tbuckley/cabot-search huggingface dataset:
Renal mechanism of action of rat atrial natriuretic factor.
Authors: C L Huang, J Lewicki, L K Johnson, M G Cogan
Journal: Journal of Clinical Investigation (1985)

There has been conflict as to whether crude extracts of atrial natriuretic factor increase renal solute excretion by a hemodynamic mechanism or by direct inhibition of tubular transport. To investigate this issue, seven rats were studied during a euvolemic control period and following continuous administration of pure, synthetic 24 amino acid atrial natriuretic factor. A 10-25-fold increase in urinary sodium and chloride excretion occurred with a brisk kaliuresis but little bicarbonaturia. Atrial natriuretic factor caused whole kidney glomerular filtration rate to increase from 1.17 +/- 0.04 to 1.52 +/- 0.07 ml/min (P less than 0.005). A parallel increase in single nephron glomerular filtration rate, from 34 +/- 1 to 44 +/- 2 nl/min (P less than 0.001), and from 26 +/- 1 to 37 +/- 2 nl/min (P less than 0.005) was measured at the end-proximal and early distal nephron sites, respectively. Appropriate for the higher flows were an increase in absolute proximal and loop reabsorptive rates for bicarbonate, chloride, and water, with a slight decrease in fractional solute and volume reabsorption in proximal and loop segments. To exclude the possibility that atrial natriuretic factor increased filtration rate only in anesthetized animals, eight unanesthetized rats were studied. Glomerular filtration rate increased by 45%, from 2.04 +/- 0.17 to 2.97 +/- 0.27 ml/min (P less than 0.005) without significant change in renal plasma flow, as reflected by 14C-para-aminohippurate clearance (5.4 +/- 0.5-5.6 +/- 0.9 ml/min). The clearance and micropuncture data did not preclude changes in relative blood flow distribution to or in transport by deep nephron segments. In conclusion, atrial natriuretic factor appears to increase renal solute excretion predominantly by a hemodynamic mechanism without directly inhibiting superficial tubular transport.
Adverse Effects of Excessive Consumption of Amino Acids
Authors: N. J. Benevenga, R. D. Steele
Journal: Annual Review of Nutrition (1984)

PHENYLALANINE TOXICITY   158 Developing the 0. -M ethylphenylalanine Model. . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Use of the a-Methyl phenylalanine Model in Brain Protein Synthesis . . . . . . . . . . . . . . . . . . . 161 TYROSINE TOXICITY   162 General Nutritional Observations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 Factors Affecting Tissue Concentrations of Tyrosine . ... .. .. .. ......   . . . . . . .. . . 163 Probable Cause of Tyrosine Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 A New Animal Model for Human Tyrosinemia II  165 TRYPTOPHAN TOXICITy  165 General Nutritional Observations . .. ....... . ....... . .... . . .. . . . .. . .. .   .. ..... ......... 165 Factors Affecting Tryptophan Toxicity . . . .. . . . . . . . .... .   ........   166 Tryptophan and Ruminant Interstitial Pulmonary Emphysema and Edema ..... . . . . . . . 167 HISTIDINE TOXICITY   168 General Nutritional Observations ...... ........ . . . . ..... . ...... .. .   168 Metabolic Aspects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 Alleviation of Histidine Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 METHIONINE TOXICITY   171 General Nutritional Observations . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 Tissue Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 172 Protective Effect of Glycine, Serine, or Retinol . . . .. ....... . ......... . ......... .. . .. . . ...... 172 Chemical Characteristics Related to the Toxicity of Methionine . . . . . . . . . . . . . . . . . . . . . . . . . 173 Damaging Effects of Methanethiol. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 173 Met�io,!ine To�i.city in Chickens   174 EthlOnme TOxIcIty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . ... . 174
TAP-1 indirectly regulates CD4+ T cell priming in <i>Toxoplasma gondii</i> infection by controlling NK cell IFN-γ production
Authors: Romina S. Goldszmid, Andre Bafica, Dragana Jankovic, Carl G. Feng, Pat Caspar, Robin Winkler-Pickett, Giorgio Trinchieri, Alan Sher
Journal: The Journal of Experimental Medicine (2007)

To investigate if transporter associated with antigen processing (TAP)–1 is required for CD8+ T cell–mediated control of Toxoplasma gondii in vivo, we compared the resistance of TAP-1−/−, CD8−/−, and wild-type (WT) mice to infection with the parasite. Unexpectedly, TAP-1−/− mice displayed greater susceptibility than CD8−/−, β2-microglobulin−/− (β2m−/−), or WT mice to infection with an avirulent parasite strain. The decreased resistance of the TAP-1−/− mice correlated with a reduction in the frequency of activated (CD62Llow CD44hi) and interferon (IFN)-γ–producing CD4+ T cells. Interestingly, infected TAP-1−/− mice also showed reduced numbers of IFN-γ–producing natural killer (NK) cells relative to WT, CD8−/−, or β2m−/− mice, and after NK cell depletion both CD8−/− and WT mice succumbed to infection with the same kinetics as TAP-1−/− animals and displayed impaired CD4+ T cell IFN-γ responses. Moreover, adoptive transfer of NK cells obtained from IFN-γ+/+, but not IFN-γ−/−, animals restored the CD4+ T cell response of infected TAP-1−/− mice to normal levels. These results reveal a role for TAP-1 in the induction of IFN-γ–producing NK cells and demonstrate that NK cell licensing can influence host resistance to infection through its effect on cytokine production in addition to its role in cytotoxicity.
HEPATITIS C: An Overview
Authors: Bhupinder N. Bhandari, M.D, Teresa L. Wright, M.D
Journal: Annual Review of Medicine (1995)

▪ Abstract Hepatitis C virus (HCV) has been associated with acute and chronic posttransfusion and with sporadic non-A non-B (NANB) hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Cloning of the sequence encoding an antigenic component of HCV in 1989 led to the development of tests to detect antibody to HCV in serum. Viral HCV RNA can be detected and estimated with polymerase chain reaction (PCR) and branched-chain DNA (bDNA) signal amplification tests. The entire viral genome has been sequenced. The HCV envelope region varies considerably, and infections with mutant HCV have been described. Approximately 0.5–1.5% of healthy blood donors test positive, and HCV infection can be acquired by blood transfusion or i.v. drug abuse. Vertical and sexual transmission of the virus is rare, and the transmission mode remains obscure in a large group of patients. Acute hepatitis C is mild and often asymptomatic. Chronic hepatitis C has an indolent course but may progress to cirrhosis and HCC. Recombinant alpha interferon (IF) is used to treat chronic HCV disease, but no consensus has been reached on patient selection, dose, and duration of treatment. Approximately 50% of treated patients respond, but 50–80% of responders relapse over time. Liver transplantation in patients with end-stage, HCV-related liver disease is often followed by allograft infection. Short-term survival with reinfection is good, but the long-term consequences remain to be defined.
The renin–angiotensin system and experimental heart failure
Authors: Kai C Wollert, Helmut Drexler
Journal: Cardiovascular Research (1999)

Experimental studies suggest that the renin–angiotensin system (RAS) and its primary effector peptide, angiotensin II (Ang II), are involved in the pathophysiology of cardiac hypertrophy and failure. All the components required for Ang II production are present in the heart, and cardiac Ang II formation appears to be regulated independent from the circulating RAS. In animal models and in patients with heart failure, the cardiac RAS is activated and, presumably, local Ang II formation is enhanced. Several cardiac cell types express Ang II type 1 (AT1) and/or type 2 (AT2)-receptors and represent potential targets for Ang II-mediated effects. In neonatal cardiac myocytes, Ang II induces a hypertrophic response via the AT1-receptor. Likewise, activation of the AT1-receptor triggers hypertrophy in terminally differentiated cardiac myocytes and in perfused heart preparations. In the neonatal system, Ang II appears to be a major autocrine/paracrine mediator of cardiac myocyte hypertrophy in response to passive mechanical stretch. By contrast, AT1-receptor activation apparently is not required to trigger load-induced hypertrophy in the adult cardiomyocyte. Recent studies suggest that the AT2-receptor opposes AT1-receptor-mediated growth signals in neonatal and in adult cardiac myocytes. Pharmacological studies have established that a blockade of the RAS at the level of the angiotensin-converting enzyme (ACE) or the AT1-receptor ameliorates the remodeling process of the heart and prolongs long-term survival in animal models of cardiac hypertrophy and failure. The therapeutic effects of ACE inhibitors and AT1-receptor antagonists clearly suggest an important role for the ACE–Ang II–AT1-receptor axis in the development of cardiac hypertrophy and failure. It must be kept in mind, however, that these drugs enhance AT2-receptor and B2-kinin receptor-dependent signaling pathways which may contribute significantly to the beneficial effects observed in vivo. Molecular and physiological analyses of transgenic mice with a cardiac-specific overexpression of the AT1 or AT2-receptor confirm that AT1 and AT2-receptor-dependent signaling cascades potently modulate cardiac myocyte function and growth. However, studies in AT1-receptor knockout mice demonstrate that cardiac hypertrophy in response to hemodynamic overload can occur independent from the AT1-receptor. In this paper, we review recent experimental evidence suggesting a critical role for the RAS in cardiac hypertrophy and failure with special emphasis on the putative role of Ang II and Ang II-receptor signaling in cardiac myocytes.
Management of diastolic heart failure in older adults
Authors: Ali Ahmed
Journal: BMJ (2004)

A 69 year old woman has come to you for follow up after having attended a hospital's emergency department.She has had progressive dyspnoea and undue tiredness for more than six months.Recently, her dyspnoea has got worse.At the emergency department her blood pressure and heart rate were high, and a chest radiograph showed mild pulmonary oedema.A diagnosis of heart failure was made.Her symptoms improved after treatment with intravenous furosemide and metoprolol.An echocardiography later showed her to have a left ventricular ejection fraction > 55%.
T cell receptor interaction with peptide/major histocompatibility complex (MHC) and superantigen/MHC ligands is dominated by antigen.
Authors: E W Ehrich, B Devaux, E P Rock, J L Jorgensen, M M Davis, Y H Chien
Journal: The Journal of Experimental Medicine (1993)

While recent evidence strongly suggests that the third complementarity determining regions (CDR3s) of T cell receptors (TCRs) directly contact antigenic peptides bound to major histocompatibility complex (MHC) molecules, the nature of other TCR contact(s) is less clear. Here we probe the extent to which different antigens can affect this interaction by comparing the responses of T cells bearing structurally related TCRs to cytochrome c peptides and staphylococcal enterotoxin A (SEA) presented by 13 mutant antigen-presenting cell (APC) lines. Each APC expresses a class II MHC molecule (I-Ek) with a single substitution of an amino acid residue predicted to be located on the MHC alpha helices and to point "up" towards the TCR. We find that very limited changes (even a single amino acid) in either a CDR3 loop of the TCR or in a contact residue of the antigenic peptide can have a profound effect on relatively distant TCR/MHC interactions. The extent of these effects can be as great as that observed between T cells bearing entirely different TCRs and recognizing different peptides. We also find that superantigen presentation entails a distinct mode of TCR/MHC interaction compared with peptide presentation. These data suggest that TCR/MHC contacts can be made in a variety of ways between the same TCR and MHC, with the final configuration apparently dominated by the antigen. These observations suggest a molecular basis for recent reports in which either peptide analogues or superantigens trigger distinct pathways of T cell activation.
Hypoplastic Left Heart Syndrome With Intact or Highly Restrictive Atrial Septum
Authors: Antonios P. Vlahos, James E. Lock, Doff B. McElhinney, Mary E. van der Velde
Journal: Circulation (2004)

Background— Hypoplastic left heart syndrome (HLHS) with intact or very restrictive atrial septum is a highly lethal combination. We review our 13-year institutional experience treating this high-risk subgroup of patients with emergent catheter therapy. Methods and Results— Infants with HLHS requiring catheter septostomy within the first 2 days of life were compared with a matched control group with adequate interatrial communication. Preoperative, early postoperative, and medium-term survival were evaluated. Earlier experience was compared with recent results to assess the effect of changes in catheterization and surgical and intensive care unit management strategies over the study period. From 1990 to 2002, 33 newborns with HLHS (11% of newborns with HLHS managed during this period) underwent urgent/semiurgent catheterization to create or enlarge an interatrial communication before surgical palliation. Preoperative and early postoperative mortality were high (48%) compared with control HLHS patients, regardless of prenatal diagnosis and despite successful catheter-based atrial septostomy with clinical stabilization. Mortality trended down during the later part of the study period. Those who survived the neonatal period had late survival, pulmonary artery pressure, and resistance similar to those of control subjects. Conclusions— Neonatal mortality in the subgroup of HLHS patients with intact or highly restrictive atrial septum remains high despite successful urgent septostomy. Persistently poor outcomes for these patients have prompted efforts at our center to develop techniques for fetal intervention for this condition, in the hope that prenatal relief of left atrial and pulmonary venous hypertension may promote normal pulmonary vascular and parenchymal development and improve both short- and long-term outcomes.
Clinical course and prognosis of never-smokers with severe alpha-1-antitrypsin deficiency (PiZZ)
Authors: H A Tanash, P M Nilsson, J-A Nilsson, E Piitulainen
Journal: Thorax (2008)

<h3>Background:</h3> Previous studies of non-smoking individuals with severe α<sub>1</sub>-antitrypsin deficiency (PiZZ) have been sparse and included only a limited number of individuals, mostly identified by respiratory symptoms. The aim of this study was to estimate the prognosis of non-smoking PiZZ individuals and to analyse the most common causes of death by including a large number of individuals who had been identified by other means than respiratory symptoms. <h3>Methods:</h3> The study included 568 non-smoking PiZZ subjects who were selected from the Swedish National AAT Deficiency Registry and followed up from 1991 to September 2007. Of these, 156 (27%) were identified by respiratory symptoms (respiratory cases) and 412 were identified by extrapulmonary symptoms or screening (non-respiratory cases). <h3>Results:</h3> 93 subjects (16%) died during the follow-up period. The specific standardised mortality rate (SMR) for the whole study population was 2.32 (95% CI 1.87 to 2.83) with no significant difference between men and women. The SMR was 2.55 (95% CI 1.91 to 2.83) for the respiratory cases and 2.07 (95% CI 1.49 to 2.81) for the non-respiratory cases. Further calculation of SMR for subgroups in the non-respiratory cases showed that the SMR was 0.70 (95% CI 0.14 to 2.04) for individuals identified by family/population screening. Emphysema and liver cirrhosis were the most common causes of death (45% and 28%, respectively). Malignant transformation was found in 38% of the cases with cirrhosis. <h3>Conclusion:</h3> Non-smoking PiZZ individuals identified by screening do not have an increased mortality risk compared with the Swedish general population.
Physical activity for preventing strokes
Authors: G D. Batty
Journal: BMJ (2002)

protection of patients' long term interests.Patients dislike isolation from family and friends and are vulnerable to changes in the institution's niche in the market.But these detained users of private services have little influence over their circumstances.The network is a "virtual asylum," dispersed, invisible, and inadequately regulated.Patients often arrive in the virtual asylum after lengthy, unproductive stays in acute psychiatric wards.Others come from prisons, special hospitals, and NHS secure units.Many have been moved from institution to institution since childhood.Some have a bad reputation with local NHS services, which have lost the will to deal with them.In the absence of appropriate NHS provision, these patients are placed in the private sector.In smaller nursing homes, where low profit margins do not allow the employment of full multidisciplinary teams, patients are subjected to little purposeful activity.Often, few fully trained nursing or medical staff are available.Care tends to be basic.Larger and more expensive facilities are able to attract better qualified staff.Patients entering this part of the virtual asylum are likely to receive rehabilitation, albeit often focused on acculturation to institutional life.Even where care in these institutions exceeds NHS standards, this is offset by severe difficulties in integrating patients back into reluctant local community services.The cost of placement in secure services is £2000-2250 per week ($3100-3500; 3100-3500). 6 The cost of non-secure services shows much greater variation.The annual national cost probably greatly exceeds £100m, but no mechanism is in place to monitor the value for money of this substantial expenditure.Variability of care is endemic in the NHS, but it is at least possible to measure it.Until now it has been possible for patients to live in the virtual asylum, with little or no monitoring of quality of care.Nursing home inspection teams and the Mental Health Act Commission can monitor legal requirements but cannot adequately oversee the quality of individual care.It is hard to see how the new National Care Standards Commission will be able to function any better at the level of the individual. 8The incoherence of the current approach may worsen as commissioning transfers to primary care trusts each with a tiny number of such patients.Few primary care trusts have developed the commissioning capability for this specialist task.Episodes of moral panic continue to dominate formation of mental health policy in the United Kingdom.Concern about neglect and abuse in mental hospitals in the 1970s gave way to concern over the perceived danger of mentally ill people in the community in the
Ocular Anti-VEGF Therapy for Diabetic Retinopathy: The Role of VEGF in the Pathogenesis of Diabetic Retinopathy
Authors: Rafael Simó, Jeffrey M. Sundstrom, David A. Antonetti
Journal: Diabetes Care (2014)

Diabetic retinopathy is the leading cause of visual impairment and preventable blindness, and represents a significant socioeconomic cost for health care systems worldwide. Therefore, new approaches beyond current standards of diabetes care are needed. Based on the crucial pathogenic role of vascular endothelial growth factor (VEGF) in the development of diabetic macular edema (DME), intravitreal anti-VEGF agents have emerged as new treatments. To provide an understanding of the rationale for use and clinical efficacy of anti-VEGF treatment, we examine this topic in a two-part Bench to Clinic narrative. In the Bench narrative, we provide an overview of the role of VEGF in the pathogenesis of diabetic retinopathy, the molecular characteristics of anti-VEGF agents currently used, and future perspectives and challenges in this area. In the Clinic narrative that follows our contribution, Cheung et al. provide an overview of the current evidence from clinical trials on anti-VEGF therapy for diabetic retinopathy.
The promoter for intestinal cell kinase is head-to-head with F-Box 9 and contains functional sites for TCF7L2 and FOXA factors
Authors: Thomas W Sturgill, Paul B Stoddard, Steven M Cohn, Marty W Mayo
Journal: Molecular Cancer (2010)

Intestinal cell kinase (ICK; GeneID 22858) is a conserved MAPK and CDK-like kinase that is widely expressed in human tissues. Data from the Cancer Genome Anatomy Project indicated ICK mRNA is increased in cancer, and that its expression correlated with expression of mRNA for an uncharacterized F-box protein, FBX9 (GeneID: 26268). ICK and FBX9 genes are arranged head-to-head on opposite strands, with start sites for transcription separated by ~3.3 kb. We hypothesized ICK and FBX9 are potentially important genes in cancer controlled by a bidirectional promoter. We assessed promoter activity of the intergenic region in both orientations in cancer cell lines derived from breast (AU565, SKBR3), colon (HCT-15, KM12), and stomach (AGS) cancers, as well as in embryonic human kidney (HEK293T) cells. The intergenic segment was active in both orientations in all of these lines, and ICK promoter activity was greater than FBX9 promoter activity. Results from deletions and truncations defined a minimal promoter for ICK, and revealed that repressors and enhancers differentially regulate ICK versus FBX9 promoter activity. The ICK promoter contains consensus motifs for several FOX-family transcription factors that align when mouse and human are compared using EMBOSS. FOXA1 and FOXA2 increase luciferase activity of a minimal promoter 10-20 fold in HEK293T cells. Consensus sites for TCF7L2 (TCF4) (Gene Id: 6934) are also present in both mouse and human. The expression of β-catenin increased activity of the minimal promoter ~10 fold. ICK reference mRNAs (NM_014920.3, NM_016513) are expressed in low copy number and increased in some breast cancers, using a ten base tag 5'-TCAACCTTAT-3' specific for both ICK transcripts. ICK and FBX9 are divergently transcribed from a bidirectional promoter that is GC-rich and contains a CpG island. A minimal promoter for ICK contains functional sites for β-cateinin/TCF7L2 and FOXA. These data are consistent with functions that have been proposed for ICK in development and in proliferation or survival of some breast and colon cancers.