tbuckley/cabot-search huggingface dataset:
Confirmation of the efficacy of hepatic tissue iron index in differentiating genetic haemochromatosis from alcoholic liver disease complicated by alcoholic haemosiderosis.
Authors: R W Sallie, W D Reed, K B Shilkin
Journal: Gut (1991)

The hepatic tissue iron index proposed by Bassett et al was evaluated in 35 patients with homozygous genetic haemochromatosis, 67 patients with alcoholic liver disease, and 18 patients with other forms of chronic liver disease with and without cirrhosis. In patients with cirrhosis hepatic tissue iron concentration reliably differentiated alcoholic liver disease from genetic haemochromatosis. Although mean iron concentration was greater in patients with prefibrotic haemochromatosis than in those with prefibrotic alcoholic liver disease, some overlap occurred and complete differentiation of the two conditions was not possible. This overlap was particularly evident in some young patients with haemochromatosis in whom the tissue iron concentration grade fell in the range commonly seen in alcoholic haemosiderosis. Inability to differentiate early genetic haemochromatosis from alcoholic liver disease complicated by haemosiderosis was also a problem with standard Perls9s staining. When the hepatic tissue iron index was calculated (hepatic tissue iron concentration/patient9s age in years), clear differentiation of genetic haemochromatosis from both alcoholic liver disease and other forms of chronic liver disease was obtained in both cirrhotic and precirrhotic patients. This study confirms that the hepatic tissue iron index is a useful means of differentiating patients with genetic haemochromatosis from those with alcoholic liver disease. We suggest that biochemical estimation of tissue iron concentration and calculation of the tissue iron index in all patients in whom genetic haemochromatosis is a possible diagnosis will reduce the likelihood of misdiagnosing this as alcoholic liver disease.
Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial
Authors: Robert Pirker, Jose R Pereira, Aleksandra Szczesna, Joachim von Pawel, Maciej Krzakowski, Rodryg Ramlau, Ihor Vynnychenko, Keunchil Park, Chih-Teng Yu, Valentyn Ganul, Jae-Kyung Roh, Emilio Bajetta, Kenneth O'Byrne, Filippo de Marinis, Wilfried Eberhardt, Thomas Goddemeier, Michael Emig, Ulrich Gatzemeier
Journal: The Lancet (2009)
A Meta-Analysis of Cognitive Remediation in Schizophrenia
Authors: Susan R McGurk, Elizabeth W Twamley, David I Sitzer, Gregory J McHugo, Kim T Mueser
Journal: American Journal of Psychiatry (2007)

Objective: This study evaluated the effects of cognitive remediation for improving cognitive performance, symptoms, and psychosocial functioning in schizophrenia. Method: A meta-analysis was conducted of 26 randomized, controlled trials of cognitive remediation in schizophrenia including 1,151 patients. Results: Cognitive remediation was associated with significant improvements across all three outcomes, with a medium effect size for cognitive performance (0.41), a slightly lower effect size for psychosocial functioning (0.36), and a small effect size for symptoms (0.28). The effects of cognitive remediation on psychosocial functioning were significantly stronger in studies that provided adjunctive psychiatric rehabilitation than in those that provided cognitive remediation alone. Conclusions: Cognitive remediation produces moderate improvements in cognitive performance and, when combined with psychiatric rehabilitation, also improves functional outcomes.
Risk of cardiovascular disease measured by carotid intima-media thickness at age 49-51: lifecourse study
Authors: D Lamont, L Parker, M White, N Unwin, S M Bennett, M Cohen, D Richardson, H O Dickinson, A Adamson, K G Alberti, A W Craft
Journal: BMJ (2000)

Objective: To quantify the direct and indirect effects of fetal life, childhood, and adult life on risk of cardiovascular disease at age 49–51 years. Design: Follow up study of the "Newcastle thousand families" birth cohort established in 1947. Participants: 154 men and 193 women who completed a health and lifestyle questionnaire and attended for clinical examination between October 1996 and December 1998. Main outcome measures: Correlations between mean intima-media thickness of the carotid artery (carotid intima-media thickness) and family history, birth weight, and socioeconomic position around birth; socioeconomic position, growth, illness, and adverse life events in childhood; and adult socioeconomic position, lifestyle, and biological risk markers. Proportions of variance in carotid intima-media thickness that were accounted for by each stage of the lifecourse. Results: Socioeconomic position at birth and birth weight were negatively associated with carotid intima-media thickness, although only social class at birth in women was a statistically significant covariate independent of adult lifestyle. These early life variables accounted directly for 2.2% of total variance in men and 2.0% in women. More variation in carotid intima-media thickness was explained by adult socioeconomic position and lifestyle, which accounted directly and indirectly for 3.4% of variance in men (95% confidence interval 0.5% to 6.2%) and 7.6% in women (2.1% to 13.0%). Biological risk markers measured in adulthood independently accounted for a further 9.5% of variance in men (2.4% to 14.2%) and 4.9% in women (1.6% to 7.4%). Conclusions: Adult lifestyle and biological risk markers were the most important determinants of the cardiovascular health of the study members of the Newcastle thousand families cohort at age 49–51 years. The limited overall effect of early life factors may reflect the postwar birth year of this cohort.
Francis Collins
Authors: Ruth Williams
Journal: Circulation Research (2010)

he had developed a technique called chromosome jumping, which allowed gene hunters to jump over large sections of chromosomes to reach the location of disease genes. 5Later, at the University of Michigan, where he became Professor of Internal Medicine and Human Genetics, he used these and other tools to track down the genes for cystic fibrosis, 6,7 Huntington disease, 8 neurofibromatosis, 9 and the M4 subtype of acute myeloid leukemia. 10He also helped identify numerous other disease genes and their mutations-work that continues at his laboratory at the NHGRI.The first rough draft of the human genome sequence was announced by Collins and J. Craig Venter on June 26, 2000, and just 3 years later, the final version was completed. 3,4The project had been finished ahead of schedule and under budgetwords that should be music to any politician's ear.As an unquestionably first-class scientist and leader, it was not surprising to many that Collins should be picked to head the NIH.Collins, who grew up on a farm in Virginia and was homeschooled until the 6th grade, has reached the loftiest possible heights of academia.However, at 60 years of age, Collins remains an ebullient optimist and told Circulation Research that he likes to think the best of his career is yet to come.
Gene Expression Changes and Signaling Events Associated with the Direct Antimelanoma Effect of IFN-γ
Authors: Jared A. Gollob, Catherine J. Sciambi, Zhiqing Huang, Holly K. Dressman
Journal: Cancer Research (2005)

Abstract IFN-γ plays a role in the response to melanoma indirectly through its effect on the immune system and directly through its antiproliferative and proapoptotic effects on melanoma cells. To understand the molecular basis for the direct antimelanoma effect of IFN-γ, we studied IFN-induced changes in gene expression and signaling among three human melanoma cell lines (DM6, DM93, and 501mel). These were resistant to the antimelanoma effect of IFN-α, and only DM6 cells exhibited growth inhibition and apoptosis with IFN-γ. Through DNA microarray analysis, we found that the antimelanoma effect of IFN-γ in DM6 was associated with the down-regulation of multiple genes involved in G-protein signaling and phospholipase C activation (including Rap2B and calpain 3) as well as the down-regulation of genes involved in melanocyte/melanoma survival (MITF and SLUG), apoptosis inhibition (Bcl2A1 and galectin-3), and cell cycling (CDK2). The antimelanoma effect of IFN-γ was also associated with the up-regulation of the proapoptotic dependence receptor UNC5H2 and the Wnt inhibitor Dkk-1. Whereas both IFNs were able to activate Stat1 in all cell lines, the delayed activation of the extracellular signal-regulated kinase, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinases occurred only in DM6 with IFN-γ, and the effect of IFN-γ on cell growth and survival as well as gene expression in DM6 was dependent on the coordinate activation of MEK1 and p38. These findings provide new insights into the signaling events and gene expression changes associated with growth inhibition and apoptosis in melanoma and may thereby assist in identifying new targets for the treatment of melanoma.
Maternal Obesity, Metabolism, and Pregnancy Outcomes
Authors: Janet C. King
Journal: Annual Review of Nutrition (2006)

About one third of all pregnant women in the United States are obese. Maternal obesity at conception alters gestational metabolic adjustments and affects placental, embryonic, and fetal growth and development. Neural tube defects and other developmental anomalies are more common in infants born to obese women; these defects have been linked to poor glycemic control. Preeclampsia, a gestational disorder occurring more frequently in obese women, appears to be due to a subclinical inflammatory state that impairs early placentation and development of its blood supply. Fetal growth and development during the last half of pregnancy depends on maternal metabolic adjustments dictated by placental hormones and the subsequent oxygen and nutrient supply. Maternal obesity affects these metabolic adjustments as well. Basal metabolic rates are significantly higher in obese women, and maternal fat gain is lower, possibly in response to altered leptin function. The usual increase in insulin resistance seen in late pregnancy is enhanced in obese mothers, causing marked postprandial increases in glucose, lipids, and amino acids and excessive fetal exposure to fuel sources, which in turn increases fetal size, fat stores, and risk for disease postnatally. Impaired glucose tolerance, gestational diabetes, and hyperlipidemia are more common among obese mothers. To date, little attention has been given to the role of diet among obese women in preventing these problems. However, studies of women with impaired glucose tolerance show that replacing refined carbohydrates and saturated fat with complex, low-glycemic carbohydrates and polyunsaturated fatty acids improves metabolic homeostasis and pregnancy outcomes. Thus, current dietary guidelines regarding the amount and type of carbohydrates and fat for nonpregnant women seem appropriate for pregnant women as well.
Biological Pacemaker Implanted in Canine Left Bundle Branch Provides Ventricular Escape Rhythms That Have Physiologically Acceptable Rates
Authors: Alexei N. Plotnikov, Eugene A. Sosunov, Jihong Qu, Iryna N. Shlapakova, Evgeny P. Anyukhovsky, Lili Liu, Michiel J. Janse, Peter R. Brink, Ira S. Cohen, Richard B. Robinson, Peter Danilo, Michael R. Rosen
Journal: Circulation (2004)

Background— We hypothesized that administration of the HCN2 gene to the left bundle-branch (LBB) system of intact dogs would provide pacemaker function in the physiological range of heart rates. Methods and Results— An adenoviral construct incorporating HCN2 and green fluorescent protein (GFP) as a marker was injected via catheter under fluoroscopic control into the posterior division of the LBB. Controls were injected with an adenoviral construct of GFP alone or saline. Animals were monitored electrocardiographically for up to 7 days after surgery, at which time they were anesthetized and subjected to vagal stimulation to permit emergence of escape pacemakers. Hearts were then removed and injection sites visually identified and removed for microelectrode study of action potentials, patch clamp studies of pacemaker current, and/or immunohistochemical studies of HCN2. For 48 hours postoperatively, 7 of 7 animals subjected to 24-hour ECG monitoring showed multiple ventricular premature depolarizations and/or ventricular tachycardia attributable to injection-induced injury. Thereafter, sinus rhythm prevailed. During vagal stimulation, HCN2-injected dogs showed rhythms originating from the left ventricle, the rate of which was significantly more rapid than in the controls. Excised posterior divisions of the LBB from HCN2-injected animals manifested automatic rates significantly greater than the controls. Isolated tissues showed immunohistochemical and biophysical evidence of overexpressed HCN2. Conclusions— A gene-therapy approach for induction of biological pacemaker activity within the LBB system provides ventricular escape rhythms that have physiologically acceptable rates. Long-term stability and feasibility of the approach remain to be tested.
Rate of cartilage loss at two years predicts subsequent total knee arthroplasty: a prospective study
Authors: F M Cicuttini
Journal: Annals of the Rheumatic Diseases (2004)

To determine whether cartilage volume loss is an independent predictor of knee replacement.Prospective community based, four year prospective cohort study.123 subjects with mild to moderate symptomatic radiographic knee osteoarthritis were recruited by either advertising, the Victorian branch of the Arthritis Foundation of Australia, treating general practitioners, orthopaedic surgeons, or rheumatologists; 113 completed the study. Magnetic resonance imaging was carried out at baseline and at 2 years on the symptomatic knee. Rate of change in tibial cartilage volume was calculated. Subjects were then followed up at year 4 to determine whether they had undergone a knee replacement.The rate of tibial cartilage loss over two years was an independent predictor of knee replacement at four years. For every 1% increase in the rate of tibial cartilage loss there was a 20% increase risk of undergoing a knee replacement at four years (95% confidence interval, 10% to 30%). Those in the highest tertile of tibial cartilage loss had 7.1 (1.4 to 36.5) higher odds of undergoing a knee replacement than those in the lowest tertile. WOMAC score at baseline, female sex, and tibial bone size (but not age and radiographic score) were also predictors of knee replacement.The data suggest that treatment targeted at reducing the rate of knee cartilage loss in subjects with symptomatic osteoarthritis may delay knee replacement. This has important implications in terms of prevention and therapeutic interventions in osteoarthritis.
Genetic Disorders of Cardiac Morphogenesis
Authors: Elizabeth Goldmuntz, Beverly S. Emanuel
Journal: Circulation Research (1997)

The phenotype associated with a 22q11 deletion is highly variable and still under investigation. Of particular interest to cardiologists and cardiac developmental biologists is the finding that many patients with a 22q11 deletion have conotruncal cardiac defects and aortic arch anomalies. Despite the phenotypic variability, the vast majority of patients have a similar large deletion spanning approximately 2 megabases. The low-frequency repeated sequences at either end of the commonly deleted region may be responsible for the size of the deletion and account for the instability of this chromosomal region. Molecular studies of patients with the DGS/VCFS phenotype and unique chromosomal rearrangements have allowed a minimal critical region for the disease to be defined. Multiple genes have been identified in the minimal critical and larger deleted region. These genes are being investigated for their potential role in the disease pathophysiology by screening for mutations in nondeleted patients with the phenotype and by analysis of the pattern of expression in the developing mouse embryo. Further experimentation in the mouse mammalian model system will be of great utility to help determine whether haploinsufficiency of one critical gene or several genes within the DGCR results in the disease phenotype. Modifying factors, both genetic and environmental, must also be considered. Further investigation into the disease mechanism leading to the DGS/VCFS phenotype will hopefully further our understanding of cardiac development and disease.
“Living Together Apart”: The Hidden Genetic Diversity of Sponge Populations
Authors: Andrea Blanquer, Maria-J. Uriz
Journal: Molecular Biology and Evolution (2011)

Intraorganism genetic stability is assumed in most organisms. However, here we show for the first time intraorganism genetic heterogeneity in natural populations of marine sponges. A total of 36 different multilocus genotypes (MLGs) were detected in 13 individuals of Scopalina lophyropoda sampled at 4 distant points within each sponge. All genotypes (showing a mosaic distribution), were transmitted to the progeny, thus contributing to the high genetic diversity and low clonality reported for this species, although its populations are small and structured and show high fission rates. There did not seem to be intraindividual genotype conflicts; on the contrary, chimeric individuals are expected to show low mortality thanks to the differential mortality of their different MLGs. This novel mechanism may also counterbalance genetic constraints in other benthic invertebrate species. The presence of sponge chimerism also suggests that results from previous population genetics studies could have been misinterpreted.
Down-Regulation of BRCA1 in Chronic Pancreatitis and Sporadic Pancreatic Adenocarcinoma
Authors: Carmela Beger, Marco Ramadani, Stephan Meyer, Gerd Leder, Martin Krüger, Karl Welte, Frank Gansauge, Hans G. Beger
Journal: Clinical Cancer Research (2004)

Abstract Purpose: BRCA1 and BRCA2 are considered to be breast cancer susceptibility genes that may also contribute to pancreatic cancer development because family studies revealed mutation carriers to have an increased risk of developing pancreatic cancer. However, as demonstrated for breast and ovarian cancer, inactivation of BRCA in sporadic diseases is based on alteration in gene expression or functional alteration. Experimental Design: To study a potential correlation of BRCA1 and BRCA2 to chronic pancreatitis and development of sporadic pancreatic adenocarcinoma, we have analyzed the expression of these genes by quantitative PCR and performed immunohistochemical analyses in normal pancreatic tissues, chronic pancreatitis, and pancreatic cancer specimens. Results: BRCA1 expression was down-regulated in chronic alcoholic pancreatitis, in particular on the RNA level. Furthermore, our data indicate suppressed BRCA1 expression in pancreatic cancer on both the RNA and protein levels. Quantitative analysis of BRCA1 protein expression demonstrated regular staining in 50% of tumor specimens tested and reduced staining in 50% of tumor specimens tested. Correlation with the clinical outcome revealed a significantly better 1-year overall survival for patients with BRCA1-regular as compared with BRCA1-reduced or BRCA1-absent tumors. In contrast, no substantial differences in BRCA2 expression were found in chronic pancreatitis and pancreatic cancer samples. Conclusions: Our data demonstrate alteration of BRCA1 expression in chronic pancreatitis and sporadic pancreatic adenocarcinoma. We, for the first time, provide evidence for a role of BRCA1 in pancreatic carcinogenesis of noninherited tumors and for clinical outcome.
Long-Term Central Venous Catheter Use and Risk of Infection in Older Adults With Cancer
Authors: Allison Lipitz-Snyderman, Kent A. Sepkowitz, Elena B. Elkin, Laura C. Pinheiro, Camelia S. Sima, Crystal H. Son, Coral L. Atoria, Peter B. Bach
Journal: Journal of Clinical Oncology (2014)

Long-term central venous catheters (CVCs) are often used in patients with cancer to facilitate venous access to administer intravenous fluids and chemotherapy. CVCs can also be a source of bloodstream infections, although this risk is not well understood. We examined the impact of long-term CVC use on infection risk, independent of other risk factors such as chemotherapy, in a population-based cohort of patients with cancer.We conducted a retrospective analysis using SEER-Medicare data for patients age > 65 years diagnosed from 2005 to 2007 with invasive colorectal, head and neck, lung, or pancreatic cancer, non-Hodgkin lymphoma, or invasive or noninvasive breast cancer. Cox proportional hazards regression was used to examine the relationship between CVC use and infections, with CVC exposure as a time-dependent predictor. We used multivariable analysis and propensity score methods to control for patient characteristics.CVC exposure was associated with a significantly elevated infection risk, adjusting for demographic and disease characteristics. For patients with pancreatic cancer, risk of infections during the exposure period was three-fold greater (adjusted hazard ratio [AHR], 2.93; 95% CI, 2.58 to 3.33); for those with breast cancer, it was six-fold greater (AHR, 6.19; 95% CI, 5.42 to 7.07). Findings were similar when we accounted for propensity to receive a CVC and limited the cohort to individuals at high risk of infections.Long-term CVC use was associated with an increased risk of infections for older adults with cancer. Careful assessment of the need for long-term CVCs and targeted strategies for reducing infections are critical to improving cancer care quality.
Strong priming of T cells adoptively transferred into scid mice.
Authors: G H Sunshine, B L Jimmo, C Ianelli, L Jarvis
Journal: The Journal of Experimental Medicine (1991)

We have examined the requirements for activating unprimed T cells in vivo by transferring T cells into scid mice, which lack mature B and T cells. Purified adult thymocytes and a protein antigen, keyhole limpet hemocyanin (KLH), were injected into scid mice. scid mice injected with T cells and KLH developed cellular lymph nodes containing CD4+ and CD8+ T cells. Cells recovered from the lymph nodes of injected scid mice proliferated and secreted interleukin 2 in response to KLH in vitro. The results indicate that T cells can be primed to KLH in the scid mouse in the absence of B cells.
Pancolonic chromoendoscopy with indigo carmine versus standard colonoscopy for detection of neoplastic lesions: a randomised two-centre trial
Authors: J. Pohl, A. Schneider, H. Vogell, G. Mayer, G. Kaiser, C. Ell
Journal: Gut (2010)

Colonoscopy is the accepted gold standard for detecting colorectal adenomas, but the miss rate, especially for small and flat lesions, remains unacceptably high. The aim of this study was to determine whether enhanced mucosal contrast using pancolonic chromoendoscopy (PCC) allows higher rates of adenoma detection.In a prospective, randomised two-centre trial, PCC (with 0.4% indigo carmine spraying during continuous extubation) was compared with standard colonoscopy (control group) in consecutive patients attending for routine colonoscopy. The histopathology of the lesions detected was confirmed by evaluating the endoscopic resection or biopsy specimens.A total of 1008 patients were included (496 in the PCC group, 512 in the control group). The patients' demographic characteristics and indications for colonoscopy were similar in the two groups. The proportion of patients with at least one adenoma was significantly higher in the PCC group (46.2%) than in the control group (36.3%; p = 0.002). Chromoendoscopy increased the overall detection rate for adenomas (0.95 vs 0.66 per patient), flat adenomas (0.56 vs 0.28 per patient) and serrated lesions (1.19 vs 0.49 per patient) (p < 0.001). There was a non-significant trend towards increased detection of advanced adenomas (103 vs 81; p = 0.067). Mean extubation times were slightly but significantly longer in the PCC group in comparison with the control group (11.6 ± 3.36 min vs 10.1 ± 2.03 min; p < 0.001).Pancolonic chromoendoscopy markedly enhances adenoma detection rates in an average-risk population and is practicable enough for routine application.