tbuckley/cabot-search huggingface dataset:
Adaptive sex-dependent changes in the zonation of carbohydrate and lipid metabolism in rat liver lobules after partial hepatectomy
Authors: C. J. F. Van Noorden, I. M. C. Vogels, J. James
Journal: Hepatology (1994)

To evaluate changes in metabolic heterogeneity in rat liver lobules after partial hepatectomy, we measured parameters of carbohydrate and lipid metabolism cytophotometrically in periportal and pericentral zones of livers of mature female and male rats. Glycogen content was shown to be always higher in pericentral zones than in periportal zones. After a rapid depletion of glycogen stores during the first 8 hr after partial hepatectomy, the levels were restored to normal after 24 hr, but a significant depletion was found again at 48 hr after operation. These fluctuations were similar in female and male rat livers. The lipid content in control rat livers was low and was mainly localized in periportal zones. Partial hepatectomy caused a significant increase in lipid content after 24 to 48 hr in periportal zones only, which was distinctly higher in female than in male rat livers. Activity of NADPH-producing glucose-6-phosphate dehydrogenase was heterogeneously distributed in lobules of female control rats with highest activity in pericentral zones, whereas a lower but evenly distributed activity was found in lobules of control male rats. The activity was not affected by partial hepatectomy in male rats, whereas the activity in female rat livers decreased to levels found in male rats at 24 to 48 hr after operation. Another NADPH-producing enzyme, malate dehydrogenase, showed the highest activity pericentrally in female rats, and a low activity was evenly distributed in male rats. The activity did not change significantly after partial hepatectomy. The ketogenic enzyme beta-hydroxybutyrate dehydrogenase showed the highest activity in pericentral zones of control livers. The activity in male rat livers was almost twice as high as in female rat livers in both zones. Partial hepatectomy caused a distinct reduction in activity in both zones and both sexes, but the strongest reduction was found periportally. Alkaline phosphatase activity, which is linked with bile acid secretion by hepatocytes, was low in control male and female rats and was mainly found periportally. The activity was increased dramatically at 24 to 48 hr after partial hepatectomy in both zones and particularly in male rat livers. The index for the Krebs cycle, succinate dehydrogenase activity, was highest in periportal zones. At 24 to 48 hr after partial hepatectomy, this preferential zonation was lost, and the activity was slightly higher in pericentral zones. This reversal of zonation was found in all livers of female and male rats investigated.(ABSTRACT TRUNCATED AT 400 WORDS)
Dictyostelium Development Shows a Novel Pattern of Evolutionary Conservation
Authors: Xiangjun Tian, Joan E. Strassmann, David C. Queller
Journal: Molecular Biology and Evolution (2013)

von Baer's law states that early stages of animal development are the most conserved. More recent evidence supports a modified "hourglass" pattern in which an early but somewhat later stage is most conserved. Both patterns have been explained by the relative complexity of either temporal or spatial interactions; the greatest conservation and lowest evolvability occur at the time of the most complex interactions, because these cause larger effects that are harder for selection to alter. This general kind of explanation might apply universally across independent multicellular systems, as supported by the recent finding of the hourglass pattern in plants. We use RNA-seq expression data from the development of the slime mold Dictyostelium to demonstrate that it does not follow either of the two canonical patterns but instead tends to show the strongest conservation and weakest evolvability late in development. We propose that this is consistent with a version of the spatial constraints model, modified for organisms that never achieve a high degree of developmental modularity.
Description and simulation of a physiological pharmacokinetic model for the metabolism and enterohepatic circulation of bile acids in man. Cholic acid in healthy man.
Authors: A F Hofmann, G Molino, M Milanese, G Belforte
Journal: Journal of Clinical Investigation (1983)

A multicompartmental pharmacokinetic model based on physiological principles, experimental data, and the standard mathematical principles of compartmental analysis has been constructed that fully describes the metabolism and enterohepatic cycling in man of cholic acid, a major bile acid. The model features compartments and linear transfer coefficients. The compartments are aggregated into nine spaces based on physiological considerations (liver, gallbladder, bile ducts, jejunum, ileum, colon, portal blood sinusoidal blood, and general circulation). The transfer coefficients are also categorized according to function: flow, i.e., emptying of gallbladder or intestinal spaces, and circulation of the blood; biotransformation, i.e., conjugation, deconjugation, or dehydroxylation; and transport, i.e., active or passive transport. The model is made time dependent by introducing meals, which trigger discrete increases in gallbladder emptying and intestinal flow. Each space contains three compartments. For cholic acid, these are unconjugated cholic acid, cholylglycine, and cholyltaurine. The model was then used with all existing experimental data to simulate cholic acid metabolism in healthy man over a 24-h period. Satisfactory agreement was obtained between simulated and experimental results for serum bile acid levels, hepatic bile acid secretion, and bile acid secretion into the intestine. The model was also used to classify 16 clinical instances in which the enterohepatic circulation of bile acids is altered by drugs or disease. The model can be extended to describe completely the metabolism and enterohepatic circulation of any bile acids in man in health and digestive disease. The model should also be broadly applicable to the description of the pharmacokinetics of all other drugs whose metabolism is similar to that of bile acids, i.e., drugs for which there are tissue and bacterial biotransformations, enterohepatic cycling, and appreciable first-pass clearance.
Transcriptional regulation of hepatic stellate cell activation
Authors: D A Mann
Journal: Gut (2002)

The hepatic stellate cell (HSC) is now well established as the key cellular element involved in the development of hepatic fibrosis and because of this there is considerable interest in establishing the molecular events that trigger and perpetuate HSC activation. HSC activation at the level of gene transcription requires the coordinated activity of several key transcriptional regulators of the HSC genome. The considerable advances that have been made in the past five years into the mechanisms by which specific families of transcription factors regulate the profibrogenic characteristics of the activated HSC are reviewed.
Guideline-concordant therapy and outcomes in healthcare-associated pneumonia
Authors: R.T. Attridge, C.R. Frei, M.I. Restrepo, K.A. Lawson, L. Ryan, M.J.V. Pugh, A. Anzueto, E.M. Mortensen
Journal: European Respiratory Journal (2011)

Healthcare-associated pneumonia (HCAP) guidelines were first proposed in 2005 but have not yet been validated. The objective of this study was to compare 30-day mortality in HCAP patients treated with either guideline-concordant (GC)-HCAP therapy or GC community-acquired pneumonia (CAP) therapy. We performed a population-based cohort study of &gt;150 hospitals in the US Veterans Health Administration. Patients were included if they had one or more HCAP risk factors and received antibiotic therapy within 48 h of admission. Critically ill patients were excluded. Independent risk factors for 30-day mortality were determined in a generalised linear mixed-effect model, with admitting hospital as a random effect. Propensity scores for the probability of receiving GC-HCAP therapy were calculated and incorporated into a second logistic regression model. A total of 15,071 patients met study criteria and received GC-HCAP therapy (8.0%), GC-CAP therapy (75.7%) or non-GC therapy (16.3%). The strongest predictors of 30-day mortality were recent hospital admission (OR 2.49, 95% CI 2.12–2.94) and GC-HCAP therapy (OR 2.18, 95% CI 1.86–2.55). GC-HCAP therapy remained an independent risk factor for 30-day mortality (OR 2.12, 95% CI 1.82–2.48) in the propensity score analysis. In nonsevere HCAP patients, GC-HCAP therapy is not associated with improved survival compared with GC-CAP therapy.
Phase II Trial of Pemetrexed and Gemcitabine in Chemotherapy-Naïve Malignant Pleural Mesothelioma
Authors: Pasi A. Jänne, George R. Simon, Corey J. Langer, Robert N. Taub, Afshin Dowlati, Panos Fidias, Matthew Monberg, Coleman Obasaju, Hedy Kindler
Journal: Journal of Clinical Oncology (2008)

Purpose Pemetrexed and gemcitabine have single-agent activity in malignant pleural mesothelioma (MPM). The combination of pemetrexed/gemcitabine has not previously been studied in MPM to our knowledge. Patients and Methods Patients with histologic or cytologic diagnosis of MPM were included. Cohort 1 received gemcitabine 1,250 mg/m 2 on days 1 and 8, with pemetrexed 500 mg/m 2 on day 8, and cohort 2 received gemcitabine 1,250 mg/m 2 on days 1 and 8, with pemetrexed 500 mg/m 2 on day 1. Cycles were repeated every 21 days; all patients were supplemented with folic acid and vitamin B 12 and received dexamethasone. Results One hundred eight patients (cohort 1, n = 56; cohort 2, n = 52) with pleural mesothelioma were enrolled. Among assessable patients, response rate was 26.0% in cohort 1 and 17.1% in cohort 2. Median time to disease progression was 4.34 months for cohort 1 and 7.43 months for cohort 2. Median survival was 8.08 months for cohort 1 (1-year survival = 31.14%) and 10.12 months for cohort 2 (1-year survival = 45.80%). In cohorts 1 and 2, incidence of grade 4 neutropenia was 25.0% and 29.4%, grade 4 thrombocytopenia was 14.3% and 3.9%, grade 3 or 4 anemia was 5.4% and 5.9%, and grade 3 or 4 fatigue was 23.2% and 15.7%, respectively. Conclusion The combination of pemetrexed and gemcitabine resulted in moderate clinical activity in MPM. However, the median survival times are similar to those with single-agent pemetrexed and inferior to outcomes observed with cisplatin in combination with an antifolate.
Prognostic Characteristics of Breast Cancer Among Postmenopausal Hormone Users in a Screened Population
Authors: Karla Kerlikowske, Diana L. Miglioretti, Rachel Ballard-Barbash, Donald L. Weaver, Diana S.M. Buist, William E. Barlow, Gary Cutter, Berta M. Geller, Bonnie Yankaskas, Stephen H. Taplin, Patricia A. Carney
Journal: Journal of Clinical Oncology (2003)

We determined the risk of breast cancer and tumor characteristics among current postmenopausal hormone therapy users compared with nonusers, by duration of use.From January 1996 to December 2000, data were collected prospectively on 374,465 postmenopausal women aged 50 to 79 years who underwent screening mammography. We calculated the relative risk (RR) of breast cancer (invasive or ductal carcinoma-in-situ) and type of breast cancer within 12 months of postmenopausal therapy use among current hormone users with a uterus (proxy for estrogen and progestin use) and without a uterus (proxy for estrogen use), compared with nonusers.Compared with nonusers, women using estrogen and progestin for >/= 5 years were at increased risk of breast tumors of stage 0 or I (RR, 1.51; 95% CI, 1.37 to 1.66), stage II or higher (RR, 1.46; 95% CI, 1.30 to 1.63), size </= 20 mm (RR, 1.59; 95% CI, 1.43 to 1.76), size greater than 20 mm (RR, 1.24; 95% CI, 1.09 to 1.42), grade 1 or 2 (RR, 1.60; 95% CI, 1.44 to 1.77), grade 3 or 4 (RR, 1.54; 95% CI, 1.37 to 1.73), and estrogen receptor-positive (RR, 1.72; 95% CI, 1.55 to 1.90). Estrogen-only users were slightly more likely to have estrogen receptor-positive breast cancer compared with nonusers (RR, 1.14; 95% CI, 1.06 to 1.23).Use of estrogen and progestin postmenopausal hormone therapy for five years or more increased the likelihood of developing breast cancer, including both tumors with favorable prognostic features and tumors with unfavorable prognostic features.
Exercise-induced asthma and cardiovascular fitness in asthmatic children.
Authors: B. J. Thio, A. F. Nagelkerke, A. G. Ketel, B. L. van Keeken, J. E. Dankert-Roelse
Journal: Thorax (1996)

BACKGROUND: The role of physical training in the management of children with exercise-induced asthma is controversial. A study was undertaken to determine whether a relationship could be found between the occurrence of exercise-induced asthma and the degree of cardiovascular fitness in asthmatic children. METHODS: Twenty eight children aged 6-13 with mild to moderate asthma and dyspnoea during or after physical exercise were tested. All patients had a basal forced expiratory volume in one second (FEV1) of &gt; 80% predicted. Twelve patients were taking corticosteroid maintenance medication by inhalation and 16 were not. Two exercise tests were performed on a treadmill to assess peak oxygen consumption rate (VO2max) and the percentage decrease in FEV1 after exercise. RESULTS: There was no correlation between the VO2max and the percentage decrease in FEV1. Patients not taking steroids showed a greater fall in FEV1 than those receiving corticosteroid medication (mean fall in FEV1 28.7% versus 6.6%). Four of the 12 children treated with steroids and two of the 16 children not taking steroids had a level of cardiovascular fitness lower than the 5th percentile for healthy Dutch children. CONCLUSION: Normal cardiovascular fitness does not prevent exercise-induced asthma.
Antitumor Responses Stimulated by Dendritic Cells Are Improved by Triiodothyronine Binding to the Thyroid Hormone Receptor β
Authors: Vanina A. Alamino, Iván D. Mascanfroni, María M. Montesinos, Nicolás Gigena, Ana C. Donadio, Ada G. Blidner, Sonia I. Milotich, Sheue-yann Cheng, Ana M. Masini-Repiso, Gabriel A. Rabinovich, Claudia G. Pellizas
Journal: Cancer Research (2015)

Bidirectional cross-talk between the neuroendocrine and immune systems orchestrates immune responses in both physiologic and pathologic settings. In this study, we provide in vivo evidence of a critical role for the thyroid hormone triiodothyronine (T3) in controlling the maturation and antitumor functions of dendritic cells (DC). We used a thyroid hormone receptor (TR) β mutant mouse (TRβPV) to establish the relevance of the T3-TRβ system in vivo. In this model, TRβ signaling endowed DCs with the ability to stimulate antigen-specific cytotoxic T-cell responses during tumor development. T3 binding to TRβ increased DC viability and augmented DC migration to lymph nodes. Moreover, T3 stimulated the ability of DCs to cross-present antigens and to stimulate cytotoxic T-cell responses. In a B16-OVA mouse model of melanoma, vaccination with T3-stimulated DCs inhibited tumor growth and prolonged host survival, in part by promoting the generation of IFNγ-producing CD8(+) T cells. Overall, our results establish an adjuvant effect of T3-TRβ signaling in DCs, suggesting an immediately translatable method to empower DC vaccination approaches for cancer immunotherapy.
THE INDUCED DEVELOPMENT OF NON-ACID-FAST FORMS OF BACILLUS TUBERCULOSIS AND OTHER MYCO-BACTERIA
Authors: Franklin R. Miller
Journal: The Journal of Experimental Medicine (1932)

Six strains of mycobacteria,-three human strains, Saranac H-37, T. S., and No. 90, a bovine strain, B-1, a smegma strain, No. 74, and a Saranac strain of B. phlei,-have been made to grow as non-acid-fast organisms by the addition to the culture media of a filtered extract of the chromogenic H-37 strain of B. tuberculosis. The action of the extract produced acceleration of growth of the treated culture, followed by macroscopic and microscopic changes, and differentiation into non-acid-fast forms. The bacterial forms grown from these treated cultures were pleomorphic, usually consisting of cocci and small rods; but branching forms and spore-like bodies also developed. The sterility of the extract causing the changes was demonstrated by frequent control inoculations on various media, including Kendall's K medium; and autoclaved extracts had the same effects as non-autoclaved. After transfer to media suitable for acid growths four of the strains reverted not only to acid-fastness but to their original cultural characteristics, providing evidence that the non-acid-fast forms were specific for the strain.
Prediction of worsening of skin fibrosis in patients with diffuse cutaneous systemic sclerosis using the EUSTAR database
Authors: Britta Maurer, Nicole Graf, Beat A Michel, Ulf Müller-Ladner, László Czirják, Christopher P Denton, Alan Tyndall, Carola Metzig, Vivian Lanius, Dinesh Khanna, Oliver Distler
Journal: Annals of the Rheumatic Diseases (2014)

Objectives To identify predictive parameters for the progression of skin fibrosis within 1 year in patients with diffuse cutaneous SSc (dcSSc). Methods An observational study using the EUSTAR database was performed. Inclusion criteria were dcSSc, American College of Rheumatology (ACR) criteria fulfilled, modified Rodnan skin score (MRSS) ≥7 at baseline visit, valid data for MRSS at 2nd visit, and available follow-up of 12±2 months. Worsening of skin fibrosis was defined as increase in MRSS &gt;5 points and ≥25% from baseline to 2nd visit. In the univariate analysis, patients with progressive fibrosis were compared with non-progressors, and predictive markers with p&lt;0.2 were included in the logistic regression analysis. The prediction models were then validated in a second cohort. Results A total of 637 dcSSc patients were eligible. Univariate analyses identified joint synovitis, short disease duration (≤15 months), short disease duration in females/patients without creatine kinase (CK) elevation, low baseline MRSS (≤22/51), and absence of oesophageal symptoms as potential predictors for progressive skin fibrosis. In the multivariate analysis, by employing combinations of the predictors, 17 models with varying prediction success were generated, allowing cohort enrichment from 9.7% progressive patients in the whole cohort to 44.4% in the optimised enrichment cohort. Using a second validation cohort of 188 dcSSc patients, short disease duration, low baseline MRSS and joint synovitis were confirmed as independent predictors of progressive skin fibrosis within 1 year resulting in a 4.5-fold increased prediction success rate. Conclusions Our study provides novel, evidence-based criteria for the enrichment of dcSSc cohorts with patients who experience worsening of skin fibrosis which allows improved clinical trial design.
Mesothelin and osteopontin
Authors: Ioannis Pantazopoulos, Theodoros Xanthos, Paraskevi Boura, Konstantinos Syrigos
Journal: European Respiratory Journal (2013)

The review by PANTAZOPOULOS et al. [1] on mesothelin and osteopontin was timely and well written.However, I would like to comment on some of the statements that were made.Firstly, it states that ''patients with early-stage disease can survive for more than 5 years if the tumour is promptly resected''.This implies that resection would benefit the patient, which is far from proven; there is no randomised study showing this, except for the much criticised the Mesothelioma and Radical Surgery (MARS) study [2] in England, which showed that resection considerably shortened survival.The good survival seen by SUGARBAKER et al.[3] and in other studies can be explained by very strict selection and these patients are likely to survive at least as long without resection, as seen from studies where ''operable'' patients were treated conservatively.Furthermore, the authors claim that ''early diagnosis offers the best hope for a favourable prognosis'', which is an interesting but unproven hypothesis.There is of course a lead time bias, the earlier the diagnosis the longer the survival, but unfortunately we do not know whether early intervention will in fact prolong survival.Thus, screening for mesothelioma in risk groups is not indicated at present, screening should only be performed in diseases where the prognosis has been shown to be improved by early discovery.I fully agree with the other main conclusions in the review, namely that mesothelin, in serum or pleura, can be a useful aid in the diagnostic setup and also used for monitoring patients for recurrence.
Spatial Changes in Transmembrane Potential During Extracellular Electrical Shocks in Cultured Monolayers of Neonatal Rat Ventricular Myocytes
Authors: Anne M. Gillis, Vladimir G. Fast, Stephan Rohr, André G. Kléber
Journal: Circulation Research (1996)

This study investigated the role of different types of discontinuities in tissue architecture on the spatial distribution of the transmembrane potential. Specifically, we tested the occurrence of so-called “secondary sources,” ie, localized hyperpolarizations and depolarizations during the application of extracellular electrical shocks (EESs). Changes in transmembrane potential relative to action potential amplitude (ΔV m /APA) were measured in patterned cultures of neonatal rat myocytes, stained with voltage-sensitive dye (RH-237), by optical mapping (96-channel photodiode array, 6- to 30-μm resolution) during the application of EES (field strength, 8 to 22 V/cm; duration, 6 ms). Across narrow cell strands (width, 218±59 [mean±SD] μm), EES applied during the relative refractory period produced a linear and symmetrical profile of ΔV m /APA (−65±23% maximal hyperpolarization versus +64±15% maximal depolarization). In contrast, the profile of ΔV m /APA was asymmetrical when EESs were applied during the action potential plateau (−95±32% versus +37±14%). At high magnification, no secondary sources were observed at the borders between cells. In dense isotropic cell monolayers or in monolayers and strands showing intercellular clefts, secondary sources were frequently observed. Intercellular clefts of the size of one to several myocytes were sufficient to produce secondary sources of the same magnitude as those that elicited action potentials in dense cell strands. There was a close correlation between the location of secondary sources during EES and localized conduction slowing during propagation. Thus, densely packed cultured cell strands behave as an electrical continuum with no secondary sources occurring at cell borders. Small intercellular clefts can create secondary sources of sufficient magnitude to exert a stimulatory effect.