tbuckley/cabot-search huggingface dataset:
Inhibition of Prostaglandin E <sub>2</sub> Synthesis in Abdominal Aortic Aneurysms
Authors: Lesley J. Walton, Ian J. Franklin, Trevor Bayston, Louise C. Brown, Roger M. Greenhalgh, Graham W. Taylor, Janet T. Powell
Journal: Circulation (1999)

Background —There is no treatment proven to limit the growth of abdominal aortic aneurysms, in which the histological hallmarks include inflammation and medial atrophy, with apoptosis of smooth muscle cells and destruction of elastin. Methods and Results —Aneurysm biopsies were used for explant cultures, the preparation of smooth muscle cell cultures, and isolation of macrophages. Tissue macrophages stained strongly for cyclooxygenase 2. Prostaglandin E 2 (PGE 2 ) concentrations in aneurysm tissue homogenates, conditioned medium from explants, and isolated macrophages were 49±22 ng/g, 319±38 ng/mL, and 22±21 ng/mL, respectively. PGE 2 inhibited DNA synthesis and proliferation in normal aortic smooth muscle cells (IC 50 , 23.2±3.8 and 23.6±4.5 ng/mL, respectively). In smooth muscle cells derived from aneurysmal aorta, PGE 2 also caused cell death, with generation of oligonucleosomes. Conditioned medium from the mixed smooth muscle and monocyte cultures derived from explants also had potent growth-inhibitory effects, and fractionation of this medium showed that the growth-inhibitory molecule(s) coeluted with PGE 2 . In explants, indomethacin 10 μmol/L or mefenamic acid 10 μmol/L abolished PGE 2 secretion and significantly reduced IL-1β and IL-6 secretion. In a separate case-control study, the expansion of abdominal aortic aneurysms was compared in 15 patients taking nonsteroidal anti-inflammatory drugs and 63 control subjects; median growth rates were 1.5 and 3.2 mm/y, respectively, P =0.001. Conclusions —The adverse effects of PGE 2 on aortic smooth muscle cell viability and cytokine secretion in vitro and the apparent effect of anti-inflammatory drugs to lower aneurysm growth rates suggest that selective inhibition of PGE 2 synthesis could be an effective treatment to curtail aneurysm expansion.
Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS
Authors: Oleg Butovsky, Shafiuddin Siddiqui, Galina Gabriely, Amanda J. Lanser, Ben Dake, Gopal Murugaiyan, Camille E. Doykan, Pauline M. Wu, Reddy R. Gali, Lakshmanan K. Iyer, Robert Lawson, James Berry, Anna M. Krichevsky, Merit E. Cudkowicz, Howard L. Weiner
Journal: Journal of Clinical Investigation (2012)

Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with neuronal cell death that is thought to involve aberrant immune responses. Here we investigated the role of innate immunity in a mouse model of ALS. We found that inflammatory monocytes were activated and that their progressive recruitment to the spinal cord, but not brain, correlated with neuronal loss. We also found a decrease in resident microglia in the spinal cord with disease progression. Prior to disease onset, splenic Ly6Chi monocytes expressed a polarized macrophage phenotype (M1 signature), which included increased levels of chemokine receptor CCR2. As disease onset neared, microglia expressed increased CCL2 and other chemotaxis-associated molecules, which led to the recruitment of monocytes to the CNS by spinal cord-derived microglia. Treatment with anti-Ly6C mAb modulated the Ly6Chi monocyte cytokine profile, reduced monocyte recruitment to the spinal cord, diminished neuronal loss, and extended survival. In humans with ALS, the analogous monocytes (CD14+CD16-) exhibited an ALS-specific microRNA inflammatory signature similar to that observed in the ALS mouse model, linking the animal model and the human disease. Thus, the profile of monocytes in ALS patients may serve as a biomarker for disease stage or progression. Our results suggest that recruitment of inflammatory monocytes plays an important role in disease progression and that modulation of these cells is a potential therapeutic approach.
Interleukin-18 (Interferon-γ–inducing Factor) Is Produced by Osteoblasts and Acts Via Granulocyte/Macrophage Colony-stimulating Factor and Not Via Interferon-γ to Inhibit Osteoclast Formation
Authors: Nobuyuki Udagawa, Nicole J. Horwood, Jan Elliott, Alan Mackay, Jane Owens, Haruki Okamura, Masashi Kurimoto, Timothy J. Chambers, T.  John Martin, Matthew T. Gillespie
Journal: The Journal of Experimental Medicine (1997)

We have established by differential display polymerase chain reaction of mRNA that interleukin (IL)-18 is expressed by osteoblastic stromal cells. The stromal cell populations used for comparison differed in their ability to promote osteoclast-like multinucleated cell (OCL) formation. mRNA for IL-18 was found to be expressed in greater abundance in lines that were unable to support OCL formation than in supportive cells. Recombinant IL-18 was found to inhibit OCL formation in cocultures of osteoblasts and hemopoietic cells of spleen or bone marrow origin. IL-18 inhibited OCL formation in the presence of osteoclastogenic agents including 1α,25-dihydroxyvitamin D3, prostaglandin E2, parathyroid hormone, IL-1, and IL-11. The inhibitory effect of IL-18 was limited to the early phase of the cocultures, which coincides with proliferation of hemopoietic precursors. IL-18 has been reported to induce interferon-γ (IFN-γ) and granulocyte/macrophage colony-stimulating factor (GM–CSF) production in T cells, and both agents also inhibit OCL formation in vitro. Neutralizing antibodies to GM–CSF were able to rescue IL-18 inhibition of OCL formation, whereas neutralizing antibodies to IFN-γ did not. In cocultures with osteoblasts and spleen cells from IFN-γ receptor type II–deficient mice, IL-18 was found to inhibit OCL formation, indicating that IL-18 acted independently of IFN-γ production: IFN-γ had no effect in these cocultures. Additionally, in cocultures in which spleen cells were derived from receptor-deficient mice and osteoblasts were from wild-type mice and vice versa, we identified that the target cells for IFN-γ inhibition of OCL formation were the hemopoietic cells. The work provides evidence that IL-18 is expressed by osteoblasts and inhibits OCL formation via GM–CSF production and not via IFN-γ production.
THE NEED FOR UNIFORM DISCHARGE STATISTICS IN PUBLIC PSYCHIATRIC HOSPITALS
Authors: WALTER E. BARTON, HARVEY J. TOMPKINS, AARON B. NADEL
Journal: American Journal of Psychiatry (1949)

1. In the year July 1, 1946 to June 30, 1947 there were admitted to the Boston State Hospital 1,220 patients, 859 of whom were first admissions. At the end of the study period, 60% were out of the hospital, 20% were dead, and 20% were still in residence. 2. Analysis of the 727 patients who were out of the hospital reveals that 50% were released in less than 30 days with an average hospital residence of 9 days; 20% left in 3 months to a year with an average stay of 4 months; and 30% were released after a year of hospital residence with an average of 1.42 years. The average stay in the hospital of all those leaving was 6 months. 3. Of the patients admitted in the year studied, 250 died after an average hospital residence of 160 days. The average age of those who died was 73 years. 4. A study of what happened to the admissions to 2 veterans hospitals during 3 months after 180 days had elapsed showed that over 70% were out of the hospitals at that time. Examinations of the sample in each hospital revealed the prevailing diagnostic categories were psychoses, 34-40%; alcoholic intoxication and drug addiction, 31-35%; psychoneurotic disorders, 14-13%. At the end of the 180-day period, of those remaining in the hospital 81% and 87% were with psychoses. 5. Statistical reports would gain in value if all psychiatric hospitals employed a standard diagnostic group such as the following: Transient personality reactions. Psychoneurotic disorders. Character and behavior disorders. Alcoholic intoxication and drug intoxication. Disorders of intelligence. Psychoses. Neurological disorders. No disease following observation. 6. A simple method of reporting discharge statistics has been presented. It is recommended that all psychiatric hospitals adopt it. Discharge figures so reported relating directly to admissions would serve as a crude measure of the efficiency of treatment that would be comparable if compiled by all hospitals. 7. The basis for the proposed simplified method of reporting discharge statistics is the answer to the questions: (1) Where is the patient admitted one year ago? (a) First admissions. (b) Re-admissions. (2) How long was the stay in the hospital (of those who left within the year or died)? ( a) Average length of stay. (b) Median length of stay. (3) What patients were discharged after more than 12 months from time of admission? (a) What was the length of stay: Average? Median?
Mutational Signature of Aristolochic Acid Exposure as Revealed by Whole-Exome Sequencing
Authors: Margaret L. Hoang, Chung-Hsin Chen, Viktoriya S. Sidorenko, Jian He, Kathleen G. Dickman, Byeong Hwa Yun, Masaaki Moriya, Noushin Niknafs, Christopher Douville, Rachel Karchin, Robert J. Turesky, Yeong-Shiau Pu, Bert Vogelstein, Nickolas Papadopoulos, Arthur P. Grollman, Kenneth W. Kinzler, Thomas A. Rosenquist
Journal: Science Translational Medicine (2013)

The mutational signature of aristolochic acid exemplifies how genome-wide sequencing can be used to identify environmental exposures leading to cancer.
Hemodynamic effects of a clonidine-induced decrease in sympathetic tone in patients with cirrhosis
Authors: Richard Moreau, Samuel S. Lee, Antoine Hadengue, Alain Braillon, Didier Lebrec
Journal: Hepatology (1987)

A decrease in plasma noradrenaline—a reflection of sympathetic nervous system activity—by clonidine, a centrally acting α2-agonist, could reduce the hyperdynamic circulation observed in cirrhosis and may thereby decrease portal hypertension. Plasma noradrenaline concentration and plasma renin activity as well as systemic and splanchnic hemodynamics were measured in 12 patients with cirrhosis and ascites before and after administration of either 150 μg of clonidine or placebo. Plasma noradrenaline concentration significantly decreased in all patients after clonidine administration, whereas plasma renin activity did not change significantly. There were statistically significant reductions of cardiac output (−17.4%), mean arterial pressure (−12.2%), hepatic venous pressure gradient (−19.7%) and azygos blood flow (−26.6%) after administration of clonidine. No significant correlation was found between the reduction of plasma noradrenaline concentration and changes in systemic or splanchnic hemodynamics. Hepatic blood flow was not changed by clonidine. Placebo administration had no effect on any laboratory or hemodynamic measurement. We conclude that the reduction in sympathetic nervous system activity by clonidine and the subsequent decrease in the hyperdynamic circulation suggests that sympathetic overactivity contributes to the circulatory derangements in patients with cirrhosis.
STUDIES ON THE PATHOGENESIS OF KERNICTERUS
Authors: F. Stephen Vogel
Journal: The Journal of Experimental Medicine (1953)

Kernicteric pigment was extracted by means of chloroform from the brains of 3 infants. Solutions of it gave a positive diazo reaction, and, as determined electrophotometrically, gave maximum absorption of light having a wavelength of 425 mmicro, being identical in these properties with chloroform solutions of crystalline mesobilirubin. Experimental kernicterus was regularly induced by injecting crystalline mesobilirubin intracerebrally in newborn kittens, the pigment staining the cerebral tissues a bright canary-yellow and being deposited abundantly in the nerve cells, as microscopic examinations showed, although these latter were otherwise intact. Bilirubin, likewise injected intracerebrally in newborn kittens, had no such effects. The possibility is discussed that the blood-brain barrier is altered in some infants with hyperbilirubinemia in such a way that bilirubin crosses it and is then reduced within the brain to mesobilirubin thus giving rise to the cerebral pigmentation of kernicterus. The fact that the pigment itself does not seem to damage the neurons, as the present studies show, makes it necessary to seek some other cause for the neuronal damage that is sometimes seen, in association with the pigmentation, in the naturally occurring disease.
Principles of Corticosteroid Therapy
Authors: David D'cruz
Journal: Journal of the Royal Society of Medicine (2003)

Since their introduction in 1948, with the almost miraculous responses seen in rheumatoid arthritis, corticosteroids have had a central role in a huge variety of medical conditions. However, devastating adverse effects soon emerged and both clinicians and patients have a healthy respect for these potent anti-inflammatory agents.

In Principles of Corticosteroid Therapy Andrew Lin and Stephen Paget provide a thorough overview of the biochemistry, clinical applications and adverse effects of corticosteroids. The first two chapters cover the history and the many formulations, dose regimens and clinical uses of corticosteroids and include sound guidelines on the initiation of steroid therapy. The subsequent chapters provide an in-depth overview of the physiology and actions of corticosteroids, including a discussion on glucocorticoid receptors, intracellular signalling and the central role of NF-κB.

Section 3 covers the systemic effects of corticosteroid therapy on the various organ systems of the body and I particularly enjoyed chapter 14, on the behavioural disturbances seen with steroids. Fortunately, true steroid psychosis is uncommon but a special dilemma is presented by the patient with cerebral lupus who has an organic brain syndrome of visual and auditory hallucinations. For such patients the use of methylprednisolone and high-dose oral steroids does increase the likelihood of steroid psychosis—a risk that can be lessened by use of immunosuppressive drugs to minimize the necessary dose of steroids. Close involvement of the psychiatric department is essential in the management of these patients. More common and less serious adverse effects include anxiety, depression and sleep disturbance.

Section 4 describes the clinical usage of corticosteroids and covers the whole spectrum of medical conditions where these agents are central to reducing morbidity and mortality. Junior clinicians are often taught that 1 mg per kg per day is the dose of oral prednisone for patients with serious manifestations. However, there seems no strong evidence at all for this dosage and many clinicians now use much smaller doses, perhaps in combination with pulse methylprednisolone and immuno-suppressive agents. In this last section I particularly enjoyed the part on rheumatic disease and the chapter on pulse intravenous corticosteroid therapy. High-dose intravenous methylprednisolone is widely used and this chapter highlights the rare adverse effects of seizures, arrhythmias and sudden death. I strongly recommend this book—well set out, easy to read and reasonably priced.
Sitaxentan-induced hepatic failure in two patients with pulmonary arterial hypertension
Authors: A. Lavelle, R. Sugrue, G. Lawler, N. Mulligan, B. Kelleher, D. M. Murphy, S. P. Gaine
Journal: European Respiratory Journal (2009)

Sitaxentan-induced hepatic failure in two patients with pulmonary arterial hypertensionTo the Editor:Sitaxentan sodium is an endothelin receptor antagonist (ERA) recently approved for the management of pulmonary arterial hypertension (PAH) [1].While hepatotoxicity is a recognised side-effect of treatment with the ERA bosentan, it is considered to be less common with sitaxentan [2-4].We recently admitted two patients with severe hepatotoxicity on sitaxentan to the Pulmonary Hypertension Unit at the Mater Misericordiae University Hospital (Dublin, Ireland).
New Strategies in Hepatocellular Carcinoma: Genomic Prognostic Markers
Authors: Augusto Villanueva, Yujin Hoshida, Sara Toffanin, Anja Lachenmayer, Clara Alsinet, Radoslav Savic, Helena Cornella, Josep M. Llovet
Journal: Clinical Cancer Research (2010)

Accurate prognosis prediction in oncology is critical. In patients with hepatocellular carcinoma (HCC), unlike most solid tumors, the coexistence of two life-threatening conditions, cancer and cirrhosis, makes prognostic assessments difficult. Despite the usefulness of clinical staging systems for HCC in routine clinical decision making (e.g., Barcelona-Clinic Liver Cancer algorithm), there is still a need to refine and complement outcome predictions. Recent data suggest the ability of gene signatures from the tumor (e.g., EpCAM signature) and adjacent tissue (e.g., poor-survival signature) to predict outcome in HCC (either recurrence or overall survival), although independent external validation is still required. In addition, novel information is being produced by alternative genomic sources such as microRNA (miRNA; e.g., miR-26a) or epigenomics, areas in which promising preliminary data are thoroughly explored. Prognostic models need to contemplate the impact of liver dysfunction and risk of subsequent de novo tumors in a patient's life expectancy. The challenge for the future is to precisely depict genomic predictors (e.g., gene signatures, miRNA, or epigenetic biomarkers) at each stage of the disease and their specific influence to determine patient prognosis.
ON THE SIGNIFICANCE OF THE SUBMILIARY MYOCARDIAL NODULES OF ASCHOFF IN RHEUMATIC FEVER
Authors: William Thalhimer, M. A. Rothschild
Journal: The Journal of Experimental Medicine (1914)

1. In rheumatic myocarditis, foci, termed submiliary nodules of Aschoff, are present which are characteristic of the rheumatic infection. 2. They are most frequently found in the walls of the left ventricle, the auricles usually escaping. 3. The nodules were found in three cases of chorea without joint manifestations, proving the close relation of this condition to rheumatism. 4. They were absent in fourteen cases of subacute bacterial endocarditis due to Streptococcus mitis. 5. They were not found in infections of the endocardium with the gonococcus, staphylococcus, streptococcus, or pneumococcus. 6. Even in the absence of a rheumatic history we believe, in accordance with Fraenkel, that the presence of Aschoff bodies signifies a previous rheumatic infection. 7. Aschoff bodies are not always found in rheumatic carditis, where the infection antedates death by a long period, but the healed remains, represented by sclerotic patches ("Schwielen"), are present. 8. We suggest that the cases of arthritis characterized by the presence of the submiliary nodules of Aschoff in the myocardium be placed in one group and called for the time being "rheumatism"; and the cases with articular manifestations, yielding positive bacteriological findings and no Aschoff bodies, should be classified according to the infecting microörganisms concerned, and not as rheumatism.
Indomethacin secretion in the isolated perfused proximal straight rabbit tubule. Evidence for two parallel transport mechanisms.
Authors: D de Zeeuw, H R Jacobson, D C Brater
Journal: Journal of Clinical Investigation (1988)

We studied indomethacin as a probe of anion transport across the isolated perfused proximal straight tubule of the rabbit and discovered that a substantial component of transport may occur by anion exchange at the basolateral membrane. Various perturbations involving direct or indirect dissipation of the cellular sodium gradient (ouabain, sodium- or potassium-free solutions, cooling to 18 degrees C) resulted in only a 50% inhibition of indomethacin transport, which raised the question of a co-existent alternative pathway for secretion. Similarly, the anion exchange inhibitor, 4,4'-diisothiocyanostilbene (DIDS), diminished indomethacin secretion by only 50%. Cooling followed by DIDS or the reverse sequence resulted in additive inhibition such that the combination abolished active secretion of indomethacin. We conclude that active secretion of indomethacin by the proximal straight tubule appears to be in part sodium gradient dependent; the remainder may be driven by an anion exchanger on the basolateral membrane.
Acquirement of Rituximab Resistance in Lymphoma Cell Lines Is Associated with Both Global<i>CD20</i>Gene and Protein Down-Regulation Regulated at the Pretranscriptional and Posttranscriptional Levels
Authors: Myron S. Czuczman, Scott Olejniczak, Aruna Gowda, Adam Kotowski, Arvinder Binder, Harman Kaur, Joy Knight, Petr Starostik, Julie Deans, Francisco J. Hernandez-Ilizaliturri
Journal: Clinical Cancer Research (2008)

Abstract Acquirement of resistance to rituximab has been observed in lymphoma patients. To define mechanisms associated with rituximab resistance, we developed various rituximab-resistant cell lines (RRCL) and studied changes in CD20 expression/structure, lipid raft domain (LRD) reorganization, calcium mobilization, antibody-dependent cellular cytotoxicity, and complement-mediated cytotoxicity (CMC) between parental and RRCL. Significant changes in surface CD20 antigen expression were shown in RRCL. Decreased calcium mobilization and redistribution of CD20 into LRD were found in RRCL. Western blotting identified a unique 35 kDa protein band in RRCL, which was not seen in parental cells and was secondary to an increase in surface and cytoplasmic expression of IgM light chains. CD20 gene expression was decreased in RRCL. In vitro exposure to PS341 increased CD20 expression in RRCL and minimally improved the sensitivity to rituximab-associated CMC. Our data strongly suggest that the acquisition of rituximab resistance is associated with global gene and protein down-regulation of the CD20 antigen affecting LRD organization and downstream signaling. CD20 expression seems to be regulated at the pretranscriptional and posttranscriptional levels. Proteasome inhibition partially reversed rituximab resistance, suggesting the existence of additional mediators of rituximab resistance. Future research is geared to identify drugs and/or biological agents that are effective against RRCL.
Painful Diabetic Neuropathy
Authors: Dan Ziegler
Journal: Diabetes Care (2009)

Neuropathic pain exerts a substantial impact on quality of life, particularly by causing considerable interference in sleep, daily activities, and enjoyment of life. Chronic neuropathic pain is present in 13–26% of diabetic patients (1–4). In a recent survey from Augsburg, Germany, the prevalence of painful polyneuropathy was found to be 13.3% in diabetic subjects, 8.7% in individuals with impaired glucose tolerance, 4.2% in individuals with impaired fasting glucose, and 1.2% in individuals with normal glucose tolerance (3). Independent factors significantly associated with diabetic painful neuropathy (DPN) were age, weight, and peripheral arterial disease. Pain is a subjective symptom of major clinical importance, since it is often this complaint that motivates patients to seek health care. However, in a survey from the U.K., only 65% of diabetic patients received treatment for their neuropathic pain, although 96% had reported the pain to their physician. Pain treatment consisted of antidepressants in 43.5% of cases, anticonvulsants in 17.4%, opiates in 39%, and alternative treatments in 30% (combinations possible). Whereas 77% of the patients reported persistent pain over 5 years, 23% were pain free over at least 1 year (1). Thus, neuropathic pain persists in the majority of diabetic patients over periods of several years.

Chronic DPN with persistent or episodic pain that typically may worsen at night, and improve during walking, is localized predominantly in the feet. The pain is often described as a deep-seated ache, but there may be superimposed lancination, or it may be of burning thermal quality. In a clinical survey including 105 patients with DPN, the following locations of pain were most frequent: 96% feet, 69% balls of feet, 67% toes, 54% dorsum of foot, 39% hands, 37% plantum of foot, 37% calves, and 32% heels. The pain was most often described by the patients as “burning/hot,” “electric,” …