tbuckley/cabot-search huggingface dataset:
p38 Mitogen-Activated Protein Kinase Contributes to Autoimmune Renal Injury in MRL-Fas lpr Mice
Authors: Yasunori Iwata, Takashi Wada, Kengo Furuichi, Norihiko Sakai, Kouji Matsushima, Hitoshi Yokoyama, Ken-ichi Kobayashi
Journal: Journal of the American Society of Nephrology (2003)

The phosphorylation of p38 mitogen-activated protein kinase (MAPK) is responsible for the production and signal transduction of cytokines and chemokines. This study hypothesized that p38 MAPK activation is required for spontaneous autoimmune renal injury in MRL-Fas(lpr) mice, resembling human lupus erythematosus. FR167653, a specific inhibitor of p38 MAPK, is orally administrated from 3 or 4 mo of age in MRL-Fas(lpr) mice (at doses of 10 or 32mg/kg per day) until 6 mo of age. The phosphorylated p38 MAPK in kidneys of MRL-Fas(lpr) mice was evaluated. The number of phosphorylated p38 MAPK-positive cells was increased in diseased kidneys. The daily oral administration of FR167653 decreased p38 MAPK phosphorylation in kidneys, especially in a group of mice administered FR167653 (32 mg/kg per day) daily from 3 to 6 mo of age. FR167653 reduced the accumulation of macrophages and T cell and prevented kidney pathology, resulting in prolonged survival. In addition, FR167653 reduced expression of MCP-1 and TNF-alpha in the diseased kidneys and cultured tubular epithelial cells. Furthermore, FR167653 decreased IgG levels in the diseased kidneys and circulation. These results suggest that the phosphorylation of p38 MAPK is required for the pathogenesis of renal injury in MRL-Fas(lpr) mice followed by subsequent expression of renal cytokine/chemokine and IgG production. This study provides evidence that the regulation of p38 MAPK is a novel target for the therapy of renal injury in systemic lupus erythematosus.
Exhaled nitric oxide and asthma control: a longitudinal study in unselected patients
Authors: A. Michils, S. Baldassarre, A. Van Muylem
Journal: European Respiratory Journal (2007)

Controlled studies have shown that monitoring of the exhaled nitric oxide fraction ( F eNO ) improves asthma management. However, the studies seldom consider the full range of patients seen in clinical practise. In the present study, the ability of F eNO to reflect asthma control over time is investigated in a regular clinical setting, and meaningful F eNO cut-off points and changes are identified. Answers to the Asthma Control Questionnaire and F eNO were recorded at least once in 341 unselected asthma patients. The whole population and subgroups were considered, i.e. both inhaled corticosteroid (ICS)-naïve and low or high-to-medium (≤ or &gt;500 μg beclomethasone dipropionate equivalents·day −1 ) ICS-dose groups. An F eNO decrease &lt;40% or increase &lt;30% precludes asthma control optimisation or deterioration, respectively (negative predictive value 79 and 82%, respectively). In the present study’s low-dose group, a decrease &gt;40% indicated asthma control optimisation (positive predictive value (PPV) 83%). In ICS-naïve patients, F eNO &gt;35 ppb predicted asthma control improvement in response to ICS (PPV 68%). In most cases, forced expiratory volume in one second assessments were not useful. In conclusion, in a given patient, exhaled nitric oxide fraction was found to be significantly related to asthma control over time. The overall ability of exhaled nitric oxide fraction to reflect asthma control was reduced in patients using high doses of inhaled corticosteroids. Forced expiratory volume in one second had little additional value in assessing asthma control.
Molecular monitoring to improve outcomes in patients with chronic myeloid leukemia in chronic phase: Importance of achieving treatment-free remission
Authors: Harry P. Erba
Journal: American Journal of Hematology (2014)

Imatinib was the first BCR-ABL1 tyrosine kinase inhibitor (TKI) developed for the treatment of patients with chronic myeloid leukemia (CML); subsequently, the introduction of more potent BCR-ABL1 TKIs has raised expectations regarding the speed and depth of response. This review discusses how molecular monitoring is being used as an integral part of the treatment regimen to achieve improved outcomes in patients with CML. The long-term prognostic implications of achieving early molecular response to TKI therapy and the feasibility of maintaining treatment-free remission will also be discussed in light of current clinical data.
Optimizing Treatment of Desmoid Tumors
Authors: Dina Lev, Dhanasekaran Kotilingam, Caimiao Wei, Matthew T. Ballo, Gunar K. Zagars, Peter W.T. Pisters, Alexander A. Lazar, Shreyaskumar R. Patel, Robert S. Benjamin, Raphael E. Pollock
Journal: Journal of Clinical Oncology (2007)

Purpose This study compared a large series of desmoid patients treated at a single institution to a previously published series from the same institution to determine if patient population characteristics, treatment approaches, and clinical outcomes had undergone change over the two study periods. Materials and Methods Data from a prospective soft tissue tumor database was used to analyze clinical courses of 189 desmoid patients treated at The University of Texas M.D. Anderson Cancer Center (UTMDACC) from 1995 to 2005 as compared with 189 UTMDACC desmoid patients treated between 1965 and 1994. Results A nearly three-fold increase in annualized UTMDACC desmoid referral volume with significantly higher percentages and numbers of primary desmoid tumor referrals to UTMDACC was observed in the most recent study period. Significantly increased systemic therapy use and decreased reliance on surgery alone was observed more recently. While the recent series patients had higher rates of macroscopic residual disease and equivalent rates of positive microscopic margins after definitive surgery, the estimated 5-year local recurrence rate of 20% was improved compared with the 30% rate observed in the earlier series. Conclusion Increased awareness of the complex multidisciplinary management needed for desmoid tumor control may underlie significantly increased numbers of referrals to UTMDACC, especially primary untreated desmoids. Increased neoadjuvant treatments may be associated with improved desmoid patient outcomes. These trends should be supported, particularly if personalized molecular-based therapies are to be rapidly and effectively deployed for the benefit of those afflicted by this rare and potentially debilitating disease.
Are Cognitive Impairments Associated With Sensitivity to Stress in Schizophrenia? An Experience Sampling Study
Authors: Inez Myin-Germeys, Lydia Krabbendam, Jelle Jolles, Philippe A. Delespaul, Jim van Os
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Patients with a diagnosis of schizophrenia display cognitive impairments and abnormal sensitivity to stress. However, little is known about the relationship between these two endophenotypes. METHOD: Neuropsychological tests were administered to 42 patients with schizophrenia or other psychosis to assess cognitive functioning, and the experience sampling method (a structured diary technique assessing current context and mood in daily life) was used to assess 1) appraised subjective stress related to daily events and activities and 2) emotional reaction to these daily life stressors. RESULTS: Multilevel random regression analyses showed that in some instances, cognitive functioning did not alter emotional reaction to stress. In other instances, an inverse relationship was found, indicating that a better performance on neuropsychological tests was related to greater emotional reaction to stress. CONCLUSIONS: The results indicate that emotional reaction to stress in the daily lives of patients with schizophrenia may not be a consequence of cognitive impairments and that the two mechanisms may act through different pathways. Such pathways may be related to the extremes of clinical outcome that have been observed in schizophrenia: an episodic, reactive, good outcome and a more chronic form characterized by high levels of negative symptoms and cognitive impairments.
The Lie That Heals: The Ethics of Giving Placebos
Authors: HOWARD BRODY
Journal: Annals of Internal Medicine (1982)

The 170-year-long debate in the medical literature about the ethics of prescribing placebos in medical therapeutics needs to be reevaluated in light of recent placebo research and improved understanding of the placebo effect as an integral part of the doctor-patient relationship. It has traditionally been assumed that deception is an indispensible component of successful placebo use. Therefore, placebos have been attacked because they are deceptive, and defended on the grounds that the deception is illusory or that the beneficent intentions of the physician justify the deception. However, a proper understanding of the placebo effect shows that deception need play no essential role in eliciting this powerful therapeutic modality; physicians can use nondeceptive means to promote a positive placebo response in their patients.
Facial basal cell carcinoma
Authors: J. M. Baxter, A. N. Patel, S. Varma
Journal: BMJ (2012)

#### Summary points

Basal cell carcinoma (BCC) is a locally invasive cancer of epidermal basaloid cells. It is the most common cancer in humans,1 and its incidence will soon surpass that of all other cancers.2 Skin cancers are categorised into two groups—melanomas and non-melanoma skin cancers. Of the non-melanoma skin cancers, 75-80% are BCCs3 4 5 and up to 85% of these are on the head and neck.4 5 6 7 8 9 10 11 12 13 14 15 16 The remainder are predominately squamous cell carcinomas. Delay in presentation is associated with increased tumour growth.17 Timely recognition is important because early identification can limit the extent of facial tissue involvement and subsequent resection, thereby resulting in a better cosmetic and functional reconstruction. Evidence suggests that denial is the main reason for delay in presentation with non-melanoma skin cancer.17

This review focuses on the diagnosis, investigation, and management of BCC of the head and neck.

#### Sources and selection criteria

We searched PubMed using keywords “basal cell carcinoma”, “facial basal cell carcinoma”, “facial non-melanoma skin cancer”, “head and neck basal cell carcinoma”, and “head and neck non-melanoma skin cancer”. We targeted more recent studies and review articles. We also consulted National Institute for Health and Clinical Excellence guidelines and other national guidance.

The incidence of BCC varies geographically (table⇓) and is increasing worldwide.10 11 12 13 14 15 18 19 20 21 …
Diclofenac patch for topical treatment of acute impact injuries: a randomised, double blind, placebo controlled, multicentre study
Authors: H G Predel, R Koll, H Pabst, R Dieter, G Gallacchi, B Giannetti, M Bulitta, J L Heidecker, E A Mueller
Journal: British Journal of Sports Medicine (2004)

Objectives: To investigate the clinical efficacy and safety of a newly developed diclofenac patch in the topical treatment of blunt impact injuries. Methods: This was a randomised, placebo controlled, double blind, multicentre study in 120 patients with traumatic blunt soft tissue injury. Within 3 h of the injury participants of sport competitions and training camps were enrolled and treated twice daily with the diclofenac or a placebo patch over a period of 7 days. Patients were randomised (1:1) to two parallel groups. Tenderness produced by pressure was measured twice daily during the first 3 days after enrolment as well as at day 7. Tenderness was defined as the amount of pressure (measured by a calibrated caliper at the centre of the injury) that first produced a pain reaction as reported by the patient. Results: The primary efficacy variable was the area under the curve for tenderness over the first 3 days. The diclofenac patch was significantly more effective than placebo (p&lt;0.0001). The treatment effect was 64.7 kp h/cm 2 (95% confidence interval 48.7 to 80.9) between diclofenac and placebo patches. These results were supported by all secondary efficacy variables. The diclofenac patch produced rapid pain relief as reflected by the time to reach resolution of pain at the injured site which was significantly shorter compared to placebo (p&lt;0.0001). The diclofenac patch was well tolerated. The most frequently observed adverse events were local cutaneous adverse reactions (pruritus, rash) of minor severity occurring with the same frequency as in the placebo group. Conclusions: A newly developed diclofenac patch is effective and safe for the treatment of blunt impact injuries.
Blood Pressure Targets Recommended by Guidelines and Incidence of Cardiovascular and Renal Events in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)
Authors: Giuseppe Mancia, Helmut Schumacher, Josep Redon, Paolo Verdecchia, Roland Schmieder, Garry Jennings, Khalid Yusoff, Lars Ryden, G. Lisheng Liu, Koon Teo, Peter Sleight, Salim Yusuf
Journal: Circulation (2011)

Background— Hypertension treatment guidelines recommend that blood pressure (BP) be lowered to &lt;140/90 mm Hg, but that a reduction to &lt;130/80 mm Hg be adopted in patients at high cardiovascular (CV) risk. We investigated the CV and renal benefits associated with these BP targets in the high-CV-risk population of the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET). Methods and Results— Patients were divided into 4 groups according to the proportion of in-treatment visits before the occurrence of an event (&lt;25%–&gt;75%) in which BP was reduced to &lt;140/90 or &lt;130/80 mm Hg. After adjustment for demographic and clinical variables, a progressive increase in the proportion of visits in which BP was reduced to &lt;140/90 or &lt;130/80 mm Hg was associated with a progressive reduction in the risk of stroke, new onset of microalbuminuria or macroalbuminuria, and return to normoalbuminuria in albuminuric patients. An increased frequency of BP control to either target did not have any consistent effect on the adjusted risk of myocardial infarction and heart failure. The adjusted risk of CV events was reduced by increasing the frequency of BP control to &lt;140/90 mm Hg, but not to &lt;130/80 mm Hg. Similar findings were obtained for the achievement of the BP target in the visit preceding a CV event. Conclusion— The more frequent achievement of the BP targets recommended by guidelines led to cerebrovascular and renal protection, but did not increase cardiac protection. Overall, CV protection was favorably affected by the less tight but not by the tighter BP target. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00153101.
Effect of salicylates on histamine and L-histidine metabolism. Inhibition of imidazoleacetate phosphoribosyl transferase.
Authors: J Moss, M C De Mello, M Vaughan, M A Beaven
Journal: Journal of Clinical Investigation (1976)

In man and other animals, urinary excretion of the histidine and histamine metabolite, imidazoleacetate, is increased and that of its conjugated metabolite, ribosylimidazoleacetate, decreased by salicylates. Imidazoleacetate has been reported to produce analgesia and narcosis. Its accumulation as a result of transferase inhibition could play a part in the therapeutic effects of salicylates. To determine the locus of salicylate action, we have investigated the effect of anti-inflammatory drugs on imidazoleacetate phosphoribosyl transferase, the enzyme that catalyzes the ATP-dependent conjugation of imidazoleacetate with phosphoribosylpyrophosphate. As little as 0.2 mM aspirin produced 50% inhibition of the rat liver transferase. In vivo, a 30% decrease in the urinary excretion of ribosylimidazoleacetate has been observed with plasma salicylate concentrations of 0.4 mM. The enzyme was also inhibited by sodium salicylate but not by salicylamide, sodium gentisate, aminopyrine, phenacetin, phenylbutazone, or indomethacin. The last four drugs have been shown previously not to alter the excretion of ribosylimidazoleacetate when administered in vivo. Since both the drug specificity and inhibitory concentrations are similar in vivo and in vitro, it seems probable that the effect of salicylates on imidazoleacetate conjugation results from inhibition of imidazoleacetate phosphoribosyl transferase.
Ventilatory Function in Bronchial Asthma
Authors: W. A. Briscoe, G. A. McLemore
Journal: Thorax (1952)

<h3>Abstract</h3> Lip movements facilitate speech comprehension, especially under adverse listening conditions, but the neural mechanisms of this perceptual benefit at the phonemic and feature levels remain unclear. This fMRI study addresses this question by quantifying regional multivariate representation and network organization underlying audiovisual speech-in-noise perception. We found that valid lip movements enhanced neural representations of phoneme, place of articulation, or voicing feature of speech differentially in dorsal stream regions, including frontal speech motor areas and supramarginal gyrus. Such local changes were accompanied by strengthened dorsal stream effective connectivity. Moreover, the neurite orientation dispersion of left arcuate fasciculus, a structural basis of speech dorsal stream, predicted the visual enhancements of neural representations and effective connectivity. Our findings provide novel insight to speech science that lip movements promote both local phonemic and feature encoding and network connectivity in speech dorsal pathway and the functional enhancement is mediated by the microstructural architecture of the circuit.
Pregnancy-Associated Cardiomyopathy
Authors: Uri Elkayam, Mohammed W. Akhter, Harpreet Singh, Salman Khan, Fahed Bitar, Afshan Hameed, Avraham Shotan
Journal: Circulation (2005)

Cardiomyopathy associated with pregnancy was first described more than half a century ago. However, because of its rare occurrence and geographical differences, the clinical profile of this condition has remained incompletely defined.Data obtained from 123 women with a history of cardiomyopathy diagnosed during pregnancy or the postpartum period were reviewed. One hundred women met traditional criteria of peripartum cardiomyopathy; 23 were diagnosed with pregnancy-associated cardiomyopathy earlier than the last gestational month. Peripartum cardiomyopathy patients had a mean age of 31+/-6 years and were mostly white (67%). Common associated conditions were gestational hypertension (43%), tocolytic therapy (19%), and twin pregnancy (13%). Left ventricular ejection fraction at the time of diagnosis was 29+/-11% and improved to 46+/-14% (P< or =0.0001) at follow-up. Normalization of left ventricular ejection fraction occurred in 54% and was more likely in patients with left ventricular ejection fraction >30% at diagnosis. Maternal mortality was 9%. A comparison between the peripartum cardiomyopathy and early pregnancy-associated cardiomyopathy groups revealed no differences in age, race, associated conditions, left ventricular ejection fraction at diagnosis, its rate and time of recovery, and maternal outcome.This study helps to define the clinical profile of patients with pregnancy-associated cardiomyopathy diagnosed in the United States. Clinical presentation and outcome of patients with pregnancy-associated cardiomyopathy diagnosed early in pregnancy are similar to those of patients with traditional peripartum cardiomyopathy. These 2 conditions may represent a continuum of a spectrum of the same disease.
Molecular Genetics of Nephronophthisis and Medullary Cystic Kidney Disease
Authors: FRIEDHELM HILDEBRANDT, EDGAR OTTO
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Nephronophthisis (NPH) and medullary cystic kidney disease (MCKD) constitute a group of renal cystic diseases that share the macroscopic feature of cyst development at the corticomedullary border of the kidneys. The disease variants also have in common a characteristic renal histologic triad of tubular basement membrane disintegration, tubular atrophy with cyst development, and interstitial cell infiltration with fibrosis. NPH and, in most instances, MCKD lead to chronic renal failure with an onset in the first two decades of life for recessive NPH and onset in adult life for autosomal dominant MCKD. There is extensive genetic heterogeneity with at least three different loci for NPH ( NPHP1, NPHP2 , and NPHP3 ) and two different loci for MCKD ( MCKD1 and MCKD2 ). Juvenile nephronophthisis, in addition, can be associated with extrarenal organ involvement. As a first step toward understanding the pathogenesis of this disease group, the gene ( NPH1 ) for juvenile nephronophthisis (NPH1) has been identified by positional cloning. Its gene product, nephrocystin, is a novel protein of unknown function that contains a src -homology 3 domain. It is hypothesized that the pathogenesis of NPH might be related to signaling processes at focal adhesions (the contact points between cells and extracellular matrix) and/or adherens junctions (the contact points between cells). This hypothesis is based on the fact that most src -homology 3-containing proteins are part of focal adhesion signaling complexes, on animal models that exhibit an NPH-like phenotype, and on the recent finding that nephrocystin binds to the protein p130 cas , a major mediator of focal adhesion signaling.
Effect of the Time to Change anti-stigma campaign on trends in mental-illness-related public stigma among the English population in 2003–13: an analysis of survey data
Authors: Sara Evans-Lacko, Elizabeth Corker, Paul Williams, Claire Henderson, Graham Thornicroft
Journal: The Lancet Psychiatry (2014)

Understanding trends and effective mechanisms that are likely to reduce public stigma and discrimination towards people with mental illness is important. We aimed to assess changes in public stigma in England after the introduction of the Time to Change anti-stigma campaign.We used data from the 2003 and 2007-13 national Attitudes to Mental Illness surveys to investigate 10-year trends in public attitudes across England before and during the Time to Change anti-stigma campaign. We present annual mean scores for attitude items related to prejudice and exclusion, and tolerance and support for community care. We also present an extrapolated linear trend line for the years 2009-13 and estimate population attitude scores without the campaign. We present unadjusted and adjusted linear regression models. In addition, we used multivariable linear regression models fitted to data aggregated by region to investigate whether a dose-effect response exists between campaign awareness and regional outcomes related to knowledge, attitudes, and intended behaviour.About 1700 respondents were surveyed each year. Significant increases in positive attitudes related to prejudice and exclusion occurred after the Time to Change campaign. In the multivariable analysis, we noted a significant increase in positive attitudes in relation to prejudice and exclusion after the launch of Time to Change (reverse-coded Z score 0·02, 95% CI 0·01 to 0·05; p=0·01), but not for tolerance and support for community care (Z score 0·01, -0·01 to 0·03; p=0·27). We also found evidence for a dose-effect relation between campaign awareness and regional improvement in knowledge (p=0·004) and attitudes (tolerance and support p<0·0001; prejudice and exclusion p=0·001), but not intended behaviour (p=0·20).The positive effects of Time to Change seem to be significant and moderate. Although attitudes are probably more at risk of deterioration during times of economic hardship, anti-stigma programmes might still play an active part in long-term reduction of stigma and discrimination, especially in relation to prejudice and exclusion of people with mental health problems.UK Department of Health, Comic Relief, Big Lottery.