening and annual dental visits. Covariate adjustment did not affect year differences.The ACA provisions appear to increase insurance coverage and receipt of preventive services among young adults. Further studies are needed to replicate these findings as other ACA provisions are implemented.
Restorative proctocolectomy for distal ulcerative colitis
Authors: M Brunel, C Penna, E Tiret, P Balladur, R Parc
Journal: Gut (1999)

Chronic distal colitis may cause troublesome symptoms and alter quality of life. When medical treatment fails to control symptoms, patients and doctors are often reluctant to consider surgical resection because of the relatively small portion of the large bowel affected by the disease.To assess the outcome of restorative proctocolectomy (RP) in patients with distal colitis who required surgery for chronic debilitating symptoms and failed medical management.From 1986 to 1996, of 263 patients receiving RP for ulcerative colitis, 27 (16 men) were operated on for distal ulcerative colitis limited to the rectum and sigmoid colon. Bowel function and quality of life were compared before and one year after RP.The mean (SD) duration of ulcerative colitis was 11 (6) years. RP was performed at a mean age of 46 (10) years. All the pouches were J-shaped, and a diverting loop ileostomy was always performed. Mean (SD) hospital stay was 25 (10) days. Seven complications occurred in six patients. Previously unknown severe dysplasia was discovered on the colectomy specimen in two patients. After RP there was a significant decrease in mean (SD) daytime stool frequency (8.2 (4) v 4.7 (2), p<0.05), night-time stool frequency (2 (2) v 1 (1), p = 0.05), and the number of patients with urgency to defecate (26/27 v 1/27, p<0.001). Sex life was improved in eight patients, social life in 26, and professional life in eight. Twenty six patients were satisfied with the results, and 25 wished that they had received surgery earlier in the course of their disease.RP can improve bowel function and quality of life in patients with disabling chronic symptoms of distal ulcerative colitis.
Blockade of EGFR and ErbB2 by the Novel Dual EGFR and ErbB2 Tyrosine Kinase Inhibitor GW572016 Sensitizes Human Colon Carcinoma GEO Cells to Apoptosis
Authors: Yunfei Zhou, Song Li, Yi P. Hu, Jing Wang, Jennie Hauser, Alexis N. Conway, Michelle A. Vinci, Lisa Humphrey, Elizabeth Zborowska, James K.V. Willson, Michael G. Brattain
Journal: Cancer Research (2006)

Abstract Coexpression of the epidermal growth factor receptor (EGFR) family receptors is found in a subset of colon cancers, which may cooperatively promote cancer cell growth and survival, as heterodimerization is known to provide for diversification of signal transduction. Recently, efforts have been made to develop novel 4-anilinoquinazoline and pyridopyrimidine derivatives to inhibit EGFR and ErbB2 kinases simultaneously. In this study, we tested the efficacy of a novel reversible dual inhibitor GW572016 compared with the selective EGFR and ErbB2 tyrosine kinase inhibitors (TKI) AG1478 and AG879 and their combination, using the human colon adenocarcinoma GEO mode. GEO cells depend on multiple ErbB receptors for aberrant growth. A synergistic effect on inhibition of cell proliferation associated with induction of apoptosis was observed from the combination of AG1478 and AG879. Compared with AG1478 or AG879, the single TKI compound GW572016 was a more potent inhibitor of GEO cell proliferation and was able to induce apoptosis at lower concentrations. Western blot analysis revealed that AG1478 and AG879 were unable to suppress both EGFR and ErbB2 activation as well as the downstream mitogen-activated protein kinase (MAPK) and AKT pathways as single agents. In contrast, GW572016 suppressed the activation of EGFR, ErbB2, MAPK, and AKT in a concentration-dependent manner. Finally, in vivo studies showed that GW572016 treatment efficiently blocked GEO xenograft growth at a dose range of 30 to 200 mg/kg with a twice-daily schedule. In summary, our study indicates that targeting both EGFR and ErbB2 simultaneously could enhance therapy over that of single agents directed at EGFR or ErbB2 in cancers that can be identified as being primarily heterodimer-dependent. (Cancer Res 2006; 66(1): 404-11)
Dual Blockade of the Renin-Angiotensin System
Authors: Igor Codreanu, Norberto Perico, Giuseppe Remuzzi
Journal: Journal of the American Society of Nephrology (2005)

The prevalence of chronic renal diseases is increasing worldwide. There is a great need to identify therapies that arrest disease progression to end-stage renal failure. Inhibition of the renin-angiotensin system both by angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists is probably the best therapeutic option available. Several large, multicenter studies have indeed shown a significant reduction in the risk for doubling baseline serum creatinine or progression toward end-stage renal failure in patients who do and do not have diabetes and have chronic nephropathies that are treated with angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists. However, the number of patients who reach end-stage renal failure is still considerably high. Significant reduction of the incidence of ESRD is likely to be achieved in the near future for chronic nephropathies, provided that the degree of renoprotection can be improved. This goal may be attainable with a more complex strategy than with a single or dual pharmacologic intervention on the renin-angiotensin system. Strict control of BP and protein excretion rate, lowering of blood lipids, tight glucose control for individuals with diabetes, and lifestyle changes form part of the future multimodal protocol for treatment of patients with chronic nephropathies.
Does concomitant extrapulmonary involvement changes characteristic features of pulmonary sarcoidosis
Authors: Esra Uzaslan, Asli Gorek Dilektasli, Ezgi Demirdogen Cetinoglu, Nilufer Aylin Acet, Funda Coskun, Ahmet Ursavas
Journal: European Respiratory Journal (2013)

Background: Sarcoidosis is a multisystem granulomatous inflammatory disorder. Extrapulmonary involvement (EPI) is common and frequently accompany pulmonary involvement (PI). Methods: We retrospectively reviewed the medical records of sarcoidosis patients in a university hospital in the last eight years. We aimed to investigate the clinical properties of sarcoidosis patients with extrapulmonary involvement. Results: Two hundred and nineteen sarcoidosis patients (72.1%females,27.9%males) were included. Females were older than the male patients at the moment of diagnosis (50.4±11.9 females,47.8±14.9 males, p <0.05). Of these 72.6% had PI, while 27.4% had concomitant EPI. Eye and skin were the most common EPI sites. Cough and fever were most frequent initial symptoms in patients with lone PI. Skin lesions and peripheral lymphadenopathy were more frequent initial signs in patients with concomitant EPI. Pulmonary nodules were more common in patients with concomitant EPI on radioloy. Forced vital capacitypredicted and carbon monoxide diffusion capacity were lower in patients with concomitant EPI (79.2±23.3% vs.87.1±16.1%, p <0.05;63.2±26.6% vs.74.4±19.2%, p <0.05). Bronchoalveolar lavage CD4+/CD8+ lymphocyte ratio ≥3.5 was more frequent in patients with concomitant EPI than the lone PI (72.4%vs.42.4%, p <0.05). Conclusion: In our study, over a quarter of sarcoidosis patients with PI had concomitant EPI. Eye, skin and peripheral lymph nodes were the most common EPI sites. Pulmonary function tests were more influenced if additional EPI was present. Beyond the biopsies from the involved site, bronchoalveolar lavage CD4+/CD8+ lymphocyte≥3.5 has diagnostic value in EPI with concomitant PI.
On a form of Concealed Haemorrhage before the Expulsion of the Placenta, Rarely Noticed
Authors: J. B. Hicks
Journal: BMJ (1872)

sidered as a gradual return to the physical state.Organic matter, whether animal or vegetable, when undergoing decomposition, is being gradually transformed from colloids into crystalloids; ammonia, car- bonic acid, and mineral carbonates and phosphates, being the main final crystalloid products, which diffuse away readily through the agency of water.They are taken up by plants, and again converted into col- loids, thus establishing an interesting rotation in nature.The wet state of muscular tissue in phthisis which I have frequently observed, espe- cially when there is much emaciation, appears to me to be due to the same cause as that which makes a piece of meat become damp and tender from spontaneous decomposition some time before it emits any smell.Now this post mortem phenomenon of the separation of the water from the solid constituents of tissues is due to a loss of the property pos- sessed by living tissues, by means of which they hold in a colloid (gelatinous) condition the water which they contain; and it is this Post mortemt change which, I believe, commences before death in con-
beta-Adrenergic regulation of total systemic intravascular volume in the dog.
Authors: D L Rutlen, E N Supple, W J Powell
Journal: Circulation Research (1981)

While it is known that /?-adrenergic receptor stimulation is associated with an increase in venous return, the mechanism by which this increase is mediated has not been well defined.A total of 55 dogs were anesthetized, placed on cardiopubnonary bypass, and perfused at a constant rate.In 23 of these animals, changes in total systemic intravascular volume were measured as reciprocal changes in extracorporeal reservoir volume during isoproterenol (6 /ig/min) or norepinephrine infusion (30 pg/ min).At central venous pressures of 3, 8, and 13 cm H 2 O, isoproterenol was associated with decreases in intravascular volume of 70 ± 20 (standard error of the mean) (P < 0.02), 50 ± 20 (P < 0.05), and 20 ± 30 (NS) ml, respectively, and norepinephrine was associated with decreases of 300 ± 60 (P < 0.001), 230 ± 30 (P< 0.001), and 190 ± 40 (P< 0.001) ml, respectively.The splanchnic vasculature was perfused selectively at a constant rate and drained separately in another 18 animals.In these dogs, an isoproterenol-associated decrease in splanchnic volume occurred concomitantly with a decrease in postsinusoidal hepatic vascular resistance from 38 ± 5 to 18 ± 3 cm H 2 O«min/liter (P< 0.001).A norepinephrine-associated decrease in splanchnic volume occurred simultaneously with a decrease in hepatic vascular resistance from 33 ± 6 to 18 ± 2 cm H 2 O«min/liter (P < 0.001).The decreases in total intravascular volume obtained with either isoproterenol or norepinephrine were abolished after the splanchnic vasculature had been removed in two other animals.Decreases in hepatic resistance, splanchnic volume, and total volume were abolished after propranolol.Thus, yS-adrenergic receptor stimulation with either isoproterenol or norepinephrine is associated with a decrease in transhepatic vascular resistance and subsequent decreases in splanchnic and total systemic intravascular volume. Circ Res 48:112-120, 1981CARDIAC performance is dependent upon ventricular filling and, hence, upon venous return.Alterations in venous return are dependent upon changes in the capacitance vasculature.Thus, cardiac performance is importantly related to alterations in total systemic capacity.While the direct effects of /S-adrenergic receptor stimulation on myocardial contractility, heart rate, and the arterial resistance vasculature have been well defined, the influence of yS-adrenergic stimulation on total systemic capacity is less well understood.The present study was undertaken to examine this influence.Kaiser et al. (1964) andImai et al. (1978) have demonstrated that the infusion of isoproterenol is associated with an increase in venous return.Whereas Kaiser et al. postulated that the increase was due to yS-adrenergic-mediated venoconstriction and Imai et al. postulated that the increase was a result of decreased venous outflow resistance, neither study elucidated the mechanism of action of From the Cardiac Unit,
Central Pattern Generators for Locomotion, with Special Reference to Vertebrates
Authors: Sten Grillner, Peter Wallén
Journal: Annual Review of Neuroscience (1985)

There is a gap to be bridged in vertebrate neurobiology, a gap between our knowledge of cellular mechanisms and behavior. We have achieved a widely expanded knowledge of how individual neurons function, and about synaptic transmission and membrane channels. We also increasingly understand the overall organization of different patterns of behavior, which principles apply, and which parts of eNS are important. We know much about how cells in the visual cortex respond, but little about how we perceive visual images; we know much about neuronal activity in motor cortex in relation to hand move­ ments, but little about how they are actually generated. One great challenge is to bridge this gap to understand how individual eNS neurons interact to generate different patterns of behavior, or make us perceive the environment, or memorize what we experience. Invertebrate neurobiologists have had considerable success in describing somc vcry important aspects of the cellular bases of behavior, such as asso­ ciative learning in molluscs (Kandel & Schwartz 1982) and basic patterns of behavior (Getting 1983a, Bullock 1982). In this chapter we deal with one limited aspect: how the central pattern generators that control locomotion function. Although the review is general, it emphasizes the vertebrates. We try to outline not only what we know, but also what directions seem most promising for gaining insight into how the eNS controls behavior. 233
Contribution of Selection for Protein Folding Stability in Shaping the Patterns of Polymorphisms in Coding Regions
Authors: Adrian W.R. Serohijos, Eugene I. Shakhnovich
Journal: Molecular Biology and Evolution (2013)

The patterns of polymorphisms in genomes are imprints of the evolutionary forces at play in nature. In particular, polymorphisms have been extensively used to infer the fitness effects of mutations and their dynamics of fixation. However, the role and contribution of molecular biophysics to these observations remain unclear. Here, we couple robust findings from protein biophysics, enzymatic flux theory, the selection against the cytotoxic effects of protein misfolding, and explicit population dynamics simulations in the polyclonal regime. First, we recapitulate results on the dynamics of clonal interference and on the shape of the DFE, thus providing them with a molecular and mechanistic foundation. Second, we predict that if evolution is indeed under the dynamic equilibrium of mutation–selection balance, the fraction of stabilizing and destabilizing mutations is almost equal among single-nucleotide polymorphisms segregating at high allele frequencies. This prediction is proven true for polymorphisms in the human coding region. Overall, our results show how selection for protein folding stability predominantly shapes the patterns of polymorphisms in coding regions.
Homeostatic T Cell Proliferation
Authors: Charles D. Surh, Jonathan Sprent
Journal: The Journal of Experimental Medicine (2000)

Through positive and negative selection, the thymus allows a small fraction of immature CD4+8+ double positive thymocytes to differentiate into mature CD4+8− or CD4−8+ single positive cells; these cells are released into the periphery to establish the mature T cell pool. Positive selection
Early Mental Hospitals in Spain
Authors: AMPARO S. CHAMBERLAIN
Journal: American Journal of Psychiatry (1966)

In an age when the mentally ill were likely to be persecuted and feared, attempts were being made in 15th-century Spain to care for and treat them. During that century Spain witnessed the founding of seven hospitals for the mentally ill—in Valencia, Zaragoza, Seville, Valladolid, Palma de Mallorca, Toledo, and Barcelona. These institutions were founded to protect the patient from society rather than to hide him.