tbuckley/cabot-search huggingface dataset:
Drug targeting to the liver with lactosylated albumins: Does the glycoprotein target the drug or is the drug targeting the glycoprotein?
Authors: Peter van der Sluijs, Hans P. Bootsma, Bart Postema, Frits Moolenaar, Dirk K. F. Meijer
Journal: Hepatology (1986)

The isolated perfused rat liver preparation was employed to study hepatic disposition of the model drugcarrier conjugate fluorescein-lactosylated albumin (F-L n HSA) with special reference to the influence of the organic anion fluorescein on liver cell specificity of the endocytosed neoglycoprotein. Hepatic clearance of fluoresceinated neoglycoproteins was significantly faster than clearance of radioiodinated neoglycoproteins. Perfusate clearance of F-L 7 HSA and F-L 25 HSA could not completely be inhibited by a dose of 10 mg asialoorosomucoid that saturates the hepatocyte receptor-mediated endocytic process. From these data, we inferred an additional hepatic uptake mechanism, competing with the Ashwell-receptor-mediated internalization of galactoseterminated glycoproteins. Clearance experiments with fluoresceinated 125 I-human serum albumin in the presence of the polyanionic probe dextran sulfate revealed a nearly complete (˜90%) inhibition of hepatic uptake, while also a pronounced effect was obtained with colloidal carbon. These data point to nonparenchymal cell uptake of fluoresceinated protein via interaction with scavenger receptors. In wash-out studies, it was shown that about 25% of ligand sequestrated by sinusoidal liver cells escaped degradation and recycled to the perfusion medium. Our results show that care should be taken in the use of neoglycoproteins as drug carriers to hepatocytes, since a load of only 2 to 3 moles fluorescein permole neoglycoprotein considerably affects intrahepatic distribution. The relative contribution of nonparenchymal cell uptake by coupling of acidic drugs to the neoglycoproteins is very probably inversely related to the number of exposing galactose groups per molecule neoglycoprotein. This phenomenon of “inversed targeting” could therapeutically both be useful or detrimental, dependent on the spectrum of cell types that should be reached by the drug.
Intravital Imaging Illuminates Transforming Growth Factor β Signaling Switches during Metastasis
Authors: Silvia Giampieri, Sophie Pinner, Erik Sahai
Journal: Cancer Research (2010)

Abstract Transforming growth factor β (TGFβ) has seemingly contradictory roles in tumor progression: it can promote metastatic invasion but also act as a tumor suppressor. Recently, two studies have used intravital imaging to unravel the role of TGFβ at different stages of the metastatic process. TGFβ promotes single cell motility, which enables invasion into blood vessels. However the activation of TGFβ signaling is a transient event and is not maintained at distant sites. The downregulation of TGFβ signaling at secondary sites then permits growth of secondary tumors. In the absence of TGFβ, cells are restricted to collective movement and lymphatic spread. Here, we discuss these findings and their potential implications. Cancer Res; 70(9); 3435–9. ©2010 AACR.
THE MECHANISM OF ALLOXAN PROTECTION IN EXPERIMENTAL ATHEROSCLEROSIS
Authors: D. L. Cook, Lois M. Mills, D. M. Green
Journal: The Journal of Experimental Medicine (1954)

Experiments were performed to compare the effects of cholesterol feeding in (a) control rabbits, (b) alloxan-diabetic rabbits, and (c) rabbits injected with alloxan while the pancreas was temporarily occluded from the circulation. The alloxan-diabetic rabbits consumed significantly higher quantities of cholesterol and food and had serum cholesterol and lipoprotein (Sf 5–9 and Sf 16–30) concentrations significantly increased over the control levels. They failed to show a commensurate increase in the degree of atherosclerosis. Rabbits in which the diabetogenic action of alloxan was prevented by temporary occlusion of the pancreas from the circulation during its administration developed grades of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis not significantly different from the controls. The results are interpreted as indicating that the effects of alloxan on tissues other than the pancreas do not protect against experimental atherosclerosis produced by cholesterol feeding.
Doctors’ self-reported physical activity, their counselling practices and their correlates in urban Trivandrum, South India: should a full-service doctor be a physically active doctor?
Authors: Lipika Patra, G K Mini, Elezebeth Mathews, K R Thankappan
Journal: British Journal of Sports Medicine (2013)

Doctors' self-reported physical activity (PA) is associated with their propensity for prescribing PA.We surveyed 146 doctors (median age 42 years; men 58.9%), selected by multistage random sampling. Information on demographic details, self-reported PA and counselling offered to their patients was collected using a pretested, structured, self-administered questionnaire. Multivariate logistic regression analysis was carried out to find the predictors of PA and PA counselling offered to the patients.Moderate PA was reported by 37.7% (95% CI 29.8 to 45.5) of the doctors and the remaining 62.3%reported being inactive. Doctors who were motivated to perform PA (OR 4.01, 95% CI 1.82 to 8.86), who used exercise equipment at home (OR 3.97, CI 1.68 to 9.36) and who used a neighbourhood facility for PA (OR 2.36, CI 1.11 to 5.02) were more likely to perform moderate PA compared with their counterparts. 25% of the doctors always asked and advised their patients on PA. Doctors who believed that their own healthy lifestyle influenced advice practices (OR 9.13, CI 2.49 to 33.41), who consulted less than 30 patients/day (OR 5.35, CI 1.41 to 20.25) and who reported previous participation in sports activities (OR 4.22, CI 1.77 to 10.04) were more likely to always ask and advise their patients on PA compared with their counterparts.A majority of the doctors in our study were inactive and did not ask or advise their patients on PA. Measures are warranted to enhance doctors' own PA and their counselling practices.
Estimated Global, Regional, and National Disease Burdens Related to Sugar-Sweetened Beverage Consumption in 2010
Authors: Gitanjali M. Singh, Renata Micha, Shahab Khatibzadeh, Stephen Lim, Majid Ezzati, Dariush Mozaffarian
Journal: Circulation (2015)

Background— Sugar-sweetened beverages (SSBs) are consumed globally and contribute to adiposity. However, the worldwide impact of SSBs on burdens of adiposity-related cardiovascular diseases (CVDs), cancers, and diabetes mellitus has not been assessed by nation, age, and sex. Methods and Results— We modeled global, regional, and national burdens of disease associated with SSB consumption by age/sex in 2010. Data on SSB consumption levels were pooled from national dietary surveys worldwide. The effects of SSB intake on body mass index and diabetes mellitus, and of elevated body mass index on CVD, diabetes mellitus, and cancers were derived from large prospective cohort pooling studies. Disease-specific mortality/morbidity data were obtained from Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We computed cause-specific population-attributable fractions for SSB consumption, which were multiplied by cause-specific mortality/morbidity to compute estimates of SSB-attributable death/disability. Analyses were done by country/age/sex; uncertainties of all input data were propagated into final estimates. Worldwide, the model estimated 184 000 (95% uncertainty interval, 161 000–208 000) deaths/y attributable to SSB consumption: 133 000 (126 000–139 000) from diabetes mellitus, 45 000 (26 000–61 000) from CVD, and 6450 (4300–8600) from cancers. Five percent of SSB-related deaths occurred in low-income, 70.9% in middle-income, and 24.1% in high-income countries. Proportional mortality attributable to SSBs ranged from &lt;1% in Japanese &gt;65 years if age to 30% in Mexicans &lt;45 years of age. Among the 20 most populous countries, Mexico had largest absolute (405 deaths/million adults) and proportional (12.1%) deaths from SSBs. A total of 8.5 (2.8, 19.2) million disability-adjusted life years were related to SSB intake (4.5% of diabetes mellitus–related disability-adjusted life years). Conclusions— SSBs are a single, modifiable component of diet that can impact preventable death/disability in adults in high-, middle-, and low-income countries, indicating an urgent need for strong global prevention programs.
Chemotherapy Regimen Predicts Steatohepatitis and an Increase in 90-Day Mortality After Surgery for Hepatic Colorectal Metastases
Authors: Jean-Nicolas Vauthey, Timothy M. Pawlik, Dario Ribero, Tsung-Teh Wu, Daria Zorzi, Paulo M. Hoff, Henry Q. Xiong, Cathy Eng, Gregory Y. Lauwers, Mari Mino-Kenudson, Mauro Risio, Andrea Muratore, Lorenzo Capussotti, Steven A. Curley, Eddie K. Abdalla
Journal: Journal of Clinical Oncology (2006)

Chemotherapy before resection of hepatic colorectal metastases (CRM) may cause hepatic injury and affect postoperative outcome.Four hundred six patients underwent hepatic resection of CRM between 1992 and 2005. Pathologic review of the nontumorous liver was performed using established criteria for steatosis, steatohepatitis, and sinusoidal injury. The effect of chemotherapy and liver injury on perioperative outcome was analyzed.One hundred fifty-eight patients (38.9%) received no preoperative chemotherapy, whereas 248 patients (61.1%) did. The median duration of chemotherapy was 16 weeks (range, 2 to 70 weeks). Chemotherapy consisted of fluoropyrimidine-based regimens (fluorouracil [FU] alone, 15.5%; irinotecan plus FU, 23.1%; and oxaliplatin plus FU, 19.5%) and other therapy (3.0%). On pathologic analysis, 36 patients (8.9%) had steatosis, 34 (8.4%) had steatohepatitis, and 22 (5.4%) had sinusoidal dilation. Oxaliplatin was associated with sinusoidal dilation compared with no chemotherapy (18.9% v 1.9%, respectively; P < .001; odds ratio [OR] = 8.3; 95% CI, 2.9 to 23.6). In contrast, irinotecan was associated with steatohepatitis compared with no chemotherapy (20.2% v 4.4%, respectively; P < .001; OR = 5.4; 95% CI, 2.2 to 13.5). Patients with steatohepatitis had an increased 90-day mortality compared with patients who did not have steatohepatitis (14.7% v 1.6%, respectively; P = .001; OR = 10.5; 95% CI, 2.0 to 36.4).Steatohepatitis is associated with an increased 90-day mortality after hepatic surgery. In patients with hepatic CRM, the chemotherapy regimen should be carefully considered because the risk of hepatotoxicity is significant.
Caveolae, caveolins, and cavins: complex control of cellular signalling and inflammation
Authors: J. H. Chidlow, W. C. Sessa
Journal: Cardiovascular Research (2010)

Caveolae are specialized lipid rafts that form flask-shaped invaginations of the plasma membrane. They are involved in cell signalling and transport and have been shown critically regulate vascular reactivity and blood pressure. The organization and functions of caveolae are mediated by coat proteins (caveolins) and support or adapter proteins (cavins). The caveolins, caveolin-1, -2, and -3, form the structural backbone of caveolae. These proteins are also highly integrated into caveolae function and have their own activity independent of caveolae. The cavins, cavins 1-4, are involved in regulation of caveolae and modulate the function of caveolins by promoting the membrane remodelling and trafficking of caveolin-derived structures. The relationships between these different proteins are complex and intersect with many aspects of cell function. Caveolae have also been implicated in chronic inflammatory conditions and other pathologies including atherosclerosis, inflammatory bowel disease, muscular dystrophy, and generalized dyslipidaemia. The pathogenic role of the caveolins is an emerging area, however, the roles of cavins in disease is just beginning to be explored. This review will examine the relationship between caveolins and cavins and explore the role of caveolae in inflammatory signalling mechanisms.
Violence Against Women
Authors: Yank D. Coble
Journal: JAMA (1992)

Evidence collected over the last 20 years indicates that physical and sexual violence against women is an enormous problem. Much of this violence is perpetrated by women's intimate partners or in relationships that would presumably carry some protective aura (eg, father-daughter, boyfriend-girlfriend). This violence carries with it both short- and long-term sequelae for women and affects both their physical and psychological well-being. The high prevalence of violence against women brings them into regular contact with physicians; at least one in five women seen in emergency departments has symptoms relating to abuse. However, physicians frequently treat the injuries only symptomatically or fail to recognize the injuries as abuse. Even when recognized, physicians are often without resources to address the needs of abused women. This report documents the extent of violence against women and suggests paths that the physician community might take to address the needs of victims. (<i>JAMA</i>. 1992;267:3184-3189)
Immunocytochemical localization of distinct isoforms of nitric oxide synthase in the juxtaglomerular apparatus of normal rat kidney.
Authors: A Tojo, S S Gross, L Zhang, C C Tisher, H H Schmidt, C S Wilcox, K M Madsen
Journal: Journal of the American Society of Nephrology (1994)

Nitric oxide (NO) is a messenger molecule that functions as a vasodilator and accounts for the biologic activity of endothelium-derived relaxing factor (EDRF). The enzyme responsible for NO production, NO synthase (NOS), exists in different isoforms. Some are expressed constitutively in various tissues, whereas others require induction by endotoxin and cytokines. There is evidence that NO plays an important role in the regulation of basal renal vascular resistance and in the tubuloglomerular feedback response. Specific antibodies to a constitutive NOS isolated from rat brain (B-NOS) and an inducible NOS isolated from rat aortic smooth muscle (VSM-NOS) were used to establish the cellular and subcellular distribution of NOS in the kidney. Kidneys from normal rats were preserved and processed for light and electron microscopic immunohistochemical studies using both a preembedding and a postembedding horseradish peroxidase technique. By light microscopy, strong immunostaining for B-NOS was observed in the juxtaglomerular apparatus, where it was located in cells of the macula densa. In contrast, immunostaining for VSM-NOS was specifically located in the terminal afferent arteriole and occasionally also in the initial efferent arteriole in the juxtaglomerular apparatus. In addition, faint immunostaining was present in the entire distal tubule. There was no labeling of arcuate or interlobular arteries. The injection of lipopolysaccharide was associated with increased immunostaining for VSM-NOS in the afferent arteriole but had no effect on B-NOS staining. By electron microscopy, B-NOS immunostaining was present throughout the cytoplasm of the macula densa cells, where it appeared to be associated mainly with small vesicles. Immunostaining for VSM-NOS in the afferent arteriole exhibited a patchy distribution in some cells, whereas other cells were stained throughout the cytoplasm. These results indicate that two distinct isoforms of NOS are present in the juxtaglomerular apparatus and support the hypothesis that NOS is involved in the regulation of tubuloglomerular feedback and glomerular capillary pressure.
Role of prostaglandins in the reversal of one-kidney hypertension in the rabbit.
Authors: J C Romero, C E Ott, J J Aguilo, V E Torres, C G Strong
Journal: Circulation Research (1975)

Hypertensive rabbits with a clip on the renal artery of their solitary remaining kidney show an abrupt decrease in blood pressure after the arterial constriction is released. Although the mechanism underlying this phenomenon remains controversial, some experimental evidence suggests that it could be humorally mediated. The involvement of prostaglandins was investigated by examining the effect of the release of the arterial constriction on blood pressure, renal blood flow, glomerular filtration rate, and urinary output in five conscious single-kidney hypertensive rabbits in which prostaglandin synthesis was blocked with indomethacin (priming intravenous injection of 9 mg/kg followed by a constant infusion of 1 mg/kg hour-1). The results were compared with those obtained in another group of five single-kidney hypertensive rabbits submitted to the same protocol but not treated with indomethacin. The blockade of prostaglandin synthesis with indomethacin prevented the increments in renal blood flow and glomerular filtration rate seen in the control rabbits after unclipping a significantly retarded the appearance of diuresis and the fall in blood pressure. Despite these observations, the results do not indicate a major participation of prostaglandins in the reversal of single-kidney hypertension, because the decrease in blood pressure 9 hours after the removal of the arterial constriction was similar in both groups.
CD207+ CD103+ dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells
Authors: Sandrine Henri, Lionel Franz Poulin, Samira Tamoutounour, Laurence Ardouin, Martin Guilliams, Béatrice de Bovis, Elisabeth Devilard, Christophe Viret, Hiroaki Azukizawa, Adrien Kissenpfennig, Bernard Malissen
Journal: The Journal of Experimental Medicine (2009)

Recent studies have challenged the view that Langerhans cells (LCs) constitute the exclusive antigen-presenting cells of the skin and suggest that the dermal dendritic cell (DDC) network is exceedingly complex. Using knockin mice to track and ablate DCs expressing langerin (CD207), we discovered that the dermis contains five distinct DC subsets and identified their migratory counterparts in draining lymph nodes. Based on this refined classification, we demonstrated that the quantitatively minor CD207+ CD103+ DDC subset is endowed with the unique capability of cross-presenting antigens expressed by keratinocytes irrespective of the presence of LCs. We further showed that Y-Ae, an antibody that is widely used to monitor the formation of complexes involving I-Ab molecules and a peptide derived from the I-E α chain, recognizes mature skin DCs that express I-Ab molecules in the absence of I-E α. Knowledge of this extra reactivity is important because it could be, and already has been, mistakenly interpreted to support the view that antigen transfer can occur between LCs and DDCs. Collectively, these data revisit the transfer of antigen that occurs between keratinocytes and the five distinguishable skin DC subsets and stress the high degree of functional specialization that exists among them.
Enzymes, detergents and skin: facts and fantasies
Authors: D.A. Basketter, J.S.C. English, S.H. Wakelin, I.R. White
Journal: British Journal of Dermatology (2008)

In their raw state, enzymes of bacterial/fungal origin cause allergic reactions in the lung. Proteolytic enzymes also cause irritation to skin, eyes and the respiratory tract. For 40 years, encapsulated enzymes have been used worldwide in detergent products, especially laundry formulations, and have increasing importance due to biodegradability and functionality at low temperatures, offering environmental benefits. Uniquely to the U.K., for years it has been suggested that the inclusion of enzymes in such products leads to adverse skin reactions, including erythema, pruritus and exacerbation of eczema. In this review, we look at the facts, asking whether there is evidence that the hazards identified for enzymes translate into any risk for consumer health. By considering the actual exposures in consumer use and exaggerated product usage, it is concluded that the irritating and allergenic hazards of enzyme raw materials do not translate into a risk of skin reactions, either irritant or allergic. Investigations of numerous individuals with skin complaints attributed to laundry products demonstrate convincingly that enzymes were not responsible. Indeed, enzyme‐containing laundry products have an extensive history of safe use. Thus, the supposed adverse effects of enzymes on skin seem to be a consequence of a mythology. The important practical lesson is that when primary or secondary care practitioners are presented with a skin complaint, it should not be dismissed as a result of using an enzyme‐containing laundry product as the diagnosis will certainly lie elsewhere. Education for healthcare professionals could usefully be enhanced to take this on board.
Inferring gene function from evolutionary change in signatures of translation efficiency
Authors: Anita Krisko, Tea Copic, Toni Gabaldón, Ben Lehner, Fran Supek
Journal: Genome biology (2014)

The genetic code is redundant, meaning that most amino acids can be encoded by more than one codon. Highly expressed genes tend to use optimal codons to increase the accuracy and speed of translation. Thus, codon usage biases provide a signature of the relative expression levels of genes, which can, uniquely, be quantified across the domains of life.Here we describe a general statistical framework to exploit this phenomenon and to systematically associate genes with environments and phenotypic traits through changes in codon adaptation. By inferring evolutionary signatures of translation efficiency in 911 bacterial and archaeal genomes while controlling for confounding effects of phylogeny and inter-correlated phenotypes, we linked 187 gene families to 24 diverse phenotypic traits. A series of experiments in Escherichia coli revealed that 13 of 15, 19 of 23, and 3 of 6 gene families with changes in codon adaptation in aerotolerant, thermophilic, or halophilic microbes. Respectively, confer specific resistance to, respectively, hydrogen peroxide, heat, and high salinity. Further, we demonstrate experimentally that changes in codon optimality alone are sufficient to enhance stress resistance. Finally, we present evidence that multiple genes with altered codon optimality in aerobes confer oxidative stress resistance by controlling the levels of iron and NAD(P)H.Taken together, these results provide experimental evidence for a widespread connection between changes in translation efficiency and phenotypic adaptation. As the number of sequenced genomes increases, this novel genomic context method for linking genes to phenotypes based on sequence alone will become increasingly useful.