tbuckley/cabot-search huggingface dataset:
Endotoxin Uptake by S1 Proximal Tubular Segment Causes Oxidative Stress in the Downstream S2 Segment
Authors: Rabih Kalakeche, Takashi Hato, Georges Rhodes, Kenneth W. Dunn, Tarek M. El-Achkar, Zoya Plotkin, Ruben M. Sandoval, Pierre C. Dagher
Journal: Journal of the American Society of Nephrology (2011)

Gram-negative sepsis carries high morbidity and mortality, especially when complicated by acute kidney injury (AKI). The mechanisms of AKI in sepsis remain poorly understood. Here we used intravital two-photon fluorescence microscopy to investigate the possibility of direct interactions between filtered endotoxin and tubular cells as a possible mechanism of AKI in sepsis. Using wild-type (WT), TLR4-knockout, and bone marrow chimeric mice, we found that endotoxin is readily filtered and internalized by S1 proximal tubules through local TLR4 receptors and through fluid-phase endocytosis. Only receptor-mediated interactions between endotoxin and S1 caused oxidative stress in neighboring S2 tubules. Despite significant endotoxin uptake, S1 segments showed no oxidative stress, possibly as a result of the upregulation of cytoprotective heme oxygenase-1 and sirtuin-1 (SIRT1). Conversely, S2 segments did not upregulate SIRT1 and exhibited severe structural and functional peroxisomal damage. Taken together, these data suggest that the S1 segment acts as a sensor of filtered endotoxin, which it takes up. Although this may limit the amount of endotoxin in the systemic circulation and the kidney, it results in severe secondary damage to the neighboring S2 segments.
Surfactant protein gene A, B, and D marker alleles in chronic obstructive pulmonary disease of a Mexican population
Authors: X. Guo, H-M. Lin, Z. Lin, M. Montaño, R. Sansores, G. Wang, S. DiAngelo, A. Pardo, M. Selman, J. Floros
Journal: European Respiratory Journal (2001)

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation. It is most likely the result of complex interactions of environmental and genetic factors. Because pulmonary surfactant components play important roles in normal lung function, innate host defence, and inflammation in the lung, this study investigated the hypothesis that the surfactant protein genes are involved in certain cases of COPD. Genotype analysis of surfactant protein (SP)-A, SP-B, SP-B-linked microsatellite, and SP-D marker alleles was performed in patients with COPD (n=97) and smoker (n=82) or nonsmoker (n=99) controls. Univariate and multiple logistic regression analyses were performed. The regression analysis results between COPD and smokers revealed several COPD susceptibility alleles (AA62_A, B1580_C, D2S388_5), based on an odds ratio (OR &gt;2.5). The predictive ability of this model for developing COPD is good (c=0.926). Allele-allele (B1580_C and D2S388_5) and allele-environment ( i.e. smoking) interactions were detected. When smoker controls were compared to nonsmoker controls, marker D2S388_5 appeared to be smoking-independent (p=0.874), whereas marker alleles AA62_A (p=0.045) and B1580_5 (p=0.007) were smoking-dependent. Males were at higher risk (OR=6.05, p=0.001), and smoking (&gt;50 packs·yr −1 ) increased risk (OR=5.38, p=0.007). Males and alleles of loci flanking SP-B were associated with more severe cases (forced expiratory volume in one second/forced vital capacity ⪕40%). The present results indicate that the surfactant protein alleles may be useful in chronic obstructive pulmonary disease by either predicting the disease in a subgroup and/or by identifying disease subgroups that may be used for therapeutic intervention. These observations should now be confirmed in a larger study, designed according to strict epidemiological criteria.
Extra-uterine pregnancy following assisted conception treatment
Authors: N. Abusheikha
Journal: Human Reproduction Update (2000)

Ectopic pregnancy may be the only life-threatening disease in which prevalence has increased as mortality has declined. The most prominent theory to explain this phenomenon involves increased sensitivity of serum -human chorionic gonadotrophin (HCG) immunoassay and improved quality of transvaginal ultrasound, combined with a heightened awareness and increased suspicion of the condition among clinicians which has allowed early detection of ectopic pregnancy. Laparotomy, once the standard treatment of ectopic pregnancy, has been replaced almost entirely by operative laparoscopy. This is associated with a shorter hospital stay, fewer post-operative analgesic requirements, reduced costs and lower risk of adhesion formation. Laparotomy, however, remains necessary in cases with haemodynamic instability and with exceptional locations, e.g. cervical, abdominal and interstitial implantation. In selected cases, non-surgical management has also obtained high success rates. Among medical therapies, the most common is systemic or local administration of methotrexate. The other option is expectant management involving follow-up using serial serum HCG measurements and ultrasound scans. Thus, life-threatening ectopic pregnancy is now evolving into a medical disease, with the possibility of lower-cost treatment, faster recovery and higher subsequent fertility. In this review we assess the risk of extra-uterine implantation after assisted conception treatment, the accuracy of various diagnostic tools and focus on the efficacy, safety and the fertility outcomes of surgical and non-surgical management of ectopic pregnancy.
Guanidine in Botulism
Authors: S. Benson Werner
Journal: JAMA (1979)

<h3>To the Editor.—</h3> A recent article by Puggiari and Cherington, "Botulism and Guanidine: Ten Years Later" (240:2276, 1978), reported on two additional cases of botulism treated with guanidine hydrochloride. The authors noted improved strength of ocular and limb muscles but not of respiratory muscles. They then reviewed the literature and noted that "some benefit" was reported in 39 cases and "little or no benefit" was shown in 13 others treated with guanidine. Contributing to these figures, but not directly called to the reader's attention by citation, was an important article by Faich et al,<sup>1</sup>"Failure of Guanidine Therapy in Botulism A." This article cites one of the more careful and complete studies on the value, or rather, the nonvalue, of guanidine. Faich and associates stressed in their conclusion that they could find "no objective or subjective clinical benefits from guanidine therapy... [in their four cases] during the acute or recovery
The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells
Authors: Satoshi Kubo, Kunihiro Yamaoka, Masahiro Kondo, Kaoru Yamagata, Jidong Zhao, Shigeru Iwata, Yoshiya Tanaka
Journal: Annals of the Rheumatic Diseases (2013)

Tofacitinib, which is a Janus kinase (JAK) inhibitor, has shown clinical effects in the treatment of rheumatoid arthritis. JAKs are important kinases in lymphocyte differentiation; however, their function in dendritic cells (DCs) is unknown. In this study, the function of JAKs in DCs was investigated with tofacitinib.The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide (LPS) stimulation were investigated. In addition, its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA-positive T cells.Tofacitinib decreased expression of CD80/CD86 in a concentration-dependent manner in LPS-stimulated DCs; however, it did not affect HLA-DR expression. Tofacitinib suppressed tumour necrosis factor, interleukin (IL)-6 and IL-1β production without affecting transforming growth factor (TGF)-β and IL-10 production. Meanwhile, CD80/CD86 expression in DCs was enhanced by type I interferon (IFN) stimulation, and the LPS-induced CD80/CD86 expression was inhibited by an antibody to type I IFN receptor. Furthermore, tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor (IRF)-7, which is a transcription factor involved in CD80/CD86 and type I IFN expression. Tofacitinib also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2.Tofacitinib, a JAK1/JAK3 inhibitor, affected the activities of human DCs. It decreased CD80/CD86 expression and T cell stimulatory capability through suppression of type I IFN signalling. These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs.
Photothermal Response of Human and Murine Cancer Cells to Multiwalled Carbon Nanotubes after Laser Irradiation
Authors: Jessica W. Fisher, Saugata Sarkar, Cara F. Buchanan, Christopher S. Szot, Jon Whitney, Heather C. Hatcher, Suzy V. Torti, Christopher G. Rylander, Marissa Nichole Rylander
Journal: Cancer Research (2010)

This study demonstrates the capability of multiwalled carbon nanotubes (MWNTs) coupled with laser irradiation to enhance treatment of cancer cells through enhanced and more controlled thermal deposition, increased tumor injury, and diminished heat shock protein (HSP) expression. We also explored the potential promise of MWNTs as drug delivery agents by observing the degree of intracellular uptake of these nanoparticles. To determine the heat generation capability of MWNTs, the absorption spectra and temperature rise during heating were measured. Higher optical absorption was observed for MWNTs in water compared with water alone. For identical laser parameters, MWNT-containing samples produced a significantly greater temperature elevation compared to samples treated with laser alone. Human prostate cancer (PC3) and murine renal carcinoma (RENCA) cells were irradiated with a 1,064-nm laser with an irradiance of 15.3 W/cm(2) for 2 heating durations (1.5 and 5 minutes) alone or in combination with MWNT inclusion. Cytotoxicity and HSP expression following laser heating was used to determine the efficacy of laser treatment alone or in combination with MWNTs. No toxicity was observed for MWNTs alone. Inclusion of MWNTs dramatically decreased cell viability and HSP expression when combined with laser irradiation. MWNT cell internalization was measured using fluorescence and transmission electron microscopy following incubation of MWNTs with cells. With increasing incubation duration, a greater number of MWNTs were observed in cellular vacuoles and nuclei. These findings offer an initial proof of concept for the application of MWNTs in cancer therapy.
Increased expression of blood mononuclear cell nitric oxide synthase type 2 in rheumatoid arthritis patients.
Authors: E W St Clair, W E Wilkinson, T Lang, L Sanders, M A Misukonis, G S Gilkeson, D S Pisetsky, D I Granger, J B Weinberg
Journal: The Journal of Experimental Medicine (1996)

Nitric oxide (NO) is an important inflammatory mediator in nonhuman animal models of rheumatoid arthritis (RA). The purpose of the present study was to determine whether blood mononuclear cells from patients with active RA (as compared to control subjects) have higher levels of NO synthase type 2 (NOS2) and produce more NO in vitro. Leukocytes from 25 RA patients and 20 normal subjects were examined. Arthritis activity was assessed by tender and swollen joint counts, duration of morning stiffness, patient assessment of pain, physician and patient global assessment of disease activity, the modified Stanford Health Assessment Questionnaire, and by blood levels of acute phase reactants. Blood mononuclear cell NOS enzyme activity/antigen content and nitrite/nitrate formation in vitro were measured. Blood mononuclear cells from RA patients had increased NOS activity and increased NOS2 antigen content as compared to those from normal subjects, and responded to interferon-gamma with increased NOS expression and nitrite/nitrate production in vitro. NOS activity of freshly isolated blood mononuclear cells correlated significantly with disease activity, as assessed by render and swollen joint counts. Our results demonstrate that patients with RA have systemic activation for NOS2 expression, and that the degree of activation correlates with disease activity. Increased NOS2 expression and NO generation may be important in the pathogenesis of RA.
Running shoes and running injuries: mythbusting and a proposal for two new paradigms: ‘preferred movement path’ and ‘comfort filter’
Authors: BM Nigg, J Baltich, S Hoerzer, H Enders
Journal: British Journal of Sports Medicine (2015)

In the past 100 years, running shoes experienced dramatic changes. The question then arises whether or not running shoes (or sport shoes in general) influence the frequency of running injuries at all. This paper addresses five aspects related to running injuries and shoe selection, including (1) the changes in running injuries over the past 40 years, (2) the relationship between sport shoes, sport inserts and running injuries, (3) previously researched mechanisms of injury related to footwear and two new paradigms for injury prevention including (4) the ‘preferred movement path’ and (5) the ‘comfort filter’. Specifically, the data regarding the relationship between impact characteristics and ankle pronation to the risk of developing a running-related injury is reviewed. Based on the lack of conclusive evidence for these two variables, which were once thought to be the prime predictors of running injuries, two new paradigms are suggested to elucidate the association between footwear and injury. These two paradigms, ‘the preferred movement path’ and ‘the comfort filter’, suggest that a runner intuitively selects a comfortable product using their own comfort filter that allows them to remain in the preferred movement path. This may automatically reduce the injury risk and may explain why there does not seem to be a secular trend in running injury rates.
Evolution of an idiotypic determinant: anti-Val.
Authors: R A Karol, M Reichlin, R W Noble
Journal: The Journal of Experimental Medicine (1977)

An antibody population which reacts only with human sickle cell hemoglobin (HbS) and not with normal human hemoglobin, has been isolated from goat, sheep, and guinea pig antisera. These antibody populations termed anti-Val (Val), isolated from an individual goat (no. 6) and sheep (no. 26) have been used to elicit anti-idiotypic responses in rabbits. These anti-idiotypic sera were used to study the idiotypic cross-reactions between the goat and sheep anti-Val. Strong cross-reactions were present using either Ra anti-goat anti-Val or Ra anti-sheep anti-Val. Guinea pig anti-Val did not cross-react with these anti-idiotypic sera. Binding of HbS to the anti-Val of the goat and sheep could be blocked by the anti-idiotypic sera, but the binding of HbS to the guinea pig anti-Val could not. These data demonstrate idiotypic cross-reactivity between two closely related species.
Promoting Physical Activity in a Low-Income Multiethnic District: Effects of a Community Intervention Study to Reduce Risk Factors for Type 2 Diabetes and Cardiovascular Disease
Authors: Anne Karen Jenum, Sigmund A. Anderssen, Kåre I. Birkeland, Ingar Holme, Sidsel Graff-Iversen, Catherine Lorentzen, Yngvar Ommundsen, Truls Raastad, Ann Kristin Ødegaard, Roald Bahr
Journal: Diabetes Care (2006)

The aim was to assess the net effects on risk factors for type 2 diabetes and cardiovascular disease of a community-based 3-year intervention to increase physical activity.A pseudo-experimental cohort design was used to compare changes in risk factors from an intervention and a control district with similar socioeconomic status in Oslo, Norway, using a baseline investigation of 2,950 30- to 67-year-old participants and a follow-up investigation of 1,776 (67% of those eligible, 56% women, 18% non-Western immigrants) participants. A set of theory-based activities to promote physical activity were implemented and tailored toward groups with different psychosocial readiness for change. All results reported are net changes (the difference between changes in the intervention and control districts). At both surveys, the nonfasting serum levels of lipids and glucose were adjusted for time since last meal.The increase in physical activity measured by two self-reported questionnaires was 9.5% (P = 0.008) and 8.1% (P = 0.02), respectively. The proportion who increased their body mass was 14.2% lower in the intervention district (P < 0.001), implying a 50% relative reduction compared with the control district, and was lower across subgroups. Beneficial effects were seen for triglyceride levels (0.16 mmol/l [95% CI 0.06-0.25], P = 0.002), cholesterol-to-HDL cholesterol ratio (0.12 [0.03-0.20], P = 0.007), systolic blood pressure (3.6 mmHg [2.2-4.8], P < 0.001), and for men also in glucose levels (0.35 mmol/l [0.03-0.67], P = 0.03). The net proportion who were quitting smoking was 2.9% (0.1-5.7, P = 0.043).Through a theory-driven, low-cost, population-based intervention program, we observed an increase in physical activity levels, reduced weight gain, and beneficial changes in other risk factors for type 2 diabetes and cardiovascular disease.
Concordance among gene expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen
Authors: A. Prat, J.S. Parker, C. Fan, M.C.U. Cheang, L.D. Miller, J. Bergh, S.K.L. Chia, P.S. Bernard, T.O. Nielsen, M.J. Ellis, L.A. Carey, C.M. Perou
Journal: Annals of Oncology (2012)

BackgroundER-positive (ER+ ) breast cancer includes all of the intrinsic molecular subtypes, although the luminal A and B subtypes predominate. In this study, we evaluated the ability of six clinically relevant genomic signatures to predict relapse in patients with ER+ tumors treated with adjuvant tamoxifen only.MethodsFour microarray datasets were combined and research-based versions of PAM50 intrinsic subtyping and risk of relapse (PAM50-ROR) score, 21-gene recurrence score (OncotypeDX), Mammaprint, Rotterdam 76 gene, index of sensitivity to endocrine therapy (SET) and an estrogen-induced gene set were evaluated. Distant relapse-free survival (DRFS) was estimated by Kaplan–Meier and log-rank tests, and multivariable analyses were done using Cox regression analysis. Harrell's C-index was also used to estimate performance.ResultsAll signatures were prognostic in patients with ER+ node-negative tumors, whereas most were prognostic in ER+ node-positive disease. Among the signatures evaluated, PAM50-ROR, OncotypeDX, Mammaprint and SET were consistently found to be independent predictors of relapse. A combination of all signatures significantly increased the performance prediction. Importantly, low-risk tumors (>90% DRFS at 8.5 years) were identified by the majority of signatures only within node-negative disease, and these tumors were mostly luminal A (78%–100%).ConclusionsMost established genomic signatures were successful in outcome predictions in ER+ breast cancer and provided statistically independent information. From a clinical perspective, multiple signatures combined together most accurately predicted outcome, but a common finding was that each signature identified a subset of luminal A patients with node-negative disease who might be considered suitable candidates for adjuvant endocrine therapy alone.
Nifedipine does not prevent acute mountain sickness.
Authors: E Hohenhaus, F Niroomand, S Goerre, P Vock, O Oelz, P Bärtsch
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

Nifedipine has been shown effective for prevention and treatment of high altitude pulmonary edema (HAPE). Because acute mountain sickness (AMS) and HAPE may share common pathophysiologic mechanisms, we evaluate the prophylactic effect of nifedipine on the development of AMS in 27 mountaineers not susceptible to HAPE. They were randomly assigned to receive in a double-blind manner either nifedipine or placebo during rapid ascent to 4559 m and a subsequent three-day sojourn at this altitude. Nine of 14 subjects on nifedipine and eight of 13 subjects on placebo felt ill at high altitude. Pulmonary artery pressures (PAP) estimated by Doppler echocardiography were significantly lower with nifedipine, but arterial PO2, oxygen saturation, and alveolar-arterial oxygen pressure gradient were not significantly different between groups at high altitude. This study demonstrates that lowering PAP has no beneficial effect on gas exchange and symptoms of AMS in subjects not susceptible to HAPE. Therefore, nifedipine cannot be recommended for prevention of AMS, and its use in high altitude medicine should be limited to prevention and treatment of HAPE.
Horseshoe lung with left lung hypoplasia.
Authors: A Ersoz, H Soncul, L Gokgoz, S Kalaycioglu, S Tunaoglu, M Kaptanoglu, A Yener
Journal: Thorax (1992)

Horseshoe lung is an uncommon congenital malformation in which the bases of the right and the left lungs are fused to each other by a narrow isthmus posterior to the cardiac apex. So far 22 cases have been described: most of these were associated with right lung hypoplasia and the scimitar syndrome. A horseshoe lung anomaly with left lung hypoplasia is described.
Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis
Authors: Sung Hee Choi, Byung-Gyu Kim, Janet Robinson, Steve Fink, Min Yan, Michael B. Sporn, Sanford D. Markowitz, John J. Letterio
Journal: Journal of Clinical Investigation (2014)

Colitis-associated colon cancer (CAC) develops as a result of inflammation-induced epithelial transformation, which occurs in response to inflammatory cytokine-dependent downregulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and subsequent suppression of prostaglandin metabolism. Agents that both enhance 15-PGDH expression and suppress cyclooxygenase-2 (COX-2) production may more effectively prevent CAC. Synthetic triterpenoids are a class of small molecules that suppress COX-2 as well as inflammatory cytokine signaling. Here, we found that administration of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-C28-methyl ester (CDDO-Me) suppresses CAC in mice. In a spontaneous, inflammation-driven intestinal neoplasia model, deletion of Smad4 specifically in T cells led to progressive production of inflammatory cytokines, including TNF-α, IFN-γ, iNOS, IL-6, IL-1β; as well as activation of STAT1 and STAT3; along with suppression of 15-PGDH expression. Oral administration of CDDO-Me to mice with SMAD4-deficient T cells increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators and increasing expression of 15-PGDH. Induction of 15-PGDH by CDDO-Me was dose dependent in epithelial cells and was abrogated following treatment with TGF-β signaling inhibitors in vitro. Furthermore, CDDO-Me–dependent 15-PGDH induction was not observed in Smad3–/– mice. Similarly, CDDO-Me suppressed azoxymethane plus dextran sodium sulfate–induced carcinogenesis in wild-type animals, highlighting the potential of small molecules of the triterpenoid family as effective agents for the chemoprevention of CAC in humans.