tbuckley/cabot-search huggingface dataset:
Endothelin as a natriuretic hormone: the case for a paracrine action mediated by nitric oxide
Authors: Y Kotelevtsev
Journal: Cardiovascular Research (2001)

Time for primary review 26 days. 

There is a widely held view that function of the kidney is the key to understanding human essential hypertension. Indeed, all of the currently recognised human monogenic causes of hypertension reflect abnormalities in the genes that determine ion transport in the distal portion of the nephron [1]. It is also recognised that permanent elevation of blood pressure in experimental models of hypertension, and both primary and secondary hypertension in man, requires the shifting of the natriuretic response curve of the kidney towards higher pressures [2]. However, the mechanism underlying pressure-natriuresis, and its resetting in hypertension, remains poorly understood. In this review we have analysed experiments indicating a role for endothelin (ET)-1 as a key natriuretic hormone and propose a new and testable hypothesis for a paracrine action of ET-1 through NO that accommodates the existing experimental findings.

ET-1 is a 21 amino acid peptide, synthesised mainly by endothelial cells (ECs) and produced from an inactive precursor peptide by several rounds of specific proteolysis. The last step is performed by endothelin converting enzyme (ECE), which releases ET-1 from big ET-1. ET-1 acts in an autocrine and paracrine fashion on two subtypes of ET receptors, termed the ETA (ETAR) and ETB receptors (ETBR). Both ETAR and ETBR are located on vascular smooth muscle cells and binding of ET-1 to these receptors results in sustained vasoconstriction. ETBR are also present on ECs where their activation results in the production of NO and dilator prostanoids, and subsequent vasodilatation. The ET system is now known to play an important role in the regulation of vascular tone and blood pressure [3,4].

However, the role of ET-1 produced and secreted in the kidney may be independent of the systemic vascular effects. Analysis of different tissues found the highest … 

*Corresponding author. Tel.: +44-131-651-11-94; fax: +44-131-650-65-27 Yuri.Kotelevtsev{at}ed.ac.uk
Aggressive combination therapy with intra-articular glucocorticoid injections and conventional disease-modifying anti-rheumatic drugs in early rheumatoid arthritis: second-year clinical and radiographic results from the CIMESTRA study
Authors: M L Hetland, K Stengaard-Pedersen, P Junker, T Lottenburger, I Hansen, L S Andersen, U Tarp, A Svendsen, J K Pedersen, H Skjodt, U B Lauridsen, T Ellingsen, G V O Hansen, H Lindegaard, A Vestergaard, A G Jurik, M Ostergaard, K Horslev-Petersen
Journal: Annals of the Rheumatic Diseases (2007)

To investigate whether clinical and radiographic disease control can be achieved and maintained in patients with early, active rheumatoid arthritis (RA) during the second year of aggressive treatment with conventional disease-modifying antirheumatic drugs (DMARDs) and intra-articular corticosteroid. This paper presents the results of the second year of the randomised, controlled double-blind CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) study.160 patients with early RA (duration <6 months) were randomised to receive intra-articular betamethasone in any swollen joint in combination with step-up treatment with either methotrexate and placebo-ciclosporine (monotherapy) or methotrexate plus ciclosporine (combination therapy) during the first 76 weeks. At week 68 hydroxychlorochine 200 mg daily was added. From week 76-104 ciclosporine/placebo-ciclosporine was tapered to zero.American College of Rheumatology 20% improvement (ACR20), ACR50 and ACR70 levels were achieved in 88%, 79% and 59% of patients in the combination vs 72%, 62% and 54% in the monotherapy group (p = 0.03, 0.02 and 0.6 between groups). The patients globally declined from 50 to 12 vs 52 to 9, with 51% and 50% in Disease Activity Score (DAS) remission, respectively. Mean (SD) progressions in total Sharp-van der Heijde scores were 1.42 (3.52) and 2.03 (5.86) in combination and monotherapy groups, respectively (not significant). Serum creatinine levels increased by 7% in the combination group (4% in monotherapy), but hypertension was not more prevalent.Continuous methotrexate and intra-articular corticosteroid treatment resulted in excellent clinical response and disease control at 2 years, and the radiographic erosive progression was minimal. Addition of ciclosporine during the first 76 weeks resulted in significantly better ACR20 and ACR50 responses, but did not have any additional effect on remission rate and radiographic outcome.
Nonmyeloablative Allogeneic Immunotherapy for Solid Tumors
Authors: Richard W. Childs, John Barrett
Journal: Annual Review of Medicine (2004)

Over the past decade, considerable advances have been made in the field of allogeneic hematopoietic stem cell transplantation. Recognition that transplanted donor immune cells can cure patients with leukemia has led to the development of nonmyeloablative or "low-intensity" conditioning regimens, which have expanded the application of allogeneic transplantation to a growing number of hematological malignancies. The improved safety and preliminary success of this transplant approach have justified applying allogeneic immunotherapy to patients with treatment-refractory solid tumors.
Is it the primetime for endoglin (CD105) in the clinical setting?
Authors: M MAIO, M ALTOMONTE, E FONSATTI
Journal: Cardiovascular Research (2006)

See article by Jerkic et al.  [12]  (pages 845–854) in this issue. 

Initial studies carried out at the beginning of the past century identified increased vascularity as a common feature associated with tumor growth; based on these morphological observations, it was then demonstrated that local tumor growth and distant metastasis of neoplastic cells are strictly dependent on adequate blood supply. The latter was subsequently shown to be provided by blood vessels neoformed from pre-existing ones whose growth is directly promoted by neoplastic cells through the local release of angiogenic factors. Altogether, these observations provided a strong scientific rationale to hypothesize the clinical use of an anti-angiogenic approach based on therapeutic tools able to inhibit molecularly characterized regulators of angiogenesis as an effective strategy to treat cancer [1,2]. Nevertheless, among a large array of novel therapeutic agents with anti-angiogenic activity tested in the clinical setting in the past decade, the humanized version of a murine anti-vascular endothelial growth factor (VEGF) monoclonal antibody (mAb) (bevacizumab) is the only such agent that has received approval for the treatment of mestatastic colorectal cancer in association with chemotherapy [2]; thus, plenty of room is still available for the clinical development of new … 

*Corresponding author. Division of Medical Oncology and Immunotherapy, University Hospital of Siena, Strada delle Scotte 14, 53100 Siena, Italy. Tel.: +39 0577 586335; fax: +39 0577 586303. Email address: mmaio{at}cro.it
Mitogenic Signaling via G Protein-Coupled Receptors
Authors: TIM van BIESEN, LOUIS M. LUTTRELL, BRIAN E. HAWES, ROBERT J. LEFKOWITZ
Journal: Endocrine Reviews (1996)

RECEPTORS coupled to heterotrimeric GTP-binding proteins (G proteins) comprise the largest known family of cell surface receptors and mediate cellular responses to a diverse array of signaling molecules, including peptide and glycopeptide hormones, neurotransmitters, phospholipids, odorants, and photons. The basic unit of G protein-coupled receptor (GPCR) signaling is comprised of three parts; receptor, which detects ligand in the extracellular milieu; heterotrimeric G protein, which is dissociated into active Gα-GTP and Gβγ-subunits after interaction with the liganded receptor; and effector, which interacts with dissociated Gα-GTP and Gβγ-subunits to mediate the intracellular effects of ligand binding. In a given cell type, the responsiveness to stimulus, as well as the nature of the response, is dictated by the available complement of receptor, G protein, and effector. Despite the diverse array of ligands with which they interact, GPCRs share a conserved predicted tertiary structure characterized by seven transmembrane domains joined by intracellular and extracellular loops. G protein coupling specificity is dictated by the intracellular domains, particularly the second and third intracellular loops and the Cterminal tail. Indeed, it is possible to alter the G proteincoupling specificity of GPCRs by exchanging relatively small regions within the third intracellular loop (1).
Impact of Dialysis Adequacy on the Mortality and Morbidity of Anuric Chinese Patients Receiving Continuous Ambulatory Peritoneal Dialysis
Authors: CHEUK-CHUN SZETO, TERESA YUK-HWA WONG, KAI-MING CHOW, CHI-BON LEUNG, MAN-CHING LAW, ANGELA YEE-MOON WANG, SIU-FAI LUI, PHILIP KAM-TAO LI
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Dialysis adequacy has a major impact on the outcome of continuous ambulatory peritoneal dialysis (CAPD) patients. However, most studies on peritoneal dialysis adequacy have focused on patients with significant residual renal function. The present study examined the effect of dialysis adequacy on anuric CAPD patients. A single-center prospective observational study on 140 anuric CAPD patients was performed. These patients were followed for 22.0 ± 11.9 mo. Dialysis adequacy and nutritional indices, including Kt/V, creatinine clearance (CCr), protein equivalent nitrogen appearance, percentage of lean body mass, and serum albumin level were monitored. Clinical outcomes included actuarial patient survival, technique survival, and duration of hospitalization. In the study population, 64 were male, 36 (25.7%) were diabetic, and 59 (42.1%) were treated with 6 L exchanges per day. The body weight was 59.2 ± 10.2 kg. Average Kt/V was 1.72 ± 0.31, and CCr was 43.7 ± 11.5 L/wk per 1.73m 2 . Two-yr patient survival was 68.8%, and technique survival was 61.4%. Multivariate analysis showed that DM, duration of dialysis before enrollment, serum albumin, and index of dialysis adequacy (Kt/V or CCr) were independent factors of both patient survival and technique survival. It was estimated that for two patients who differed only in weekly Kt/V, a 0.1 higher value was associated with a 6% decrease in the RR of death ( P &lt; 0.05; 95% confidence interval, 0.92 to 0.99). Serum albumin and CCr were the only independent factors that predicted hospitalization. It was found that even when there is no residual renal function, higher dialysis dosage is associated with better actuarial patient survival, better technique survival, and shorter hospitalization. Dialysis adequacy has a significant impact on the clinical outcome of CAPD patients, and the beneficial effect is preserved in anuric patients as well as in an ethnic group that has a low overall mortality.
The hand eczema proteome: imbalance of epidermal barrier proteins
Authors: S. Molin, J. Merl, K.A. Dietrich, M. Regauer, M. Flaig, V. Letulé, T. Saucke, T. Herzinger, T. Ruzicka, S.M. Hauck
Journal: British Journal of Dermatology (2014)

Chronic hand eczema (CHE) is a common skin disease with a high socioeconomic impact. While some light has been shed on the genetic factors that predispose individuals to the disease, little is known about its actual pathogenesis. We aimed to carry out a systematic and comprehensive analysis of the differential protein expression in CHE using modern mass spectrometry. We performed liquid chromatography with tandem mass spectrometry analyses and label‐free quantification to analyse the proteomic profile of palmar skin from 12 individuals (six patients with hand eczema and six healthy volunteers). Immunohistochemistry of the palmar skin from seven different patients with hand eczema and seven different healthy volunteers was performed in a second step. With this method we were able to identify 185 candidate proteins with a significantly different abundance in the hand eczema samples. Among them we found several barrier proteins: filaggrin (FLG), FLG‐2 and hornerin were all downregulated in the hand eczema samples, as were the desquamation‐related enzymes kallikrein‐related peptidase (KLK)5 and KLK7 and cystatin E/M. The antimicrobial peptides S100A7 and S100A8/A9 and the small proline‐rich protein 2B and S100A11 were upregulated in the diseased skin. Immunohistochemistry confirmed these findings. Our results corroborate the assumption that skin barrier dysfunction plays an essential role in the pathogenesis of CHE.
A Clinical Prediction Rule To Identify Patients with Low Back Pain Most Likely To Benefit from Spinal Manipulation: A Validation Study
Authors: John D. Childs, Julie M. Fritz, Timothy W. Flynn, James J. Irrgang, Kevin K. Johnson, Guy R. Majkowski, Anthony Delitto
Journal: Annals of Internal Medicine (2004)

Background: Conflicting evidence exists about the effectiveness of spinal manipulation. Objective: To validate a manipulation clinical prediction rule. Design: Multicenter randomized, controlled trial. Setting: Physical therapy clinics. Patients: 131 consecutive patients with low back pain, 18 to 60 years of age, who were referred to physical therapy. Intervention: Patients were randomly assigned to receive manipulation plus exercise or exercise alone by a physical therapist for 4 weeks. Measurements: Patients were examined according to the clinical prediction rule criteria (symptom duration, symptom location, fear–avoidance beliefs, lumbar mobility, and hip rotation range of motion). Disability and pain at 1 and 4 weeks and 6 months were assessed. Results: Outcome from spinal manipulation depends on a patient's status on the prediction rule. Treatment effects are greatest for the subgroup of patients who were positive on the rule (at least 4 of 5 criteria met); health care utilization among this subgroup was decreased at 6 months. Compared with patients who were negative on the rule and received exercise, the odds of a successful outcome among patients who were positive on the rule and received manipulation were 60.8 (95% CI, 5.2 to 704.7). The odds were 2.4 (CI, 0.83 to 6.9) among patients who were negative on the rule and received manipulation and 1.0 (CI, 0.28 to 3.6) among patients who were positive on the rule and received exercise. A patient who was positive on the rule and received manipulation has a 92% chance of a successful outcome, with an associated number needed to treat for benefit at 4 weeks of 1.9 (CI, 1.4 to 3.5). Limitations: The response rate for the 6-month follow-up resulted in inadequate power to detect statistically significant differences for some comparisons. Conclusions: The spinal manipulation clinical prediction rule can be used to improve decision making for patients with low back pain.
Invasion patterns in brain metastases of solid cancers
Authors: Anna S. Berghoff, Orsolya Rajky, Frank Winkler, Rupert Bartsch, Julia Furtner, Johannes A. Hainfellner, Simon L. Goodman, Michael Weller, Jens Schittenhelm, Matthias Preusser
Journal: Neuro-Oncology (2013)

Brain metastases are generally considered to be well demarcated from the surrounding brain parenchyma, although infiltrative growth patterns have been observed. We systemically investigated infiltration patterns and expression of adhesion molecules in a large and well-defined series of autopsy cases of brain metastases. Ninety-seven autopsy specimens from 57 brain metastasis patients (primary tumor: 27 lung cancer, 6 breast cancer, 8 melanoma, 2 colorectal cancer, 1 kidney cancer, and 13 other) were evaluated for patterns of invasion into surrounding brain parenchyma. Expression of integrins αv; cytoplasmic β3, αvβ3, αvβ5, αvβ6, and αvβ8; and of E and N cadherin were evaluated using immunohistochemistry. Three main invasion patterns were seen: well-demarcated growth (29/57, 51%), vascular co-option (10/57, 18%), and diffuse infiltration (18/57, 32%). There was no statistically significant association of invasion pattern with primary tumor type, although vascular co-option was most common in melanoma brain metastases (4/10). Invasion patterns of different brain metastases of the same patient were highly concordant (P < .001, chi-square test). Distance of infiltration from the main tumor mass ranged from 12.5 µm to 450 µm (median 56.2 µm) and was not significantly different between the vascular co-option and the diffuse infiltration groups. Levels of αvβ6 were significantly higher in the well-demarcated group than in the vascular co-option and the diffuse infiltration groups (P = .033, Kruskal-Wallis test). Expression of αvβ5 in tumor cells was higher in brain metastasis lesions previously treated with stereotactic radiosurgery (P = .034, chi-square test). Distinct invasion patterns of brain metastases into the brain parenchyma are not specific for primary tumor types, seem to be influenced by expression of αv integrin complexes, and may help to guide clinical decision-making.
Methyldibromoglutaronitrile in leave-on products elicits contact allergy at low concentration
Authors: L. Kynemund Pedersen, T. Agner, E. Held, J.D. Johansen
Journal: British Journal of Dermatology (2004)

Background The rapidly increasing level of contact allergy to methyldibromoglutaronitrile (MDBGN) in Europe is of concern. In April 2003, the EU Commission prohibited the use of MDBGN in leave‐on cosmetic products, such as creams and lotions, until a level of safe use can be defined. Industry risk assessment has indicated that such a safe level could be 50–100 p.p.m. Objectives To determine whether 50 p.p.m. or 100 p.p.m. could be tolerated by MDBGN‐sensitized individuals, and to evaluate if the risk for elicitation of MDBGN allergy is higher for a leave‐on product with a high lipid content than for a product with a low lipid content. Methods Eighteen volunteers with contact allergy to MDBGN and 10 healthy controls were exposed to repeated open application tests (ROATs) with two moisturizers with a high and a low lipid content, respectively, both containing MDBGN at a concentration of 50 p.p.m. The ROATs were performed on the left and the right side of the neck for 14 days, or until a positive reaction was seen. If a positive reaction did not develop within the first 14 days, two analogous moisturizers containing 100 p.p.m. MDBGN were applied for a further 14 days. Clinical assessments were done on days 2, 3, 7, 14, 21 and 28 or when a reaction developed. Results Eleven of 18 (61%) subjects developed dermatitis on the test area, of whom 10 developed a positive reaction to the 50 p.p.m. moisturizer, seven having a positive reaction on day 2 or 3. Reactions to the low‐lipid moisturizer were the more frequent. All participants used more of the low‐lipid moisturizer than the high‐lipid moisturizer. The controls all had negative ROATs. Conclusions Even 50 p.p.m. cannot be regarded as a safe concentration for use and the prohibition of MDBGN is scientifically well founded.
Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis
Authors: S. Anand
Journal: Journal of Clinical Investigation (2006)

LIGHT is an important costimulatory molecule for T cell immunity. Recent studies have further implicated its role in innate immunity and inflammatory diseases, but its cellular and molecular mechanisms remain elusive. We report here that LIGHT is upregulated and functions as a proinflammatory cytokine in 2 independent experimental hepatitis models, induced by concanavalin A and Listeria monocytogenes. Molecular mutagenesis studies suggest that soluble LIGHT protein produced by cleavage from the cell membrane plays an important role in this effect through the interaction with the lymphotoxin-beta receptor (LTbetaR) but not herpes virus entry mediator. NK1.1+ T cells contribute to the production, but not the cleavage or effector functions, of soluble LIGHT. Importantly, treatment with a mAb that specifically interferes with the LIGHT-LTbetaR interaction protects mice from lethal hepatitis. Our studies thus identify a what we believe to be a novel function of soluble LIGHT in vivo and offer a potential target for therapeutic interventions in hepatic inflammatory diseases.
Effects of H<sub>1</sub>antagonists on the cutaneous vascular response to histamine and bradykinin: a study using scanning laser Doppler imaging
Authors: None Clough, None Bennett, None Church
Journal: British Journal of Dermatology (1998)

Histamine plays an important part in the cutaneous weal and flare response which underlies many allergic skin conditions. It has a direct effect on the local vasculature to promote vasodilatation and increase microvascular permeability and may also initiate the more widely spread neurogenic flare. Quantification of these responses and studies of the mediator mechanisms underlying them have been limited by the lack of appropriate techniques to investigate them. To address this we have used two relatively new techniques, scanning laser Doppler imaging (LDI) and dermal microdialysis to measure changes in skin blood flow and the release of histamine within the weal and flare, following intradermal injection of histamine or bradykinin. These measurements have been made both in the absence and presence of the H1 receptor blockers cetirizine and loratadine. Scanning LDI of the inflammatory response revealed marked differences in both the development and steady state responses to the intradermal injection of histamine (1-3 mumol/L) and bradykinin (1 mumol/L). The development of the flare and the weal response to both histamine and bradykinin was significantly reduced by cetirizine but not by loratadine. The histamine-induced flare area fell by 57 +/- 4% (mean +/- SEM, n = 10, P < 0.001) after cetirizine and the area of the weal fell by 73 +/- 11% (P < 0.009). Bradykinin-induced inflammatory responses were similarly reduced by cetirizine, the weal by 60 +/- 16% (P < 0.02) and the flare by 61 +/- 4% (P < 0.005). Measurement of histamine concentration in skin using microdialysis, in six subjects, confirmed that histamine levels rose in the dialysate collected from the weal to 310 +/- 16 nmol/L following injection of histamine. Histamine levels also rose following bradykinin injection in some subjects (mean 147 +/- 46 nmol/L, range 18-336). Little increase in histamine concentration was seen in the dialysate from the flare following injection of either histamine or bradykinin. The histamine concentration in dialysate from unprovoked skin was 4.19 +/- 0.75 nmol/L. These data reveal differences in the dermal responses to different mediators when assessed using scanning LDI. They confirm that histamine is released within the weal but not the flare response to the intradermal injection of both histamine and bradykinin and that its effects on the local vasculature to cause the oedematous weal and the axon reflex-mediated flare are significantly attenuated by the H1 antagonist cetirizine and to a lesser extent by the H1 antagonist loratadine.