tbuckley/cabot-search huggingface dataset:
P30 Are we under using diagnostic investigations in the management of abdominal tuberculosis (TB) in high endemic areas of London?
Authors: C Stevens, S Sithamparanathan, T O'Shaughnessy
Journal: Thorax (2013)

<h3>Introduction</h3> Abdominal tuberculosis presents with non-specific clinical symptoms. Diagnosis is based on clinical reasoning supported by radiological findings either by ultrasound or computer tomography. The gold standard of diagnosis remains with culture <i>Mycobacteria tuberculosis</i> complex. Therefore in areas with high endemic rates of TB are we under using investigations to gain tissues samples in suspected cases? <h3>Method</h3> We undertook a retrospective analysis of 46 cases coded as abdominal tuberculosis from our local hospital register. Data was collected from case notes and computer systems regarding pathology and radiology results. <h3>Results</h3> The majority of patients were born in the Indian subcontinent: India 39%, Pakistan 20% and Bangladesh 8%. More than half the patients had lived in the UK for less than 5 years. 54% of patients had symptoms for 1–4 months before presentation. None of the cases had TB in the past and 13% could recall possible TB contact. 67% of CXR was normal, and of those who had abnormal films, only 4 cases had features that were specific for TB. Focused imaging taken included: CT abdomen 77%, US abdomen 18%, MR abdomen 1%, Barium follow through 5%. 48% of patients had procedures to obtain histological and microbiological results, including laparoscopy, laparotomy, colonoscopy, gastroscopy or ascitic tap. 26% of patients underwent laparoscopy. Of the remaining patients, 18% obtained microbiological samples from alternative sites. Thus, 42% patients were treated on clinical symptoms and radiological image findings alone. <h3>Discussion</h3> Laparoscopy has been regarded as the gold standard and diagnostic investigation of choice in the management of abdominal TB<sup>1, 2</sup>. In our cohort 26% underwent laparoscopy. The reason for this unclear but could be due perceived risk with the procedure, lack of availability of service or in many cases is used as a last resort. In TB endemic areas, we suggest the development of an acceptable evidence based investigational pathway incorporating our surgical and gastrointestinal colleagues leading to more prompt and through management of abdominal tuberculosis. <h3>References</h3> McLaughlin S, Jones T, Pitcher M, Evans P. Laparoscopic diagnosis of abdominal tuberculosis. <i>Aust NZ J Surg</i> 1998;68: 599–601 Rai S, Thomas W M. Diagnosis of abdominal tuberculosis: the importance of laparoscopy. <i>J R Soc Med</i>. 2003 December; 96(12): 586–588.
Chondrocalcinosis after parathyroidectomy [Proceedings].
Authors: J S Glass, R Grahame
Journal: Annals of the Rheumatic Diseases (1976)

At a joint meeting with the Spanish Society of Rheumatology held at Madrid on October 3-4, 1975, the following papers were given.Chondrocalcinosis after parathyroidectomy.J. S. Glass and R. Grahame (Guy's Hospital, London) The one form of chondrocalcinosis that is in theory potentially reversible is that associated with hyperparathyroidism.In the present study the influence of parathyroidectomy has been assessed on the chondro- calcinosis and its clinical sequelae.57 patients suffering from primary hyperparathyroidism and who underwent parathyroidectomy between 1952 and 1974 were reviewed.Chondrocalcinosis was deemed to be present at some time in 14 (40%) out of the 35 patients in whom x-rays were available.Meaningful comparisons of patients' symptoms and x-ray changes before and after operation were possible in 30 and 11 patients, respectively.Contrary to expectation patients did not improve either clinically or radiologically.Evidence was given (including composite slide showing serial x-ray changes) that in several patients chondrocalcinosis progresses after parathyroidectomy, and in a few makes its first appearance years after the operation.
Effects of ethanol on intercellular communications and polarization of hepatocytes in short-term culture
Authors: Imad Abou Hashieh, Sylvie Mathieu, André Gerolami
Journal: Hepatology (1992)

ABSTRPlCT The formation of intracellular lumina with apical differentiation is observed in several cancerous epithelial cell lines including human hepatocarcinoma. This disorder of cell polarization can be induced by the inhibition of cell–cell communication, a known factor of carcinogenesis. This work was designed to study the effects of ethanol on the differentiation of hepatocytes in short–term culture. Isolated hepatocytes were plated on plastic culture dishes that were 35 mm in diameter (10 6 cells/dish). Three hours after plating, the hepatocytes were incubated in the presence of 20 mmol/L ethanol for 1 hr. Treated cells were compared with controls using morphometric methods after conventional treatment for ultramicroscopy and by measuring cellular dye coupling by the fluorescent Lucifer Yellow CH transfer method. Bile canaliculi formation decreased in alcoholtreated cells (6.5% vs. 9.9%, 2p &lt; 0.05), whereas intracellular lumina incidence increased (3.1% vs. 0.5%, 2p &lt; 0.01). In parallel, the dye–coupling capacity decreased significantly when hepatocytes were treated with alcohol (2p &lt; 0.01). This work shows that short–term ethanol treatment induces significant disturbances of cell polarization and inhibits the reestablishment of cell–cell communication in cultured hepatocytes. These disorders could, at least in part, explain the carcinogenic effects of ethanol. (Hepatology 1992;15:751-756).
ADP-Ribosyl Cyclase in Rat Vascular Smooth Muscle Cells
Authors: Frederico G. S. de Toledo, Jingfei Cheng, Mingyu Liang, Eduardo N. Chini, Thomas P. Dousa
Journal: Circulation Research (2000)

Abstract —We investigated whether ADP-ribosyl cyclase (ADPR-cyclase) in rat vascular smooth muscle cells (VSMCs) has enzymatic properties that differ from the well-characterized CD38-antigen ADPR-cyclase, expressed in HL-60 cells. ADPR-cyclase from VSMCs, but not CD38 ADPR-cyclase from HL-60 cells, was inhibited by gangliosides (10 μmol/L) GT 1B , GD 1 , and GM 3 . Preincubation of membranes from CD38 HL-60 cells, but not from VSMCs, with anti-CD38 antibodies increased ADPR-cyclase activity; CD38 antigen was detected both in VSMCs and in HL-60 cells. ADPR-cyclase in VSMC membranes was more sensitive than CD38 HL-60 ADPR-cyclase to inactivation by N- endoglycosidase F and to thermal inactivation at 45°C. The specific activity of ADPR-cyclase in membranes from VSMCs was &gt;20-fold higher than in membranes from CD38 HL-60 cells. Most importantly, VSMC ADPR-cyclase was inhibited by Zn 2+ and Cu 2+ ions; the inhibition by Zn 2+ was dose dependent, noncompetitive, and reversible by EDTA. In contrast, Zn 2+ stimulated the activity of CD38 HL-60 ADPR-cyclase and other known types of ADPR-cyclases. Retinoids act either via the nuclear receptor retinoic acid receptor or retinoid X receptor, including all- trans retinoic acid (atRA), and panagonist 9- cis -retinoic acid–upregulated VSMC ADPR-cyclase; the stimulatory effect of atRA was blocked by actinomycin D and cycloheximide. 1,25(OH) 2 –Vitamin D 3 (calciferol) stimulated VSMC ADPR-cyclase dose dependently at subnanomolar concentrations (ED 50 ≅56 pmol/ l ). Oral administration of atRA to rats resulted in an increase of ADPR-cyclase activity in aorta (≅+60%) and, to a lesser degree, in myocardium of left ventricle (+18%), but atRA had no effect on ADPR-cyclases in lungs, spleen, intestinal smooth muscle, skeletal muscle, liver, or testis. Administration of 3,5,3′-triiodothyronine (T 3 ) to rats resulted in an increase of ADPR-cyclase activity in aorta (≅+89%), but not in liver or brain. We conclude the following: (1) ADPR-cyclase in VSMCs has enzymatic properties distinct from “classic” CD38 ADPR-cyclase, especially sensitivity to inhibition by Zn 2+ and Cu 2+ ; (2) ADPR-cyclase in VSMCs is upregulated by various retinoids, calcitriol, and T 3 in vitro; and (3) administration of atRA and T 3 increases ADPR-cyclase in aorta in vivo. We suggest that the cADPR signaling system plays an important role in the regulation of VSMC functions in response to steroid superfamily hormones.
A double blind placebo controlled study to determine the effects of intermittent cyclical etidronate on bone mineral density in patients on long term oral corticosteroid treatment
Authors: P Pitt, F Li, P Todd, D Webber, S Pack, C Moniz
Journal: Thorax (1998)

<h3>BACKGROUND</h3> A double blind, placebo controlled study was undertaken to determine the effects of 104 weeks of intermittent cyclical etidronate therapy on bone mineral density (BMD) in patients undergoing long term oral corticosteroid therapy. <h3>METHODS</h3> Forty nine patients of mean age 59 years on long term (&gt;6 months) corticosteroid treatment were randomised to receive either 400 mg/day etidronate or placebo for 14 days followed in both groups by calcium (equivalent to 97 mg elemental Ca/day) with vitamin D (400 IU) for 76 days. The cycle was repeated a total of eight times over a period of two years. Dual energy <i>x</i> ray absorptiometry (DEXA) measurements of the lumbar spine and hip BMD and biochemical bone marker analyses were performed at baseline and every six months. <h3>RESULTS</h3> Twenty six patients (10 men) received cyclical etidronate and 23 (nine men) received placebo. The mean (SD) dose of corticosteroid (prednisone or equivalent) at baseline in the etidronate group was 8 (4) mg/day and in the placebo group was 7 (4) mg/day. Most of the patients (43%) suffered from asthma. Forty one patients completed the study (22 in the etidronate group and 19 in the placebo group). All had a low BMD at entry and with treatment a significant difference was observed between groups in the mean (SE) percentage change from baseline in lumbar spine BMD at week 104 of 4.5 (1.65)% (p = 0.007) with a 95% confidence interval (CI) of 1.12 to 7.87%. No clinically or statistically significant treatment differences were observed at the hip or with bone markers. The incidence of adverse events was similar in the two groups. <h3>CONCLUSIONS</h3> The results show that intermittent cyclical etidronate therapy with calcium and vitamin D supplementation significantly increases lumbar spine BMD in patients with osteoporosis resulting from long term treatment with corticosteroids.
Iterative Microarray and RNA Interference–Based Interrogation of the Src-Induced Invasive Phenotype
Authors: Rosalyn B. Irby, Renae L. Malek, Greg Bloom, Jennifer Tsai, Noah Letwin, Bryan C. Frank, Kathleen Verratti, Timothy J. Yeatman, Norman H. Lee
Journal: Cancer Research (2005)

Abstract Src kinase has long been recognized as a factor in the progression of colorectal cancer and seems to play a specific role in the development of the metastatic phenotype. In spite of numerous studies conducted to elucidate the exact role of Src in cancer progression, downstream targets of Src remain poorly understood. Gene expression profiling has permitted the identification of large sets of genes that may be functionally interrelated but it is often unclear as to which molecular pathways they belong. Here we have developed an iterative approach to experimentally reconstruct a network of gene activity regulated by Src and contributing to the invasive phenotype. Our strategy uses a combination of phenotypic anchoring of gene expression profiles and loss-of-function screening by way of RNA-mediated interference. Using a panel of human colon cancer cell lines exhibiting differential Src-specific activity and invasivity, we identify the first two levels of gene transcription responsible for the invasive phenotype, where first-tier genes are controlled by Src activity and the second-tier genes are under the influence of the first tier. Specifically, perturbation of first-tier gene activity by either pharmacologic inhibition of Src or RNA-mediated interference–directed knockdown leads to a loss of invasivity and decline of second-tier gene activity. The targeting of first-tier genes may be bypassed altogether because knockdown of second-tier genes led to a similar loss of invasive potential. In this manner, numerous members of a “transcriptional cascade” pathway for metastatic activity have been identified and functionally validated.
Modulation of hepatotoxicity by macrophages in the liver
Authors: Yasushi Shiratori, Tateo Kawase, Shuichiro Shiina, Ken’Ichi Okano, Tsuneaki Sugimoto, Hitoshi Teraoka, Sunao Matano, Kazunori Matsumoto, Kazuo Kamii
Journal: Hepatology (1988)

In an attempt to elucidate the role of hepatic macrophages in liver injury, we investigated galactosamine-treated rats (500 mg per kg body weight). The rats received an i.v. injection of latex particles (2 × 10 9 particles per animal) prior to (latex-galactosamine) or 12 to 16 hr subsequent to the galactosamine treatment (galactosamine-latex). Effect of superoxide dismutase on hepatic injury induced by galactosamine or galactosamine-latex treatment was also examined. Oxygen-derived free radical-generating capacity of isolated hepatic macrophages was measured as chemiluminescence with the stimulation of phorbol myristate acetate or latex particles. As compared with normal rats, chemiluminescence of hepatic macrophages from galactosamine-treated rats was 5- to 10-fold enhanced 12 hr following galactosamine treatment and remained elevated for 48 hr. Chemiluminescence of the latex particle-pretreated macrophages in the liver was markedly suppressed even following the galactosamine treatment (p &lt; 0.01). Compared to galactosamine-treated rats, both lipid peroxide level in the liver tissue and AST and ALT concentration in serum were significantly decreased in the latex-galactosamine-treated rats &lt; p &lt; 0.01) and increased in the galactosamine-latex-treated rats (p &lt; 0.01). Furthermore, superoxide dismutase supplementation protected against liver injury induced by the galactosamine-latex treatment. From these results, pretreatment with latex particles suppressed the free radical-generating capacity of hepatic macrophages and protected against hepatic injury induced by galactosamine. In contrast, injection of latex particles after galactosamine treatment aggravated hepatic injury, which was prevented by superoxide dismutase. These data suggest that liver injury induced by galactosamine is modulated by oxygen-derived free radicals from hepatic macrophages.
Targeted Drug Delivery to Treat Pain and Cerebral Hypoxia
Authors: Patrick T. Ronaldson, Thomas P. Davis
Journal: Pharmacological Reviews (2013)

Limited drug penetration is an obstacle that is often encountered in treatment of central nervous system (CNS) diseases including pain and cerebral hypoxia. Over the past several years, biochemical characteristics of the brain (i.e., tight junction protein complexes at brain barrier sites, expression of influx and efflux transporters) have been shown to be directly involved in determining CNS permeation of therapeutic agents; however, the vast majority of these studies have focused on understanding those mechanisms that prevent drugs from entering the CNS. Recently, this paradigm has shifted toward identifying and characterizing brain targets that facilitate CNS drug delivery. Such targets include the organic anion–transporting polypeptides (OATPs in humans; Oatps in rodents), a family of sodium-independent transporters that are endogenously expressed in the brain and are involved in drug uptake. OATP/Oatp substrates include drugs that are efficacious in treatment of pain and/or cerebral hypoxia (i.e., opioid analgesic peptides, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors). This clearly suggests that OATP/Oatp isoforms are viable transporter targets that can be exploited for optimization of drug delivery to the brain and, therefore, improved treatment of CNS diseases. This review summarizes recent knowledge in this area and emphasizes the potential that therapeutic targeting of OATP/Oatp isoforms may have in facilitating CNS drug delivery and distribution. Additionally, information presented in this review will point to novel strategies that can be used for treatment of pain and cerebral hypoxia.
Differences in Sleep-induced Hypoxia between A/J and DBA/2J Mouse Strains
Authors: Arnon E. Rubin, Vsevolod Y. Polotsky, Alexander Balbir, Jerry A. Krishnan, Alan R. Schwartz, Philip L. Smith, Robert S. Fitzgerald, Clarke G. Tankersley, Machiko Shirahata, Christopher P. O'Donnell
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

In obstructive sleep apnea, hypoxic ventilatory sensitivity may affect the degree of hypoxic stress and sleep disruption that occurs in response to upper airway obstruction. We induced (1) sleep-induced hypoxia (SIH) or (2) sleep fragmentation (SF) without hypoxia for 5 days (12-hour light/dark cycle) in two inbred mouse strains with low (A/J) and high (DBA/2J) hypoxic ventilatory sensitivities. During SIH, the time to arousal (26.4 +/- 1.1 vs. 21.3 +/- 1.5 seconds, p<0.025) and the severity of hypoxic exposure (nadir FIO2: 11.5 +/- 0.4 vs. 13.6 +/- 0.1%, p<0.002) was greater in A/J than DBA/2J mice. Furthermore, A/J mice had a greater frequency of hypoxic events (640 +/- 29 vs. 368 +/- 33 events per 24 hours, p<0.001) and total sleep time (47.5 +/- 2.8% vs. 26.5 +/- 2.4% per 24 hours, p<0.0001) during SIH than DBA/2J mice. In contrast, the event characteristics and total sleep time during SF were the same in both strains. Furthermore, in the light phase, both strains showed a longer (p<0.01) time to arousal during SIH and SF compared with the dark phase. We conclude that genetic background can influence respiratory events and sleep architecture during SIH and that the arousal threshold is subject to circadian variation. Our data imply that individuals with low hypoxic sensitivity may be at a greater risk for hypoxia-related complications of obstructive sleep apnea.
Autocrine control of vitamin D metabolism in synovial cells from arthritic patients
Authors: S. J Smith, M. E Hayes, P. L Selby, E B. Mawer
Journal: Annals of the Rheumatic Diseases (1999)

<h3>OBJECTIVE</h3> This study was designed to investigate whether 1,25-dihydroxyvitamin D<sub>3</sub> (1,25-(OH)<sub>2</sub>D<sub>3</sub>), produced by activated synovial fluid macrophages, promotes its own catabolism by upregulating vitamin D-24-hydroxylase (24-OHase) in synovial fibroblasts through a vitamin D receptor (VDR) mediated mechanism. <h3>METHODS</h3> Synovial macrophages and fibroblasts were derived from patients with rheumatoid arthritis. Expression of VDR and 24-OHase mRNAs was determined using in situ hybridisation. Vitamin D hydroxylase activity was determined by incubating cells with [<sup>3</sup>H]-25-(OH)D<sub>3</sub>, or [<sup>3</sup>H]-1,25-(OH)<sub>2</sub>D<sub>3</sub>, and metabolite synthesis quantified using high performance liquid chromatography. <h3>RESULTS</h3> 1,25-(OH)<sub>2</sub>D<sub>3</sub>increased expression of mRNA for both VDR and 24-OHase in fibroblasts by approximately threefold over 24 hours. 1,25-(OH)<sub>2</sub>D<sub>3</sub> increased fibroblast 24-OHase activity, yielding 24-hydroxylated, and more polar, metabolites. In co-culture, fibroblasts were able to catabolise macrophage derived 1,25-(OH)<sub>2</sub>D<sub>3</sub>. <h3>CONCLUSIONS</h3> 1,25-(OH)<sub>2</sub>D<sub>3</sub>is produced by macrophages in vitro at biologically relevant concentrations and can increase its own catabolism by synovial fibroblasts; this effect is probably mediated via upregulation of both synovial fibroblast VDR and 24-OHase.
Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts
Authors: Xiaohua Ni, Yonggang Zhang, Judit Ribas, Wasim H. Chowdhury, Mark Castanares, Zhewei Zhang, Marikki Laiho, Theodore L. DeWeese, Shawn E. Lupold
Journal: Journal of Clinical Investigation (2011)

Dose-escalated radiation therapy for localized prostate cancer (PCa) has a clear therapeutic benefit; however, escalated doses may also increase injury to noncancerous tissues. Radiosensitizing agents can improve ionizing radiation (IR) potency, but without targeted delivery, these agents will also sensitize surrounding normal tissues. Here we describe the development of prostate-targeted RNAi agents that selectively sensitized prostate-specific membrane antigen–positive (PSMA-positive) cells to IR. siRNA library screens identified DNA-activated protein kinase, catalytic polypeptide (DNAPK) as an ideal radiosensitization target. DNAPK shRNAs, delivered by PSMA-targeting RNA aptamers, selectively reduced DNAPK in PCa cells, xenografts, and human prostate tissues. Aptamer-targeted DNAPK shRNAs, combined with IR, dramatically and specifically enhanced PSMA-positive tumor response to IR. These findings support aptamer-shRNA chimeras as selective sensitizing agents for the improved treatment of high-risk localized PCa.
THE EFFECT OF UNDERNUTRITION ON CHOLESTEROL ATHEROSCLEROSIS IN THE RABBIT
Authors: Gardner C. McMillan, J. H. Whiteside, G. Lyman Duff
Journal: The Journal of Experimental Medicine (1954)

Experiments were done to determine whether undernutrition with consequent loss of weight or failure to gain weight inhibited the development or promoted the regression of the aortic lesions of experimental cholesterol atherosclerosis in the rabbit. The experiments were conducted in such a way as to determine whether undernourished and adequately nourished rabbits fed the same daily doses of cholesterol would manifest different degrees of atherosclerosis at the end of an experiment. Different experiments tested the effect of undernutrition in young, growing animals that failed to gain weight normally (Experiments 1 and 2); in young rabbits subjected to marked undernutrition both before and during cholesterol feeding (Experiment 3); in fully grown, mature rabbits that lost weight during undernutrition (Experiment 4); and in rabbits that had completed a period of cholesterol feeding before caloric restriction was begun (Experiment 5). In every experiment it was observed that, if two groups of rabbits were fed cholesterol, one group being subjected to caloric restriction while the other received an adequate diet, no difference in aortic atherosclerosis was observed between the two groups at the termination of the experiment. Furthermore, no obvious effect of undernutrition on the regression of atherosclerotic lesions was observed in the rabbit. At the same time, undernutrition was found to promote hypercholesterolemia in the rabbit fed cholesterol. The possible significance of this result was discussed.