tbuckley/cabot-search huggingface dataset:
The Autosomal Recessive Polycystic Kidney Disease Protein Is Localized to Primary Cilia, with Concentration in the Basal Body Area
Authors: Shixuan Wang, Ying Luo, Patricia D. Wilson, George B. Witman, Jing Zhou
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Recent evidence suggests that structural and functional abnormalities of primary cilia in kidney epithelia are associated with mouse and human autosomal dominant polycystic kidney disease. To determine whether fibrocystin/polyductin/tigmin (FPC), the protein product encoded by the <i>PKHD1</i> gene that is responsible for autosomal recessive polycystic kidney disease among human subjects, is also a component of primary cilia in the kidney, antipeptide antibodies to the carboxyl-terminal intracellular domain and amino-terminal extracellular domain of FPC were generated and were characterized with immunoblotting and immuno-light and -electron microscopy. Immunolocalization in normal kidney tissue sections and cultured kidney cells demonstrated that FPC was localized to the primary cilia and concentrated on the basal bodies in both kidney tissue sections and cultured kidney cells. The FPC expression pattern was not altered in kidney cells with <i>Pkd1</i> mutations. These findings suggest that FPC is a functional and/or structural component of primary cilia in kidney tubular cells. It is proposed that the pathogenesis of autosomal recessive polycystic kidney disease is linked to the dysfunction of primary cilia.
Natriuretic Peptide Receptor Guanylyl Cyclase-A Protects Podocytes from Aldosterone-Induced Glomerular Injury
Authors: Yoshihisa Ogawa, Masashi Mukoyama, Hideki Yokoi, Masato Kasahara, Kiyoshi Mori, Yukiko Kato, Takashige Kuwabara, Hirotaka Imamaki, Tomoko Kawanishi, Kenichi Koga, Akira Ishii, Takeshi Tokudome, Ichiro Kishimoto, Akira Sugawara, Kazuwa Nakao
Journal: Journal of the American Society of Nephrology (2012)

Natriuretic peptides produced by the heart in response to cardiac overload exert cardioprotective and renoprotective effects by eliciting natriuresis, reducing BP, and inhibiting cell proliferation and fibrosis. These peptides also antagonize the renin-angiotensin-aldosterone system, but whether this mechanism contributes to their renoprotective effect is unknown. Here, we examined the kidneys of mice lacking the guanylyl cyclase-A (GC-A) receptor for natriuretic peptides under conditions of high aldosterone and high dietary salt. After 4 weeks of administering aldosterone and a high-salt diet, GC-A knockout mice, but not wild-type mice, exhibited accelerated hypertension with massive proteinuria. Aldosterone-infused GC-A knockout mice had marked mesangial expansion, segmental sclerosis, severe podocyte injury, and increased oxidative stress. Reducing the BP with hydralazine failed to lessen such changes; in contrast, blockade of the renin-angiotensin-aldosterone system markedly reduced albuminuria, ameliorated podocyte injury, and reduced oxidative stress. Furthermore, treatment with the antioxidant tempol significantly reduced albuminuria and abrogated the histologic changes. In cultured podocytes, natriuretic peptides inhibited aldosterone-induced mitogen-activated protein kinase phosphorylation. Taken together, these results suggest that renoprotective properties of the endogenous natriuretic peptide/GC-A system may result from the local inhibition of the renin-angiotensin-aldosterone system and oxidative stress in podocytes.
The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion
Authors: Christian Hundhausen, Dominika Misztela, Theo A. Berkhout, Neil Broadway, Paul Saftig, Karina Reiss, Dieter Hartmann, Falk Fahrenholz, Rolf Postina, Vance Matthews, Karl-Josef Kallen, Stefan Rose-John, Andreas Ludwig
Journal: Blood (2003)
Diabetes Screening in Canada (DIASCAN) Study
Authors: Lawrence A. Leiter, Aiala Barr, André Bélanger, Stanley Lubin, Stuart A. Ross, Hugh D. Tildesley, Nathalie Fontaine
Journal: Diabetes Care (2001)

OBJECTIVE—To assess the prevalence of undiagnosed diabetes and glucose intolerance in individuals ≥40 years of age who contacted their family physician for routine care. RESEARCH DESIGN AND METHODS—The study used a stratified randomized selection of family physicians across Canada that was proportional to provincial and urban/rural populations based on Statistics Canada Census data (1996). Consecutive patients ≥40 years of age were screened for diabetes. If a casual fingerprick blood glucose was &amp;gt;5.5 mmol/l, the patient returned for a fasting venous blood glucose test. If the fasting blood glucose was 6.1–6.9 mmol/l, a 2-h 75-g post–glucose load venous blood glucose was obtained. Results of these tests were used to classify patients in diagnostic categories. RESULTS—Data were available for 9,042 patients. Previously undiagnosed diabetes was discovered in 2.2% of the patients, and new glucose intolerance was found in an additional 3.5% of patients. Overall, 16.4% of patients had previously known diabetes. The decrease in fasting plasma glucose criterion from 7.8 to 7.0 mmol/l resulted in a 2.2% versus a 1.6% prevalence of new diabetes. Several risk factors were reported in a significantly greater proportion of patients with new glucose intolerance and either new and known diabetes compared with the normal glucose tolerance group of patients. CONCLUSIONS—Routine screening for diabetes by family physicians is justified in patients ≥40 years of age, given the finding of previously undiagnosed diabetes in 2.2% of these patients and newly diagnosed glucose intolerance in an additional 3.5% of these patients. Another 16.4% of primary care patients ≥40 years of age have known diabetes. This has important implications regarding health resources and physician education.
Serial high sensitivity cardiac troponin T measurement in acute heart failure: insights from the <scp>RELAX‐AHF</scp> study
Authors: G. Michael Felker, Robert J. Mentz, John R. Teerlink, Adriaan A. Voors, Peter S. Pang, Piotr Ponikowski, Barry H. Greenberg, Gerasimos Filippatos, Beth A. Davison, Gad Cotter, Margaret F. Prescott, Tsushung A. Hua, Sara Lopez‐Pintado, Thomas Severin, Marco Metra
Journal: European Journal of Heart Failure (2015)
Fibrillin microfibrils are reduced in skin exhibiting striae distensae
Authors: None Watson, None Parry, None Humphries, None Jones, None Polson, None Kielty, None Griffiths
Journal: British Journal of Dermatology (1998)

Striae distensae (striae: stretch marks) are a common disfiguring condition associated with continuous and progressive stretching of the skin--as occurs during pregnancy. The pathogenesis of striae is unknown but probably relates to changes in those structures that provide skin with its tensile strength and elasticity. Such structures are components of the extracellular matrix, including fibrillin, elastin and collagens. Using a variety of histological techniques, we assessed the distribution of these extracellular matrix components in skin affected by striae. Pregnant women were assessed for the presence of striae, and punch biopsies were obtained from lesional striae and adjacent normal skin. Biopsies were processed for electron microscopy, light microscopy and immunohistochemistry. For histological examination, 7 microns frozen sections were stained so as to identify the elastic fibre network and glycosaminoglycans. Biopsies were also examined with a panel of polyclonal antibodies against collagens I and III, and fibrillin and elastin. Ultrastructural analysis revealed alterations in the appearance of skin affected by striae compared with that of normal skin in that the dermal matrix of striae was looser and more floccular. Light microscopy revealed an increase in glycosaminoglycan content in striae. Furthermore, the number of vertical fibrillin fibres subjacent to the dermal-epidermal junction (DEJ) and elastin fibres in the papillary dermis was significantly reduced in striae compared with normal skin. The orientation of elastin and fibrillin fibres in the deep dermis showed realignment in that the fibres ran parallel to the DEJ. However, no significant alterations were observed in any other extracellular matrix components. This study identifies a reorganization and diminution of the elastic fibre network of skin affected by striae. Continuous strain on the dermal extracellular matrix, as occurs during pregnancy, may remodel the elastic fibre network in susceptible individuals and manifest clinically as striae distensae.
Unzipping RyR2 in adult cardiomyocytes: Getting closer to mechanisms of inherited ventricular arrhythmias?
Authors: M FERNANDEZVELASCO, A GOMEZ, S RICHARD
Journal: Cardiovascular Research (2006)

Malignant ventricular arrhythmias (VA) are a major cause of mortality and morbidity worldwide.Causative mechanisms are multiple and complex.VA can be generated by abnormal or instable repolarization of the action potential (AP) in myocytes.Perverted repolarization results mainly from congenital channelopathies, acquired diseases, including hypertrophy and heart failure (HF), or therapeutic intervention.Inherited arrhythmias are due to mutations, mostly in transmembrane ionic channels (Na + , K + , Ca 2+ ) [1,2].However, because Ca 2+ regulates several ionic currents involved in AP repolarization [3], it was not counterintuitive to find that mutations in proteins regulating intracellular Ca 2+ homeostasis can also generate VA and sudden cardiac death (SCD).For example, mutations in the cardiac Ca 2+ release channel (ryanodine receptor; RyR2) of the sarcoplasmic reticulum (SR) are involved in type 2 arrhythmogenic right ventricular cardiomyopathy and catecholaminergic polymorphic ventricular tachycardia (CPVT) characterized by effort-induced VA in structurally normal hearts [2,4,5].CPVT are also caused by mutations in calsequestrin, a protein binding Ca 2+ and associated to the RyR2 in the lumenal side of the SR [2,4].
Osteoarthritis of finger joints in Finns aged 30 or over: prevalence, determinants, and association with mortality
Authors: M M Haara
Journal: Annals of the Rheumatic Diseases (2003)

<b>Background:</b> Prevalence and risk factors of osteoarthritis (OA) in finger joints have been amply explored in previous studies. However, no study has focused on finger joint OA as a predictor of mortality. <b>Objective:</b> To investigate finger joint OA for its associations with alleged risk factors and with life expectancy in an extensive health survey. <b>Methods:</b> From 1978 to 1980 a representative population sample of 8000 Finns aged 30 years or over was invited to participate in a comprehensive health examination; 90% accepted. Hand radiographs were taken from 3595 subjects. By the end of 1994, 897 of these had died. <b>Results:</b> The prevalence of OA of Kellgren's grade 2 to 4 in any finger joint and in at least two symmetrical pairs of distal interphalangeal joints (DIPs) was 44.8% and 16.0%, respectively. Age and body mass index were significant determinants for OA both in any finger joint and in symmetrical DIP OA. The history of physical workload in women showed a positive association with OA in any finger joint. Smoking in men seemed to protect against symmetrical DIP OA. As adjusted for the determinants above, symmetrical DIP OA predicted mortality in women (relative risk (RR), 1.23; 95% confidence interval (95% CI) 1.01 to 1.51), but not in men (RR 0.89; 95% CI 0.68 to 1.16). In men, however, OA in any finger joint significantly predicted cardiovascular deaths (RR 1.42; 95% CI 1.05 to 1.92). <b>Conclusion:</b> OA in any finger joint and symmetrical DIP OA have different risk factor profiles and predict mortality in different patterns between men and women.
Antisense oligonucleotides targeting c-fos mRNA inhibit rheumatoid synovial fibroblast proliferation
Authors: Y. Morita, N. Kashihara, M. Yamamura, H. Okamoto, S. Harada, M. Kawashima, H. Makino
Journal: Annals of the Rheumatic Diseases (1998)

To determine whether antisense oligonucleotides targeting c-fos mRNA have the ability to inhibit the growth of interleukin 1 (IL1) stimulated fibroblast-like cells from the synovium in rheumatoid arthritis (RA).Fibroblast-like cells established from RA synovium were stimulated by IL1 with antisense or sense oligonucleotides complementary to c-fos mRNA, and the proliferation of these cells was determined by 3H-thymidine incorporation. Effect of antisense oligonucleotides on expression of activator protein 1 (AP1) activity was evaluated using electrophoretic mobility shift assay.C-fos antisense oligonucleotides inhibited IL1 stimulated synovial fibroblast proliferation. The expression of AP1 activity induced by IL1 was suppressed by treatment with antisense oligonucleotides.These results suggest the feasibility of antisense strategies designed to suppress c-fos expression as therapeutic agents for RA.
Endotoxin induction of tumor necrosis factor is enhanced by acid-labile interferon-alpha in acquired immunodeficiency syndrome.
Authors: A S Lau, J F Livesey
Journal: Journal of Clinical Investigation (1989)

High levels of an acid-labile IFN-alpha have been demonstrated in the sera of patients with symptomatic HIV infection. IFNs have been shown to enhance the cytotoxic and antiproliferative actions of tumor necrosis factor (TNF), which is a potent mediator of inflammation and sepsis. We show that the acid-labile IFN-alpha present in AIDS sera can induce TNF synthesis and sensitize blood monocytes (BM) to endotoxin stimulation resulting in further synthesis of TNF in vitro. TNF production by BM from patients with HIV infections and normal controls was measured by a cytotoxicity assay on L929 cells using human TNF alpha as a standard. BM from AIDS patients spontaneously produce high levels of TNF and are hypersensitive to endotoxin stimulation, resulting in enhanced synthesis of TNF. In determining the mechanism involved, we demonstrated that treatment of normal BM with AIDS sera results in induction of TNF. Neutralization of the acid-labile IFN-alpha in AIDS sera with polyclonal anti-IFN-alpha antibodies results in diminution of TNF induction. In addition, pretreatment of normal BM with AIDS sera, IFN-alpha, or IFN-gamma renders the cells hypersensitive to endotoxin. Consequently, activation of the TNF system by the acid-labile IFN-alpha contributes to some of the physiological disturbances, such as the wasting syndrome, and to the pathophysiology of sepsis in AIDS patients.
Blockade of the Kinin B1 Receptor Ameloriates Glomerulonephritis
Authors: Julie Klein, Julien Gonzalez, Stéphane Decramer, Flavio Bandin, Eric Neau, David J. Salant, Peter Heeringa, Joao-Bosco Pesquero, Joost-Peter Schanstra, Jean-Loup Bascands
Journal: Journal of the American Society of Nephrology (2010)

Severe inflammation characterizes rapidly progressive glomerulonephritides, and expression of the kinin B1 receptor (B1R) associates with inflammation. Delayed B1R blockade reduces renal inflammation in a model of unilateral ureteral obstruction, but whether B1R modulates the pathophysiology of glomerulonephritides is unknown. Here, we observed an association of B1R protein expression and inflammation, in both glomeruli and the renal interstitium, in biopsies of patients with glomerulonephritides, Henoch-Schönlein purpura nephropathy, and ANCA-associated vasculitis. In the nephrotoxic serum-induced glomerulonephritis model, we observed upregulation of the B1R receptor; treatment with a B1R antagonist beginning 2 weeks after the onset of disease reduced both glomerular and tubular lesions and improved renal function. B1R blockade reduced renal chemokine expression and macrophage accumulation. Collectively, our data demonstrate that blockade of the kinin B1R has significant potential for the treatment of glomerulonephritis.
Postpartum Diabetes Screening
Authors: Sarah Kwong, Rebecca S. Mitchell, Peter A. Senior, Constance L. Chik
Journal: Diabetes Care (2009)

To determine the rate of adherence to postpartum glycemic testing in women with gestational diabetes mellitus (GDM) and the performance of fasting plasma glucose (FPG) versus the 75-g oral glucose tolerance test (OGTT) in detecting postpartum glucose intolerance.The study was a retrospective cohort of 1,006 women with GDM attending a pregnancy diabetes clinic.Postpartum screening was completed in 438 (48%) women. Women nonadherent to testing had higher parity (1.10 vs. 0.87) and were less likely to require insulin for management of their GDM. Among women who were tested, 89 (21%) had an abnormal result, only 25 (28%) of whom were identified by FPG. Factors associated with abnormal postpartum diabetes screening include non-Caucasian ethnicity, previous GDM, higher A1C, and OGTT values during pregnancy and treatment with insulin.The rate of postpartum diabetes screening is low, and FPG lacks sensitivity as a screening test in comparison with OGTT.
Adhesion Molecule–dependent Mechanisms Regulate the Rate of Macrophage Clearance During the Resolution of Peritoneal Inflammation
Authors: Geoffrey John Bellingan, Ping Xu, Helen Cooksley, Helen Cauldwell, Anthony Shock, Stephen Bottoms, Christopher Haslett, Steven Eugene Mutsaers, Geoffrey John Laurent
Journal: The Journal of Experimental Medicine (2002)

Macrophage clearance is essential for the resolution of inflammation. Much is known about how monocytes enter the inflammatory site but little is known about how resultant macro-phages are cleared. We have previously demonstrated that macrophage clearance from resolving peritonitis occurs by emigration into draining lymphatics rather than local apoptosis. We now examine mechanisms for this process, in particular by evaluating the hypothesis that modulation of adhesion interactions between macrophages and cells lining the lymphatics regulates the rate of macrophage clearance. We demonstrate in vivo that macrophages adhere specifically to mesothelium overlying draining lymphatics and that their emigration rate is regulated by the state of macrophage activation. We observed that macrophage–mesothelial adhesion is Arg-Gly-Asp (RGD) sensitive and partially mediated by very late antigen (VLA)-4 and VLA-5 but not αv or β2 integrins. Moreover, macrophage clearance into lymphatics can be blocked in vivo by RGD peptides and VLA-4 and VLA-5 but not β2 blocking antibodies. This is the first evidence that macrophage emigration from the inflamed site is controlled and demonstrates that this is exerted through specific adhesion molecule regulation of macrophage–mesothelial interactions. It highlights the importance of adhesion molecules governing entry of cells into the lymphatic circulation, thus opening a new avenue for manipulating the resolution of inflammation.
Gender bias in research
Authors: Richard Walden
Journal: Journal of the Royal Society of Medicine (2007)

Holdcroft1 writes about the very real shortage of clinical trials data from studies in women. While this is true in a number of disease areas; it is not true of studies in hormone replacement and related fields, for example.

The exclusion of women from clinical research studies was the direct result of the Thalidomide disaster, which led to the setting up of the Dunlop Committee, forerunner to the Medicine's Control Agency. It was for many years considered to be unethical to include women in clinical trials who were known to be, or who might possibly have been, pregnant. This effectively excluded females from between 12 and 55 years of age. There was no intent to deny women the benefits of medical advances and any suggestion that this situation accorded a lower status to women is misconceived.

It is true that the difference between the sexes has been neglected in research at all levels,2 something that requires much greater emphasis and more investigation in the future.
Prognostic Significance of Early Weight Gain in Underweight Patients with Tuberculosis
Authors: Wing Wai Yew, Chi Chiu Leung
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

There is an error in the last sentence of the second paragraph of the editorial “Prognostic Significance of Early Weight Gain in Underweight Patients with Tuberculosis,” which appears on pages 236 and 237 of the August 1 issue of the Journal (1). The incorrect text reads: A relapse rate as high as 61% occurred among those 10% underweight at diagnosis, and 62% of the relapses in this group in turn occurred among those patients failing to gain 5% weight in the induction phase of treatment. The corrected text should read: As many as 61% of the relapses in that trial occurred among those 10% or more underweight at diagnosis, and 62% of these relapses in turn occurred in those failing to gain 5% weight in the induction phase of treatment. The editorial comments on the article by Khan and colleagues, beginning on page 344 of the issue (2). The authors of the editorial apologize for any confusion the error may have caused.
Lymphoreticular Tumors in Costa Rica&lt;xref ref-type="fn" rid="FN1"&gt;1&lt;/xref&gt;
Authors: P. Correa, G. T. O'Conor, Jorge Salas
Journal: JNCI Journal of the National Cancer Institute (1973)

A revision was made of the surgical and autopsy material of lymphoreticular tumors from the Hospital San Juan de Dios in Costa Rica from 1960 to 1964. This material was tabulated according to the classification suggested by the Subcommittee on Geographic Pathology of the International Union Against Cancer. Reviewed were 133 lymphoreticular solid tumors, which corresponded to 3.8% of all malignancies diagnosed during the period. Lymphosarcoma comprised 36% of the cases; reticulosarcoma, 14.2%; Hodgkin's disease, 35.3%; and Burkit's tumor, 5.2%. There was 1 nasal lymphoma in a 66-year-old man. We call attention to the high frequency of lymphosarcoma and Hodgkints disease in children, which contrasts with what is observed in well-developed countries. We also call attention to the rarity of the nodular sclerosis type of Hedskln's disease. Our figures for multiple myeloma and leukemia are not representative. However, from these and other data, the most frequent type of leukemia can be considered to be acute lymphocytic and to predominate in persons ≤20 years old.
The canine heart as an electrocardiographic generator. Dependence on cardiac cell orientation.
Authors: L V Corbin, A M Scher
Journal: Circulation Research (1977)

Traditionally it is assumed that during cardiac depolarization the macroscopic current generators that produce electrocardiographic voltages can be represented as a uniform double-layer source, coincident with the macroscopic boundary between resting and depolarized cardiac fibers as measured with extracellular electrodes ("uniform" hypothesis). A segment of this boundary is thus considered as a current dipole oriented perpendicular to the boundary. We present evidence that, contrary to the above, the effective dipoles largely parallel the long axes of cardiac fibers ("axial" hypothesis). Calculated potentials in volume conductors differ markedly in the two cases. The magnitudes of rapid local "intrinsic" deflections also differ markedly. In our experiments, potential fields prodlced by stimulation at several cardiac sites and measured magnitudes of intrinsic deflections during normal depolarization and that caused by stimulation support the axial hypothesis and are incompatible with the uniform hypothesis. Our results suggest that axial orientation of sources is sufficiently strong so that predictions assuming the uniform hypothesis would be seriously in error, although the axial theory alone does not exactly describe all the measured potentials. Axial orientation of current generators must be considered in quantitative prediction of electrocardiographic potentials. tfurther study of the geometry of the intracellular depolarization boundary and its relation to fiber direction and to the frequency of lateral intercellular junctions is required to describe the generators exactly.