tbuckley/cabot-search huggingface dataset:
Treatment of Neuropsychiatric Symptoms in Patients with Dementia
Authors: Kristine Yaffe
Journal: New England Journal of Medicine (2007)

Although cognitive deficits are the clinical hallmark of dementia syndromes, noncognitive symptoms are common and can dominate the disease course. These include a range of neuropsychiatric symptoms, such as agitation, delusions, hallucinations, repetitive vocalizations, and wandering. Neuropsychiatric symptoms develop in as many as 60% of community-dwelling patients with dementia1 and in more than 80% of patients living in nursing homes. These symptoms are associated with greater morbidity, higher costs of care, and reduced quality of life for the patient as well as increased burden and depression for the caregiver. Indeed, neuropsychiatric symptoms are a primary predictor of nursing home placement. . . .
Octamer 4 (Oct4) mediates chemotherapeutic drug resistance in liver cancer cells through a potential Oct4-AKT-ATP-binding cassette G2 pathway
Authors: Xiao Qi Wang, Weg M. Ongkeko, Lin Chen, Zhen Fan Yang, Ping Lu, Kwok Kin Chen, Jay P. Lopez, Ronnie T.P. Poon, Sheung Tat Fan
Journal: Hepatology (2010)

Chemoresistance presents a major obstacle to the efficacy of chemotherapeutic treatment of cancers. Using chemotherapeutic drugs to select drug-resistant cancer cells in hepatocellular carcinoma (HCC) and several other cancer cell lines, we demonstrate that chemoresistant cells displayed cancer stem cell features, such as increased self-renewal ability, cell motility, multiple drug resistance, and tumorigenicity. Octamer 4 (Oct4) messenger RNA (mRNA) levels were dramatically increased in chemoresistant cancer cells due to DNA demethylation regulation of Oct4. By functional study, Oct4 overexpression enhanced whereas Oct4 knockdown reduced liver cancer cell resistance to chemotherapeutic drugs in vitro and in xenograft tumors. It is known that the Oct4-TCL1-AKT pathway acts on embryonic stem cells and cancer stem cells in cell proliferation through inhibition of apoptosis. We further demonstrate that Oct4 overexpression induced activation of TCL1, AKT, and ABCG2 to mediate chemoresistance, which can be overcome by addition of the PI3K/AKT inhibitor; therefore, a direct pathway of Oct4-TCL1-AKT-ABCG2 or a combination of Oct4-TCL1-AKT with the AKT-ABCG2 pathway could be a potential new mechanism involved in liver cancer cell chemoresistance. Moreover, the clinical significance of the Oct4-AKT-ABCG2 pathway can be demonstrated in HCC patients, with a strong correlation of expression patterns in human HCC tumors. The role of the Oct4-AKT-ABCG2 axis in cancer cell chemoresistant machinery suggests that AKT pathway inhibition (PI3K inhibitors) not only inhibits cancer cell proliferation, but may also enhance chemosensitivity by target potential chemoresistant cells. Conclusion: Oct4, a transcriptional factor of pluripotent cells, can mediate chemoresistance through a potential Oct4-AKT-ABCG2 pathway. (HEPATOLOGY 2010;)
Abstract 142: Tumor suppressor BRCA1 epigenetically controls oncogenic miRNA-155
Authors: Suhwan Chang, Shyam Sharan
Journal: Cancer Research (2012)

Abstract BRCA1, a well-known breast and ovarian cancer susceptibility gene with multiple interacting partners, is predicted to have diverse biological functions. However, to date its only well-established role is in the repair of damaged DNA and cell cycle regulation. In this regard, the etiopathological study of low penetrant variants of BRCA1 provides an opportunity to uncover its other physiologically important functions. Using this rationale, we studied the R1699Q variant of BRCA1, a potentially moderate risk variant, and found that it does not impair DNA damage repair but abrogates the repression of miR-155, a bona fide oncomir. We further show that in the absence of functional BRCA1, miR-155 is up-regulated in BRCA1-deficient mouse mammary epithelial cells, human and mouse BRCA1-deficienct breast tumor cell lines as well as BRCA1 mutant tumors. Mechanistically, we found that BRCA1 represses miR-155 expression via its association with HDAC2, which deacetylates H2A and H3 on the miR-155 promoter. Finally, we show that over-expression of miR-155 accelerates whereas the knockdown of miR-155 attenuates the growth of tumor cell lines in vivo. Taken together, our findings demonstrate a new mode of tumor suppression by BRCA1 and reveal miR-155 as a potential therapeutic target for BRCA1-deficient tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 142. doi:1538-7445.AM2012-142
567. Prevention of Bilirubin Toxicity in the Gunn Rat by Long-Term Correction of Hyperbilirubinemia with Liver-Specific Plasmid-Based Gene Transfer
Authors: Istvan Danko, Zhen Jia
Journal: Molecular Therapy (2005)

Background: We have previously demonstrated short-term correction of hyperbilirubinemia in the Gunn rat (GR), animal model of Crigler-Najjar Disease Type I, by hepatic venous delivery of naked plasmid (pDNA) expressing human bilirubin glucuronosyl transferase (hUGT1A1) under CMV promoter. Recently, long-term expression of coagulation factors in mouse liver was reported after tail vein injection of pDNA containing alpha-1 antitrypsin promoter along with other liver-specific elements, limited only by development of antibodies to some secreted proteins. In this study we investigated whether liver-specific regulatory sequences prolong expression of hUGT1A1 in the GR, whether immune response develops to this intracellular enzyme, and whether with this approach sufficiently low bilirubin levels can be maintained to prevent renal tubular damage, the principal manifestation of chronic bilirubin toxicity in GR.
Adrenocortical Function and Metabolism of 17-Hydroxycorticosteroids in Pernicious Anemia
Authors: Avery A. Sandberg, Kristen Eik-Nes, Don H. Nelson, J. G. Palmer, G. E. Cartwright, M. M. Wintrobe
Journal: New England Journal of Medicine (1954)

Strauss and Brokaw1 recently reviewed and evaluated various clinical and metabolic changes in pernicious anemia. They concluded that "the occurrence of numerous manifestations of Addison's disease of the suprarenal capsule in Addisonian pernicious anemia in relapse suggest that functional adrenocortical insufficiency may be present in certain cases of this condition." It was pointed out that, in addition to certain clinical similarities between Addison's disease and pernicious anemia, there is indirect evidence of impaired adrenocortical function in pernicious anemia. Thus, patients with pernicious anemia were unable to conserve sodium chloride or excrete a water load rapidly; the oral glucose tolerance curves . . .
Different Effects of Angiotensin Receptor Blockade on End-Organ Damage in Salt-Dependent and Salt-Independent Hypertension
Authors: Karlene Maitland, LaKeesha Bridges, Wendell P. Davis, Joseph Loscalzo, Mildred A. Pointer
Journal: Circulation (2006)

Although angiotensin II type 1 receptor blockers have emerged as effective antihypertensive agents, it is not known how efficacious these agents are in treating hypertension-associated target organ damage.The present study was undertaken to compare the effect of angiotensin type 1 receptor inhibition on the progression of the organ damage observed in 2 models of hypertension, namely, salt-sensitive and nitric oxide synthase inhibition-mediated hypertension. Effective (16.4 micromol/kg) and ineffective (0.8 to 4.9 micromol/kg) antihypertensive doses of candesartan cilexetil were initiated after hypertension was established. Both low- and high-dose candesartan cilexetil significantly reduced cardiac and renal damage in the nitric oxide synthase inhibitor model of hypertension (P < 0.05 versus untreated); however, high-dose candesartan caused a significant increase in renal damage in the Dahl salt-sensitive model of hypertension (P < 0.05 versus untreated). Interestingly, the beneficial end-organ effects of candesartan in the nitric oxide synthase inhibition model were independent of sustained antihypertensive actions of candesartan, whereas the exacerbation of renal injury with candesartan in the Dahl salt-sensitive model was inversely related to its blood pressure-lowering effect.These data show that angiotensin type 1 blockade reduces injury in the l-nitroarginine methyl ester model but increases tissue injury in the salt-sensitive model. These data suggest that angiotensin II via angiotensin type 1 receptor activation contributes to organ damage in nitric oxide-deficient salt-independent hypertension but is protective in salt-induced hypertension. These data further suggest that (1) renal injury may evolve independently of blood pressure and (2) the effectiveness of an antihypertensive agent in ameliorating renal injury may depend on the etiology of the hypertension.
A Permanent Badge for the American Medical Association.
Authors: F. E. Stewart
Journal: JAMA (1896)

Detroit, Mich., March 6, 1896. <h3>To the Editor:</h3> —I have been very much interested in the discussion on the subject of insignia of the medical department U. S. A. Now that the board of officers, of which Col. Chas. H. Alden, Assistant Surgeon General U. S. A., is president, has concluded its labors and rendered its report and recommendation to the Surgeon General, it may not be amiss to consider the subject of a permanent badge for theAmerican Medical Association. At each annual meeting of theAssociationwe are presented with a new badge. At San Francisco the badge consisted of an escutcheon bearing the arms of California, etc. The escutcheon, which was made of silver, was suspended from a pin made in the semblance of a bear, composed of some kind of metal coated with gold. It was a beautiful badge, and cost the local medical societies and
Phospholipase C β3 deficiency leads to macrophage hypersensitivity to apoptotic induction and reduction of atherosclerosis in mice
Authors: Zhenglong Wang, Bei Liu, Ping Wang, Xuemei Dong, Carlos Fernandez-Hernando, Zhong Li, Timothy Hla, Zihai Li, Kevin Claffey, Jonathan D. Smith, Dianqing Wu
Journal: Journal of Clinical Investigation (2008)

Atherosclerosis is an inflammatory disease that is associated with monocyte recruitment and subsequent differentiation into lipid-laden macrophages at sites of arterial lesions, leading to the development of atherosclerotic plaques. PLC is a key member of signaling pathways initiated by G protein–coupled ligands in macrophages. However, the role of this enzyme in the regulation of macrophage function is not known. Here, we studied macrophages from mice lacking PLC β2, PLC β3, or both PLC isoforms and found that PLC β3 is the major functional PLC β isoform in murine macrophages. Although PLC β3 deficiency did not affect macrophage migration, adhesion, or phagocytosis, it resulted in macrophage hypersensitivity to multiple inducers of apoptosis. PLC β3 appeared to regulate this sensitivity via PKC-dependent upregulation of Bcl-XL. The significance of PLC β signaling in vivo was examined using the apoE-deficient mouse model of atherosclerosis. Mice lacking both PLC β3 and apoE exhibited fewer total macrophages and increased macrophage apoptosis in atherosclerotic lesions, as well as reduced atherosclerotic lesion size when compared with mice lacking only apoE. These results demonstrate what we believe to be a novel role for PLC activity in promoting macrophage survival in atherosclerotic plaques and identify PLC β3 as a potential target for treatment of atherosclerosis.
Comparison of anti-CD20 and anti-CD45 antibodies for conventional and pretargeted radioimmunotherapy of B-cell lymphomas
Authors: John M. Pagel, Nathan Hedin, Krishnan Subbiah, Damon Meyer, Robert Mallet, Donald Axworthy, Louis J. Theodore, D. Scott Wilbur, Dana C. Matthews, Oliver W. Press
Journal: Blood (2003)
Leukotrienes B4, C4 and D4 stimulate DNA synthesis in cultured human epidermal keratinocytes
Authors: K. KRAGBALLE, L. DESJARLAIS, J.J. VOORHEES
Journal: British Journal of Dermatology (1985)

Leukotrienes in psoriatic skin lesions are potent mediators of inflammation. We have studied the capacity of leukotrienes to stimulate the DNA synthesis of cultured human epidermal keratinocytes. At concentrations ranging from 10(-12) to 10(-8) M, LTB4 produced a 100% increase of DNA synthesis determined both as the incorporation of [3H] thymidine and as the labelling index. In comparison, LTB4 had no effect on the DNA synthesis of dermal fibroblast cultures. 5S,12S-LTB4 and 5S,12S-all-trans-LTB4 did not change the DNA synthesis of keratinocytes, but the effect of LTB4 was abolished in the presence of 5S,12S-all-trans HLTB4. Being less potent than LTB4 the peptidoleukotrienes (LTC4, LTD4) also stimulated keratinocyte DNA synthesis. The effect of the peptidoleukotrienes, but not of LTB4, was antagonized by FPL 55712. These results show that leukotrienes B4, C4 and D4 exert potent and stereospecific mitogenic effects on cultured human keratinocytes. The presence of these arachidonic acid metabolites in psoriatic skin lesions may be pertinent to both inflammation and aberrant epidermal growth in psoriasis.
Tachycardia precipitated by topical homatropine.
Authors: D. Reid, J. D. Fulton
Journal: BMJ (1989)

remained.He was discharged from hospital without continuing treatment.Two weeks later he developed severe deep otalgia and an increased blood glucose concentration.Repeat computed tomography showed more extensive temporal bone erosion.Intravenous ceftazidime wjas given for two weeks followed by oral ciprofloxacin 500 mg twice a day for three months as outpatient treatment.He steadily improved, and the facial palsy resolved almost completely.The vagal and hypoglossal palsies remained, but there was good functional compensation.He subsequently remained well 22 months after completing treatment.In this case diagnosis of malignant otitis externa was delayed because of failure to culture pseudo- monas from the meatus.In our opinion intravenous antibiotic treatment remains the best initial treatment because these patients need inpatient assessment and effective high blood concentrations of antibiotic are best guaranteed by systemic administration.Oral ciprofloxacin should be given as continuation outpatient treatment to prevent relapse.The optimum length of treatment has not yet been defined, but two to three months after the resolution of symptoms and signs seems to be adequate.
Hypersensitivity of scleroderma cutaneous vascular smooth muscle to 5-hydroxytryptamine
Authors: R.K. WINKELMANN, MARC E. GOLDYNEAND, RONALD L. LINSCHEID
Journal: British Journal of Dermatology (1976)

Vascular smooth muscle strips from subcutaneous wrist vessels of patients with scleroderma (systemic sclerosis) were studied in an isolated system. No difference between catecholamine response of scleroderma or control vessel strips was observed. Three of four patients demonstrated significant hypersensitivity to 5-hydroxytryptamine as compared to control values. Serotonin hypersensitivity may play a role in the evolution of Raynaud's phenomenon and vascular scleroderma.
P204 Immune Responses To Single And Repeated Administration Of Pgm169/gl67a: The Uk Cf Gene Therapy Consortium Clinical Trials
Authors: U. Griesenbach, A. Boyd, R. Calcedo, S. Cheng, S. Cunningham, J. Davies, M. Dewar, D. Gill, A. Doherty, T. Higgins, S. Hyde, M. Manvell, C. Meng, J. Innes, M. Limberis, E. Punch, R. Scheule, N. Soussi, S. Soussi, J. Wilson, E. Alton
Journal: Thorax (2014)

<h3></h3> Although most CF patients express CFTR protein (albeit mutant) and should therefore not recognise the wild-type CFTR protein as foreign, there is an inherent risk of activation of T-cells against the recombinant wild-type protein after gene therapy. In addition, we have previously shown that approximately 10% of CF and non-CF subjects carry self-reactive CFTR-specific T-cells (<i>Calcedo <i>et al</i>, Hum Gene Ther Clin Dev 2013</i>). The reason for this is unknown and it is also unclear whether being positive for self-reactive T-cells affects disease severity or increases the risk of further T-cell activation after gene therapy. As part of the UKCFGTC Phase I/IIa Pilot study [in which patients received a single dose (5, 10 or 20 mls) of the non-viral formulation pGM169/GL67A] peripheral blood mononuclear cells (PBMC) were collected prior to dosing and approximately 4 weeks after nebulisation of 5 ml (n = 2), 10 ml (n = 6) or 20 ml (n = 17) of pGM169/GL67A. IFN-g ELISPOT to detect CFTR-specific T-cells in PBMC was performed. CFTR-specific T-cells were detectable in one patient pre- and post-dosing. In the remaining 18 patients we did not detect CFTR-specific T-cells. In addition we quantified anti-DNA antibodies (anti-nuclear and anti-cytoplasmic) in blood samples taken pre- and approximately 4 weeks post-dosing (n = 7 (5 ml), n = 10 (10 ml) and n = 17 (20 ml). We did not observe any evidence for induction of anti-DNA antibodies after a single dose of pGM169/GL67A. The UKCFGTC has now completed a Phase IIb multi-dose clinical trial in May 2014 (ClinicalTrials.gov identification number – NCT01621867). CF patients received 12 monthly doses of pGM169/GL67A (115 completed nine or more doses), or placebo by aerosol. PBMC were collected on two occasions prior to dose 1 to establish baseline levels for CFTR-specific T-cells, approximately 4 weeks after Dose 4 or 5, and 2 to 4 weeks after Dose 12 and the ELISPOT was performed. In addition anti-DNA antibodies were quantified. The Phase IIb trial will be unblinded in Summer 2014 to allow data analysis and all data will be presented at the conference. Funded by the NIHR/EME Programme and the Cystic Fibrosis Trust.
Pain is not the only feature of heart attack
Authors: T. Treasure
Journal: BMJ (1998)

EDITOR —Ruston et al conclude that if we are to minimise the time between the onset of myocardial ischaemia and the administration of thrombolysis “the myth that a heart attack is a dramatic event needs to be dispelled.”1Perhaps medical advice that includes the word “pain” is the single biggest problem. The article is based on descriptions from patients, yet the word pain is used only once, and then in the final paragraph, when the authors cite advice from health professionals. Pain is evidently the …
TCT-845 Percutaneous Coronary Intervention is Associated with Lower Mortality Compared with Optimal Medical Therapy in Patients with Stable Ischemic Heart Disease and Objective Evidence of Ischemia or Abnormal Fractional Flow Reserve: A Meta-Analysis of Randomized Controlled Trials
Authors: Ajay J. Kirtane, Hemal Gada, Sripal Bangalore, Dean Kereiakes, Gregg Stone
Journal: Journal of the American College of Cardiology (2013)
PFI deals need more scrutiny after shareholders receive big windfalls
Authors: Matthew Limb
Journal: BMJ (2005)

The National Audit Office has asked for a scrutiny of hospital deals secured under the private finance initiative (PFI) to see whether newer schemes are delivering better value for money than earlier ones as the PFI market matures. The review was suggested after an investigation by the office into the refinancing of an early PFI scheme, which gave private shareholders an £81m ($45m; €67m) windfall. The trust involved in the scheme, Norfolk and Norwich University Hospital NHS Trust, also benefited from the refinancing, but the office warned that it now faces increased risks and continues to “pay a premium” compared with more recent PFI deals with better terms.

The office reviewed the PFI deal after concerns were raised by the MP for North Norfolk, Norman Lamb (Liberal Democrat). It concluded that ministers …
Effects of Acute Bilateral Ureteral Obstruction on Deep Nephron and Terminal Collecting Duct Function in the Young Rat
Authors: John Buerkert, Mary Head, Saulo Klahr
Journal: Journal of Clinical Investigation (1977)

The effects of acute bilateral ureteral obstruction (BUO) of 18-h duration on deep nephron and collecting duct function were studied by micropuncture in 11 weanling rats. After release of BUO glomerular filtration rate was reduced (178+/-15 vs. 1,343+/-119 mul/min per g kidney weight in shams), while urine flow was increased averaging 17.5+/-1.3 vs. 6.8+/-0.72 mul/min per g kidney weight in controls. There was a marked increase in the absolute and fractional excretion of Na. Single nephron glomerular filtration rate of deep nephrons was reduced in the BUO group, mean 19.4+/-3.5 vs. 77.0+/-7.7 nl/min per g kidney weight in shams. Single nephron glomerular filtration rate of superficial nephrons fell to the same extent after relief of BUO. Mean tubular fluid to plasma inulin ratio of fluid from Henle's loop was 2.46+/-0.20 after relief of BUO vs. 8.23+/-0.85 in shams. This suggested a reduction in the reabsorption of Na and water before the bend of the loop of Henle, most likely in both the proximal tubule and descending limb. Fluid osmolality was depressed due to a decline in both Na and nonelectrolyte solute content. After release of BUO the percentage of filtered water remaining in the collecting duct (CD) at the base of the papilla was greater than in controls (13.3+/-2.0 and 1.72+/-0.01%, respectively) but fell significantly by the tip of the papilla to 7.92+/-1.12 vs. 1.17+/-0.02% in controls. These results indicate that water was reabsorbed along the terminal CD after relief of ureteral obstruction. In fact, a greater fraction was reabsorbed in this segment after release of BUO (5.37+/-1.58%) than after sham operation (0.55+/-0.15%). Similar changes were seen in Na excretion. Thus alterations in deep nephron function appear to contribute to the natriuresis and diuresis which follow release of BUO while terminal CD function in this model appears intact.
Improved postprandial glycemic control with insulin aspart. A randomized double-blind cross-over trial in type 1 diabetes.
Authors: A Lindholm, J McEwen, A P Riis
Journal: Diabetes Care (1999)

OBJECTIVE: Insulin aspart is a novel rapid-acting insulin analog. This study was performed to compare the postprandial serum glucose control after administration of insulin aspart with that of unmodified human insulin. RESEARCH DESIGN AND METHODS: The trial was a double-blind double-dummy injection three-way cross-over study in 22 subjects with type 1 diabetes. Insulin aspart was injected subcutaneously immediately before the meal, and human insulin was injected subcutaneously 30 min before the meal or immediately before the meal. RESULTS: The postprandial glucose control as assessed by the excursion of serum glucose was superior with insulin aspart as compared with that with human insulin injected immediately before or 30 min before a meal (891 +/- 521 vs. 1,311 +/- 512 vs. 1,106 +/- 571 mmol.l-1.min-1, P &amp;lt; 0.0001 and P &amp;lt; 0.02). This was accompanied by a significantly lower glucose maximum concentration [Cmax(SG)] for insulin aspart than for human insulin injected immediately before the meal (13.5 +/- 3.5 vs. 16.4 +/- 3.4 mmol/l, P &amp;lt; 0.001). Insulin aspart was, on average, absorbed twice as fast as human insulin, with median time to insulin aspart Cmax(ins) on the order of 40 min, and the maximum concentration was approximately twice as high for insulin aspart. The relative bioavailability of the insulins indicated a similar extent of absorption. Insulin aspart was well tolerated. CONCLUSIONS: This study demonstrates the ability of insulin aspart to improve postprandial glucose control when compared with human insulin.