tbuckley/cabot-search huggingface dataset:
Neurogenic Hypertension in the Rat
Authors: EDUARDO M. KRIEGER
Journal: Circulation Research (1964)

Several techniques of radical denervation of the sino-aortic depressor areas were tried in order to produce a permanent neurogenic hypertension in the rat. The aortic depressor fibers were interrupted at the neck level by resecting the nerves which usually exhibit baroreceptor activity, namely, isolated aortic nerve, sympathetic, and laryngeal nerves. The carotid sinus was denervated by stripping the carotid bifurcation and painting with phenol. When the carotid bifurcation was resected bilaterally, in a one-stage operation, all rats showed symptoms of cerebral ischemia, dying shortly thereafter. Isolated denervation of the aortic baroreceptors was followed by a transitory hypertension. No changes in preasure were observed when only the carotid sinuses were denervated. A few rats in which the usual baroreceptor pathways were interrupted, except the superior laryngeal nerve, developed chronic hypertension. Yet, to obtain consistently permanent hypertension it was necessary to include in the denervation every baroreceptor route. A simple one-stage operation for complete sino-aortic baroreceptor denervation is described. This procedure was used in 140 rats that were then studied for periods up to one year. All the operated animals presented some degree of hypertension. Blood pressure measurements made during the first week showed even then that the rats were hypertensive. This observation suggests that in the rat no latent period for the appearance of neurogenic hypertension is present. Hypertension was permanent in 75% of the rats observed up to one year; blood pressure returned to normal values in the remaining 25%, usually after the third month. Extirpation of the adrenal medulla had no effect on the evolution of the hypertension in the denervated rats. Blood pressure was measured repeatedly in unanesthetized rats by tail plethysmography. Pressure values determined by this method, though 10 to 20 mm Hg lower, approximated the mean arterial pressure recorded directly from the femoral artery in normotensive and hypertensive rats. The hypertension in denervated rats included an increase of systolic as well as diastolic pressure. The heart rates of quiet hypertensive rats were within the normal range and, in general, no close correlation was observed between increases in blood pressure and elevations in heart rate. Normal rats have marked fluctuations in both pressure and heart rate when walking or when stimulated; these fluctuations were much greater in the neurogenic hypertensive animals. Moreover, the hypertensive rats showed large oscillations of blood pressure synchronous with respiratory movements particularly when the latter were slower and deeper than normal. The rats seemed to tolerate both the denervation and the hypertension very well. Histological examination of tissues from hypertensive rats showed myocardial hypertrophy and a thickening of the basement membrane of the glomerular capsule. The severity of the latter abnormality was closely associated with the duration of the hypertension.
<i>In situ</i> High Throughput Scattering Light Analysis of Single Plasmonic Nanoparticles in Living Cells
Authors: Zhen Gu, Chao Jing, Yi-Lun Ying, Pingang He, Yi-Tao Long
Journal: Theranostics (2014)

Plasmonic nanoparticles have been widely applied in cell imaging, disease diagnosis, and photothermal therapy owing to their unique scattering and absorption spectra based on localized surface plasmon resonance (LSPR) property. Recently, it is still a big challenge to study the detailed scattering properties of single plasmonic nanoparticles in living cells and tissues, which have dynamic and complicated environment. The conventional approach for measuring the scattering light is based on a spectrograph coupled to dark-field microscopy (DFM), which is time-consuming and limited by the small sample capacity. Alternatively, RGB-based method is promising in high-throughput analysis of single plasmonic nanoparticles in dark-field images, but the limitation in recognition of nanoparticles hinders its application for intracellular analysis. In this paper, we developed an automatic and robust method for recognizing the plasmonic nanoparticles in dark-field image for RGB-based analysis. The method involves a bias-modified fuzzy C-means algorithm, through which biased illumination in the image could be eliminated. Thus, nearly all of the gold nanoparticles in the recorded image were recognized both on glass slide and in living cells. As confirmed, the distribution of peak wavelength obtained by our method is well agreed to the result measured by conventional method. Furthermore, we demonstrated that our method is profound in cell imaging studies, where its advantages in fast and high-throughput analysis of the plasmonic nanoparticles could be applied to confirm the presence and location of important biological molecules and provide efficiency information for cancer drug selection.
Development and Therapeutic Options for the Treatment of Raloxifene-Stimulated Breast Cancer in Athymic Mice
Authors: Ruth M. O'Regan, Clodia Osipo, Eric Ariazi, Eun Sook Lee, Kathleen Meeke, Caroline Morris, Anne Bertucci, Mohammad A.B. Sarker, Ronald Grigg, V. Craig Jordan
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Selective estrogen receptor modulators (SERM) are used for the treatment and prevention of breast cancer (tamoxifen) and osteoporosis (raloxifene). Mechanisms of tamoxifen-resistance in breast cancer are incompletely understood but current research is focused on crosstalk between growth factor receptors and the estrogen receptor α (ERα) pathway. There is increasing clinical use of raloxifene for the treatment of osteoporosis, but the widespread use of this SERM will have consequences for the treatment of breast cancer in raloxifene-exposed women. Experimental Design: We took the strategic step of developing a raloxifene-resistant tumor (MCF-7RALT) model in vivo and investigating the mechanisms responsible for resistance. Results: MCF-7RALT tumors exhibited phase I SERM resistance, growing in response to SERMs and 17β-estradiol. Epidermal growth factor receptor/HER1 and HER2/neu mRNAs were increased in MCF-7RALT tumors. The HER2/neu blocker, trastuzumab, but not the epidermal growth factor receptor blocker, gefitinib, decreased the growth of MCF-7RALT tumors in vivo. Consequently, trastuzumab decreased prosurvival/proliferative proteins: phospho-HER2/neu, total HER2/neu, phospho-Akt (protein kinase B), glycogen synthetase kinase-3, cyclin D1, and the antiapoptotic protein X chromosome-linked inhibitor of apoptosis, whereas increasing the proapoptotic protein, caspase-7, in raloxifene-treated MCF-7RALT tumors. Interestingly, ERα protein was overexpressed in untreated MCF-7RALT tumors and hyperactivated in cells derived from these tumors. Only fulvestrant completely inhibited the growth and ERα activity of MCF-7RALT tumors. The coactivator of ERα, amplified in breast cancer-1 protein was modestly increased in the raloxifene-treated MCF-7RALT tumors and increased both basal and estradiol-induced activity of ERα in cells derived from the MCF-7RALT tumors. Conclusions: These results suggest that overexpression and increased activity of HER2/neu might be responsible for the development of raloxifene-resistant breast cancer. The results also suggest that increased expression of basal activity of ERα could contribute to the hypersensitivity of MCF-7RALT tumors in response to estradiol because only fulvestrant blocked growth and ERα activity.
Targeting Hsp90/Hsp70-Based Protein Quality Control for Treatment of Adult Onset Neurodegenerative Diseases
Authors: William B. Pratt, Jason E. Gestwicki, Yoichi Osawa, Andrew P. Lieberman
Journal: The Annual Review of Pharmacology and Toxicology (2014)

Currently available therapies for adult onset neurodegenerative diseases provide symptomatic relief but do not modify disease progression. Here we explore a new neuroprotective approach based on drugs targeting chaperone-directed protein quality control. Critical target proteins that unfold and aggregate in these diseases, such as the polyglutamine androgen receptor in spinal and bulbar muscular atrophy, huntingtin in Huntington's disease, α-synuclein in Parkinson's disease, and tau in Alzheimer's disease, are client proteins of heat shock protein 90 (Hsp90), and their turnover is regulated by the protein quality control function of the Hsp90/Hsp70-based chaperone machinery. Hsp90 and Hsp70 have opposing effects on client protein stability in protein quality control; Hsp90 stabilizes the clients and inhibits their ubiquitination, whereas Hsp70 promotes ubiquitination dependent on CHIP (C terminus of Hsc70-interacting protein) and proteasomal degradation. We discuss how drugs that modulate proteostasis by inhibiting Hsp90 function or promoting Hsp70 function enhance the degradation of the critical aggregating proteins and ameliorate toxic symptoms in cell and animal disease models.
Orange Juice or Fructose Intake Does Not Induce Oxidative and Inflammatory Response
Authors: Husam Ghanim, Priya Mohanty, Ram Pathak, Ajay Chaudhuri, Chang Ling Sia, Paresh Dandona
Journal: Diabetes Care (2007)

We have previously shown that 300 kcal from glucose intake induces a significant increase in reactive oxygen species (ROS) generation and nuclear factor-kappaB (NF-kappaB) binding in the circulating mononuclear cells in healthy normal subjects. We hypothesized that the intake of 300 calories as orange juice or fructose, the other major carbohydrate in orange juice, would induce a significantly smaller response than that of glucose.Four groups (eight subjects each) of normal-weight subjects were given a 300-cal drink of glucose (75 g), fructose (75 g), or orange juice or water sweetened with saccharin (control group) to drink, and then blood samples were collected.There was a significant increase in ROS generation by mononuclear cells (by 130 +/- 18%, P < 0.001), polymorph nuclear cells (by 95 +/- 22%, P < 0.01), and in NF-kappaB binding in mononuclear cells by 82 +/- 16% (P < 0.01) over the baseline after 2 h of glucose intake. These changes were absent following fructose, orange juice, or water intake. There was significantly lower ROS generation and NF-kappaB binding following orange juice, fructose, and water compared with glucose (P < 0.001 for all). Furthermore, incubation of mononuclear cells in vitro with 50 mmol/l of the flavonoids hesperetin or naringenin reduced ROS generation by 52 +/- 7% and 77 +/- 8% (P < 0.01), respectively, while fructose or ascorbic acid did not cause any change.Caloric intake in the form of orange juice or fructose does not induce either oxidative or inflammatory stress, possibly due to its flavonoids content and might, therefore, represent a potentially safe energy source.
High-Throughput Genetic Testing for Thrombotic Microangiopathies and C3 Glomerulopathies
Authors: Fengxiao Bu, Nicolo Ghiringhelli Borsa, Michael B. Jones, Erika Takanami, Carla Nishimura, Jill J. Hauer, Hela Azaiez, Elizabeth A. Black-Ziegelbein, Nicole C. Meyer, Diana L. Kolbe, Yingyue Li, Kathy Frees, Michael J. Schnieders, Christie Thomas, Carla Nester, Richard J.H. Smith
Journal: Journal of the American Society of Nephrology (2015)

The thrombotic microangiopathies (TMAs) and C3 glomerulopathies (C3Gs) include a spectrum of rare diseases such as atypical hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, C3GN, and dense deposit disease, which share phenotypic similarities and underlying genetic commonalities. Variants in several genes contribute to the pathogenesis of these diseases, and identification of these variants may inform the diagnosis and treatment of affected patients. We have developed and validated a comprehensive genetic panel that screens all exons of all genes implicated in TMA and C3G. The closely integrated pipeline implemented includes targeted genomic enrichment, massively parallel sequencing, bioinformatic analysis, and a multidisciplinary conference to analyze identified variants in the context of each patient's specific phenotype. Herein, we present our 1-year experience with this panel, during which time we studied 193 patients. We identified 17 novel and 74 rare variants, which we classified as pathogenic (11), likely pathogenic (12), and of uncertain significance (68). Compared with controls, patients with C3G had a higher frequency of rare and novel variants in C3 convertase (C3 and CFB) and complement regulator (CFH, CFI, CFHR5, and CD46) genes (P<0.05). In contrast, patients with TMA had an increase in rare and novel variants only in complement regulator genes (P<0.01), a distinction consistent with differing sites of complement dysregulation in these two diseases. In summary, we were able to provide a positive genetic diagnosis in 43% and 41% of patients carrying the clinical diagnosis of C3G and TMA, respectively.
New treatment modalities for granuloma faciale
Authors: E. Ludwig, J.-P. Allam, T. Bieber, N. Novak
Journal: British Journal of Dermatology (2003)

Granuloma faciale (GF) is a rare, chronic skin disorder in which numerous treatment modalities have been used without any consistent long‐term effect. We report three cases of GF, two of which were successfully treated with the Laserscope potassium‐titanyl‐phosphate 532‐nm laser within 2 weeks and one with topical tacrolimus ointment 0·1%. Our observations suggest that these new treatment modalities for GF, which we report here for the first time, can provide effective and non‐invasive treatment for this disease.
US prison directors’ group calls for reduced use of solitary confinement
Authors: Michael McCarthy
Journal: BMJ (2015)

The leading organization of US prison administrators has described the prolonged isolation of individuals in solitary confinement in US jails and prisons as a “grave problem” and called for the measure to be used less frequently and for the conditions in which isolated prisoners are held to be improved.

The Association of State Correctional Administrators said in a statement, “The insistence on change comes not only from legislators across the political spectrum, judges, and a host of private sector voices, but also from the directors of correctional systems at both state and federal levels.” 

The statement coincided with the publication of a report by the association and the Arthur Liman Public Interest Program at Yale Law School in New Haven, Connecticut, on the number of prisoners held in solitary confinement nationwide and the conditions in which they are held.1

The report estimated that in 2014 some 80 000 to 100 000 people were held in …
Free radical generation by neutrophils: a potential mechanism of cellular injury in acute alcoholic hepatitis.
Authors: A J Williams, R E Barry
Journal: Gut (1987)

Liver membrane vesicles were prepared from operative liver biopsies from six patient volunteers undergoing abdominal surgery for non-hepatic disease. Neutrophils were extracted from their blood. The liver membrane vesicles were exposed to 1 mmol/l acetaldehyde with or without reduction of the resultant adducts formed. The production of superoxide anion by the neutrophils upon exposure to the liver membrane vesicles prepared from the same patient was assessed by measuring the rate of cytochrome c reduction before and after the addition of superoxide dismutase. Preincubation with acetaldehyde significantly increased superoxide production in response to both the reduced (from 35.5 +/- 7.1 nmol O2-/10(8) cells/min to 128 +/- 25, mean +/- SEM, p less than 0.01) and the non-reduced liver cell membranes (from 17.2 +/- 4.3 to 81 +/- 17, p less than 0.01); 1 mmol/l acetaldehyde alone caused no superoxide production. Neutrophil free radical production in response to acetaldehyde altered hepatocyte membranes could be an important mechanism of cellular injury in acute alcoholic hepatitis.
Concentrations of Low-Density Lipoprotein Cholesterol and Total Cholesterol Among Children and Adolescents in the United States
Authors: Earl S. Ford, Chaoyang Li, Guixiang Zhao, Ali H. Mokdad
Journal: Circulation (2009)

Recently, the American Academy of Pediatrics updated guidance on lipid screening in childhood. Our objective was to examine recent distributions in concentrations of total cholesterol and low-density lipoprotein cholesterol among US children and adolescents and to estimate the prevalence of adolescents who are potentially eligible for pharmacological treatment for elevated concentrations of low-density lipoprotein cholesterol.We used data from the National Health and Nutrition Examination Survey 1999 to 2006 for participants 6 to 17 years of age. The mean concentration for low-density lipoprotein cholesterol for participants 12 to 17 years of age was 90.2 mg/dL (n=2724), and the mean concentration of total cholesterol among participants 6 to 17 years of age was 163.0 mg/dL (n=9868). Depending on the cut points used, an elevated concentration of low-density lipoprotein cholesterol was noted for 5.2% to 6.6% of participants and an elevated concentration of total cholesterol for 9.6% to 10.7%. Approximately 0.8% of adolescents 12 to 17 years of age were potentially eligible for pharmacological treatment for elevated concentrations of low-density lipoprotein cholesterol.Given current guidelines, only a small percentage of US adolescents may need pharmacological treatment for elevated concentrations of low-density lipoprotein cholesterol.
Transforming Growth Factor β Receptor Type II Inactivation Induces the Malignant Transformation of Intestinal Neoplasms Initiated by <i>Apc</i> Mutation
Authors: Nina M. Muñoz, Melissa Upton, Andres Rojas, M. Kay Washington, Li Lin, Anna Chytil, Elif G. Sozmen, Blair B. Madison, Ambra Pozzi, Randall T. Moon, Harold L. Moses, William M. Grady
Journal: Cancer Research (2006)

Abstract The transforming growth factor-β (TGF-β) signaling pathway is a tumor-suppressor pathway that is commonly inactivated in colon cancer. TGF-β is a secreted ligand that mediates its effects through a transmembrane heteromeric receptor complex, which consists of type I (TGFBR1) and type II subunits (TGFBR2). Approximately 30% of colon cancers carry TGFBR2 mutations, demonstrating that it is a common target for mutational inactivation in this cancer. To assess the functional role of TGFBR2 inactivation in the multistep progression sequence of colon cancer, we generated a mouse model that recapitulates two common genetic events observed in human colon cancer by mating Apc1638N/wt mice with mice that are null for Tgfbr2 in the intestinal epithelium, Villin-Cre;Tgfbr2E2flx/E2flx mice. In this model, we observed a dramatic increase in the number of intestinal adenocarcinomas in the Apc1638N/wt;Villin-Cre;Tgfbr2E2flx/E2flx mice (called Apc1638N/wt;Tgfbr2IEKO) compared with those mice with intact Tgfbr2 (Apc1638N/wt;Tgfbr2E2flx/E2flx). Additionally, in vitro analyses of epithelial tumor cells derived from the Apc1638N/wt;Tgfbr2IEKO mice showed enhanced expression and activity of matrix metalloproteinase MMP-2 and MMP-9, as well as increased TGF-β1 secretion in the conditioned medium. Similarly, primary tumor tissues from the Apc1638N/wt;Tgfbr2IEKO mice also showed elevated amounts of TGF-β1 as well as higher MMP-2 activity in comparison with Apc1638N/wt;Tgfbr2E2flx/E2flx–derived tumors. Thus, loss of TGFBR2 in intestinal epithelial cells promotes the invasion and malignant transformation of tumors initiated by Apc mutation, providing evidence that Wnt signaling deregulation and TGF-β signaling inactivation cooperate to drive the initiation and progression, respectively, of intestinal cancers in vivo. (Cancer Res 2006; 66(20): 9837-44)
Antiphospholipid Syndrome Nephropathy in Systemic Lupus Erythematosus
Authors: Eric Daugas, Dominique Nochy, Du Le Thi Huong, Pierre Duhaut, He[Combining Acute Accent]le[Combining Grave Accent]ne Beaufils, Vale[Combining Acute Accent]rie Caudwell, Jean Bariety, Jean-Charles Piette, Gary Hill
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. In the course of the antiphospholipid syndrome (APS), the existence of vaso-occlusive lesions capable of affecting numerous organs is now well established. The renal involvement attributable to primary APS, APS nephropathy (APSN), corresponds to vaso-occlusive lesions of the intrarenal vessels, associating side-by-side, acute thromboses with chronic arterial and arteriolar lesions, leading to zones of cortical ischemic atrophy. A retrospective study of 114 lupus patients undergoing renal biopsy was undertaken to determine the following: (1) if APSN can be found in the course of systemic lupus erythematosus (SLE); (2) if certain clinical and biologic factors can permit the prediction of the presence of APSN; and (3) if APSN is a superadded renal morbidity factor in lupus patients. This study shows the following: (1) APSN occurs in SLE (32% of patients with renal biopsies) in addition to, and independently of, lupus nephritis; (2) APSN is statistically associated with lupus anticoagulant but not with anticardiolipin antibodies; (3) APSN is associated with extrarenal APS, mainly arterial thromboses and obstetrical fetal loss, but not with the venous thromboses of APS; (4) APSN is an independent risk factor, over and above lupus nephritis, that contributes to an elevated prevalence of hypertension, elevated serum creatinine, and increased interstitial fibrosis. Thus, it seems likely that, because of its associations with hypertension, elevated serum creatinine, and increased interstitial fibrosis, APSN may worsen the prognosis in these patients. APSN may also have therapeutic significance in that its recognition should permit a better balance between immunosuppressor and antithrombotic and/or vasoprotective therapy. Finally, this study suggests that APSN should be considered as an element to be included in the classification criteria of APS.
Repeated Remote Ischemic Postconditioning Protects Against Adverse Left Ventricular Remodeling and Improves Survival in a Rat Model of Myocardial Infarction
Authors: Meng Wei, Ping Xin, Shuai Li, Jianping Tao, Yapeng Li, Jing Li, Mingya Liu, Jingbo Li, Wei Zhu, Andrew N. Redington
Journal: Circulation Research (2011)

Rationale: Remote ischemic conditioning induced by repeated episodes of transient limb ischemia is a clinically applicable method for protecting the heart against injury at the time of reperfusion. Objective: To assess the effect of chronic, repeated, remote conditioning on infarct size and long-term remodeling after myocardial infarction. Methods and Results: Rats with ischemia/reperfusion injury received different protocols of remote limb conditioning. While a single early episode of remote ischemic conditioning during coronary occlusion (perconditioning) resulted in a decrease in infarct size on both day 4 and day 28, when it was repeated (postconditioning) intermittently (every 3 days) and intensively (every day), it was not associated with a further decrease in infarct size. However, the protection against adverse remodeling offered by a single episode of limb perconditioning was further enhanced by repeated remote postconditioning therapy in a dose-dependent manner. In separate experiments there was a dose-dependent improvement in survival at 84 days by Kaplan–Meier analysis. Conclusions: Whereas a single early episode of remote perconditioning reduces infarct size, repeated remote postconditioning further reduces adverse LV remodeling and improves survival in a dose-dependent fashion. These data may have clinical implications for the treatment of patients with evolving myocardial infarction.