tbuckley/cabot-search huggingface dataset:
Hepatitis Caused by Amitriptyline Therapy
Authors: Jerry Yon
Journal: JAMA (1975)

A FEW instances of hepatitis associated with the use of amitriptyline hydrochloride have been reported from other countries, but none has been reported from this country. Reports have come from Great Britain1-3of jaundice and from Sweden4of elevated transaminase levels in patients taking amitriptyline. Such abnormalities could represent the hypersensitivity reaction proposed to account for changes in hepatic function associated with administration of other tricyclic antidepressants.5In most reported cases of hepatic dysfunction associated with amitriptyline, the concomitant ingestion of other drugs, excessive use of alcohol, and possible infection with a hepatitis virus make it difficult to establish a causative role for this agent. In the case reported here, a challenge with amitriptyline showed that the drug was the cause of the patient's hepatitis.  Report of a Case  A 23-year-old obese man was admitted to the Iowa City Veterans Administration Hospital on July 5, 1973, for
383. Polyethylene Glycol Modification of Adenovirus Vectors Reduces Thrombocytopenia through Decreased Platelet Clearance and Activation
Authors: Hoyin Mok, FranciscaC. Gushkin, Sean Hofherr, JoseA. Lopez, MichaelA. Barry
Journal: Molecular Therapy (2006)

Top of pageAbstract
Thrombocytopenia is one complication for gene therapy with adenovirus serotype 5 (Ad5) vectors. Poly-ethylene glycol (PEG) modification of Ad5 protects the vector from immune responses and blunts thrombocytopenia while maintaining normal transduction. We investigated the mechanisms of Ad-induced thrombocytopenia and how PEGylation mitigates this side effect. We show that high intravascular doses of Ad5, but not PEG-Ad5, accelerated platelet loss and induced disseminated intravascular coagulation (DIC) in mice. Ad5 was demonstrated to bind to both platelets and red blood cells in vitro and PEGylation ablated these interactions. However, Ad5 did not induce platelet activation in vivo and could only activate platelets in vitro at concentrations 100-fold above that which can be delivered in vivo. In contrast, Ad5 did activate endothelial cells to initiate ultra large von Willebrand factor platelet string formation in vitro at therapeutically-relevant concentrations. These data suggest that Ad5 does not induce thrombocytopenia by direct interactions with platelets, but instead may induce this by first interacting and activating endothelial cells. Since PEGylation reduce the interactions of Ad with platelets and endothelial cells, reduced D-dimer formation, reduced thrombocytopenia, and reduced splenomegaly, these data suggest that this simple vector modification can improve the safety of Ad vectors for gene therapy.
Determination of the enantioselectivity of six chiral aryloxy aminopropanol drugs transport across Caco-2 cell monolayers
Authors: Ye Tian, Ying He, Haihong Hu, Lu Wang, Su Zeng
Journal: Acta Pharmaceutica Sinica B (2012)

This study aimed to determine the transepithelial transport characteristics of chiral drug enantiomers across Caco-2 cell monolayers, a model of human intestinal epithelial membrane. Six chiral aryloxy enantiomers (atenolol, sotalol, celiprolol, carvedilol, metoprolol and propafenone) were tested in bi-directional transport studies. The separation and quantitation of these enantiomers were performed by reversed-phase high-performance liquid chromatography (RP-HPLC) using 2, 3, 4, 6-tetra-O-acetyl-β-d-glucopyranosyl isothiocyanate (GITC) as a pre-column derivatizing agent. Bi-directional transport studies demonstrated that celiprolol and carvedilol exhibited significant enantioselectivity in polarized transport at the concentration range tested. The efflux ratio (ER) for (R)-(+)-celiprolol was 8.96, but it was much lower for (S)-(-)-celiprolol which is 3.42 at the concentration of 96.0 μM; carvedilol had the same transport behavior as celiprolol while the difference between the ER values of two enantiomers was not as significant as celiprolol at the concentration of 5.0 μM. They are 2.41 for (R)-(+)-carvedilol and 1.98 for (S)-(-)-carvedilol. But in the transport studies of racemic atenolol, sotalol, metoprolol and propafenone, no enantioselective transport were observed over the concentration range tested. Because P-glycoprotein (P-gp) is highly expressed in Caco-2 cells, we inferred that P-gp might participate in the transport processes of celiprolol and carvedilol in chirally discriminative ways.
Fair Start for Children: Lessons Learned From Seven Demonstration Projects
Authors: Abraham B. Bergman
Journal: JAMA (1993)

I do not believe that the scores of planners currently devoting long hours to health care reform would appreciate learning that payment systems for medical care have little to do with improving health. Where children are concerned, for example, housing, parental education and employment, traffic engineering, nutrition, alcohol, drugs, and guns have more impact than the services provided in physicians' offices, hospitals, and clinics. Neither "managed competition" nor any other financing scheme will help with the ravages of low birth weight, fetal alcohol syndrome, the acquired immunodeficiency syndrome, or neglect and deprivation. Even less imposing problems like chronic asthma, iron deficiency anemia, baby bottle caries, sexually transmitted diseases, and hypertension of pregnancy are unlikely to be affected by the reforms currently being discussed. What will help in the view of many of us who specialize in care of the poor are outreach services that improve coordination between medical facilities and
Two minor determinants of myelin basic protein induce experimental allergic encephalomyelitis in SJL/J mice.
Authors: D H Kono, J L Urban, S J Horvath, D G Ando, R A Saavedra, L Hood
Journal: The Journal of Experimental Medicine (1988)

Experimental allergic encephalomyelitis (EAE) is an autoimmune demyelinating disease of the central nervous system (CNS) that occurs after immunization of animals with myelin basic protein (MBP). The disease is a prototype model for the study of antigen-specific T helper cell-mediated autoimmune disease. In SJL/J mice, EAE is mediated by T helper cells directed against a 40-amino acid COOH-terminal peptic fragment of mouse small MBP. To identify the minimal T cell epitopes of MBP responsible for EAE, overlapping peptides completely encompassing the epitopes within this region were synthesized. A 28-residue peptide of mouse MBP spanning residues 87-114 (pM87-114) was able to elicit both a strong T cell response and chronic relapsing disease. To better localize the T cell epitopes, shorter peptides within this region were synthesized and two overlapping peptides, pM87-98 and pM91-104, were able to induce EAE. T cell clones and bulk lymph node cell populations reactive with pM87-98 did not respond to pM91-104. However, lymph node cells reactive with pM91-104 also reacted with pM87-98, thus showing that these two peptides represent contiguous, but distinct encephalitogenic epitopes and that both these epitopes may be contained within pM87-98. In addition, pM87-114 and pM87-98 were found to be minor determinants of the total T cell response to rat and rabbit MBP. The restricted response to MBP in SJL/J mice is similar to that of the PL/J mice in that each appears to have only a single peptide region in MBP that elicits encephalitogenic T cells. However, within the region studied, there were two if not more T cell epitopes. This differs from the single encephalitogenic PL/J epitope. These findings of a single encephalitogenic peptide region with multiple T cell epitopes and the fact that encephalitogenic T cell epitopes may be subdominant have implications for the design of treatments directed at the T cell receptor-MHC-peptide epitope complex in autoimmune disease.
Different intrahepatic distribution of phosphatidylglycerol and phosphatidylserine liposomes in the rat
Authors: T Daemen, M Velinova, J Regts, M de Jager, R Kalicharan, J Donga, J J L van der Want, G L Scherphof
Journal: Hepatology (1997)

Liposomes with diameters of 200 to 400 nm containing phosphatidylserine (PS) or phosphatidylglycerol (PG) were injected intravenously into rats. Two hours after injection, 75% of the injected dose of PS liposomes was found in the liver and only 10% found in the spleen, while 35% of the PG liposomes was found in the liver and as much as 40% was found in the spleen. Cell-isolation experiments revealed the following remarkable difference in the intrahepatic distribution between the two liposome formulations: the PS liposomes distributed in about equal amounts to Kupffer cells and hepatocytes, despite their size (200-400 nm) exceeding that of the endothelial fenestrae (average 150 nm), whereas the PG liposomes were only taken up by the Kupffer cells and not at all by the hepatocytes. Double-label studies, using liposomes in which the lipid-moiety was radio labeled with [3H]cholesteryloleylether ([3H]CE) and the water phase with [14C]sucrose, showed that the liposomes were taken up as intact particles. These observations were confirmed through electron microscopy by determining the in situ localization of liposome-encapsulated colloidal gold particles in thin sections of liver and spleen. The differences in organ distribution are ascribed to differences in opsonization patterns of the two liposomal surfaces. For the difference in intrahepatic distribution, we offer the following two explanations: the exploitation of the blood cell-mediated forced sieving concept and the indication of a PS-specific pharmacological effect on the dimensions of the fenestrations.
Sudden infant death syndrome in Maoris
Authors: S L. Tonkin
Journal: BMJ (1995)

Data collection should be integrated with patient care EDITOR,-The editorial on making routine data adequate to support clinical audit mentions the high quality of data from the St Mary's maternity information system,' citing two recent papers on its validity.23The editorial's authors, however, have missed the point about why this particular system has proved so successful.The basis of the system is that midwives enter the data themselves and then in turn use the system for practical purposes directly associated with patients' care- for example, it generates summaries and discharge letters.The system is thus integrally associated with patients' care and is not a separate task.This experience strongly suggests that abandon- ing the normal practice of relegating the input of data to clerical staff results in better quality of data.This is both because the motivation of health care professionals is higher and, crucially, because of the reinforcing feedback loop involving the use of the information for patients' care.The Department of Health has introduced an information management and technology strategy for the NHS in England, which has many positive features.4Its potential Achilles' heel, however, is precisely this question of the quality of the data.Although it includes a data quality initiative, this is concerned mainly with administrative data (the postcode and codes for the provider, health authority, and general practitioner), the only clinical element being the code for the diagnosis.5We suggest that a great deal could be learnt from the strengths and weaknesses of existing systems, especially successful ones like St Mary's maternity information system, and could then be used in the development of the future information technology for health care.
Israel is set to outlaw trafficking in human organs
Authors: Judy Siegel-Itzkovich
Journal: BMJ (2007)

A decade after Israel's health ministry first began preparing it, a bill that will make it a criminal offence to sell human organs for transplantation or to act as an intermediary in such transactions is due to be passed by the Knesset, Israel's parliament. The bill, which prohibits trafficking in human organs in Israel and by Israeli residents abroad, was approved in committee for its final readings in the full assembly.

Traffickers—but not donors or recipients in illegal transactions—will get three years in prison or a fine equivalent to $50 000 (£24 000; €34 000).

Legislators hope that the law …
Safety and Feasibility of High-pressure Transvenous Limb Perfusion With 0.9% Saline in Human Muscular Dystrophy
Authors: Zheng Fan, Keith Kocis, Robert Valley, James F Howard, Manisha Chopra, Hongyu An, Weili Lin, Joseph Muenzer, William Powers
Journal: Molecular Therapy (2011)

We evaluated safety and feasibility of the transvenous limb perfusion gene delivery method in muscular dystrophy. A dose escalation study of single limb perfusion with 0.9% saline starting with 5% of limb volume was carried out in adults with muscular dystrophies under intravenous analgesia/anesthesia. Cardiac, vascular, renal, muscle, and nerve functions were monitored. A tourniquet was placed above the knee with inflated pressure of 310 mm Hg. Infusion was carried out with a clinically approved infuser via an intravenous catheter inserted in the saphenous vein with a goal infusion rate of 80 ml/minute. Infusion volume was escalated stepwise to 20% limb volume in seven subjects. No subject complained of any post procedure pain other than due to needle punctures. Safety warning boundaries were exceeded only for transient depression of limb tissue oximetry and transient elevation of muscle compartment pressures; these were not associated with nerve, muscle, or vascular damage. Muscle magnetic resonant imaging (MRI) demonstrated fluid accumulation in muscles of the perfused lower extremity. High-pressure retrograde transvenous limb perfusion with saline up to 20% of limb volume at above infusion parameters is safe and feasible in adult human muscular dystrophy. This study will serve as a basis for future gene transfer clinical trials.
Real-time differential tracking of human neutrophil and eosinophil migration in vivo
Authors: Joanna J. Lukawska, Lefteris Livieratos, Barbara M. Sawyer, Tak Lee, Michael O'Doherty, Philip J. Blower, Martin Kofi, James R. Ballinger, Christopher J. Corrigan, Gopinath Gnanasegaran, Ehsan Sharif-Paghaleh, Gregory E.D. Mullen
Journal: Journal of Allergy and Clinical Immunology (2013)
Synovial Fluid Complement: Usefulness in Diagnosis and Classification of Rheumatoid Arthritis
Authors: THOMAS W. BUNCH
Journal: Annals of Internal Medicine (1974)

The relation between synovial fluid complement concentration and severity or prognosis of disease was studied in 62 patients with rheumatoid arthritis who were divided into 4 groups, on the basis of presence or absence of rheumatoid factor and low or normal synovial fluid complement concentration levels. The groups were similar with respect to various important criteria. Assessment of the disease by functional criteria, roentgenograms, synovial fluid polymorphonuclear leukocyte count, and synovitis showed more pronounced abnormalities in those patients with low synovial fluid complement levels or rheumatoid factor. Rheumatoid nodule formation correlated best with synovial fluid complement depletion. Low synovial fluid complement or rheumatoid factor, or both, is associated with severer disease and probably a poorer prognosis. Synovial fluid complement determination seems to be most useful in evaluation of patients with seronegative rheumatoid arthritis.
Comparison of Evidence of Treatment Effects in Randomized and Nonrandomized Studies
Authors: John P. A. Ioannidis
Journal: JAMA (2001)

There is substantial debate about whether the results of nonrandomized studies are consistent with the results of randomized controlled trials on the same topic.To compare results of randomized and nonrandomized studies that evaluated medical interventions and to examine characteristics that may explain discrepancies between randomized and nonrandomized studies.MEDLINE (1966-March 2000), the Cochrane Library (Issue 3, 2000), and major journals were searched.Forty-five diverse topics were identified for which both randomized trials (n = 240) and nonrandomized studies (n = 168) had been performed and had been considered in meta-analyses of binary outcomes.Data on events per patient in each study arm and design and characteristics of each study considered in each meta-analysis were extracted and synthesized separately for randomized and nonrandomized studies.Very good correlation was observed between the summary odds ratios of randomized and nonrandomized studies (r = 0.75; P<.001); however, nonrandomized studies tended to show larger treatment effects (28 vs 11; P =.009). Between-study heterogeneity was frequent among randomized trials alone (23%) and very frequent among nonrandomized studies alone (41%). The summary results of the 2 types of designs differed beyond chance in 7 cases (16%). Discrepancies beyond chance were less common when only prospective studies were considered (8%). Occasional differences in sample size and timing of publication were also noted between discrepant randomized and nonrandomized studies. In 28 cases (62%), the natural logarithm of the odds ratio differed by at least 50%, and in 15 cases (33%), the odds ratio varied at least 2-fold between nonrandomized studies and randomized trials.Despite good correlation between randomized trials and nonrandomized studies-in particular, prospective studies-discrepancies beyond chance do occur and differences in estimated magnitude of treatment effect are very common.
Sexual activity in middle to later life
Authors: P. Goodson
Journal: BMJ (2010)

Better health leads to frequent, good quality sex in older adults 

A cursory search of the BMJ ’s archives using the terms “sexuality” and “older adults” yields one study report and one editorial, both published in the past decade.1 2 Using the terms “sexual activity” and “elderly” yields only two additional citations, which focus on gynaecological and epidemiological topics.3 4 If for no other reason than that of filling a glaring void, the linked study by Lindau and Gavrilova (doi:10.1136/bmj.c810) represents a refreshing addition to the BMJ ’s sexuality and ageing repertoire.5 The study is equally refreshing because it offers a health enhancing, health promoting perspective: most human sexuality studies—especially those informing healthcare professionals—centre on outlining problems, diagnosing illnesses, and managing treatments. To unearth positive news amid the rubble of a trouble focused literature is just as refreshing, stimulating, and invigorating as good healthy sex. 

Lindau and Gavrilova examined data from two cross sectional surveys of ageing populations in the United States (national survey of midlife development in the United States (MIDUS) and national social life, health and aging project (NSHAP)). …
Abstract LB-345: Hypoxia-induced reprogramming cause normal glia to mimic tumor-associated glial cells.
Authors: Lina Leiss, Ivana Manini, Marta Calderon, Per Øyvind Enger
Journal: Cancer Research (2013)

Abstract Cancer-associated fibroblasts (CAFs) have been shown to foster tumor growth in several solid cancers. In the brain, the stroma is mainly composed of glial cells such as astrocytes and oligodendrocytes whose role in brain tumor-stroma interactions are poorly characterized. We have previously identified a unique gene expression profile of tumor-associated glial cells (TAGs) by fluorescence activated cell sorting (FACS) of glial cells from GFP/Nod Scid mice engrafted with human glioblastoma biopsies. Little is known about the mechanisms mediating these expression changes, but both direct tumor cell-glial cell contact and environmental stress such as hypoxia are external cues that may induce these changes. Thus, we investigated how hypoxia impacted on the phenotype of glial cells from normal mouse brains. Briefly, mouse brains were enzymatically digested to obtain single cell suspensions, and then glial cells were isolated by FACS with simultaneous removal of immune cells (CD11b+) and endothelial cells (CD31+). These cells were then seeded at a density of 50,000 cells/well in a 48-well plate and incubated under either normoxic (21% oxygen) or hypoxic (0.5% oxygen) conditions for seven days. Notably, glial cells upregulated Sox2, HIF-2a, Nestin and Vimentin in hypoxia compared to normoxic conditions. In addition glial cells also upregulated angiogenic factors such as VEGF, Angiopoietin 2 and FGF2. Furthermore, cell cycle analysis revealed a significantly higher fraction of cycling cells in hypoxia than in normoxia. To investigate how glial cells and tumor cells interact, we made co-cultures of glial cells isolated from DsRed+ mice and GFP-transfected human glioma cells. Fluorescence imaging of the co-cultures show that these two cell types establish cell contacts in vitro, and that the glial cells alter their morphology in co-cultures compared to monocultures of glial cells alone. These changes strongly resembled the changes observed in tumor-associated glial cells, suggesting that hypoxia is a major contributor to the phenotype of tumor-associated glial cells. Furthermore direct physical contact between tumor cells and glial cells may lead to phenotypical changes in the glial cells. Ongoing work aims at further characterizing the TAG population to reveal its cell composition and address the role of various subpopulations of glial host cells. Citation Format: Lina Leiss, Ivana Manini, Marta Calderon, Per Øyvind Enger. Hypoxia-induced reprogramming cause normal glia to mimic tumor-associated glial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-345. doi:10.1158/1538-7445.AM2013-LB-345
Persistence of Reflex Sympathetic Nervous System Activity in Man on Guanethidine or Reserpine
Authors: JAY D. COFFMAN
Journal: Circulation (1967)

The effect of guanethidine and reserpine on the reflex sympathetic nervous system vasoconstriction in the calf and foot induced by a prolonged, generalized stimulus (body cooling for 1 hour) was studied in 12 normal subjects. Large daily clinical-doses of guanethidine (40 to 60 mg) or reserpine (1 mg) were given orally for 2 and 3 weeks, respectively. Foot and calf blood flows were measured by venous-occlusion, water plethysmography. Two control studies were performed on each subject, one before and another long after administration of the drug; body cooling produced significant decrease in calf and foot blood flow and increases in vascular resistance in both control studies. Subjects evidenced drug effects by a significant decrease in pulse rate, postural hypotension, hypotension following exercise, and blockade or attenuation of the Valsalva maneuver "overshoot." The attenuation of the sympathetic nervous-system vasoconstrictor reflex to general body cooling was not statistically significant. Since large clinical doses of reserpine or guanethidine administered for 3 or 2 weeks, respectively, did not inhibit the reflex sympathetic vasoconstrictor effect of total body cooling, functional sympathetic neurotransmitter substance cannot be said to be absent.