tbuckley/cabot-search huggingface dataset:
A prospective survey of skin cancer referrals to a Scottish dermatology department
Authors: A.C. Kerr, S. Leonard, G. Gupta
Journal: British Journal of Dermatology (2005)

Conflicts of interest: none declared. Sir, We read with interest the article by Cox, evaluating the 2‐week referral rule for skin cancer based on data collected by a questionnaire survey of the views of hospital consultants.1 It concluded that a high volume of nonrelevant lesions was being referred urgently, yet a large proportion of patients with skin cancer was not referred within the 2‐week limit. Dermatologists in Scotland are not subject to the 2‐week rule but due to patient expectation and political pressure, patients with possible skin cancer are generally fast‐tracked. However, audit data from Scotland are lacking and it is not known whether similar problems exist north of the border. We present data from a prospective survey of patients referred with possible skin cancer. All patients referred with possible skin cancer to the Lanarkshire dermatology department were identified from the general practitioner (GP) referral letter over a 1‐month period. Such letters comprised unstructured free text with a tick box option for prioritizing as urgent, soon or routine. Patients were also included if a skin cancer was suspected in the clinic but the referral letter did not mention this diagnosis. Data from these patients were recorded on a standardized proforma for analysis. Patients given an urgent priority by the dermatologists were deemed to have a high chance of skin cancer [melanoma or squamous cell carcinoma (SCC)] on the basis of the referral letter and should therefore have been seen within 2 weeks.
Endothelial Dysfunction and Subsequent Decline in Glomerular Filtration Rate in Hypertensive Patients
Authors: Francesco Perticone, Raffaele Maio, Maria Perticone, Angela Sciacqua, Ermal Shehaj, Paola Naccarato, Giorgio Sesti
Journal: Circulation (2010)

Chronic kidney disease is a risk factor for cardiovascular disease, increasing all-cause mortality. Some evidence suggests that endothelial dysfunction is present in the early stages of renal insufficiency, but no data exist about its possible role in the progression of renal disease. Thus, we prospectively evaluated the effect of endothelial function on estimated glomerular filtration rate (eGFR) in essential hypertension.We enrolled 500 never-treated uncomplicated hypertensive subjects with serum creatinine < or =1.5 mg/dL. Endothelial function was measured by strain-gauge plethysmography during intra-arterial infusion of acetylcholine and sodium nitroprusside. eGFR was calculated by use of the Chronic Kidney Disease Epidemiology Collaboration equation. The annual rate of decline of eGFR (DeltaeGFR/y) was determined as the difference between the follow-up and baseline eGFR values, with this value divided by the time interval in years. During follow-up (92.3+/-36.2 months), mean DeltaeGFR/y was 1.49+/-1.65 mL . min(-1) . 1.73 m(-)(2), with no significant differences between men and women (1.55+/-1.72 versus 1.43+/-1.58 mL . min(-1) . 1.73 m(-)(2), respectively; P=0.455). This was correlated with acetylcholine-stimulated forearm blood flow (r=-0.256, P<0.0001), creatinine (r=0.141, P=0.001), systolic blood pressure (r=-0.103, P=0.01), and eGFR (r=0.092, P=0.020). In multivariable regression analysis, forearm blood flow and systolic blood pressure remained associated with change in eGFR. On average, eGFR changed by 0.37 mL . min(-1) . 1.73 m(-)(2) for each 100% change in forearm blood flow (P<0.001) and by 0.1 mL . min(-1) . 1.73 m(-)(2) for each difference of 10 mm Hg in systolic blood pressure (P=0.032).We demonstrated that acetylcholine-stimulated vasodilation and systolic blood pressure were associated with eGFR loss after adjustment for other cardiovascular risk factors and antihypertensive treatment.
Atypical (Dysplastic) Nevi
Authors: Kavitha K. Reddy, Michele J. Farber, Jag Bhawan, Roy G. Geronemus, Gary S. Rogers
Journal: JAMA Dermatology (2013)

To evaluate the effect of surgical excision, performed after biopsy diagnosis of dysplastic nevus, on final diagnosis, melanoma prevention, and melanoma detection.Outcome study using retrospective review conducted in an academic dermatopathology practice (Boston Medical Center Skin Pathology Laboratory) that receives specimens from community and academic practices across the United States. Consecutive patient pathology samples of dysplastic nevi and cutaneous melanomas evaluated between September 1, 1999 and March 1, 2011, and identified using systematized nomenclature of medicine codes were included.In dysplastic nevi cases, the rate of clinically significant change in diagnosis and the rate of melanoma detection as a result of excision. In melanoma cases, the rate and characteristics of association with dysplastic nevus.Of dysplastic nevi, 196 of 580 (34%) showed a positive biopsy margin, increasing with grade of atypia (P < .001); 127 of 196 with positive biopsy margin received excision (65%), performed more often as grade of atypia increased (P < .001). Two excisions (2 of 127, 1.6%) resulted in a clinically significant change in diagnosis, from biopsy-diagnosed moderately-to-severely dysplastic nevi before excision to melanoma in situ after excision. In melanomas (n = 216), in situ and superficial spreading subtypes were more often associated with dysplastic nevi (20% and 18%, respectively) (P = .002), most often of moderate-to-severe or severe grade.Excision of biopsy-diagnosed mildly or moderately dysplastic nevi is unlikely to result in a clinically significant change in diagnosis, and risk of transformation to melanoma appears very low. Moderately-to-severely and severely dysplastic nevi are more often associated with melanoma, and excision may be beneficial for melanoma detection or prevention.
Disorder in Excitation-Contraction Coupling of Cardiac Muscle from Cats with Experimentally Produced Right Ventricular Hypertrophy
Authors: RAIMUND L. KAUFMANN, HERMANN HOMBURGER, HEIKE WIRTH
Journal: Circulation Research (1971)

The contractile and electrical activity of papillary muscles from hypertrophied right ventricles of cats with artificial stenosis of the pulmonary artery was investigated. Contractility was considerably decreased along the entire force-velocity relationship, whereas no measurable alterations could be detected in the electrical activities as recorded by intracellular microelectrodes. By supramaximal Ca 2+ activation, the contractility of both the hypertrophied and the normal control preparations was increased to about the same final value. These findings are consistent with the concept that a disorder in the mechanism of excitation-contraction coupling underlies the depressed contractile state of hypertrophied cardiac muscle. In addition, it could be shown that the increase in volume of each cellular unit is clearly related to the decrease in contractility. This can tentatively be explained by the following assumptions. If the amount of Ca 2+ entering the cell per unit area is not changed in hypertrophy, then in a cell of increased diameter, the amount of Ca 2+ distributed per unit cell volume will be diminished. Since the excitation-contraction coupling of the heart is very sensitive to Ca 2+ , this Ca 2+ deficit should be reflected in a depression of contractility.
The design of transcription-factor binding sites is affected by combinatorial regulation.
Authors: Yonatan Bilu, Naama Barkai
Journal: Genome biology (2005)

Transcription factors regulate gene expression by binding to specific cis-regulatory elements in gene promoters. Although DNA sequences that serve as transcription-factor binding sites have been characterized and associated with the regulation of numerous genes, the principles that govern the design and evolution of such sites are poorly understood.Using the comprehensive mapping of binding-site locations available in Saccharomyces cerevisiae, we examined possible factors that may have an impact on binding-site design. We found that binding sites tend to be shorter and fuzzier when they appear in promoter regions that bind multiple transcription factors. We further found that essential genes bind relatively fewer transcription factors, as do divergent promoters. We provide evidence that novel binding sites tend to appear in specific promoters that are already associated with multiple sites.Two principal models may account for the observed correlations. First, it may be that the interaction between multiple factors compensates for the decreased specificity of each specific binding sequence. In such a scenario, binding-site fuzziness is a consequence of the presence of multiple binding sites. Second, binding sites may tend to appear in promoter regions that are subject to low selective pressure, which also allows for fuzzier motifs. The latter possibility may account for the relatively low number of binding sites found in promoters of essential genes and in divergent promoters.
Pulse Pressure and Risk of New-Onset Atrial Fibrillation
Authors: Gary F. Mitchell, Ramachandran S. Vasan, Michelle J. Keyes, Helen Parise, Thomas J. Wang, Martin G. Larson, Ralph B. D’Agostino, William B. Kannel, Daniel Levy, Emelia J. Benjamin
Journal: JAMA (2007)

Atrial fibrillation (AF) is responsible for considerable morbidity and mortality, making identification of modifiable risk factors a priority. Increased pulse pressure, a reflection of aortic stiffness, increases cardiac load and may increase AF risk.To examine relations between pulse pressure and incident AF.Prospective, community-based observational cohort in Framingham, Mass, including 5331 Framingham Heart Study participants aged 35 years and older and initially free from AF (median age, 57 years; 55% women).Incident AF.AF developed in 698 participants (13.1%) a median of 12 years after pulse pressure assessment. Cumulative 20-year AF incidence rates were 5.6% for pulse pressure of 40 mm Hg or less (25th percentile) and 23.3% for pulse pressure greater than 61 mm Hg (75th percentile). In models adjusted for age, sex, baseline and time-dependent change in mean arterial pressure, and clinical risk factors for AF (body mass index, smoking, valvular disease, diabetes, electrocardiographic left ventricular hypertrophy, hypertension treatment, and prevalent myocardial infarction or heart failure), pulse pressure was associated with increased risk for AF (adjusted hazard ratio [HR], 1.26 per 20-mm Hg increment; 95% confidence interval [CI], 1.12-1.43; P<.001). In contrast, mean arterial pressure was unrelated to incident AF (adjusted HR, 0.96 per 10-mm Hg increment; 95% CI, 0.88-1.05; P = .39). Systolic pressure was related to AF (HR, 1.14 per 20-mm Hg increment; 95% CI, 1.04-1.25; P = .006); however, if diastolic pressure was added, model fit improved and the diastolic relation was inverse (adjusted HR, 0.87 per 10-mm Hg increment; 95% CI, 0.78-0.96; P = .01), consistent with a pulse pressure effect. Among patients with interpretable echocardiographic images, the association between pulse pressure and AF persisted in models that adjusted for baseline left atrial dimension, left ventricular mass, and left ventricular fractional shortening (adjusted HR, 1.23; 95% CI, 1.09-1.39; P = .001).Pulse pressure is an important risk factor for incident AF in a community-based sample. Further research is needed to determine whether interventions that reduce pulse pressure will limit the growing incidence of AF.
Glutaminase-containing microvesicles from HIV-1-infected macrophages and immune-activated microglia induce neurotoxicity
Authors: Beiqing Wu, Yunlong Huang, Alexander L. Braun, Zenghan Tong, Runze Zhao, Yuju Li, Fang Liu, Jialin C. Zheng
Journal: Molecular Neurodegeneration (2015)

HIV-1-infected and/or immune-activated microglia and macrophages are pivotal in the pathogenesis of HIV-1-associated neurocognitive disorders (HAND). Glutaminase, a metabolic enzyme that facilitates glutamate generation, is upregulated and may play a pathogenic role in HAND. Our previous studies have demonstrated that glutaminase is released to the extracellular fluid during HIV-1 infection and neuroinflammation. However, key molecular mechanisms that regulate glutaminase release remain unknown. Recent advances in understanding intercellular trafficking have identified microvesicles (MVs) as a novel means of shedding cellular contents. We posit that during HIV-1 infection and immune activation, microvesicles may mediate glutaminase release, generating excessive and neurotoxic levels of glutamate. MVs isolated through differential centrifugation from cell-free supernatants of monocyte-derived macrophages (MDM) and BV2 microglia cell lines were first confirmed in electron microscopy and immunoblotting. As expected, we found elevated number of MVs, glutaminase immunoreactivities, as well as glutaminase enzyme activity in the supernatants of HIV-1 infected MDM and lipopolysaccharide (LPS)-activated microglia when compared with controls. The elevated glutaminase was blocked by GW4869, a neutral sphingomyelinase inhibitor known to inhibit MVs release, suggesting a critical role of MVs in mediating glutaminase release. More importantly, MVs from HIV-1-infected MDM and LPS-activated microglia induced significant neuronal injury in rat cortical neuron cultures. The MV neurotoxicity was blocked by a glutaminase inhibitor or GW4869, suggesting that the neurotoxic potential of HIV-1-infected MDM and LPS-activated microglia is dependent on the glutaminase-containing MVs. These findings support MVs as a potential pathway/mechanism of excessive glutamate generation and neurotoxicity in HAND and therefore MVs may serve as a novel therapeutic target.
Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people
Authors: Cécile Henquet, Lydia Krabbendam, Janneke Spauwen, Charles Kaplan, Roselind Lieb, Hans-Ulrich Wittchen, Jim van Os
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b> To investigate the relation between cannabis use and psychotic symptoms in individuals with above average predisposition for psychosis who first used cannabis during adolescence. <b>Design</b> Analysis of prospective data from a population based sample. Assessment of substance use, predisposition for psychosis, and psychotic symptoms was based on standardised personal interviews at baseline and at follow up four years later. <b>Participants</b> 2437 young people (aged 14 to 24 years) with and without predisposition for psychosis. <b>Main outcome measure</b> Psychotic symptoms at follow up as a function of cannabis use and predisposition for psychosis at baseline. <b>Results</b> After adjustment for age, sex, socioeconomic status, urbanicity, childhood trauma, predisposition for psychosis at baseline, and use of other drugs, tobacco, and alcohol, cannabis use at baseline increased the cumulative incidence of psychotic symptoms at follow up four years later (adjusted odds ratio 1.67, 95% confidence interval 1.13 to 2.46). The effect of cannabis use was much stronger in those with any predisposition for psychosis at baseline (23.8% adjusted difference in risk, 95% confidence interval 7.9 to 39.7, P = 0.003) than in those without (5.6%, 0.4 to 10.8, P = 0.033). The risk difference in the "predisposition" group was significantly greater than the risk difference in the "no predisposition" group (test for interaction 18.2%, 1.6 to 34.8, P = 0.032). There was a dose-response relation with increasing frequency of cannabis use. Predisposition for psychosis at baseline did not significantly predict cannabis use four years later (adjusted odds ratio 1.42, 95% confidence interval 0.88 to 2.31). <b>Conclusion</b> Cannabis use moderately increases the risk of psychotic symptoms in young people but has a much stronger effect in those with evidence of predisposition for psychosis.
National Assessment of Melanoma Care Using Formally Developed Quality Indicators
Authors: Karl Y. Bilimoria, Mehul V. Raval, David J. Bentrem, Jeffrey D. Wayne, Charles M. Balch, Clifford Y. Ko
Journal: Journal of Clinical Oncology (2009)

There is considerable variation in the quality of cancer care delivered in the United States. Assessing care by using quality indicators could help decrease this variability. The objectives of this study were to formally develop valid quality indicators for melanoma and to assess hospital-level adherence with these measures in the United States.Quality indicators were identified from available literature, consensus guidelines, and melanoma experts. Thirteen experts ranked potential measures for validity on the basis of the RAND/University of California, Los Angeles Appropriateness Methodology. Adherence with individual valid indicators and a composite measure of all indicators were assessed at 1,249 Commission on Cancer hospitals by using the National Cancer Data Base (NCDB; 2004 through 2005).Of 55 proposed quality indicators, 26 measures (47%) were rated as valid. These indicators assessed structure (n = 1), process (n = 24), and outcome (n = 1). Of the 26 measures, 10 are readily assessable by using cancer registry data. Adherence with valid indicators ranged from 11.8% to 96.5% at the patient level and 3.7% to 83.0% at the hospital level. (Adherence required that >OR= 90% of patients at a hospital receive concordant care.) Most hospitals were adherent with 50% or fewer of the individual indicators (median composite score, five; interquartile range, four to seven). Adherence was higher for diagnosis and staging measures and was lower for treatment indicators.There is considerable variation in the quality of melanoma care in the United States. By using these formally developed quality indicators, hospitals can assess their adherence with current melanoma care guidelines through feedback mechanisms from the NCDB and can better direct quality improvement efforts.
Combining direct coronary artery surgery with internal mammary artery implants
Authors: G. L. Hammond, I. McMillan
Journal: Thorax (1970)

The reasons for combining direct coronary artery surgery with internal mammary artery implants are discussed. A case typifying this problem is presented. It is concluded that, in certain instances, maximal myocardial protection could be provided by combining direct coronary reconstructive surgery, in order to increase immediate protection, with internal mammary artery implants, in order to provide long-term protection.
Mechanisms of Lithogenic Bile Formation in American Indian Women with Cholesterol Gallstones
Authors: Scott M. Grundy, Allan L. Metzger, Ronald D. Adler
Journal: Journal of Clinical Investigation (1972)

Hepatic secretions of biliary lipids were estimated in 43 patients with and without cholesterol gallstones. Studies were carried out by a marker dilution technique employing duodenal intubation with a three-lumen tube. Hourly secretion rates of cholesterol, bile acids, and phospholipids were determined during constant infusion with liquid formula. In 17 American Indian women with gallstones, hourly outputs of biliary bile acids were significantly less than those in 7 Indian men and 12 Caucasian women without gallstones. These findings suggest that a decreased hepatic secretion of bile acids contributes significantly to the production of a lithogenic bile in Indian women. However, in Indian women with gallstones, secretion of biliary cholesterol was also significantly increased, as compared with Caucasian women without stones. Therefore, lithogenic bile in Indian women was, in most cases, due to a combined decrease in bile acid output and increase in cholesterol secretion. In an attempt to determine the mechanisms for these abnormalities, cholesterol balance studies were done in Indian women with gallstones and normal Indian men. Balance data were compared with results reported previously in non-Indian patients studied by the same techniques, and in general, Indian women showed a slight increase in fecal excretion of bile acids. Since bile acids in the enterohepatic circulation were relatively depleted in Indian women, these patients had a reduced fractional reabsorption. However, previous studies have shown that Caucasians can rapidly replenish bile acid pools in the presence of much greater intestinal losses, and it is suggested that among Indian women with gallstones, reduced secretion rates of bile acids are primarily the result of defective homeostatic regulation of bile acid synthesis. In Indian women with gallstones, at least two factors may have contributed to an increased availability of cholesterol in the liver for secretion into bile. First, cholesterol was inadequately converted into bile acids, and secondly, an increased amount of cholesterol was synthesized, as shown by the balance technique. This enhanced production of cholesterol can partially be explained by obesity, but other factors may also play a role.
PDGF receptor alpha inhibition induces apoptosis in glioblastoma cancer stem cells refractory to anti-Notch and anti-EGFR treatment
Authors: Carlo Cenciarelli, Hany ES Marei, Manuela Zonfrillo, Pasquale Pierimarchi, Emanuela Paldino, Patrizia Casalbore, Armando Felsani, Angelo Vescovi, Giulio Maira, Annunziato Mangiola
Journal: Molecular Cancer (2014)

Cancer stem cells (CSC) represent a rare fraction of cancer cells characterized by resistance to chemotherapy and radiation, therefore nowadays there is great need to develop new targeted therapies for brain tumors and our study aim to target pivotal transmembrane receptors such as Notch, EGFR and PDGFR, which are already under investigation in clinical trials setting for the treatment of Glioblastoma Multiforme (GBM). MTS assay was performed to evaluate cells response to pharmacological treatments. Quantitative RT-PCR and Western blots were performed to state the expression of Notch1, EGFR and PDGFRα/β and the biological effects exerted by either single or combined targeted therapy in GBM CSC. GBM CSC invasive ability was tested in vitro in absence or presence of Notch and/or EGFR signaling inhibitors. In this study, we investigated gene expression and function of Notch1, EGFR and PDGFR to determine their role among GBM tumor core- (c-CSC) vs. peritumor tissue-derived cancer stem cells (p-CSC) of six cases of GBM. Notch inhibition significantly impaired cell growth of c-CSC compared to p-CSC pools, with no effects observed in cell cycle distribution, apoptosis and cell invasion assays. Instead, anti-EGFR therapy induced cell cycle arrest, sometimes associated with apoptosis and reduction of cell invasiveness in GBM CSC. In two cases, c-CSC pools were more sensitive to simultaneous anti-Notch and anti-EGFR treatment than either therapy alone compared to p-CSC, which were mostly resistant to treatment. We reported the overexpression of PDGFRα and its up-regulation following anti-EGFR therapy in GBM p-CSC compared to c-CSC. RNA interference of PDGFRα significantly reduced cell proliferation rate of p-CSC, while its pharmacological inhibition with Crenolanib impaired survival of both CSC pools, whose effects in combination with EGFR inhibition were maximized. We have used different drugs combination to identify the more effective therapeutic targets for GBM CSC, particularly against GBM peritumor tissue-derived CSC, which are mostly resistant to treatments. Overall, our results provide the rationale for simultaneous targeting of EGFR and PDGFR, which would be beneficial in the treatment of GBM.
EFFECT OF GENDER DIFFERENCE ON CLINICAL OUTCOMES AFTER CARDIAC RESYNCHRONIZATION THERAPY IN CUBIC REGISTRY
Authors: Kenji Ando, Satoshi Shizuta, Yoshimitsu Soga, Takeshi Arita, Natsuhiko Ehara, Takeshi Kimura, Takaaki Isshiki, Masakiyo Nobuyoshi
Journal: Journal of the American College of Cardiology (2012)