tbuckley/cabot-search huggingface dataset:
Serum Lipopolysaccharide Activity Is Associated With the Progression of Kidney Disease in Finnish Patients With Type 1 Diabetes
Authors: Mariann Nymark, Pirkko J. Pussinen, Anita M. Tuomainen, Carol Forsblom, Per-Henrik Groop, Markku Lehto
Journal: Diabetes Care (2009)

OBJECTIVE The aim of the study was to investigate whether serum lipopolysaccharide (LPS) activities are associated with the progression of kidney disease in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS For this prospective study, we chose 477 Finnish patients with type 1 diabetes, who were followed for 6 years. At the baseline visit, 239 patients had a normal albumin excretion rate (normoalbuminuria) and 238 patients had macroalbuminuria. Patients were further divided into nonprogressors and progressors based on their albumin excretion rate at follow-up. Eighty normoalbuminuric patients had developed microalbuminuria, and 79 macroalbuminuric patients had progressed to end-stage renal disease. Serum LPS activity was determined with the Limulus amoebocyte lysate chromogenic end point assay. RESULTS Serum LPS activity was significantly higher in the macroalbuminuric group than in the normoalbuminuric group (P &amp;lt; 0.001). Notably, normoalbuminuric progressor patients had a significantly higher LPS activity at baseline than normoalbuminuric nonprogressor patients (median 49 [interquartile range 34–87] vs. 39 [29–54] EU/ml; P = 0.001). The normoalbuminuric progressor patients exhibited features of the metabolic syndrome with higher triglyceride concentrations and lower estimated glucose disposal rate. A high LPS-to-HDL ratio was associated with the progression of kidney disease in both groups. Insulin resistance (P &amp;lt; 0.001) and serum LPS activity (P = 0.026) were independent risk factors of disease development, when A1C was removed from the regression analysis. CONCLUSIONS High serum LPS activity is associated with the development of diabetic nephropathy in Finnish patients with type 1 diabetes.
GDF15, a Cardioprotective TGF-β Superfamily Protein
Authors: Tetsuro Ago, Junichi Sadoshima
Journal: Circulation Research (2006)

he transforming growth factor-␤ (TGF-␤) superfamily proteins, comprising more than 40 members (broadly divided into the TGF-␤s/activins/nodal family and the bone morphogenetic proteins [BMPs]/Mu ¨llerrian inhibiting substance/growth and differentiation factors [GDFs] family), were originally identified as molecules important for regulating development, differentiation, and tissue repair in various organs. 1 TGF-␤1, a founding member of the TGF-␤ superfamily, plays a key role in mediating cardiac hypertrophy 2 and remodeling after myocardial infarction (MI) as an autocrine/paracrine factor. 3Increased TGF-␤1 expression is considered one of the few molecular markers that potentially discriminate between compensated and decompensated cardiac hypertrophy. 3Although TGF-␤1 may function protectively after MI by promoting scar formation, inhibiting neutrophil infiltration, and facilitating cardiomyogenic differentiation of adult hematopoietic stem cells, 4 such beneficial effects last only briefly and sustained activation of TGF-␤1 causes structural remodeling, eventually leading to cardiac failure. 5Thus, TGF-␤1 is generally regarded as detrimental, inducing cardiac hypertrophy and failure in the adult heart.Compared with the wealth of knowledge regarding the effects of TGF-␤1 on the heart, much less is known as to how other members of the TGF-␤ superfamily affect cardiac hypertrophy and failure. 6In this issue of Circulation Research, two companion articles report the effect of growth and differentiation factor 15 (GDF15), a 12-kDa secreted protein (and a 25-kDa disulfide-linked dimer) belonging to the TGF-␤ superfamily, on cardiac hypertrophy and apoptosis. 7,8GDF15 is highly expressed in the placenta and the prostate, but not normally in many other organs, including the heart. 9,10However, expression of GDF15 is induced rapidly by IL-1, TNF␣, and TGF-␤ in macrophages, thereby limiting macrophage activation and inflammation (Figure 1). 9 In addition, p53, a tumor suppressor protein, induces expression of GDF15, which acts as a growth inhibitory molecule in tumor cells (Figure 1). 10 Such growth inhibitory actions of GDF15 are unique compared with those of other targets of p53, such as p21/Waf-1, because GDF15 can act on neighboring cells as an "extracellular" messenger after being
Intracardiac Injection of Radioactive Krypton
Authors: ROBERT T. L. LONG, EUGENE BRAUNWALD, ANDREW G. MORROW
Journal: Circulation (1960)

Following injection of krypton 85 in solution into the right side of the heart, approximately 95 per cent is cleared during 1 passage through the pulmonary circulation. Arterial blood activity is low when radioactive Kr 85 is injected in the absence of, or distal to, the origin of a right-to-left shunt. However, when injected proximal to the origin of such a shunt, a fraction of the Kr 85 bypasses the pulmonary capillary bed and appears in arterial blood. Thirty to 50 µc. Kr 85 were injected into the right heart, and arterial blood was sampled during the next 15 seconds. In 19 patients without right-to-left shunts, the activity per milliliter of arterial blood was always less than 9.0 x 10 –5 and averaged 2.5 ± 2.6 x 10 –5 of the total radioactivity injected. In 9 patients with proved right-to-left shunts, the radioactivity per milliliter of arterial blood always exceeded 8.2 x 10 –5 and averaged 30.1 ± 12.2 x 10 –5 of the total activity injected. By appropriate rearrangement of the Stewart-Hamilton formula the data permit calculation of the magnitude of the right-to-left shunt. Following injection into the left heart, proximal to the origin of a left-to-right shunt, Kr 85 promptly arrives in the pulmonary vascular bed and immediately appears in the expired gas, where it may be readily detected. In 22 such patients Kr 85 appeared in the expired gas in an average of 4.0 ± 1.6 seconds. However, after injection distal to the origin of a left-to-right shunt in 18 patients, the appearance of Kr 85 in the expired gas was delayed to a mean of 15.0 ± 5.0 seconds. The technics described are convenient, simple to apply during cardiac catheterization, and sufficiently sensitive to detect and localize even small cardiac shunts.
Upregulation of Fas and downregulation of CD94/NKG2A inhibitory receptors on circulating natural killer cells in patients with new-onset psoriasis
Authors: S.W. Son, E-O. Kim, E.S. Ryu, T-J. Kim, J.N. Kim, J.E. Choi, Y.C. Kye, K-M. Lee
Journal: British Journal of Dermatology (2009)

Psoriasis has been considered as a T-helper 1 cell-mediated autoimmune disease driven by collaboration with multiple components of innate and acquired immune cells. Natural killer (NK) cells have been shown to bridge innate and acquired immunity, and thus could potentially contribute to the pathophysiology of psoriasis.To investigate the phenotypic changes of circulating NK cells in patients with new-onset psoriasis.Fifteen patients with plaque psoriasis (eight women and seven men) who visited our clinic after their first episode of psoriasis and did not have a history of previous systemic therapy or phototherapy participated in this study. Peripheral blood mononuclear cells were isolated and stained with a panel of antibodies against cell surface receptors expressed on T and/or NK cells and analysed by flow cytometry.As compared with normal healthy volunteers, patients with new-onset psoriasis showed no significant changes in numbers of peripheral NK, NK-T or T cells. NK activating receptors 2B4, CD48, NKG2D, CD16 and CD56 were found to be unchanged in new-onset psoriasis. However, the expression of Fas (activation-induced death receptor) was upregulated, whereas the expression of the NK inhibitory receptors CD94 and NKG2A was dramatically reduced on NK cells of new-onset psoriasis. These changes occurred at the level of mean fluorescent intensity, but minimally affected percentages of cells expressing Fas, CD94 and NKG2A.Our findings demonstrate that changes in the expression of Fas and CD94/NKG2A receptors on NK cells may occur during new-onset psoriasis, and are likely to contribute to the pathogenesis of psoriasis.
Macrophages and the Regulation of Adipose Tissue Remodeling
Authors: Gabriel Martinez-Santibañez, Carey Nien-Kai Lumeng
Journal: Annual Review of Nutrition (2014)

The ability of adipose tissue to adapt to a changing nutrient environment is critical to the maintenance of metabolic control. Nutrient excess and deficiency alter the shape of adipose tissue drastically and trigger many events that are collectively known as adipose tissue remodeling. Remodeling of adipose tissue involves more than adipocytes and is controlled by an extensive network of stromal cells and extracellular matrix proteins. Prominent players in this process are adipose tissue macrophages, which are a specialized leukocyte present in lean and obese states that contributes to adipose tissue inflammation. The interest in adipose tissue remodeling has been accelerated by the current epidemic of obesity and the chronic generation of signals that lead to expansion of adipose tissue. It is clear that evidence of dysfunctional remodeling events is a hallmark of obesity associated with metabolic disease. This review summarizes and highlights the recent work in this area and provides a framework in which to consider how adipose tissue macrophages contribute to the remodeling events in lean and obese states. Advancing our understanding of the involvement of macrophages in adipose tissue remodeling will promote one aspect of the new field of “immunometabolism,” which connects control systems developed for regulation of immunity with those that control metabolism. It will also provide insight into how physiologic and pathophysiologic remodeling differs in adipose tissue and identify potential nodes for intervention to break the link between obesity and disease.
Trioxsalen bath PUVA did not increase the risk of squamous cell skin carcinoma and cutaneous malignant melanoma in a joint analysis of 944 Swedish and Finnish patients with psoriasis
Authors: None Hannuksela-Svahn, None Sigurgeirsson, None Pukkala, None Lindelöf, None Berne, None Hannuksela, None Poikolainen, None Karvonen
Journal: British Journal of Dermatology (1999)

It has been suggested that trioxsalen bath and ultraviolet (UV) A (PUVA) is associated with a very low or no risk of non-melanoma skin cancer, but the numbers of patients in individual studies have been limited. In order to attain statistically relevant information about the cancer risk associated with trioxsalen bath PUVA, two follow-up studies were combined and the joined cancer incidence was analysed among 944 Swedish and Finnish patients with psoriasis. The mean follow-up time for skin cancer was 14.7 years. Standardized incidence ratios (SIR) were calculated as a ratio of observed and expected numbers of cases. The expected numbers of cases were based on the national cancer incidence rates in the respective countries. There was no excess of squamous cell skin carcinoma [SIR 1.1, 95% confidence interval (CI) 0.2-3.2] or malignant melanoma (SIR 0.9, 95% CI 0.1-3.2) in the combined cohort. Basal cell skin carcinoma was not studied. The incidence of all non-cutaneous cancers was not increased (SIR 1.1, 95% CI 0.8-1.4). A threefold excess risk of squamous cell skin carcinoma after trioxsalen bath PUVA could therefore be excluded, which is a markedly lower risk than that associated with oral 8-methoxypsoralen PUVA. The result needs to be confirmed in a future follow-up, however, as the number of patients with high PUVA exposures was low.
Dietary sulfate regulates the expression of the renal brush border Na/Si cotransporter NaSi-1.
Authors: D Markovich, H Murer, J Biber, K Sakhaee, C Pak, M Levi
Journal: Journal of the American Society of Nephrology (1998)

Dietary inorganic sulfate (Si) intake is an important factor in the regulation of renal proximal tubular sodium-dependent Si transport (Na/Si cotransport). The purpose of the present study was to determine whether modulation of Na/Si cotransport activity by dietary Si is mediated through regulation of the renal expression of the recently cloned NaSi-1 protein located in the apical brush border membrane (BBM) of the proximal tubule. It was found that rats fed a high Si diet had a marked increase in the renal excretion of Si and a concomitant decrease in BBM Na/Si cotransport activity when compared with rats on a control Si diet. The 43% decrease in BBM Na/Si cotransport activity was associated with a 33% decrease in BBM NaSi-1 protein abundance, as determined by Western blotting, and a 2.7-fold decrease in cortical NaSi-1 mRNA abundance, as determined by Northern blotting. Furthermore, cortical mRNA from rats fed a high Si diet when injected into Xenopus laevis oocytes led to a 2.2-fold decrease in Na/Si cotransport activity compared with mRNA isolated from control Si diet rats. This study indicates that adaptation to a high Si diet is accompanied by a decrease in renal cortical NaSi-1 mRNA abundance, which results in reduced expression of the NaSi-1 protein at the level of the proximal tubular BBM.
Linkage Analysis of Albuminuria
Authors: Amy K. Mottl, Suma Vupputuri, Shelley A. Cole, Laura Almasy, Harald H.H. Göring, Vincent P. Diego, Sandra Laston, Nawar Shara, Elisa T. Lee, Lyle G. Best, Richard R. Fabsitz, Jean W. MacCluer, Jason G. Umans, Kari E. North
Journal: Journal of the American Society of Nephrology (2009)

American Indians have a higher prevalence of albuminuria than the general population, likely resulting from a combination of environmental and genetic risk factors. To localize gene regions influencing variation in urinary albumin-to-creatinine ratio, we performed a linkage analysis and explored gene-by-diabetes, -hypertension, and -obesity interactions in a large cohort of American Indian families. We recruited >3600 individuals from 13 American Indian tribes from three centers (Arizona, North and South Dakota, and Oklahoma). We performed multipoint variance component linkage analysis in each center as well as in the entire cohort after controlling for center effects. We used two modeling strategies: Model 1 incorporated age, gender, and interaction terms; model 2 also controlled for diabetes, BP, body mass index, HDL, LDL, triglycerides, and smoking status. We evaluated interactions with diabetes, hypertension, and obesity using additive, interaction-specific linkage and stratified analyses. Loci suggestive for linkage to urinary albumin-to-creatinine ratio included 1q, 6p, 9q, 18q, and 20p. Gene-by-diabetes interaction was present with a quantitative trait locus specific to the diabetic stratum in the Dakotas isolated on 18q21.2 to 21.3 using model 1 (logarithm of odds = 3.3). Gene-by-hypertension interaction was present with quantitative trait loci specific to the hypertensive stratum in the Dakotas on 7q21.11 using model 1 (logarithm of odds = 3.4) and 10q25.1 using model 2 (logarithm of odds = 3.3). These loci replicate findings from multiple other genome scans of kidney disease phenotypes with distinct populations and are worthy of further study.
Immune Adjuvant Efficacy of CpG Oligonucleotide in Cancer Treatment Is Founded Specifically upon TLR9 Function in Plasmacytoid Dendritic Cells
Authors: Stefan Nierkens, Martijn H. den Brok, Zacharias Garcia, Susan Togher, Jori Wagenaars, Melissa Wassink, Louis Boon, Theo J. Ruers, Carl G. Figdor, Stephen P. Schoenberger, Gosse J. Adema, Edith M. Janssen
Journal: Cancer Research (2011)

Abstract The differences in function, location, and migratory pattern of conventional dendritic cells (cDC) and plasmacytoid DCs (pDC) not only point to specialized roles in immune responses but also signify additive and interdependent relationships required to clear pathogens. We studied the in vivo requirement of cross-talk between cDCs and pDCs for eliciting antitumor immunity against in situ released tumor antigens in the absence or presence of the Toll-like receptor (TLR) 9 agonist CpG. Previous data indicated that CpG boosted tumor-specific T-cell responses after in vivo tumor destruction and increased survival after tumor rechallenges. The present study shows that cDCs are indispensable for cross-presentation of ablation-released tumor antigens and for the induction of long-term antitumor immunity. Depletion of pDCs or applying this model in type I IFN receptor–deficient mice abrogated CpG-mediated responses. CD8α+ cDCs and the recently identified merocytic cDCs were dependent on pDCs for CpG-induced upregulation of CD80. Moreover, DC transfer studies revealed that merocytic cDCs and CD8α+ cDCs were most susceptible to pDC help and subsequently promoted tumor-free survival in a therapeutic setting. By transferring wild-type pDCs into TLR9-deficient mice, we finally showed that TLR9 expression in pDCs is sufficient to benefit from CpG as an adjuvant. These studies indicate that the efficacy of CpG in cancer immunotherapy is dependent on cross-talk between pDCs and specific subsets of cDCs. Cancer Res; 71(20); 6428–37. ©2011 AACR.
Dose-Response Effect of Pioglitazone on Insulin Sensitivity and Insulin Secretion in Type 2 Diabetes
Authors: Yoshinori Miyazaki, Masafumi Matsuda, Ralph A. DeFronzo
Journal: Diabetes Care (2002)

OBJECTIVE—To investigate the dose-response effects of pioglitazone on glycemic control, insulin sensitivity, and insulin secretion in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 58 diet-treated patients with type 2 diabetes (aged 54 ±1 years; 34 men and 24 women; BMI 31.5± 0.6 kg/m2) were randomly assigned to receive placebo (n=11) or 7.5 mg (n=13), 15 mg (n=12), 30 mg (n=11), or 45 mg (n=11) of pioglitazone per day for 26 weeks. Before and after 26 weeks, subjects underwent a 75-g oral glucose tolerance test (OGTT). RESULTS—Patients treated with 7.5 or 15 mg/day of pioglitazone had no change in fasting plasma glucose (FPG) and fasting plasma insulin (FPI) concentrations or in plasma glucose (PG) and insulin concentrations during the OGTT. Patients treated with 30 and 45 mg/day of pioglitazone, respectively, had significant decreases from placebo in HbA1c (Δ=−2.0 and −2.9%), FPG (Δ=−66 and −97 mg/dl), and mean PG during OGTT (Δ=−84 and −107 mg/dl). Fasting plasma insulin decreased significantly in the 45-mg/day pioglitazone group, but the mean plasma insulin during the OGTT did not change. The insulinogenic index (Δ area under the curve [AUC] insulin/ΔAUC glucose) during the OGTT increased significantly in the 30- and 45-mg/day pioglitazone groups (0.13± 0.03 to 0.27± 0.05, P &amp;lt; 0.05). From the OGTT, we previously have derived a composite whole-body insulin sensitivity index (ISI) that correlates well with that measured directly with the insulin clamp technique. Whole-body ISI [ISI=10,000 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\sqrt{(FPG{\times}FPI){\times}(\overline{PG}{\times}\overline{PI})}\) \end{document}, where P̅G̅ and P̅I̅ equal mean plasma glucose and insulin concentrations during OGTT] increased significantly in patients treated with 30 mg (1.8± 0.3 to 2.5± 0.3, P &amp;lt; 0.05) or 45 mg (1.6± 0.2 to 2.7± 0.6, P &amp;lt; 0.05) per day of pioglitazone. In the basal state, the hepatic ISI [k/(FPG × FPI)[k/(FPG × FPI)], which agrees closely with that measured directly with tritiated glucose, increased in patients treated with 30 mg (0.13± 0.02 to 0.21± 0.03, P &amp;lt; 0.05) and 45 mg (0.11± 0.02 to 0.24± 0.06, P &amp;lt; 0.05) per day of pioglitazone. Significant correlations between the dose of pioglitazone and the changes in HbA1c (r=−0.58), FPG (r=−0.47), mean PG during the OGTT (r=−0.46), insulinogenic index (r=0.34), hepatic ISI (r=0.44), and whole-body ISI (r=0.36) were observed. CONCLUSIONS—Pioglitazone improves glycemic control through the dose-dependent enhancement of β-cell function and improved whole-body and hepatic insulin sensitivity.
FURTHER STUDIES CONCERNING THE FILTRABLE VIRUS PRESENT IN THE SUBMAXILLARY GLANDS OF GUINEA PIGS
Authors: Ann G. Kuttner
Journal: The Journal of Experimental Medicine (1927)

1. It has been shown that the guinea pig virus localizes in the submaxillary glands of young guinea pigs following subcutaneous, intraperitoneal, or intravenous injection of active material, and that the specific lesion is demonstrable in the glands in 12 to 15 days. When an active infection of the gland has been produced in this way, the guinea pigs are refractory to intracerebral inoculation of the virus. 2. No lesion develops in the submaxillary glands of young guinea pigs injected subcutaneously with guinea pig virus which has been inactivated by heat. Young guinea pigs which have received injections of heat-killed virus do not become refractory to intracerebral inoculation of the virus. 3. When young guinea pigs from which both submaxillary glands have been removed are injected subcutaneously with active virus, the virus localizes in the parotid gland, and the animals become refractory to intracerebral inoculation. 4. It has been impossible to demonstrate virucidal properties in the sera of adult guinea pigs which have become spontaneously infected with the virus, or in the sera of young guinea pigs which have been artificially rendered refractory to intracerebral inoculation. 5. It has been possible to transmit the virus from guinea pig to guinea pig continuously in series through seven animals by direct inoculation from submaxillary gland to submaxillary gland. 6. The fact that the virus regularly localizes in the submaxillary glands following subcutaneous inoculation has been utilized in passing the virus from guinea pig to guinea pig. 2 weeks after the subcutaneous inoculation of the virus into young guinea pigs, the active agent was present in the submaxillary glands. Emulsions of the submaxillary glands of these animals were then used for the subcutaneous injection of another group of young guinea pigs. In this way the virus was transmitted continuously from skin to submaxillary gland through a series of seven animals.
Cross-sectional assessment of workers with repeated exposure to chlorine over a three year period
Authors: D Gautrin, C Leroyer, J L'Archeveque, JG Dufour, D Girard, JL Malo
Journal: European Respiratory Journal (1995)

Airflow obstruction has been described in workers who experienced symptoms after acute exposure to chlorine. Persistent bronchial hyperresponsiveness has also been assessed, but mainly in case studies. In this cross-sectional study, we have assessed the relationship between inhalational accidents ("puffs") involving chlorine and persistent symptoms as well as hyperresponsiveness in 239 out of 255 at-risk workers (94%). No relationship was found between persistent symptoms and the exposure variables studied. Forced vital capacity (FVC) was higher in subjects who had had no symptoms after a "puff", compared with those who had experienced mild symptoms. Forced expiratory volume in one second (FEV1) and FVC were significantly lower in subjects who experienced more than 10 puffs with mild symptoms than in subjects who reported no symptomatic puff. The presence of bronchial hyperresponsiveness was not related to exposure, but the methacholine dose-response slope showed a tendency to increased bronchial responsiveness with increased exposure. A significant difference was shown in subjects who experienced more than 10 puffs with mild symptoms. In this group of workers, repeated exposure to chlorine with acute respiratory symptoms was associated with a slight but significant reduction in expiratory flow rates, together with an increase in bronchial responsiveness, without long-term symptoms.