tbuckley/cabot-search huggingface dataset:
CFTR biomarkers: time for promotion to surrogate end-point
Authors: K. De Boeck, L. Kent, J. Davies, N. Derichs, M. Amaral, S.M. Rowe, P. Middleton, H. de Jonge, I. Bronsveld, M. Wilschanski, P. Melotti, I. Danner-Boucher, S. Boerner, I. Fajac, K. Southern, R.A. de Nooijer, A. Bot, Y. de Rijke, E. de Wachter, T. Leal, F. Vermeulen, M.J. Hug, G. Rault, T. Nguyen-Khoa, C. Barreto, M. Proesmans, I. Sermet-Gaudelus
Journal: European Respiratory Journal (2012)

In patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-770), VX809 and ataluren. The aim of this project was to review the literature on reliability, validity and responsiveness of nasal potential difference, sweat chloride and intestinal current measurement in patients with cystic fibrosis. Data on clinimetric properties were collected for each biomarker and reviewed by an international team of experts. Data on reliability, validity and responsiveness were tabulated. In addition, narrative answers to four key questions were discussed and agreed by the team of experts. The data collected demonstrated the reliability, validity and responsiveness of nasal potential difference. Fewer data were found on reliability of sweat chloride concentration; however, validity and responsiveness were demonstrated. Validity was demonstrated for intestinal current measurement, but further information is required on reliability and responsiveness. For all three end-points, normal values were collected and further research requirements were proposed. This body of work adds useful information to support the promotion of CFTR biomarkers to surrogate end-points and to guide further research in the area.
Electric convulsion therapy in depression: a double-blind controlled trial.
Authors: E D West
Journal: BMJ (1981)

The therapeutic effect of simulated and real bilateral electric convulsion therapy was examined in a double-blind, randomised trial on 22 patients with a primary depressive illness. Each treatment was given twice weekly for three weeks and the results assessed by the psychiatrist using a visual analogue rating scale, nurses using a nine-point rating scale, and the patients themselves using the Beck Depression Inventory. With all three methods of assessment patients given the real treatment substantially improved (p less than 0.001), whereas those given simulated treatment showed little change. Three weeks after substituting real treatment for simulated, however, these patients were also significantly improved (psychiatrist9s rating p less than 0.001; nurses9 rating p less than 0.005; Beck inventory p less than 0.005). These findings confirm the value of electric convulsion therapy in severe depressive illness and strongly suggest that the convulsion is important for the therapeutic effect.
Exercise on prescription for women aged 40-74 recruited through primary care: two year randomised controlled trial
Authors: B. A Lawton, S. B Rose, C R. Elley, A. C Dowell, A. Fenton, S. A Moyes
Journal: BMJ (2008)

To assess the effectiveness of a primary care based programme of exercise on prescription among relatively inactive women over a two year period.Randomised controlled trial.17 primary care practices in Wellington, New Zealand.1089 women aged 40-74 not undertaking 30 minutes of moderate intensity physical activity on at least five days of the week.Brief physical activity intervention led by nurse with six month follow-up visit and monthly telephone support over nine months.Physical activity assessed at baseline and 12 and 24 months. Secondary outcomes were quality of life (SF-36), weight, waist circumference,blood pressure, concentrations of fasting serum lipids,glycated haemoglobin (HbA1c), glucose, insulin, and physical fitness.Mean age was 58.9 (SD 7) years. Trial retention rates were 93% and 89% at 12 and 24 months,respectively. At baseline,10%of intervention participants and 11% of control participants were achieving 150 minutes of at least moderate intensity physical activity a week. At 12 months rates increased to 43% and 30% and at 24 months to 39.3% and 32.8% (P<0.001), respectively. SF-36 physical functioning (P = 0.03) and mental health (P<0.05) scores improved more in intervention compared with control participants, but role physical scores were significantly lower (P<0.01). There were no significant differences in clinical outcomes. More falls (P<0.001) and injuries (P=0.03) were recorded in the intervention group.This programme of exercise on prescription increased physical activity and quality of life over two years, although falls and injuries also increased. This finding supports the use of exercise on prescription programmes as part of population strategies to reduce physical inactivity.
Qualitative study of decisions about infant feeding among women in east end of London
Authors: P. Hoddinott, R. Pill
Journal: BMJ (1999)

To improve understanding of how first time mothers who belong to a socioeconomic group with particularly low rates of breast feeding decide whether or not to initiate breast feeding.Qualitative semistructured interviews early in pregnancy and 6-10 weeks after birth.Women's homes in east end of London.21 white, low income women expecting their first baby were interviewed mostly at home, often with their partner or a relative. Two focus groups were conducted.Women who had regularly seen a relative or friend successfully breast feed and described this experience positively were more confident about and committed to breast feeding. They were also more likely to succeed. Exposure to breast feeding, however, could be either a positive or a negative influence on the decision to breast feed, depending on the context. Women who had seen breast feeding only by a stranger often described this as a negative influence, particularly if other people were present. All women knew that breast feeding has health benefits. Ownership of this knowledge, however, varied according to the woman's experience of seeing breast feeding.The decision to initiate breast feeding is influenced more by embodied knowledge gained from seeing breast feeding than by theoretical knowledge about its benefits. Breast feeding involves performing a practical skill, often with others present. The knowledge, confidence, and commitment necessary to breast feed may be more effectively gained through antenatal apprenticeship to a breastfeeding mother than from advice given in consultations or from books.
Heterogeneity of Kv2.1 mRNA Expression and Delayed Rectifier Current in Single Isolated Myocytes From Rat Left Ventricle
Authors: Jobst-Hendrik Schultz, Tilmann Volk, Heimo Ehmke
Journal: Circulation Research (2001)

Abstract —Expression of the voltage-gated K + channel Kv2.1, a possible molecular correlate for the cardiac delayed rectifier current ( I K ), has recently been shown to vary between individual ventricular myocytes. The functional consequences of this cell-to-cell heterogeneity in Kv2.1 expression are not known. Using multiplex single-cell reverse transcriptase–polymerase chain reaction (RT-PCR), we detected Kv2.1 mRNA in 47% of isolated midmyocardial myocytes from the rat left ventricular free wall that were positive for α-myosin heavy chain mRNA (n=74). Whole-cell patch-clamp recordings demonstrated marked differences in the magnitude of I K (200 to 1450 pA at V Pip =40 mV) between individual myocytes of the same origin. Furthermore, the tetraethylammonium (TEA)–sensitive outward current ( I TEA ), known to be partly encoded by Kv2.1 in mice, revealed a wide range of current magnitudes between single cells (150 to 1130 pA at V Pip =40 mV). Combined patch-clamp recordings and multiplex single-cell RT-PCR analysis of the same myocytes, however, showed no differences in I K or I TEA magnitude or inactivation kinetics between myocytes expressing Kv2.1 mRNA and those that did not express Kv2.1 mRNA. In contrast, in all midmyocardial myocytes expressing the transient outward potassium current ( I to1 ), Kv4 mRNA, which has been shown to underlie I to1 , was detected (n=10). These results indicate that I K heterogeneity among individual left ventricular myocytes cannot be explained by the distribution pattern of Kv2.1 mRNA. Other mechanisms besides Kv2.1 mRNA expression appear to determine magnitude and kinetics of I K in rat ventricular myocytes.
Ductal Carcinoma In Situ of the Breast: A Systematic Review of Incidence, Treatment, and Outcomes
Authors: B. A. Virnig, T. M. Tuttle, T. Shamliyan, R. L. Kane
Journal: JNCI Journal of the National Cancer Institute (2010)

The National Institutes of Health Office of Medical Applications of Research commissioned a structured literature review on the incidence, treatment, and outcomes of ductal carcinoma in situ (DCIS) as a background article for the State of the Science Conference on Diagnosis and Management of DCIS.Published studies were identified and abstracted from MEDLINE and other sources. We include articles published between 1965 and January 31, 2009; 374 publications were identified that addressed DCIS incidence, staging, treatment, and outcomes in adult women.In the United States, DCIS incidence rose from 1.87 per 100 000 in 1973-1975 to 32.5 in 2004. Incidence increased in all ages but more so in women older than 50 years. Increased use of mammography explains some but not all of the increased incidence. Risk factors for incident DCIS include older age and family history. Although tamoxifen treatment prevented both invasive breast cancer and DCIS, raloxifene treatment decreased incidence of invasive breast cancer but not DCIS. Among patients with DCIS, magnetic resonance imaging was more sensitive than mammography for detecting multicentric disease and estimating tumor size. Because about 15% of patients with DCIS identified on core needle biopsy are diagnosed with invasive breast cancer after excision or mastectomy, the accuracy of sentinel lymph node biopsy after excision is relevant to surgical management of DCIS. Most studies demonstrated that sentinel lymph node biopsy is feasible after breast-conserving surgery (BCS). Younger age, positive surgical margins, tumor size and grade, and comedo necrosis were consistently related to DCIS recurrence. DCIS outcomes after either mastectomy or BCS plus radiation therapy were superior to BCS alone. Tamoxifen treatment after DCIS diagnosis reduced risk of recurrent disease.Scientific questions deserving further investigation include the relationship between mammography use and DCIS incidence and whether imaging technologies and treatment guidelines can be modified to focus on lesions that are most likely to become clinically problematic.
Antioxidant Intervention Prevents Renal Neovascularization in Hypercholesterolemic Pigs
Authors: Alejandro R. Chade, Michael D. Bentley, Xiangyang Zhu, Martin Rodriguez-Porcel, Sara Niemeyer, Beatriz Amores-Arriaga, Claudio Napoli, Erik L. Ritman, Amir Lerman, Lilach O. Lerman
Journal: Journal of the American Society of Nephrology (2004)

Two new preparations have been introduced for enteral feeding - Nutrauxil (KabiVitrum) and Nutranel (Roussel). This article compares them with the preparations we discussed in 1980.<sup>1</sup> Enteral therapy should not rely on 'standard' regimens and to meet each patient's needs one must know the calorie, nitrogen and electrolyte content of each feed.
The relationship of femoral neck shaft angle and adiposity to greater trochanteric pain syndrome in women. A case control morphology and anthropometric study
Authors: AM Fearon, S Stephens, JL Cook, PN Smith, T Neeman, W Cormick, JM Scarvell
Journal: British Journal of Sports Medicine (2012)

To evaluate if pelvic or hip width predisposed women to developing greater trochanteric pain syndrome (GTPS).Prospective case control study.Four groups were included in the study: those gluteal tendon reconstructions (n=31, GTR), those with conservatively managed GTPS (n=29), those with hip osteoarthritis (n=20, OA) and 22 asymptomatic participants (ASC).Anterior-posterior pelvic x-rays were evaluated for femoral neck shaft angle; acetabular index, and width at the lateral acetabulum, and the superior and lateral aspects of the greater trochanter. Body mass index, and waist, hip and greater trochanter girth were measured. Data were analysed using a one-way analysis of variance (ANOVA; posthoc Scheffe analysis), then multivariate analysis.The GTR group had a lower femoral neck shaft angle than the other groups (p=0.007). The OR (95% CI) of having a neck shaft angle of less than 134°, relative to the ASC group: GTR=3.33 (1.26 to 8.85); GTPS=1.4 (0.52 to 3.75); OA=0.85 (0.28 to 2.61). The OR of GTR relative to GTPS was 2.4 (1.01 to 5.6). No group difference was found for acetabular or greater trochanter width. Greater trochanter girth produced the only anthropometric group difference (mean (95% CI) in cm) GTR=103.8 (100.3 to 107.3), GTPS=105.9 (100.2 to 111.6), OA=100.3 (97.7 to 103.9), ASC=99.1 (94.7 to 103.5), (ANOVA: p=0.036). Multivariate analysis confirmed adiposity is associated with GTPS.A lower neck shaft angle is a risk factor for, and adiposity is associated with, GTPS in women.
OFD1 Is a Centrosomal/Basal Body Protein Expressed during Mesenchymal-Epithelial Transition in Human Nephrogenesis
Authors: Leila Romio, Andrew M. Fry, Paul J.D. Winyard, Sue Malcolm, Adrian S. Woolf, Sally A. Feather
Journal: Journal of the American Society of Nephrology (2004)

OFD1 is the gene responsible for the oral-facial-digital syndrome type 1, a cause of inherited cystic renal disease. The protein contains an N-terminal LisH motif, considered important in microtubule dynamics, and several putative coiled-coil domains. This study used a combination of microscopic, biochemical, and overexpression approaches to demonstrate that OFD1 protein is a core component of the human centrosome throughout the cell cycle. Using a series of GFP-OFD1 deletion constructs, it was determined that the N-terminus containing the LisH domain is not required for centrosomal localization; however, coiled-coil domains are critical, with at least two being necessary for centrosomal targeting. Importantly, most reported OFD1 mutations are predicted to cause protein truncation with loss of coiled-coil domains, presumably leading to loss of centrosomal localization. Kidney development constitutes a classic model of mesenchymal-epithelial transformation. By immunoprobing human metanephroi and kidney epithelial lines, it was found that, during acquisition of epithelial polarity, OFD1 became localized to the apical zone of nephron precursor cells and then to basal bodies at the origin of primary cilia in fully differentiated epithelia. These striking patterns of OFD1 localization within cells place the protein at key sites, where it may play roles not only in microtubule organization (centrosomal function) but also in mechanosensation of urine flow (a primary ciliary function).
Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable cytogenetics [t(8;21) and inv(16)]
Authors: G Perea, A Lasa, A Aventín, A Domingo, N Villamor, M Paz Queipo de Llano, A Llorente, J Juncà, C Palacios, C Fernández, M Gallart, L Font, M Tormo, L Florensa, J Bargay, J M Martí, P Vivancos, P Torres, J J Berlanga, I Badell, S Brunet, J Sierra, J F Nomdedéu
Journal: Leukemia (2005)
Do H63D homozygote patients have clinically significant iron overload?
Authors: J. R. White, R. Scott, G. Mortimore, A. Lawson, J. Freeman, A. Austin
Journal: Gut (2011)

<h3>Introduction</h3> Homozygosity H63D is present in 2% of the normal Caucasian population and is thought to carry a small risk of iron overload. The authors aim to characterise patients referred with evidence of iron overload found to be H63D homozygous. <h3>Methods</h3> Retrospective analysis of all H63D homozygotes with abnormal iron indexes identified between 2005 and 2009. Approximately 650 patients were referred with abnormal iron indexes in this time period. 16 patients were identified who fitted these criteria, medical database and notes were reviewed to ascertain these individuals clinical outcome. <h3>Results</h3> 69% of patients were male, median age 49.5 (22–75) and 88% were from a White British ethnic group. 38% of H63D patients had iron overload on liver biopsy and were all male. Biopsy demonstrated hepatocellular patten iron overload grades I (3), II (2), III (0), IV (1). 5 showed steatohepatitis, 5 fibrosis none cirrhosis. Only one patient had isolated primary iron overload. Secondary co-factors were identified in 88% patients with abnormal iron storage (NASH, ALD, Hep C). All venesected patients (4) had a marked reduction in ferritin. One patient died due to an unrelated problem. <h3>Conclusion</h3> The incidence of H63D homozygote on its own leading to iron overload is relatively low but may still be encountered during clinical practice. Although majority of individuals had co-factors that may increase iron indexes these had hepatocellular iron deposition. These deposits may be directly related to H63D gene making it clinically significant.
Unusually large von Willebrand factor multimers increase adhesion of sickle erythrocytes to human endothelial cells under controlled flow.
Authors: T M Wick, J L Moake, M M Udden, S G Eskin, D A Sears, L V McIntire
Journal: Journal of Clinical Investigation (1987)

The interactions of normal erythrocytes and erythrocytes from patients having hemoglobin S hemoglobinopathies with normal human endothelial cells (EC) were investigated under flow conditions. When EC supernatant, containing 2.8-11.0 U/dl of von Willebrand factor (vWF) antigen and vWF multimeric forms larger than those present in normal plasma, was the red blood cell (RBC)-suspending medium instead of serum-free medium (SFM), the adhesion of sickle RBC, but not normal RBC, to endothelial cells was greatly increased (range of enhancement of sickle RBC adhesion, 2- to 27-fold). Adhesion of sickle RBC to endothelial cells was reduced to near serum-free levels when EC supernatant was immunologically depleted of vWF forms. Sickle RBC suspended in SFM containing 200 U/dl of purified vWF multimers of the type found in normal human plasma or 300 micrograms/ml human fibronectin were only slightly more adhesive to endothelial cells than sickle RBC suspended in SFM alone. These data indicate that unusually large vWF multimers produced by endothelial cells are potent mediators of the adhesion of sickle erythrocytes to endothelial cells. Vaso-occlusive crises in sickle cell anemia may be caused, at least in part, by adhesive interactions between the abnormal surfaces of sickle RBC and the endothelium after the release of unusually large vWF multimeric forms from stimulated or damaged endothelial cells.
Phenomenal and attentional consciousness may be inextricable
Authors: Adam Morton
Journal: Behavioral and Brain Sciences (1995)

Abstract In common sense consciousness has a fairly determinate content – the (single) way an experience feels, the (single) line of thought being consciously followed. The determinacy of the object may be achieved by linking Block's two concepts, so that as long as we hold on to the determinacy of content we are unable to separate P and A.
Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection
Authors: Norio Iizuka, Masaaki Oka, Hisafumi Yamada-Okabe, Minekatsu Nishida, Yoshitaka Maeda, Naohide Mori, Takashi Takao, Takao Tamesa, Akira Tangoku, Hisahiro Tabuchi, Kenji Hamada, Hironobu Nakayama, Hideo Ishitsuka, Takanobu Miyamoto, Akira Hirabayashi, Shunji Uchimura, Yoshihiko Hamamoto
Journal: The Lancet (2003)
Sputum versus bronchoscopy for diagnosis of Pseudomonas aeruginosa biofilms in cystic fibrosis
Authors: S.D. Aaron
Journal: European Respiratory Journal (2004)

The present authors hypothesised that bronchoscopy with protected specimen brush may sample biofilm-forming bacteria adherent to the airway wall, whereas traditional sputum collection may not. <i>Pseudomonas aeruginosa</i> obtained from sputum, bronchoalveolar lavage and protected brush, taken from the right upper lung bronchus of 12 adult patients with cystic fibrosis, were compared. Retrieved bacteria were genotyped, and grown in planktonic cultures and as biofilms, and susceptibilities to individual antibiotics and to antibiotic combinations were determined. Bacterial cultures obtained using bronchoscopy did not yield any new strains of bacteria that were not also found in sputum. A total of 10 patients (83%) had a single strain of <i>P. aeruginosa</i> found using sputum, bronchoalveolar lavage and protected brush techniques, and two patients (17%) had two strains recovered in sputum, but only one strain was recovered using bronchoscopic techniques. Susceptibility to single antibiotics and to antibiotic combinations were not different between planktonically or biofilm-grown bacteria derived from sputum, as compared to those obtained by bronchoalveolar lavage and protected brush. In conclusion, sputum collection provides as much information as bronchoscopy for characterising the genotype and antibiotic susceptibility of chronic <i>Pseudomonas aeruginosa</i> infection in patients with stable cystic fibrosis.
Nuclear Factor κB–dependent Gene Expression Profiling of Hodgkin's Disease Tumor Cells, Pathogenetic Significance, and Link to Constitutive Signal Transducer and Activator of Transcription 5a Activity
Authors: Michael Hinz, Petra Lemke, Ioannis Anagnostopoulos, Christine Hacker, Daniel Krappmann, Stephan Mathas, Bernd Dörken, Martin Zenke, Harald Stein, Claus Scheidereit
Journal: The Journal of Experimental Medicine (2002)

Constitutive nuclear nuclear factor (NF)-κB activity is observed in a variety of hematopoietic and solid tumors. Given the distinctive role of constitutive NF-κB for Hodgkin and Reed-Sternberg (HRS) cell viability, we performed molecular profiling in two Hodgkin's disease (HD) cell lines to identify NF-κB target genes. We recognized 45 genes whose expression in both cell lines was regulated by NF-κB. The NF-κB–dependent gene profile comprises chemokines, cytokines, receptors, apoptotic regulators, intracellular signaling molecules, and transcription factors, the majority of which maintain a marker-like expression in HRS cells. Remarkably, we found 17 novel NF-κB target genes. Using chromatin immunoprecipitation we demonstrate that NF-κB is recruited directly to the promoters of several target genes, including signal transducer and activator of transcription (STAT)5a, interleukin-13, and CC chemokine receptor 7. Intriguingly, NF-κB positively regulates STAT5a expression and signaling pathways in HRS cells, and promotes its persistent activation. In fact, STAT5a overexpression was found in most tumor cells of tested patients with classical HD, indicating a critical role for HD. The gene profile underscores a central role of NF-κB in the pathogenesis of HD and potentially of other tumors with constitutive NF-κB activation.