tbuckley/cabot-search huggingface dataset:
What Does Similarity Mean in Clinical Trials?
Authors: Fabio Puglisi
Journal: Journal of Clinical Oncology (2009)

reporting the results of a phase III trial comparing gemcitabine plus docetaxel (GD) versus capecitabine plus docetaxel (CD) in patients with advanced breast cancer. The primary objective of the study was to compare progression-free survival (PFS) between treatments. Given that the investigators set out to determine whether GD was superior to CD, their conclusion seems in contrast with the methodologic features of the trial. In fact, the authors assumed a median PFS improvement from 6 months in CD to 8.2 months in GD, and a total of 250 progressions or deaths were required to achieve a power of 80%. In the last sentence of the article, they stated that “both GD and CD were similar with regard to PFS.” In addition, in the abstract, they concluded that, because of a nonhematologic toxicity profile that favors GD over approved doses of CD, gemcitabine might be a better option than capecitabine in combination with docetaxel in the setting of advanced breast cancer. However, their assertions did not seem to be supported by the methods used and the results obtained in the trial. In other words, the only possible conclusion of the study should have been that GD was not superior to CD and not that the regimens were similar, because the sample size was insufficient to demonstrate similarity. However, what does similarity mean? In clinical trials, claims of similarity are sometimes made not by thoughtful examination of the data, but by tests of statistical significance that are often misapplied or accompanied by inadequate sample sizes. 2
No “When” without “Where”
Authors: Christian Quaia, Lance M. Optican
Journal: Behavioral and Brain Sciences (1999)

Deciding where to look is a very complicated process, but deciding when to look is probably much simpler. Once the brain is certain of where it wants to look, the saccade-generating pathway may simply start autonomously. Higher cognitive areas of the brain can only override this automatic start by preventing all saccades. Hence, the brain has no ability to say when to go; it can only say “go there” or “stay here.”
Leptin and ghrelin levels in patients with obstructive sleep apnoea: effect of CPAP treatment
Authors: I.A. Harsch, P.C. Konturek, C. Koebnick, P.P. Kuehnlein, F.S. Fuchs, S. Pour Schahin, G.H. Wiest, E.G. Hahn, T. Lohmann, J.H. Ficker
Journal: European Respiratory Journal (2003)

Serum leptin and ghrelin levels were investigated in patients with obstructive sleep apnoea (OSA) syndrome before and during continuous positive airways pressure (CPAP) treatment and compared with body mass index (BMI)-matched controls without OSA. Male patients (n=30) with OSA (apnoea/hypopnoea index=58±16, BMI=32.6±5.3 kg·m −2 ) underwent CPAP treatment. Fasting leptin and ghrelin were measured atbaseline and 2 days, and in the case of leptin 2 months after initiation of treatment. Baseline plasma ghrelin levels were significantly higher in OSA patients than in controls. After 2 days of CPAP treatment, plasma ghrelin decreased in almost all OSA patients (n=9) to levels that were only slightly higher than those of controls (n=9). Leptin levels did not change significantly from baseline after 2 days of CPAP treatment, but were higher than in the control group. After 8 weeks, leptin levels decreased significantly, although the BMI of the patients showed no change. The decrease in leptin levels was more pronounced in patients with a BMI &lt;30 kg·m −2 . These data indicate that the elevated leptin and ghrelin levels are not determined by obesity alone, since they rapidly decreased during continuous positive airways pressure therapy.
Protein kinase A-activated chloride channel is inhibited by the Ca(2+)-calmodulin complex in cardiac sarcoplasmic reticulum.
Authors: S Kawano, M Hiraoka
Journal: Circulation Research (1993)

Cardiac sarcoplasmic reticulum (SR) has several chloride (Cl-) channels, which may neutralize the charge across the SR membrane generated by Ca2+ movement. We recently reported a novel 116-picosiemen Cl- channel that is activated by protein kinase A-dependent phosphorylation in cardiac SR. This Cl- channel may serve as a target protein in the receptor-dependent regulation of cardiac excitation-contraction coupling. To understand further regulatory mechanisms, the effects of Ca2+ on the Cl- channel were studied using the planar lipid bilayer-vesicle fusion technique. In the presence of calmodulin (CaM, 0.1 mumol/L per microgram SR vesicles), Ca2+ (3 mumol/L to 1 mmol/L) added to the cis solution reduced the channel openings in a concentration-dependent fashion, whereas Ca2+ (1 nmol/L to 1 mmol/L) alone or CaM (0.1 to 1 mumol/L per microgram SR vesicles) with 1 nmol/L Ca2+ did not affect the channel activity. This inhibitory effect of Ca2+ in the presence of CaM was prevented by CaM inhibitors N-(6 aminohexyl)-5-chloro-1-naphthalenesulfonamide and calmidazolium but not by CaM kinase II inhibitor KN62. These results suggest that the Ca(2+)-CaM complex itself, but not CaM kinase II, is involved in this channel inhibition. Thus, the cardiac SR 116-picosiemen Cl- channel is regulated not only by protein kinase A-dependent phosphorylation but also by the cytosolic Ca(2+)-CaM complex. This is a novel second messenger-mediated regulation of Cl- channels in cardiac SR membrane.
Isolation of diphtheroid bacilli from synovial membrane and fluid in rheumatoid arthritis.
Authors: S M Stewart, W R Alexander, J J Duthie
Journal: Annals of the Rheumatic Diseases (1969)

The view that rheumatoid arthritis might be caused by an infective agent has long been held.Although various bacteria have been isolated in the past, none has been shown to cause the disease.Much of this work was done in the 1930s and was extensively reviewed by P. S. Hench and his fellow editors of the first eight "Rheumatism Reviews" (1935-1941) published collectively in 1961.In more recent years the basis for the view has varied from purely theoretical, intuitive considerations (Bauer, Clark, and Dienes, 1951; Christian, 1964;Sharp,
CHARACTERISTICS OF AN ACUTE CONFUSIONAL STATE IN COLLEGE STUDENTS
Authors: HELEN B. CARLSON
Journal: American Journal of Psychiatry (1958)

An acute confusional state has been described, occurring in young adults in colleges in the Chicago Area with specific characteristics as to genesis, presenting complaints, onset, course, and treatment. Psychodynamic reconstruction is as follows: In childhood these patients were bound in an extraordinarily strong dependent relationship to their parents through guilt and fear, engendered by parental instability and disharmony. With subsequent dependent gratification and support these patients were able to achieve a conforming type of adjustment and gain success in academic and social achievements. However, in young adulthood when they attempted to find their own identity, through choice of heterosexual partner and choice of career, in the college environment, devoid of dependent gratification, their previous adjustment was inadequate to meet their needs. Sexual temptation or commitment led to guilt, which led to retreat. Retreat, in turn, led to shame and ridicule from the peer group. To avoid the shame, another attempt at conforming sexual behavior is attempted, and once more guilt, retreat and shame. In this way, either thrusts toward accomplishment or retreat from it are associated with anxiety. Under these circumstances, if the dependent gratification from parents is cut off due to their criticism or disapproval, the patient regresses to an early childhood fixation point, associated with primary anxiety, rage, and confusion, where he feels isolated, worthless, mistrustful and depressed. Recovery from the confusion occurs when the patient, who desperately seeks help, finds someone to lean upon. If inadequate help to meet his needs is found, introjection or projection of rage may result. Further study to delineate this confusional state would include: 1. Psychological tests for independent verification of our results, 2. biochemical tests to compare the chemical changes in this condition with that found in anxiety states associated with other conditions, 3. further understanding of treatment and preventive measures, 4. sociological study of the college community to elucidate factors related to the development of security in young adults in college, 5. study of the background (family as well as the community) from whence these patients came and 6. control studies on college students without confusion.
Apolipoprotein A-I, A-II and C-II in black and white residents of Evans County.
Authors: H A Tyroler, G Heiss, G Schonfeld, G Cooper, S Heyden, C G Hames
Journal: Circulation (1980)

Plasma levels of lipids, lipoprotein-cholesterol and three major apolipoproteins (ApoA-I, A-II and C-II) were studied in 318 black and white males and females randomly sampled in Evans County, Georgia. Black-white differences in lipid and lipoprotein-cholesterol concentrations were observed, with low-density fractions higher in whites and high-density fractions higher in blacks. Plasma levels of ApoA-I but not ApoA-II were higher in blacks than in whites and in females than in males. ApoC-II concentrations were lower in black than in white men and women. Black-white differences in atherogenic lipoprotein fractions were statistically explained (in the sense of association, not necessarily of causal process) by the differences in ApoC-II concentrations between the race groups. Black-white differences in anti etherogenic high-density lipoprotein-cholesterol were greater than statistically predicted by differences in ApoA lipoprotein levels. The findings are indicative of black-white differences in lipoprotein composition.
The benefits of whole lung lavage in pulmonary alveolar proteinosis
Authors: C. Morgan
Journal: European Respiratory Journal (2004)

Pulmonary alveolar proteinosis (PAP) is an interesting, rare and enigmatic disease, which was first described relatively recently in 1958 1. The affected individuals suffer a progressive accumulation of lipoproteins in the alveolar space, resulting in steadily worsening gas exchange, and culminating in death from hypoxia and or cor pulmonale. Even though the alveolar space is full of Periodic Acid Schiff-staining proteinaceous material, the actual lung tissue is practically normal, although a minor component of interstitial involvement is probably present in most cases. Three variants of the disease have been recognised: congenital, secondary and acquired (or idiopathic). It is the latter that is of most importance in terms of prevalence (∼0.2 cases per million of population) and response to treatment.

Successful treatment of PAP by therapeutic irrigation of the lungs was reported a few years after the disease was first described, and this led to massive whole lung lavage (WLL) 2, where, under general anaesthesia, the two lungs are separated by endobronchial intubation and one lung is ventilated while the other is flooded with warm saline to progressively wash out the alveolar space. Although there have been several refinements in this technique and developments in anaesthesia and peri-operative care, the basis of the treatment remains much the same 3–5.

It is not surprising that there have been a lot of interesting and informative review articles concerning PAP 6–8, and in the past 10 yrs it has emerged that the aetiology of the acquired form of the disease may well be an auto-immune response 9. A very high proportion of patients suffering from PAP have been shown to have high titres of an anti-granulocyte-macrophage colony-stimulating factor (GM‐CSF) antibody in plasma and the proposed disease mechanism is that interference with GM‐CSF regulation of alveolar lipoprotein …
Aberrant BCL10 nuclear expression in nasal NK/T-cell lymphoma
Authors: Lijun Shen, Anthony C. T. Liang, Liwei Lu, Wing Y. Au, Kai-Yau Wong, Pui-Chi Tin, Kwok-Wah Chan, King-Hung Ko, Yun-Wen Chen, Swan-Lip Beh, Norio Shimizu, Junjiro Tsuchiyama, Johnny C. O. Tang, Yok-Lam Kwong, Raymond H. S. Liang, Gopesh Srivastava
Journal: Blood (2003)
Ligand triggers of classical preconditioning and postconditioning
Authors: E GROSS, G GROSS
Journal: Cardiovascular Research (2006)

The cardioprotection afforded by ischemic preconditioning (IPC) and ischemic postconditioning (PC) are receptor mediated. In this review, we will focus on the major ligand classes and receptors that contribute to IPC and PC-induced cardioprotection. Ligand classes discussed include adenosine, bradykinin, opioids, erythropoietin, adrenergics and muscarinics. The cardioprotective therapeutic window of each ligand class will also be summarized, with particular focus as to whether ligands are protective when administered at or close to the time of reperfusion. Information will primarily be directed at studies in which infarct size reduction is the gold standard to assess the efficacy of IPC and PC. Myocardial stunning is a less robust endpoint for assessing cardioprotection and the use of this endpoint is only limited to studies with human tissue where infarct size assessment is not possible. Receptor cross-talk between ligands and the common signaling pathways involved for these ligands will also be briefly discussed.
Mahanine restores RASSF1A expression by down-regulating DNMT1 and DNMT3B in prostate cancer cells
Authors: Soumik Agarwal, Karishma S Amin, Shankar Jagadeesh, Gokul Baishay, Paruchuri G Rao, Nabin C Barua, Samir Bhattacharya, Partha P Banerjee
Journal: Molecular Cancer (2013)

Hypermethylation of the promoter of the tumor suppressor gene RASSF1A silences its expression and has been found to be associated with advanced grade prostatic tumors. The DNA methyltransferase (DNMT) family of enzymes are known to be involved in the epigenetic silencing of gene expression, including RASSF1A, and are often overexpressed in prostate cancer. The present study demonstrates how mahanine, a plant-derived carbazole alkaloid, restores RASSF1A expression by down-regulating specific members of the DNMT family of proteins in prostate cancer cells.Using methylation-specific PCR we establish that mahanine restores the expression of RASSF1A by inducing the demethylation of its promoter in prostate cancer cells. Furthermore, we show that mahanine treatment induces the degradation of DNMT1 and DNMT3B, but not DNMT3A, via the ubiquitin-proteasome pathway; an effect which is rescued in the presence of a proteasome inhibitor, MG132. The inactivation of Akt by wortmannin, a PI3K inhibitor, results in a similar down-regulation in the levels DNMT1 and DNMT3B. Mahanine treatment results in a decline in phospho-Akt levels and a disruption in the interaction of Akt with DNMT1 and DNMT3B. Conversely, the exogenous expression of constitutively active Akt inhibits the ability of mahanine to down-regulate these DNMTs, suggesting that the degradation of DNMT1 and DNMT3B by mahanine occurs via Akt inactivation.Taken together, we show that mahanine treatment induces the proteasomal degradation of DNMT1 and DNMT3B via the inactivation of Akt, which facilitates the demethylation of the RASSF1A promoter and restores its expression in prostate cancer cells. Therefore, mahanine could be a potential therapeutic agent for advanced prostate cancer in men when RASSF1A expression is silenced.
Diet and asthma: vitamins and methyl donors
Authors: Yueh-Ying Han, Josh Blatter, John M Brehm, Erick Forno, Augusto A Litonjua, Juan C Celedón
Journal: The Lancet Respiratory Medicine (2013)

Diet changes can partly explain the high burden of asthma in industrialised nations. Findings from experimental studies have stimulated many observational studies of the association between vitamins (A, C, D, and E) or nutrients acting as methyl donors (folate, vitamin B12, and choline) and asthma. However, observational studies are susceptible to several sources of bias; well conducted randomised controlled trials (RCTs) are the gold standard to establish whether diet has an effect on asthma. Evidence from observational studies and a few RCTs strongly justifies ongoing and future RCTs in three areas: vitamin D for the prevention or treatment of asthma, choline supplementation as adjuvant treatment for asthma, and vitamin E to prevent the detrimental effects of air pollution in patients with asthma. At present, insufficient evidence exists to recommend supplementation with any vitamin or nutrient acting as a methyl donor to prevent or treat asthma.
Safety and efficacy of multiband mucosectomy in 1060 resections in Barrett's esophagus
Authors: L. Alvarez Herrero, R. Pouw, F. van Vilsteren, F. ten Kate, M. Visser, C. Seldenrijk, M. van Berge Henegouwen, B. Weusten, J. Bergman
Journal: Endoscopy (2011)

See also: Commentaire de travail de L. Alvarez Herrero et al., pp. 177Endoscopy 2011; 43(03): 248-248DOI: 10.1055/s-0031-1291803
Huntingtin in health and disease
Authors: Anne B. Young
Journal: Journal of Clinical Investigation (2003)

After linkage of the Huntington disease (HD) gene was found in 1983, it took ten years of work by an international group to identify the mutation in the gene interesting transcript 15 (IT15) that causes the disease (1, 2). HD is an autosomal dominant inherited neurodegenerative disease that becomes manifest in midlife and causes progressive motor, psychiatric, and cognitive dysfunction. It is invariably terminal. HD symptoms can begin as early as 2 years or as late as 90 years, although the average age of onset is in the late 30s and early 40s. If a child inherits the gene from his or her father, a phenomenon called anticipation frequently occurs, whereby the child’s age of onset is lower than the father’s (3). The IT15 gene is composed of 67 exons and encodes a protein of 3,144 amino acids, called huntingtin (2). Exon 1 contains a CAG trinucleotide repeat that encodes the amino acid glutamine, followed by another repeat that encodes proline. In unaffected individuals, there are 10‐34 CAG repeats. In those affected by HD, there are more than 40 repeats. In those with 35‐39 repeats, the disease is variably penetrant (3‐5). The age of onset of the disease varies inversely with the number of CAG repeats. Individuals with juvenile onset usually have over 55 repeats, and they usually inherit the gene from their father. Men occasionally have expanded repeats in their sperm (6). The expansion is thought to occur via slippage during the DNA replication process. Wild-type huntingtin Huntingtin contains a few domains that suggest particular functions, including WW domains and caspase cleavage sites (7, 8), but the function of the protein remains unknown. Huntingtin is expressed in the cytoplasm of most cells in the body. In the brain, expression is found predominantly in neurons (2, 9‐11). Within the cell, the protein is associated with
Increased mucosal damage during parasite infection in mice fed an elemental diet.
Authors: A Ferguson, R F Logan, T T MacDonald
Journal: Gut (1980)

We have examined the effects of parasite infection on the mucosal architecture of mice maintained on an elemental diet (Vivonex). Techniques used were conventional histology, micro-dissection and measurement of individual villi and crypts, and measurement of crypt cell proliferation rate by a metaphase accumulation technique. In normal, non-parasitised mice the elemental diet caused no change in villus height, crypt depth, or crypt cell proliferation. Likewise, the only effects of chronic protozoal infection or Nippostrongylus brasiliensis infection on the intestine of mice fed a normal diet have been a slight crypt hypertrophy and an increase in crypt cell proliferation rate without villous atrophy. However, the combination of elemental diet and parasite infection resulted in increased mucosal damage when compared with infected mice on a normal diet. Elemental diet mice infected with the nematode Nippostrongylus brasiliensis had significantly reduced villus height and correspondingly raised crypt length and metaphase accumulation rate. Elemental diet mice infected with the protozoan Giardia muris did not have villous atrophy but there was a significant increase in crypt length and metaphase accumulation when compared with infected normal diet mice. These experiments show that in two animal models of enteric infection, elemental diet has altered the host parasite relationship to the detriment of the host.
Explaining variation in familial adenomatous polyposis: relationship between genotype and phenotype and evidence for modifier genes
Authors: M D Crabtree
Journal: Gut (2002)

<b>Background:</b> Familial adenomatous polyposis (FAP) is characterised by variable phenotypic expression. Part of this is attributable to a relationship between <i>APC</i> genotype and phenotype but there remains significant intrafamilial variation. In the <i>Min</i> mouse model of FAP, differences in the severity of gastrointestinal polyposis result from the action of modifier genes. <b>Aims:</b> To determine whether phenotypic variation in human FAP has an inherited component consistent with the action of modifier genes. <b>Method:</b> We systematically examined polyp numbers in colectomy specimens from patients with classical FAP. Variation both between and within families was analysed. Formal modelling of the segregation of disease severity in families was performed <b>Results:</b> There was strong evidence for a relationship between site of mutation and the number of colorectal polyps, with germline mutations in the "cluster region" causing the most severe disease and those with mutations between codons 1020 and 1169 having the mildest disease. In addition to this genotype-phenotype relationship, we found evidence for non-<i>APC</i> linked genetic modifiers of disease expression. First degree relatives had more similar polyp counts than more distant relatives. Formal modelling of the segregation of disease severity in families revealed further evidence for the action of modifier genes, with a best fit to a mixed model of inheritance. <b>Conclusion:</b> Our data provide good evidence to support the hypothesis that modifier genes influence the severity of FAP in humans.
Concussion guidelines need to move from only expert content to also include implementation and dissemination strategies
Authors: Caroline F Finch, Paul McCrory, Michael T Ewing, S John Sullivan
Journal: British Journal of Sports Medicine (2012)

Body dysmorphic disorder (BDD) is a relatively common and disabling psychiatric disorder characterised by excessive and persistent preoccupation with perceived defects or flaws in one9s appearance, which are unnoticeable to others, and associated repetitive behaviours (eg, mirror checking). The disorder generally starts in adolescence, but often goes unnoticed and is severely underdiagnosed. Left untreated, BDD typically persists and causes marked functional impairment in multiple domains. This clinical review considers recent advances in the epidemiology and classification of BDD, including its reclassification in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders under the new 'Obsessive–Compulsive and Related Disorders' chapter. Key issues in assessment are outlined including the use of validated screening instruments to minimise misdiagnosis and the importance of risk assessment in this population given the high rates of suicidality and inappropriate use of cosmetic treatments. In addition, current knowledge regarding the causes and mechanisms underlying BDD are summarised. The recommended treatments for BDD are outlined, namely cognitive behavioural therapy (CBT) and antidepressants, such as selective serotonin reuptake inhibitors. Both CBT and pharmacotherapy have been shown to be efficacious treatments for BDD in adult populations, and evidence is emerging to support their use in young people. Although the majority of patients improve with existing evidence-based treatment, a large proportion are left with clinically significant residual symptoms. Priorities for future research are therefore discussed including the need to further refine and evaluate existing interventions with the goal of improving treatment outcomes and to increase their availability.