tbuckley/cabot-search huggingface dataset:
IL-10 Suppresses Chemokines, Inflammation, and Fibrosis in a Model of Chronic Renal Disease
Authors: Wei Mu, Xiaosen Ouyang, Anupam Agarwal, Li Zhang, David A. Long, Pedro E. Cruz, Carlos A. Roncal, Olena Y. Glushakova, Vince A. Chiodo, Mark A. Atkinson, William W. Hauswirth, Terry R. Flotte, Bernardo Rodriguez-Iturbe, Richard J. Johnson
Journal: Journal of the American Society of Nephrology (2005)

IL-10 is a pluripotent cytokine that plays a pivotal role in the regulation of immune and inflammatory responses. Whereas short-term administration of IL-10 has shown benefit in acute glomerulonephritis, no studies have addressed the potential benefits of IL-10 in chronic renal disease. Chronically elevated blood levels of IL-10 in rats were achieved by administration of a recombinant adeno-associated virus serotype 1 IL-10 (rAAV1-IL-10) vector. Control rats were given a similar dose of rAAV1-GFP. Four weeks after injection, IL-10 levels in serum were measured by ELISA, and chronic renal disease was induced by a 5/6 nephrectomy (n = 6 in each group). Eight weeks later, rats were killed and renal tissue was obtained for RNA, protein, and immunohistochemical analysis. Serum levels of IL-10 were 12-fold greater in the rAAV1-IL-10 group by 4 wk after rAAV1-IL-10 administration (345 +/- 169 versus 28 +/- 15 pg/ml; P = 0.001), and levels were maintained throughout the experiment. rAAV1-IL-10 treatment resulted in less proteinuria (P < 0.05), lower serum creatinine (P < 0.05), and higher creatinine clearances (P < 0.01) compared with rAAV1-GFP-treated rats. Renal interstitial infiltration was significantly attenuated by rAAV1-IL-10 administration as assessed by numbers of CD4+, CD8+, monocyte-macrophages (ED-1+) and dendritic (OX-62+) cells (P < 0.05), and this correlated with reductions in the renal expression of monocyte (renal monocyte chemoattractant protein-1 mRNA and protein) and T cell (RANTES mRNA) chemokines. rAAV1-IL-10 administration decreased mRNA levels of IFN-gamma and IL-2 in the kidney. The reduction in inflammatory cells was associated with a significant reduction in glomerulosclerosis and interstitial fibrosis. It is concluded that IL-10 blocks inflammation and improves renal function in this model of chronic renal disease. The feasibility of long-term overexpression of a gene using the AAV serotype 1 vector system in a model of renal disease is also demonstrated.
Spuriously High Prevalence of Prediabetes Diagnosed by HbA1c in Young Indians Partly Explained by Hematological Factors and Iron Deficiency Anemia
Authors: Pallavi S. Hardikar, Suyog M. Joshi, Dattatray S. Bhat, Deepa A. Raut, Prachi A. Katre, Himangi G. Lubree, Abhay Jere, Anand N. Pandit, Caroline H.D. Fall, Chittaranjan S. Yajnik
Journal: Diabetes Care (2012)

OBJECTIVE To examine the influence of glycemic and nonglycemic parameters on HbA1c concentrations in young adults, the majority of whom had normal glucose tolerance. RESEARCH DESIGN AND METHODS We compared the diagnosis of normal glucose tolerance, prediabetes, and diabetes between a standard oral glucose tolerance test (OGTT; World Health Organization 2006 criteria) and HbA1c concentrations (American Diabetes Association [ADA] 2009 criteria) in 116 young adults (average age 21.6 years) from the Pune Children’s Study. We also studied the contribution of glycemic and nonglycemic determinants to HbA1c concentrations. RESULTS The OGTT showed that 7.8% of participants were prediabetic and 2.6% were diabetic. By ADA HbA1c criteria, 23.3% were prediabetic and 2.6% were diabetic. The negative predictive value of HbA1c was 93% and the positive predictive value was 20% (only 20% had prediabetes or diabetes according to the OGTT; this figure was 7% in anemic participants). Of participants, 34% were anemic, 37% were iron deficient (ferritin &amp;lt;15 ng/mL), 40% were vitamin B12 deficient (&amp;lt;150 pmol/L), and 22% were folate deficient (&amp;lt;7 nmol/L). On multiple linear regression analysis, HbA1c was predicted by higher 2-h glucose (R2 = 25.6%) and lower hemoglobin (R2 = 7.7%). When hematological parameters were replaced by ferritin, vitamin B12, and folate, HbA1c was predicted by higher glycemia (R2 = 25.6%) and lower ferritin (R2 = 4.3%). CONCLUSIONS The use of HbA1c to diagnose prediabetes and diabetes in iron-deficient populations may lead to a spuriously exaggerated prevalence. Further investigation is required before using HbA1c as a screening tool in nutritionally compromised populations.
Sunlight UV-Induced Skin Cancer Relies upon Activation of the p38α Signaling Pathway
Authors: Kangdong Liu, Donghoon Yu, Yong-Yeon Cho, Ann M. Bode, Weiya Ma, Ke Yao, Shengqing Li, Jixia Li, G. Tim Bowden, Ziming Dong, Zigang Dong
Journal: Cancer Research (2013)

The activation of cellular signal transduction pathways by solar ultraviolet (SUV) irradiation plays a vital role in skin tumorigenesis. Although many pathways have been studied using pure ultraviolet A (UVA) or ultraviolet B (UVB) irradiation, the signaling pathways induced by SUV (i.e., sunlight) are not understood well enough to permit improvements for prevention, prognosis, and treatment. Here, we report parallel protein kinase array studies aimed at determining the dominant signaling pathway involved in SUV irradiation. Our results indicated that the p38-related signal transduction pathway was dramatically affected by SUV irradiation. SUV (60 kJ UVA/m(2)/3.6 kJ UVB/m(2)) irradiation stimulates phosphorylation of p38α (MAPK14) by 5.78-fold, MSK2 (RPS6KA4) by 6.38-fold, and HSP27 (HSPB1) by 34.56-fold compared with untreated controls. By investigating the tumorigenic role of SUV-induced signal transduction in wild-type and p38 dominant-negative (p38 DN) mice, we found that p38 blockade yielded fewer and smaller tumors. These results establish that p38 signaling is critical for SUV-induced skin carcinogenesis.
Low Serum Vitamin D Levels Are Associated With Increased Arterial Stiffness in Youth With Type 2 Diabetes
Authors: Pranati Jha, Lawrence M. Dolan, Philip R. Khoury, Elaine M. Urbina, Thomas R. Kimball, Amy S. Shah
Journal: Diabetes Care (2015)

Adult studies demonstrate that low vitamin D (25[OH]D) is an independent risk factor for arterial stiffness. Similar studies have not been conducted in youth with type 2 diabetes mellitus (T2DM). The objective was to elicit the association between 25[OH]D and arterial stiffness in obese youth with and without T2DM. We hypothesized that 25[OH]D would be inversely correlated with arterial stiffness indices, including pulse wave velocity (PWV), augmentation index (AIx), and brachial distensibility (BrachD).Cross-sectional analysis was conducted in Cincinnati, OH, from 2004 to 2010. 25[OH]D, PWV, AIx, and BrachD were measured in 190 youth with T2DM, 190 obese control subjects without T2DM, and 190 lean control subjects without T2DM. Multivariate analyses were conducted to elicit the independent association between 25[OH]D and arterial stiffness indices by group.The mean age was 17.9 ± 3.4 years, 55% were African American, and 34% were male. The mean 25[OH]D levels were 21.27, 14.29, and 14.13 ng/mL in lean individuals, obese individuals, and obese individuals with T2DM, respectively (P < 0.01). PWV, AIx, and BrachD worsened from lean to obese to T2DM (P < 0.01). General linear models found that 25[OH]D level was independently associated with PWV in lean individuals and with AIx in the group with T2DM such that a 3 ng/mL increase in 25[OH]D was associated with an AIx decrease of 1% (baseline AIx = 5.7 ± 12.0%).25[OH]D is inversely associated with some measures of arterial stiffness in lean adolescents and obese adolescents with T2DM but not in obese normoglycemic adolescents. Future studies are needed to determine if supplemental 25[OH]D is important for cardiovascular health.
Requirement of Aryl Hydrocarbon Receptor Overexpression for CYP1B1 Up-Regulation and Cell Growth in Human Lung Adenocarcinomas
Authors: Jinghua Tsai Chang, Han Chang, Po-Hung Chen, Shong-Ling Lin, Pinpin Lin
Journal: Clinical Cancer Research (2007)

Abstract Purpose: CYP1B1 and CYP1A1 expression is up-regulated by activation of the aryl hydrocarbon receptor (AhR) through binding of ligands such as cigarette smoke components. We examined the association between AhR, CYP1B1, and CYP1A1 expression in noninvasive bronchioloalveolar carcinomas (BAC) and lung adenocarcinomas and investigated the effects of AhR overexpression on cell physiology. Experimental Design: AhR, CYP1B1, and CYP1A1 expression was examined in 107 lung adenocarcinomas and 57 BAC by immunohistochemistry. AhR expression in lung adenocarcinoma H1355 cells was stably reduced by RNA interference (RNAi). AhR, CYP1B1, and CYP1A1 expression was examined using real-time reverse transcription-PCR. Cell physiology was evaluated by measuring anchorage-independent growth and intracellular reactive oxygen species. Results: Expression of AhR and CYP1A1 was associated in smoking adenocarcinoma patients, whereas expression of AhR and CYP1B1 was associated regardless of smoking status. The level of CYP1B1, but not CYP1A1, was positively associated with AhR overexpression in BAC. 2,3,7,8-Tetrachlorobenzo-p-dioxin–induced CYP1A1/1B1 expression was reduced in AhR RNAi clones. In the absence of 2,3,7,8-tetrachlorobenzo-p-dioxin, CYP1B1 mRNA levels were reduced in AhR RNAi clones, whereas CYP1A1 mRNA levels were barely detectable. Furthermore, anchorage-independent growth and intracellular oxidative stress were significantly reduced in AhR RNAi cells. Conclusions: In the absence of exogenous AhR ligands (such as cigarette smoke components), AhR overexpression up-regulated the expression of CYP1B1 in the early stage of lung adenocarcinoma. Elevated AhR expression in lung adenocarcinoma cells could increase intracellular oxidative stress and promote cell growth, implying that disrupting AhR expression might prevent the early development of lung adenocarcinomas.
Predictors of Microalbuminuria in Individuals with IDDM: Pittsburgh Epidemiology of Diabetes Complications Study
Authors: Beth Ann Coonrod, Demetrius Ellis, Dorothy J Becker, Clareann H Bunker, Sheryl F Kelsey, Cathy E Lloyd, Allan L Drash, Lewis H Kuller, Trevor J Orchard
Journal: Diabetes Care (1993)

OBJECTIVE To examine the relationships between microalbuminuria and the development of overt diabetic nephrology, elevated blood pressure, and a more atherogenic lipid profile; and to identify risk factors for the development of microalbuminuria in individuals with IDDM. Microalbuminuria has been associated with the subsequent development of overt diabetic nephropathy in individuals with IDDM. It is associated with elevated blood pressure and a more atherogenic lipid profile, but the temporal relationship between the development of microalbuminuria and the changes in these factors is unclear. RESEARCH DESIGN AND METHODS Baseline characteristics were examined in 256 individuals with IDDM who had normal albumin excretion (urinary AER ≤20 μg/min in ≥2 timed urine collections) and were re-examined 2 yr later. RESULTS At follow-up, 24 had developed microalbuminuria (AER 20–200 (Ag/min in ≥2 timed urine collections) and 1 had developed overt nephropathy (AER ≥200 μg/min). Overall, the significant independent predictors of microalbuminuria were HbA1 (P &amp;lt; 0.001), low-density lipoprotein (P &amp;lt; 0.01), duration of IDDM (P &amp;lt; 0.05), and systolic blood pressure (P = 0.05). Sex-specific analyses showed HbA1 age, and baseline AER were particularly important for men; whereas, for women, the main predictors were duration of IDDM and triglycerides. Duration-specific analyses showed that HbA1 was an important predictor both for individuals with &amp;lt; and &amp;gt;20-yr duration. Low-density lipoprotein cholesterol was more important for subjects with shorter durations; whereas triglycerides were important for those with longer durations. CONCLUSIONS These results suggest that glycemic control, age or duration of IDDM, disturbed lipids, and possibly elevated blood pressure all may contribute to the development of microalbuminuria; and, further, that the adverse cardiovascular risk profile seen in individuals with overt nephropathy may begin to develop even before the detection of microalbuminuria.
A <i>Trypanosoma cruzi</i> Small Surface Molecule Provides the First Immunological Evidence that Chagas' Disease Is Due to a Single Parasite Lineage
Authors: Javier M. Di Noia, Carlos A. Buscaglia, Claudia R. De Marchi, Igor C. Almeida, Alberto C.C. Frasch
Journal: The Journal of Experimental Medicine (2002)

Chagas' disease is a major health and economic problem caused by the protozoan Trypanosoma cruzi. Multiple independently evolving clones define a complex parasite population that can be arranged into two broad genetic lineages termed T. cruzi I and II. These lineages have different evolutionary origin and display distinct ecological and biological traits. Here we describe a novel molecule termed TSSA for trypomastigote small surface antigen that provides the first immunological marker allowing discrimination between lineages. TSSA is a surface, glycosylphosphatidyl inositol (GPI)-anchored mucin-like protein, highly antigenic during the infection. TSSA sequences from different parasite isolates reveal a population dimorphism that perfectly matches with the two T. cruzi lineages. Interestingly, this dimorphism is restricted to the central region of the molecule, which comprises the immunodominant B cell epitopes. This sequence variability has a major impact on TSSA antigenicity, leading to no immunological cross-reactivity between both isoforms for antibodies present either in immunization or infection sera. Furthermore, the absolute seroprevalence for TSSA in confirmed Chagasic patients is restricted to T. cruzi II isoform, strongly suggesting that human infections are due to this particular subgroup. Even though association of T. cruzi II with Chagas' disease has been proposed based on molecular markers, this is the first immunological evidence supporting this hypothesis. The implications of these results for the future research on Chagas' disease could be envisaged.
Integration of Somatic Deletion Analysis of Prostate Cancers and Germline Linkage Analysis of Prostate Cancer Families Reveals Two Small Consensus Regions for Prostate Cancer Genes at 8p
Authors: Bao-li Chang, Wennuan Liu, Jishan Sun, Latchezar Dimitrov, Tao Li, Aubrey R. Turner, Siqun L. Zheng, William B. Isaacs, Jianfeng Xu
Journal: Cancer Research (2007)

Abstract The evidence for tumor suppressor genes at 8p is well supported by many somatic deletion studies and genetic linkage studies. However, it remains a challenge to pinpoint the tumor suppressor genes at 8p primarily because the implicated regions are broad. In this study, we attempted to narrow down the implicated regions by incorporating evidence from both somatic and germline studies. Using high-resolution Affymetrix arrays, we identified two small common deleted regions among 55 prostate tumors at 8p23.1 (9.8–11.5 Mb) and 8p21.3 (20.6–23.7 Mb). Interestingly, our fine mapping linkage analysis at 8p among 206 hereditary prostate cancer families also provided evidence for linkage at these two regions at 8p23.1 (5.8–11.2 Mb) and at 8p21.3 (19.6–23.9 Mb). More importantly, by combining the results from the somatic deletion analysis and genetic linkage analysis, we were able to further narrow the regions to ∼1.4 Mb at 8p23.1 and ∼3.1 Mb at 8p21.3. These smaller consensus regions may facilitate a more effective search for prostate cancer genes at 8p. [Cancer Res 2007;67(9):4098–103]
Bone marrow-derived fibroblast growth factor-2 induces glial cell proliferation in the regenerating peripheral nervous system
Authors: Victor Ribeiro-Resende, Alvaro Carrier-Ruiz, Robertha M R Lemes, Ricardo A M Reis, Rosalia Mendez-Otero
Journal: Molecular Neurodegeneration (2012)

Among the essential biological roles of bone marrow-derived cells, secretion of many soluble factors is included and these small molecules can act upon specific receptors present in many tissues including the nervous system. Some of the released molecules can induce proliferation of Schwann cells (SC), satellite cells and lumbar spinal cord astrocytes during early steps of regeneration in a rat model of sciatic nerve transection. These are the major glial cell types that support neuronal survival and axonal growth following peripheral nerve injury. Fibroblast growth factor-2 (FGF-2) is the main mitogenic factor for SCs and is released in large amounts by bone marrow-derived cells, as well as by growing axons and endoneurial fibroblasts during development and regeneration of the peripheral nervous system (PNS).Here we show that bone marrow-derived cell treatment induce an increase in the expression of FGF-2 in the sciatic nerve, dorsal root ganglia and the dorsolateral (DL) region of the lumbar spinal cord (LSC) in a model of sciatic nerve transection and connection into a hollow tube. SCs in culture in the presence of bone marrow derived conditioned media (CM) resulted in increased proliferation and migration. This effect was reduced when FGF-2 was neutralized by pretreating BMMC or CM with a specific antibody. The increased expression of FGF-2 was validated by RT-PCR and immunocytochemistry in co-cultures of bone marrow derived cells with sciatic nerve explants and regenerating nerve tissue respectivelly.We conclude that FGF-2 secreted by BMMC strongly increases early glial proliferation, which can potentially improve PNS regeneration.
High-dose 7-hexanoyltaxol-eluting stent with polymer sleeves for coronary revascularization
Authors: Eberhard Grube, Alexandra Lansky, Karl Eugen Hauptmann, Carlo Di Mario, Germano Di Sciascio, Antonio Colombo, Sigmund Silber, Juergen Stumpf, Nicolaus Reifart, Jean Fajadet, Antonio Marzocchi, Joachim Schofer, Pierre Dumas, Rainer Hoffmann, Giulio Guagliumi, Mark Pitney, Mary E. Russell
Journal: Journal of the American College of Cardiology (2004)
Annual retinal photography is not an option in India
Authors: K J Singh, R N Misra, S Bajaj, A Malik
Journal: BMJ (1995)

skills are maximised through experience and that cost efficiency is increased.The cost of identifying each true case of retinopathy needing treatment has been shown to fall as throughput increases.3Patients are recalled to the screening clinics through use of a computerised appointment system and a centralised register.Diabetes care requires several health care processes, as well as screening of the eyes, to be performed regularly in a large number of people.The Clinical Standards Advisory Group has recommended that, for this to be organised efficiently and completely, health districts should develop and maintain registers of all people with diabetes in the locality to span the boundaries of the provision of primary and secondary care.4
Increased smooth muscle contractility of intestine in the genetic null of the endothelin ETB receptor: a rat model for long segment Hirschsprung's disease
Authors: K-J Won
Journal: Gut (2002)

Background and aims: The endothelin ETB receptor null rat (ETB(−/−)R) has an intestinal segment without ganglia, and this rat is characterised by intestinal obstruction similar to that observed in human Hirschsprung9s disease. In the present study, we have examined the myogenic mechanism responsible for obstruction in the ETB(−/−)R. Results: The ETB(−/−)R had an enlarged belly and the average lifespan was 18.1 days. The bowel from the rectum to the lower part of the small ileum was constricted whereas the upper region was dilated with faecal stasis and thus presented as megaileum. The constricted muscle segments without ganglia had a greater increase in absolute force when stimulated by carbachol, high K<sup>+</sup>, and endothelin-1 compared with that of normal siblings. In contrast, in the dilated part with ganglia, the absolute contractile force due to these stimulants in the ETB(−/−)R was not different from that in the ETB(+/+)R. Such a functional hypertrophy of the musculature was observed in parts of the colon, caecum, and distal ileum without ganglia but not in the part of the proximal ileum and jejunum with ganglia. Morphological study demonstrated that the thickness of the circular and longitudinal muscle layers was greater in the constricted part of the intestine in the ETB(−/−)R, and these changes were associated with an increase in the number of smooth muscle cells. Conclusions: Our findings suggest that both increased contractility of smooth muscle and increased thickness of the intestinal muscular wall may contribute to the intestinal obstruction in the ETB(−/−)R.
Intrathymic elimination of Mlsa-reactive (V beta 6+) cells during neonatal tolerance induction to Mlsa-encoded antigens.
Authors: H R MacDonald, T Pedrazzini, R Schneider, J A Louis, R M Zinkernagel, H Hengartner
Journal: The Journal of Experimental Medicine (1988)

The cellular basis of neonatally induced T cell tolerance has been investigated in a model system in which usage of a particular TCR V beta segment (V beta 6) is strongly correlated with reactivity to antigens encoded by the Mlsa genetic locus. Expression of V beta 6 by peripheral T cells was virtually abolished in BALB/c (H-2d, Mlsb) mice rendered neonatally tolerant to DBA/2 (H-2d, Mlsa) lymphoid cells, whereas control V beta 8-bearing T cells remained at near normal levels. Further analysis revealed that elimination of V beta 6+ T cells occurred in the thymus of neonatally tolerant mice and could not be explained by receptor modulation or T cell chimerism. These data thus support the clonal deletion model of tolerance induction.
1,25-Dihydroxy-19-nor-vitamin D2, a Vitamin D Analog with Reduced Bone Resorbing Activity In Vitro
Authors: L. SHANNON HOLLIDAY, STEPHEN L. GLUCK, EDUARDO SLATOPOLSKY, ALEX J. BROWN
Journal: Journal of the American Society of Nephrology (2000)

1,25-Dihydroxy-19-nor-vitamin D(2) (19-norD(2)), a new analog of 1,25(OH)(2)D(3), suppresses parathyroid hormone in renal failure patients and in uremic rats but has less calcemic activity than 1,25(OH)(2)D(3). Although 19-norD(2) has high affinity for the vitamin D receptor and similar pharmacokinetics to those of 1,25(OH)(2)D(3), it has much less bone resorbing activity in vivo. The intrinsic activity of 19-norD(2) on osteoclastogenesis and activation of bone resorption in mouse bone marrow cultures was examined to determine the mechanism involved. 19-norD(2) and 1,25(OH)(2)D(3) (10 nM) were equivalent in stimulating the formation and maintenance of large multinucleated, tartrate-resistant acid phosphatase-positive cells. However, the amount of bone resorbed by osteoclasts stimulated by 10 nM 19-norD(2), as measured by pit-forming assays, was reduced 62% compared with 10 nM 1,25(OH)(2)D(3)-stimulated osteoclasts (P < 0. 05). This difference could not be attributed to enhanced catabolism or to downregulated vitamin D receptor. The rate of degradation of 19-norD(2) in cultures was approximately 20% greater than 1, 25(OH)(2)D(3), not enough to account for the different effects on bone resorption. The VDR levels were identical in cultures that were treated with 19-norD(2) and 1,25(OH)(2)D(3). In summary, 19-norD(2) is less effective than 1,25(OH)(2)D(3) in stimulating mouse marrow osteoclasts to resorb bone. The reason for this difference is not clear but seems to involve the late maturation and/or activation of osteoclasts as the number of pits produced by each tartrate-resistant acid phosphatase-positive cell is reduced under stimulation by 19-norD(2) compared with 1,25(OH)(2)D(3).