tbuckley/cabot-search huggingface dataset:
Pin1 has opposite effects on wild-type and P301L tau stability and tauopathy
Authors: Jormay Lim, Martin Balastik, Tae Ho Lee, Kazuhiro Nakamura, Yih-Cherng Liou, Anyang Sun, Greg Finn, Lucia Pastorino, Virginia M.-Y. Lee, Kun Ping Lu
Journal: Journal of Clinical Investigation (2008)

Tau pathology is a hallmark of many neurodegenerative diseases including Alzheimer disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Genetic tau mutations can cause FTDP-17, and mice overexpressing tau mutants such as P301L tau are used as AD models. However, since no tau mutations are found in AD, it remains unclear how appropriate tau mutant mice are as an AD model. The prolyl isomerase Pin1 binds and isomerizes tau and has been implicated in protecting against neurodegeneration, but whether such Pin1 regulation is affected by tau mutations is unknown. Consistent with earlier findings that Pin1 KO induces tauopathy, here we demonstrate that Pin1 knockdown or KO increased WT tau protein stability in vitro and in mice and that Pin1 overexpression suppressed the tauopathy phenotype in WT tau transgenic mice. Unexpectedly, Pin1 knockdown or KO decreased P301L tau protein stability and abolished its robust tauopathy phenotype in mice. In contrast, Pin1 overexpression exacerbated the tauopathy phenotype in P301L tau mice. Thus, Pin1 has opposite effects on the tauopathy phenotype depending on whether the tau is WT or a P301L mutant, indicating the need for disease-specific therapies for tauopathies.
Biscarbamate cross-linked low molecular weight PEI for delivering IL-1 receptor antagonist gene to synoviocytes for arthritis therapy
Authors: Shengnan Xiang, Jing Su, Haijun Tong, Fei Yang, Wenxue Tong, Weien Yuan, Fei Wu, Chuandong Wang, Tuo Jin, Kerong Dai, Xiaoling Zhang
Journal: Biomaterials (2012)
A longitudinal analysis of physical functional disability over the course of juvenile idiopathic arthritis
Authors: S Magni-Manzoni, A Pistorio, E Labo, S Viola, P Garcia-Munitis, S Panigada, C Visconti, A Buoncompagni, A Martini, A Ravelli
Journal: Annals of the Rheumatic Diseases (2007)

To describe the longitudinal course of physical functioning in children with juvenile idiopathic arthritis (JIA) and identify predictors of long-term functional impairment.Between January 1987 and December 2002, 227 patients had two or more functional ability questionnaires completed by a parent. The total number of questionnaires was 1356 and the follow-up between first and last questionnaire administration was 949.7 patient years. At each questionnaire administration, patients were assigned to one of three functional disability states (1 = no disability; 2 = mild to moderate disability; 3 = severe disability), based on their functional ability score. Predictor variables included sex, onset age, JIA category, age at visit, disease duration, presence of antinuclear antibodies, joint counts, acute phase reactants and initial disability state.Despite patient variability in the course of physical functioning, the following three longitudinal patterns were observed: (1) a stable state of disability throughout the entire study period, with continued absence of disability in 27.8% of patients and persistently moderate disability in 3.5% of patients; (2) a steady improvement (22.9% of patients) or deterioration (5.7% of patients) in disability over time; (3) a fluctuating course of disability, with deterioration and improvement (40.1% of patients). Younger age at disease onset and a greater restricted joint count were the strongest predictors of long-term functional impairment.A wide within-patient and between-patient variability in the longitudinal course of functional disability was found. Children with early disease onset and a greater number of restricted joints had the highest risk of developing long-term physical disability.
US Immunization Policy
Authors: Jon S. Abramson
Journal: JAMA (2002)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Increased Shear Stress Overcomes the Antithrombotic Platelet Inhibitory Effect of Aspirin in Stenosed Dog Coronary Arteries
Authors: Nabil Maalej, John D. Folts
Journal: Circulation (1996)

Background Shear stress is one of the known platelet activating mechanisms that leads to thrombosis. Increased shear stress has also been postulated to reverse the antithrombotic effect of some drugs such as aspirin (ASA). Methods and Results Experiments were conducted in five dogs to determine the minimal shear stress levels that produce acute platelet thrombus formation in mechanically stenosed arteries and the increase in shear required to reverse the antithrombotic effect of ASA. After intimal and medial damage, stenosis was produced in the circumflex coronary artery. We used the finite-difference numerical solution of the Navier-Stokes equation to determine the wall shear stresses in the area of stenosis. At 70±6% coronary diameter reduction, cyclic flow reductions (CFRs) caused by acute platelet thrombus formation were observed in the stenosed lumen. At this level of stenosis, the shear stress was 144±15 Pa. ASA given at a dose of 5 mg/kg IV inhibited in vivo acute platelet-mediated thrombus formation and abolished CFRs in all dogs. However, increasing the stenosis level to 80±5% caused the CFRs to return. The shear stress increased with the increased level of stenosis to 226±22 Pa. Thus, an average 10% increase in diameter narrowing caused a 56±20% increase in shear stress ( P &lt;.005) and renewed platelet activation and thrombus formation despite ASA pretreatment. Conclusions Individuals who take ASA daily to prevent coronary artery thrombus formation may not be well protected when a change in hemodynamics, such as an acute hypertensive episode, or an increase in stenosis severity due to a ruptured atherosclerotic plaque causes an increase in shear stress.
Clinical guidelines: Developing guidelines
Authors: P. G Shekelle, S. H Woolf, M. Eccles, J. Grimshaw
Journal: BMJ (1999)

<i>Background:</i> Although two types of cervical cryotherapy tips are widely used, there have been no randomized prospective comparison studies reported in the medical literature. Shallow conical tip proponents theorize that a greater depth of freeze near the os yields better treatment of cervical intraepithelial neoplasia (CIN) without elevating the squamocolumnar junction into the cervical canal. Flat tip proponents theorize an equally effective CIN treatment with lower incidence of posttreatment squamocolumnar junction location in the cervical canal. <i>Methods:</i> A comparative descriptive study was performed to evaluate 117 cryotherapy candidates with biopsy-proved CIN who were classified by location of their squamocolumnar junctions (ectocervix, at the os, or in the canal). They were then randomized to receive double-freeze cervical cryotherapy with either a flat or shallow conical tip. Four or more months later, repeated colposcopy and Papanicolaou smears were performed to assess resolution of CIN and posttreatment location of the squamocolumnar junction. <i>Results:</i> Eighty-four patients (71%) completed the study. Analysis indicated no important difference between the two tips in eliminating CIN. The squamocolumnar junction was colposcopically visualized at all posttreatment examinations. When the pretreatment squamocolumnar junction location was on the ectocervix, data analysis indicated that squamocolumnar junction movement was greater with the shallow conical tip (<i>P</i> = .037), particularly into the canal, where it is clinically more difficult to visualize (<i>P</i> = .019). There were no Significant differences in movement of the squamocolumnar junction when it was originally at the os or in the canal. <i>Conclusions:</i> This study found no significant difference in effectiveness of the two types of tips in eliminating CIN and supports the practice of using one type—either flat or shallow conical tips—to treat all candidates for cervical cryotherapy. Using the flat tip when the pretreatment squamocolumnar junction is on the ectocervix will allow easier posttreatment visualization of the squamocolumnar junction. Further studies with a greater number of subjects are indicated.
Brief Physician Advice for Problem Drinkers-Reply
Authors: Michael Fleming
Journal: JAMA (1997)

In Reply.  —We appreciate Dr Bradley's comments regarding the differences in hospital days between the intervention and control groups reported in our article. It is important to clarify that the health care utilization data were based on patient self-report. We also collected utilization data from medical records, claims data, and family member corroborative interviews, but we opted to delay presenting this information until the 48-month follow-up of our study is completed in 1998.  The issue of multiple comparisons probably is not a factor because the statistical differences between the groups were large, and the total number of outcome variables, based on previous alcohol treatment trials, was 9. Although bias is always a concern, our trial used randomized controlled trial methods, had a large sample size, recruited subjects from community practices, and had high follow-up rates. In addition, the analysis followed intention-to-treat procedures.  Bradley also noted the potential bias of patient self-report. Health
Gentamicin–Collagen Sponge for Infection Prophylaxis in Colorectal Surgery
Authors: Elliott Bennett-Guerrero, Theodore N. Pappas, Walter A. Koltun, James W. Fleshman, Min Lin, Jyotsna Garg, Daniel B. Mark, Jorge E. Marcet, Feza H. Remzi, Virgilio V. George, Kerstin Newland, G.R. Corey
Journal: New England Journal of Medicine (2010)

Despite the routine use of prophylactic systemic antibiotics, surgical-site infection continues to be associated with significant morbidity and cost after colorectal surgery. The gentamicin-collagen sponge, an implantable topical antibiotic agent, is approved for surgical implantation in 54 countries. Since 1985, more than 1 million patients have been treated with the sponges.In a phase 3 trial, we randomly assigned 602 patients undergoing open or laparoscopically assisted colorectal surgery at 39 U.S. sites to undergo either the insertion of two gentamicin-collagen sponges above the fascia at the time of surgical closure (the sponge group) or no intervention (the control group). All patients received standard care, including prophylactic systemic antibiotics. The primary end point was surgical-site infection occurring within 60 days after surgery, as adjudicated by a clinical-events classification committee that was unaware of the study-group assignments.The incidence of surgical-site infection was higher in the sponge group (90 of 300 patients [30.0%]) than in the control group (63 of 302 patients [20.9%], P=0.01). Superficial surgical-site infection occurred in 20.3% of patients in the sponge group and 13.6% of patients in the control group (P=0.03), and deep surgical-site infection in 8.3% and 6.0% (P=0.26), respectively. Patients in the sponge group were more likely to visit an emergency room or surgeon's office owing to a wound-related sign or symptom (19.7%, vs. 11.0% in the control group; P=0.004) and to be rehospitalized for surgical-site infection (7.0% vs. 4.3%, P=0.15). The frequency of adverse events did not differ significantly between the two groups.Our large, multicenter trial shows that the gentamicin-collagen sponge is not effective at preventing surgical-site infection in patients who undergo colorectal surgery; paradoxically, it appears to result in significantly more surgical-site infections. (Funded by Innocoll Technologies; ClinicalTrials.gov number, NCT00600925.)
ERYTHROPOIETIC PROTOPORPHYRIA: TWO DEATHS FROM HEPATIC CIRRHOSIS
Authors: E. M. Donaldson, A. J. Mccall, I. A. Magnus, J. R. Simpson, R. A. Caldwell, T. Hargreaves
Journal: British Journal of Dermatology (1971)

SUMMARY.— Two patients suffering from erythropoietic protoporphyria who died from liver failure with jaundice and portal hypertension are presented. The hepatic lesion was characteristic—a micronodular cirrhosis with massive deposits of protoporphyrin. The term erythrohepatic protoporphyria is preferred to erythropoietic protoporphyria.
Nansi Eirlys James (nee Harry)
Authors: E T R James
Journal: BMJ (2002)

Former senior assistant professorial medical unit Welsh National School of Medicine, Cardiff (b 1913; q Cardiff 1936; BSc, MRCP), d 28 Apri1 2002.

While she was at the professorial medical unit at the Welsh National School of Medicine, Nansi James enjoyed teaching Cardiff medical students and also University College Hospital students who had been evacuated from London. She retired from active medical practice for a number of years, but returned to work as a child psychiatrist in Swansea in 1959. In 1984 she became a clinical research officer at the Department of Child Health in Cardiff. She retired in 1983. Predeceased by her husband, Toby, she leaves three sons and two grandchildren.
Abstract 4925: The natural enzyme sequestration in signaling cascades provides inherent opportunities for off-target effects induced by kinase inhibitors
Authors: Michelle L. Wynn, Alejandra C. Ventura, Jacques-A. Sepulchre, Hector J. Garcia, Sofia D. Merajver
Journal: Cancer Research (2012)

Abstract Off-target effects from targeted therapies are often attributed to cross-talk, which usually refers to inter-pathway molecular interactions that occur because of explicit regulatory feedback connections between two pathways. Recent experimental and theoretical studies have demonstrated, however, that covalently modified cascades naturally exhibit bidirectional signal propagation via a phenomenon termed retroactivity. This phenomenon arises due to enzyme sequestration where each cycle is coupled, not only to the next cycle, but also to the previous cycle. While retroactivity occurs naturally in covalently modified cascades, signaling pathways likely evolved to propagate information in a downstream manner. An important consequence of retroactivity, however, is that a downstream perturbation can induce an upstream response without the presence of regulatory feedback connections. We hypothesize that kinase inhibitors can produce off-target effects as a consequence of retroactivity alone via the following mechanism: a signal travels upstream from the site of a downstream perturbation through retroactivity and, upon reaching a shared upstream component, is delivered to an independent parallel pathway. To test the hypothesis we used a computational model to simulate the targeted inhibition of a specific kinase in a series signaling networks using physiologically and therapeutically relevant ranges for all parameters. Surprisingly, our results suggest that an off-target effect due to retroactive signaling is more likely when the first cycle in a non-inhibited cascade is “off” and not consuming large amounts of a shared up-stream activator. Our results also suggest that the kinetics governing covalently modified cycles in a cascade are more important for propagating an upstream off-target effect than the binding affinity of the drug to the targeted protein, which is a commonly optimized property in drug development. Finally, our results suggest that a single mutation has the capacity to produce a large spontaneous off-target effect without any direct regulatory connections between the targeted protein and the effected protein. Together, our results suggest that retroactivity may play an important role in the dysregulated signaling networks of cancer cells as well as the cellular response to targeted therapies. These findings have important implications for somatic evolution in cancer and the onset of therapeutic resistance, which has been widely reported for many targeted cancer therapeutics, including kinase inhibitors. 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 4925. doi:1538-7445.AM2012-4925
Abstract LB-194: Phosphorylation-dependent dimerization of forkhead-associated domain regulates MDC1 function in response to DNA damage
Authors: Jinping Liu, Shukun Luo, David Stern, Keqiong Ye, Xingzhi Xu
Journal: Cancer Research (2011)

Abstract MDC1 is a key mediator of DNA damage response in mammals. Here, we show that the N-terminal FHA domain of MDC1 mediates regulated dimerization in response to DNA damage. DNA damage induces phosphorylation of threonine 4 of MDC1 and FHA binds reciprocally to phospho-threonine-4 (pT4) from the other molecule. We determined the crystal structures of the MDC1 FHA domain in the free state and in complex with a pT4 peptide. FHA forms a dimer with pseudo 2-fold symmetry and face-to-face β-sheet contact. The FHA dimer is marginally stable, but is greatly stabilized in vitro and in vivo by the intermolecular binding between FHA and the preceding pT4 peptide. Forms of MDC1 with FHA deletion or mutations compromising dimerization are defective in foci formation at the sites of DNA damage, but could be largely rescued by an artificial dimerization module. Our results support a novel regulation mechanism of MDC1 function through T4 phosphorylation and FHA-mediated dimerization. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-194. doi:10.1158/1538-7445.AM2011-LB-194
Admissions to hospital due to drugs.
Authors: T. Parkinson, A. H. Knight
Journal: BMJ (1969)

some such as 1 7a-hydroxyprogesterone 17-npaproate and norethynodrel have been shown ,to be free of these unfortunate side-effects.I would have thought that progestins are best avoided in the treatment of pregnancy prurigo, and the simpler measures that you advocated are best adhered to.-I am, etc., J.
Effect of isosorbide dinitrate, verapamil, and labetalol on portal pressure in cirrhosis.
Authors: J G Freeman, J R Barton, C O Record
Journal: BMJ (1985)

The effects on portal pressure of the vasodilatory drugs isosorbide dinitrate and verapamil and of an alpha and beta blocking agent, labetalol, were assessed in 21 patients with cirrhosis and portal hypertension. The wedged hepatic venous pressure gradient (wedged minus free hepatic venous pressures) was used as an index of portal pressure and was not significantly changed by treatment with labetalol (n = 5) but was significantly decreased by verapamil (n = 6; p less than 0.05) and isosorbide dinitrate (n = 10; p less than 0.01). Long term administration of isosorbide dinitrate also had a significant effect (p less than 0.01).
Thyroxine Toxicosis
Authors: Robert H. Caplan
Journal: JAMA (1980)

To determine the frequency of thyroxine (T<sub>4</sub>) toxicosis, we calculated a free triiodothyronine index (FT<sub>3</sub>I) on 124 patients who displayed elevations of the free T<sub>4</sub>index (FT<sub>4</sub>I) on initial screening. If the clinical presentation was not characteristic of hyperthyroidism or if the FT<sub>3</sub>I was not elevated, a thyrotropin-releasing hormone (TRH) test was performed. Of 83 hyperthyroid patients, 70 displayed elevations of both the FT<sub>4</sub>and FT<sub>3</sub>indices. Thirteen patients, however, had elevations of the FT<sub>4</sub>I alone. This frequency of T<sub>4</sub>toxicosis is higher than generally appreciated. Forty-one patients, most of whom were ill with nonthyroidal diseases, had normal TRH test results and were classified euthyroid. We conclude that FT<sub>4</sub>I elevations owing to T<sub>4</sub>toxicosis and nonthyroidal illnesses are common and that the laboratory differentiation between the syndromes may be difficult. (<i>JAMA</i>244:1934-1938, 1980)
PROLAPSE OF IRIS AFTER CATARACT EXTRACTION
Authors: ALBERT E. BULSON
Journal: JAMA (1925)

Prolapse of the iris as a postoperative complication of cataract extraction usually is considered serious. The chief danger, as expressed by numerous authorities, is the liability of an eye in which it is present to become affected with inflammation of the uveal tract, weeks, months or years after the healing of the wound. It is quite probable that the danger is overestimated, as every operator of considerable experience will testify; and yet the fact that the condition does occur, and that it offers even a minimum amount of danger, should prompt us to adopt those measures most likely to avert it, and give it proper attention when it does occur. There can be little doubt that the rather general tendency on the part of nearly all operators to do the combined operation has lessened the number of cases of postoperative iris prolapse, especially when a generous conjunctival flap has been
Serum Nerve Growth Factor Concentration and Its Role in the Preclinical Stage of Dementia
Authors: Rainer T. Schaub, Dirk Anders, Gisela Golz, Kristian Göhringer, Rainer Hellweg
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Nerve growth factor is important for the development and function of the cholinergic basal forebrain. The authors examined the hypothesis that the concentration of nerve growth factor is lower than normal in the preclinical phase of neurodegenerative dementia, especially Alzheimer's disease. METHOD: The serum nerve growth factor concentration of subjects from the Berlin Aging Study and the Berlin Memory Clinic who later developed Alzheimer's disease were compared with those of subjects who were free of dementia and subjects who were already suffering from Alzheimer's disease. RESULTS: There were 17 subjects in each group, matched for age and sex. The three groups differed in log-10-transformed mean nerve growth factor concentrations: 1.62 (SD=0.59) for the healthy comparison subjects, 0.92 (SD=0.30) for the subjects with preclinical dementia, and 1.44 (SD=0.61) for the subjects with Alzheimer's disease. CONCLUSIONS: These results support the hypothesis of disturbed nerve growth factor regulation in the serum of patients with preclinical Alzheimer's disease. Mechanisms by which these disturbances appear are unclear, but they may reflect the situation in the preclinical Alzheimer's disease brain.
Surfing on consciousness, or, a deliberately shallow outline of cognition
Authors: Luis Jiménez
Journal: Behavioral and Brain Sciences (2002)

By assuming that conscious states are the only constructs entitled to bear a cognitive status, while denying this status both to the learning processes and to their nonconscious outcomes, the SOC view leaves consciousness alone as the single tool to explain itself. This does not endow consciousness with any self-organizing properties, but rather, draws a deliberately shallow outline of cognition.