tbuckley/cabot-search huggingface dataset:
Large-Scale Proteomics and Phosphoproteomics of Urinary Exosomes
Authors: Patricia A Gonzales, Trairak Pisitkun, Jason D Hoffert, Dmitry Tchapyjnikov, Robert A Star, Robert Kleta, Nam Sun Wang, Mark A Knepper
Journal: Journal of the American Society of Nephrology (2008)

Normal human urine contains large numbers of exosomes, which are 40- to 100-nm vesicles that originate as the internal vesicles in multivesicular bodies from every renal epithelial cell type facing the urinary space. Here, we used LC-MS/MS to profile the proteome of human urinary exosomes. Overall, the analysis identified 1132 proteins unambiguously, including 177 that are represented on the Online Mendelian Inheritance in Man database of disease-related genes, suggesting that exosome analysis is a potential approach to discover urinary biomarkers. We extended the proteomic analysis to phosphoproteomic profiling using neutral loss scanning, and this yielded multiple novel phosphorylation sites, including serine-811 in the thiazide-sensitive Na-Cl co-transporter, NCC. To demonstrate the potential use of exosome analysis to identify a genetic renal disease, we carried out immunoblotting of exosomes from urine samples of patients with a clinical diagnosis of Bartter syndrome type I, showing an absence of the sodium-potassium-chloride co-transporter 2, NKCC2. The proteomic data are publicly accessible at http://dir.nhlbi.nih.gov/papers/lkem/exosome/.
Micafungin at a standard dosage of 100 mg/day achieves adequate plasma exposure in critically ill patients with severe burn injuries
Authors: M. J. Asensio, M. Sánchez, B. Galván, E. Herrero, L. Cachafeiro, A. Agrifoglio, E. Perales, S. Luque, A. García-de-Lorenzo
Journal: Intensive Care Medicine (2014)
Connexin 40 Mediates the Tubuloglomerular Feedback Contribution to Renal Blood Flow Autoregulation
Authors: Armin Just, Lisa Kurtz, Cor de Wit, Charlotte Wagner, Armin Kurtz, William J. Arendshorst
Journal: Journal of the American Society of Nephrology (2009)

Connexins are important in vascular development and function. Connexin 40 (Cx40), which plays a predominant role in the formation of gap junctions in the vasculature, participates in the autoregulation of renal blood flow (RBF), but the underlying mechanisms are unknown. Here, Cx40-deficient mice (Cx40-ko) had impaired steady-state autoregulation to a sudden step increase in renal perfusion pressure. Analysis of the mechanisms underlying this derangement suggested that a marked reduction in tubuloglomerular feedback (TGF) in Cx40-ko mice was responsible. In transgenic mice with Cx40 replaced by Cx45, steady-state autoregulation and TGF were weaker than those in wild-type mice but stronger than those in Cx40-ko mice. Nω-Nitro-L-arginine-methyl-ester (L-NAME) augmented the myogenic response similarly in all genotypes, leaving autoregulation impaired in transgenic animals. The responses of renovascular resistance and arterial pressure to norepinephrine and acetylcholine were similar in all groups before or after L-NAME inhibition. Systemic and renal vasoconstrictor responses to L-NAME were also similar in all genotypes. We conclude that Cx40 contributes to RBF autoregulation by transducing TGF-mediated signals to the afferent arteriole, a function that is independent of nitric oxide (NO). However, Cx40 is not required for the modulation of the renal myogenic response by NO, norepinephrine-induced renal vasoconstriction, and acetylcholine- or NO-induced vasodilation.
Psychopathology After Rape
Authors: Carlo Faravelli, Alice Giugni, Stefano Salvatori, Valdo Ricca
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: This study evaluated the psychopathological consequences of a single rape occurring in adult women. METHOD: The psychiatric symptoms reported by 40 women who were victims of rape during the previous 9 months as decided by a court of law were compared with the symptoms of 32 women who underwent severe, nonsexual, life-threatening events (car accidents, physical attacks, or robberies). None of the raped women had experienced previous sexual abuse during childhood or adolescence. RESULTS: The raped women showed a significantly greater prevalence of posttraumatic stress disorder, as well as sexual, eating, and mood disorders. CONCLUSIONS: These findings indicate that the psychopathological consequences of a rape could be specific and may warrant particular attention.
Dendritic cell ontogeny as an aetiological factor in respiratory tract diseases in early life
Authors: P G HOLT
Journal: Thorax (2001)

Large populations of dendritic cells (DCs) are found throughout the respiratory tract, the most prominent comprising a contiguous network dispersed throughout the epithelium and underlying mucosa of the conducting airways. Most of the available information on these cells comes from studies on tissues from experimental animals; however, comparable networks of DCs have also been formally demonstrated in humans.1-3 

These populations of DCs in the lung and airway wall are now known to play a central role in the maintenance of immunological homeostasis in the respiratory tract (reviewed by Holt and Stumbles1). As the principal resident antigen presenting cells (APC) in these tissues under steady state conditions, they serve as the local “gatekeepers” of the immune system. The principal function of these DCs is surveillance for incoming (inhaled) antigens deposited on airway mucosal surfaces, which they sample principally via receptor mediated endocytosis.4 Resident airway cells perform this function avidly but are relatively inefficient in presenting these antigens to T cells, due principally to poor surface expression of co-stimulator molecules such as CD80/CD86 which are obligatory second signals for T cell activation. Maturation of DCs from antigen acquirers into antigen presenters normally does not occur until the cells emigrate from peripheral tissues (bearing the antigens they have acquired) into the T cell zones of regional lymph nodes.5 During or immediately after this migration they mature under the influence of a variety of different cytokines including interleukin (IL)-1, tumour necrosis factor (TNF)α, and IL-4, but in particular granulocyte-macrophage colony stimulating factor (GM-CSF) which appears to serve as the “master regulator” in this process.5 This functional maturation is readily …
Clinical Importance of Estrogen Receptor β Isoforms in Breast Cancer
Authors: Valerie Speirs, Andrew R. Green, Thomas A. Hughes, Ian O. Ellis, Philippa T.K. Saunders, Abeer M. Shaaban
Journal: Journal of Clinical Oncology (2008)

Since its discovery in 1996, 1 progress in under- standing the potential role of estrogen receptor ␤ (ER␤) in the clinical management of breast cancer has been hindered by the publication of contradictory data from studies that used small numbers of cases, relied on poorly validated primary antibodies, or failed to account for the contribution of the five known ER␤ isoforms. 2,3 Recently, the situation has improved through the publication of two large studies.In Journal of Clinical Oncology, in one of the largest immunohistochemical studies conducted to date, Honma et al 4 examined total ER␤, ER␤1, and ER␤2 in 442 breast tumors from a group of Japanese patients who all received tamoxifen monotherapy.They showed that ER␤1 was an independent predictor of recurrence, disease-free survival, and overall survival, particularly in the so-called triple-negative breast cancers, which do not express ER␣, progesterone, or HER2.In our immunohistochemical study, we evaluated expression of ER␤1, ER␤2, and ER␤5 in a cohort of 880 unselected breast tumors of European origin. 5 In contrast to the Honma et al study, our study revealed that ER␤2 was the most significant ER␤ isoform in breast cancer, as it was predictive of disease-free and overall survival and response to hormone therapy.Using the same antibody as Honma et al, 4 we found that ER␤1 was uninformative, irrespective of scoring method or cutoff used.Our study revealed a moderate association of ER␤5 with improved survival, but only when it was strongly expressed.It is possible that ethnic differences between the two cohorts may have contributed to these contrasting observations, as significant differences in expression of ER␤ isoforms have been reported at the mRNA level in African-American versus Caucasian women. 6A comparison of these cohorts showed that the former group expressed significantly higher levels of ER␤1 and, in particular, ER␤5.No differences were seen with ER␣, and ER␤2 was not examined.These three studies 4-6 strongly suggest that the specific type and level of ER␤ isoform expression may contribute to breast cancer survival across different ethnic groups.Finally, the presence of cytoplasmic ER␤ immunoreactivity has been consistently noted in a number of studies, including that of Honma et al. 4 We have formally examined this and have shown that
Granzyme B (GraB) Autonomously Crosses the Cell Membrane and Perforin Initiates Apoptosis and GraB Nuclear Localization
Authors: Lianfa Shi, Sabine Mai, Sara Israels, Kylie Browne, Joseph A. Trapani, Arnold H. Greenberg
Journal: The Journal of Experimental Medicine (1997)

Granzyme B (GraB) induces apoptosis in the presence of perforin. Perforin polymerizes in the cell membrane to form a nonspecific ion pore, but it is not known where GraB acts to initiate the events that ultimately lead to apoptosis. It has been hypothesized that GraB enters the target cell through a perforin channel and then initiates apoptosis by cleaving and activating members of the ICE/Ced-3 family of cell death proteases. To determine if GraB can enter the cell, we treated YAC-1 or HeLa cells with FITC-labeled GraB and measured intracellular fluorescence with a high sensitivity CCD camera and image analyzer. GraB was internalized and found diffusely dispersed in the cell cytoplasm within 10 min. Uptake was inhibited at low temperature (4°C) and by pretreatment with metabolic inhibitors, NaF and DNP, or cytochalasin B, a drug that both blocks microfilament formation, and FITC-GraB remained on the cell membrane localized in patches. With the simultaneous addition of perforin and FITC-GraB, no significant increase in cytoplasmic fluorescence was observed over that found in cells treated only with FITC-GraB. However, FITC-GraB was now detected in the nucleus of apoptotic cells labeling apoptotic bodies and localized areas within and along the nuclear membrane. The ability of GraB to enter cells in the absence of perforin was reexamined using anti-GraB antibody immunogold staining of ultrathin cryosections of cells incubated with GraB. Within 15 min, gold particles were detected both on the plasma membrane and in the cytoplasm of cells with some gold staining adjacent to the nuclear envelope but not in the nucleus. Cells internalizing GraB in the absence of perforin appeared morphologically normal by Hoechst staining and electron microscopy. GraB directly microinjected into the cytoplasm of B16 melanoma cells induced transient plasma membrane blebbing and nuclear coarsening but the cells did not become frankly apoptotic unless perforin was added. We conclude that GraB can enter cells autonomously but that perforin initiates the apoptotic process and the entry of GraB into the nucleus.
Increase in age at onset of rheumatoid arthritis in Japan over a 30 year period
Authors: T. Imanaka, K. Shichikawa, K. Inoue, Y. Shimaoka, Y. Takenaka, S. Wakitani
Journal: Annals of the Rheumatic Diseases (1997)

<h3>OBJECTIVES</h3> To determine changes in demographic variables and severity of rheumatoid arthritis (RA) that may have occurred during the 30 year period from 1960 to 1990 in Japan. <h3>METHODS</h3> Using records of patients diagnosed with RA from two hospitals, demographic and clinical features at initial visit were compared between two groups, one from 1960 to 1965 (group I) and the other from 1985 to 1990 (group II). <h3>RESULTS</h3> Mean age at the time of onset of the disease increased significantly from 37.5 years in group I to 46.9 in group II. The peak age at onset of RA shifted from the third to the fifth decade between group I and group II. There was no obvious change in morbidity as determined by seropositivity, rheumatoid nodules, and assessments of hip involvement. <h3>CONCLUSION</h3> The age at onset of RA was delayed during a recent 30 year period in Japan. This increase in age at onset might result from environmental changes that occurred in Japan or may reflect a birth cohort phenomenon. Improvement of severity of disease was not found in this study.
Hepatic cell-to-cell transmission of small silencing RNA can extend the therapeutic reach of RNA interference (RNAi)
Authors: Qiuwei Pan, Vedashree Ramakrishnaiah, Scot Henry, Suomi Fouraschen, Petra E de Ruiter, Jaap Kwekkeboom, Hugo W Tilanus, Harry L A Janssen, Luc J W van der Laan
Journal: Gut (2011)

<h3>Background/aims</h3> RNA interference (RNAi), a sequence-specific gene silencing technology triggered by small interfering RNA (siRNA), represents promising new avenues for treatment of various liver diseases including hepatitis C virus (HCV) infection. In plants and invertebrates, RNAi provides an important mechanism of cellular defence against viral pathogens and is dependent on the spread of siRNA to neighbouring cells. A study was undertaken to investigate whether vector-delivered RNAi can transfer between hepatic cells in vitro and in mice, and whether this exchange could extend the therapeutic effect of RNAi against HCV infection. <h3>Methods</h3> Transmission of RNAi was investigated in culture by assessing silencing of HCV replication and expression of viral entry receptor CD81 using a human hepatic cell line and primary B lymphocytes transduced with siRNA-expressing vectors. In vivo transmission between hepatic cells was investigated in NOD/SCID mice. Involvement of exosomes was demonstrated by purification, uptake and mass spectrometric analysis. <h3>Results</h3> Human and mouse liver cells, as well as primary human B cells, were found to have the ability to exchange small RNAs, including cellular endogenous microRNA and delivered siRNA targeting HCV or CD81. The transmission of RNAi was largely independent of cell contact and partially mediated by exosomes. Evidence of RNAi transmission in vivo was observed in NOD/SCID mice engrafted with human hepatoma cells producing CD81 siRNA, causing suppression of CD81 expression in mouse hepatocytes. <h3>Conclusion</h3> Both human and mouse hepatic cells exchange small silencing RNAs, partially mediated by shuttling of exosomes. Transmission of siRNA potentially extends the therapeutic reach of RNAi-based therapies against HCV as well as other liver diseases.
Diverging Association of Reduced Glomerular Filtration Rate and Albuminuria With Coronary and Noncoronary Events in Patients With Type 2 Diabetes
Authors: Anna Solini, Giuseppe Penno, Enzo Bonora, Cecilia Fondelli, Emanuela Orsi, Maura Arosio, Roberto Trevisan, Monica Vedovato, Mauro Cignarelli, Francesco Andreozzi, Antonio Nicolucci, Giuseppe Pugliese
Journal: Diabetes Care (2011)

Although a reduced estimated glomerular filtration rate (eGFR) was shown to be a powerful independent predictor of cardiovascular disease (CVD), other studies suggested that it confers a much lower risk than albuminuria alone, whereas the combination of the two abnormalities is associated with multiplicative risk. This study aimed at assessing the independent association of previous CVD events, either total or by vascular bed, with eGFR and albuminuria and chronic kidney disease (CKD) phenotypes.This cross-sectional study evaluated 15,773 patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study in 19 outpatient diabetes clinics in years 2007-2008. Albuminuria was assessed by immunonephelometry or immunoturbidimetry. GFR was estimated by the simplified Modification of Diet in Renal Disease Study and the Chronic Kidney Disease-Epidemiology Collaboration equation. CKD was defined as an eGFR <60 mL/min/1.73 m(2) or micro- or macroalbuminuria. Major acute CVD events were adjudicated based on hospital discharge records or specialist visits.CVD risk increased linearly with eGFR decline and albuminuria and became significant for values <78 mL/min/1.73 m(2) and ≥10.5 mg/24 h, respectively. Beyond traditional CVD risk factors, total CVD showed an independent association with albuminuria alone (odds ratio 1.20 [95% CI 1.08-1.33]), reduced eGFR alone (1.52 [1.34-1.73]), and both abnormalities (1.90 [1.66-2.19]). However, coronary events were associated predominantly with reduced eGFR alone, whereas cerebrovascular and peripheral events showed a stronger correlation with the albuminuric CKD phenotypes.These data, although cross-sectional, show that reduced eGFR, irrespective of albuminuria, is associated with significant CVD, particularly in the coronary district.
Office-Based Treatment of Opiate Addiction with a Sublingual-Tablet Formulation of Buprenorphine and Naloxone
Authors: Paul J. Fudala, T. Peter Bridge, Susan Herbert, William O. Williford, C. Nora Chiang, Karen Jones, Joseph Collins, Dennis Raisch, Paul Casadonte, R. Jeffrey Goldsmith, Walter Ling, Usha Malkerneker, Laura McNicholas, John Renner, Susan Stine, Donald Tusel
Journal: New England Journal of Medicine (2003)

Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone has been proposed, but its efficacy and safety have not been well studied.We conducted a multicenter, randomized, placebo-controlled trial involving 326 opiate-addicted persons who were assigned to office-based treatment with sublingual tablets consisting of buprenorphine (16 mg) in combination with naloxone (4 mg), buprenorphine alone (16 mg), or placebo given daily for four weeks. The primary outcome measures were the percentage of urine samples negative for opiates and the subjects' self-reported craving for opiates. Safety data were obtained on 461 opiate-addicted persons who participated in an open-label study of buprenorphine and naloxone (at daily doses of up to 24 mg and 6 mg, respectively) and another 11 persons who received this combination only during the trial.The double-blind trial was terminated early because buprenorphine and naloxone in combination and buprenorphine alone were found to have greater efficacy than placebo. The proportion of urine samples that were negative for opiates was greater in the combined-treatment and buprenorphine groups (17.8 percent and 20.7 percent, respectively) than in the placebo group (5.8 percent, P<0.001 for both comparisons); the active-treatment groups also reported less opiate craving (P<0.001 for both comparisons with placebo). Rates of adverse events were similar in the active-treatment and placebo groups. During the open-label phase, the percentage of urine samples negative for opiates ranged from 35.2 percent to 67.4 percent. Results from the open-label follow-up study indicated that the combined treatment was safe and well tolerated.Buprenorphine and naloxone in combination and buprenorphine alone are safe and reduce the use of opiates and the craving for opiates among opiate-addicted persons who receive these medications in an office-based setting.
Which is the principal early-life infection-related risk factor for asthma?
Authors: Matti Korppi, Mari Hyvärinen, Eija Piippo-Savolainen
Journal: European Respiratory Journal (2012)

Which is the principal early-life infection-related risk factor for asthma?To the Editors:In a previous issue of the European Respiratory Journal, KUSEL et al.[1] reported very interesting 10-yr results of their prospective birth cohort study.Originally, 263 children at risk for asthma and allergy were recognised pre-natally and recruited as newborns, and 198 (75.3%) attended the 5-yr [2] and 147 (55.9%) the 10-yr follow-up study [1].The drop-out rate of 44% is understandable but needs evaluation.The data were collected very carefully during the first year including diaries completed by parents and home visits with sampling for virus detection by PCR during all acute infections [2].Respiratory infections were classified as upper (URI) and lower (LRI), and both URIs and LRIs further as wheezy and nonwheezy.At age 10 yrs, 18.4% of the 147 children had current asthma and 20.4% persistent wheeze [1].During the first year of life, 35.8% had experienced at least one LRI with fever and/or wheeze.The figure was 26.5% for febrile LRI and, likewise, 26.5% for wheezy LRI.Atopy determined by skin-prick tests to a panel of two food and five inhaled allergens was present in 31 (21.1%)infants at age 6 months, and in 63 (42.9%) and 56 (38.1%) children at age 5 and 10 yrs, respectively.
Trastuzumab in the Treatment of Metastatic Breast Cancer
Authors: Arthur M. Feldman, Beverly H. Lorell, Steven E. Reis
Journal: Circulation (2000)

Abstract —Trastuzumab, a monoclonal antibody against the HER2 receptor, was recently approved for the treatment of metastatic breast cancer. However, 28% of patients receiving both an anthracycline and trastuzumab developed heart failure. Although HER2 overexpression has been associated with the development of cancer, HER2 receptors seem to be cardioprotective because they mediate the activation of important cardiac survival pathways. Because the morbidity and mortality of heart failure surpasses that of many cancers, prudent medical practice mandates that physicians learn more about the mechanisms of trastuzumab-induced cardiotoxicity and develop algorithms for assessing risk/benefit ratios before extending the use of this agent to patients with less invasive forms of breast cancer.
Correlation and sex differences between ankle and knee cartilage morphology determined by quantitative magnetic resonance imaging
Authors: F Eckstein
Journal: Annals of the Rheumatic Diseases (2004)

To study the correlation between ankle and knee cartilage morphology to test the hypothesis that knee joint cartilage loss in gonarthritis can be estimated retrospectively using quantitative MRI analysis of the knee and ankle and established regression equations; and to test the hypothesis that sex differences in joint surface area are larger in the knee than the ankle, which may explain the greater incidence of knee osteoarthritis in elderly women than in elderly men.Sagittal MR images (3D FLASH WE) of the knee and hind foot were acquired in 29 healthy subjects (14 women, 15 men; mean (SD) age, 25 (3) years), with no signs joint disease. Cartilage volume, thickness, and joint surface area were determined in the knee, ankle, and subtalar joint.Knee cartilage volumes and joint surface areas showed only moderate correlations with those of the ankle and subtalar joint (r = 0.33 to 0.81). The correlations of cartilage thickness between the two joints were weaker still (r = -0.05 to 0.53). Sex differences in cartilage morphology at the knee and the ankle were similar, with surface areas being -17.5% to -23.5% lower in women than in men.Only moderate correlations in cartilage morphology of healthy subjects were found between knee and ankle. It is therefore impractical to estimate knee joint cartilage loss a posteriori in cross sectional studies by measuring the hind foot and then applying a scaling factor. Sex differences in cartilage morphology do not explain differences in osteoarthritis incidence between men and women in the knee and ankle.