tbuckley/cabot-search huggingface dataset:
Female Predominance and Transmission Distortion in the Long-QT Syndrome
Authors: Medea Imboden, Heikki Swan, Isabelle Denjoy, Irene Marijke Van Langen, Päivi Johanna Latinen-Forsblom, Carlo Napolitano, Véronique Fressart, Guenter Breithardt, Myriam Berthet, Silvia Priori, Bernard Hainque, Arthur Arnold Maria Wilde, Eric Schulze-Bahr, Josué Feingold, Pascale Guicheney
Journal: New England Journal of Medicine (2006)

Congenital long-QT syndrome is a disorder resulting in ventricular arrhythmias and sudden death. The most common forms of the long-QT syndrome, types 1 and 2, are caused by mutations in the potassium-channel genes KCNQ1 and KCNH2, respectively. Although inheritance of the long-QT syndrome is autosomal dominant, female predominance has often been observed and has been attributed to an increased susceptibility to cardiac arrhythmias in women. We investigated the possibility of an unbalanced transmission of the deleterious trait.
Lesson of the month: extrinsic allergic (bronchiolo)alveolitis and metal working fluids
Authors: Paul Cullinan, Eva D'Souza, Rachel Tennant, Chris Barber
Journal: Thorax (2014)

One of us was asked to consider a diagnosis of occupational asthma for a man who had worked for 20 years as a metal turner in a large, modern factory producing specialised machine parts. He described a 2 year history of severe breathlessness that improved when he was not at work. His spirometry was restrictive with a FEV1 of 1.35 L (40% predicted) and FVC of 1.8 L (45% predicted), a ratio of 75%. Other lung function measurements indicated gas trapping; his TLC was 5.01 L (79% predicted) and RV/TLC 170% predicted. A high resolution CT scan of his lungs revealed a widespread ‘mosaic’ pattern of attenuation indicative of small airflow obstruction. We made a diagnosis of occupational extrinsic allergic bronchioloalveolitis and recommended that he change his work. After 12 months working elsewhere in the same company, away from the machine shop, his dyspnoea was greatly improved but had not disappeared; his FVC had increased to 2.41 L, his FEV1 to 1.45 L and his TLC to 5.36 L.

Four months later we were referred a man who was also a metal turner in the same factory. For 2 years he had been a patient in a specialist interstitial lung disease clinic with a diagnosis of chronic hypersensitivity pneumonitis. A marked lymphocytosis in his bronchoalveolar lavage suggested ongoing exposure to an external cause. The nature of this had not been established although the positive findings of an autoimmune screen had led to conjecture of an ‘autoimmune’ aetiology, and of a high level of serum-specific IgG antibodies to Aspergillus species, that exposure to ‘mould at home or work’ might be relevant; an occupational history noted only that he worked for a machine parts manufacturer. While continuing to work …
Second Look at Coronary Angiography
Authors: Richard J. Mark
Journal: JAMA (1973)

Twenty-eight patients who had two or more coronary angiograms with no intervening surgical procedure were studied in order to evaluate natural progression of coronary artery disease. Various clinical and laboratory data were examined to determine if any of these factors would be helpful in predicting which patients would have an accelerated progression in their coronary lesions. In the criteria studied, no correlation was found. However, we found that progression can occur in as short an interval as five weeks, and that it does not always correlate with symptoms.
2 Adrenoceptor gene single nucleotide polymorphisms are associated with rheumatoid arthritis in northern Sweden
Authors: B-Y Xu
Journal: Annals of the Rheumatic Diseases (2004)

<b>Background:</b> β<sub>2</sub> Adrenoceptor (β<sub>2</sub>-AR) represents a link between the sympathetic nervous system and the immune system, and may be involved in human rheumatoid arthritis (RA). The gene encoding β<sub>2</sub>-AR contains three single nucleotide polymorphisms (SNPs) at amino acid positions 16, 27, and 164. <b>Objective:</b> To examine the common variants at positions 16 and 27 and their association with RA. <b>Methods:</b> An allele-specific polymerase chain reaction to determine the common variants at positions 16 and 27 was used in 154 patients with RA and 198 ethnically matched healthy subjects from northern Sweden. <b>Results:</b> Carriage of Arg16 and of Gln27 was associated with RA. Carriage of Gln27 was associated with activity of the disease and in combination with non-carriage of Arg16 with higher levels of rheumatoid factor. <b>Conclusion:</b> The β2-AR SNPs may thus constitute an additional non-major histocompatibility complex association in RA.
Effect of a 48-hour discontinuation of beta blockers before dobutamine atropine stress echocardiography on the occurrence of sustained arrhythmic events during the test
Authors: Benhalima Bouziane, Hamdaoui Brahim, Rahman Waheedur, Necib Inthidar, Piquet Valerie, Sahraie Hassan, Ziskind Bernard, Buoncuore Antoine, Cohen Ariel
Journal: Journal of the American College of Cardiology (2002)
Effects of a low-fat, high-carbohydrate diet on VLDL-triglyceride assembly, production, and clearance
Authors: Elizabeth J. Parks, Ronald M. Krauss, Mark P. Christiansen, Richard A. Neese, Marc K. Hellerstein
Journal: Journal of Clinical Investigation (1999)

Low-fat, high-carbohydrate (LF/HC) diets commonly elevate plasma triglyceride (TG) concentrations, but the kinetic mechanisms responsible for this effect remain uncertain. Subjects with low TG (normolipidemic [NL]) and those with moderately elevated TG (hypertriglyceridemic [HTG]) were studied on both a control and an LF/HC diet. We measured VLDL particle and TG transport rates, plasma nonesterified fatty acid (NEFA) flux, and sources of fatty acids used for the assembly of VLDL-TG. The LF/HC diet resulted in a 60% elevation in TG, a 37% reduction in VLDL-TG clearance, and an 18% reduction in whole-body fat oxidation, but no significant change in VLDL-apo B or VLDL-TG secretion rates. Significant elevations in fasting apo B-48 concentrations were observed on the LF/HC in HTG subjects. In both groups, fasting de novo lipogenesis was low regardless of diet. The NEFA pool contributed the great majority of fatty acids to VLDL-TG in NL subjects on both diets, whereas in HTG subjects, the contribution of NEFA was somewhat lower overall and was reduced further in individuals on the LF/HC diet. Between 13% and 29% of VLDL-TG fatty acids remained unaccounted for by the sum of de novo lipogenesis and plasma NEFA input in HTG subjects. We conclude that (a) whole-food LF/HC diets reduce VLDL-TG clearance and do not increase VLDL-TG secretion or de novo lipogenesis; (b) sources of fatty acids for assembly of VLDL-TG differ between HTG and NL subjects and are further affected by diet composition; (c) the presence of chylomicron remnants in the fasting state on LF/HC diets may contribute to elevated TG levels by competing for VLDL-TG lipolysis and by providing a source of fatty acids for hepatic VLDL-TG synthesis; and (d) the assembly, production, and clearance of elevated plasma VLDL-TG in response to LF/HC diets therefore differ from those for elevated TG on higher-fat diets.
Urinary Incontinence after Vaginal Delivery or Cesarean Section
Authors: Guri Rortveit, Anne Kjersti Daltveit, Yngvild S. Hannestad, Steinar Hunskaar
Journal: New England Journal of Medicine (2003)

It is uncertain whether women who deliver by cesarean section have an increased risk of urinary incontinence as compared with nulliparous women and whether women who deliver vaginally have an even higher risk.
Relationship between guideline treatment and health-related quality of life in asthma
Authors: L.G. Pont, T. van der Molen, P. Denig, G.T. van der Werf, F.M. Haaijer-Ruskamp
Journal: European Respiratory Journal (2004)

The aim of this study was to compare the health-related quality of life (HRQL) of asthma patients treated according to the 1997 National Institute of Health (NIH) international asthma guideline and that of asthmatics receiving non-guideline treatment. The suitability of 146 asthmatics9 medication regimes was determined according to the 1997 NIH asthma guideline. Quality of life was assessed on a seven-point scale using the Asthma Quality of Life questionnaire. Just over half of the patients were not currently using the treatment considered necessary for controlling their asthma. Patients treated according to the guideline (n=72) had a significantly higher overall HRQL than patients with non-guideline treatment (5.7 <i>versus</i> 5.3). The differences were also significant for the subscales measuring symptoms and environmental exposure, but not for activities or emotional function. An association between non-guideline treatment and a poorer health-related quality of life in asthma patients treated in general practice was observed. This study supports the role of evidence-based guidelines in daily practice. Further studies are needed to determine if guideline treatment is responsible for the increase in health-related quality of life observed in this work.
Measurement of functional recovery in individuals with acute anterior cruciate ligament rupture
Authors: K Button, R van Deursen, P Price
Journal: British Journal of Sports Medicine (2005)

To measure functional recovery following acute anterior cruciate ligament (ACL) rupture using a simple and reliable clinical movement analysis system. Clinic based methods that simultaneously quantify different aspects of movement over a range of activities and model functional recovery will help guide rehabilitation.A longitudinal study was used to measure gait variables at initial physiotherapy attendance and then at monthly intervals using a digital camcorder and computer for quantitative analysis. Jogging and distance hopping were added during recovery. A sample of 63 ACL deficient subjects entered the study and 48 subjects were measured at least three times. To determine the pattern of recovery, repeated measurements were analysed using a least square fit of the data.Gait variables took between 95 and 130 days post injury to reach the control mean and stabilise shortly after this. Hopping distance for the injured leg took 62 days to recover to within normal limits and 5 months post injury to reach the control mean. Jogging was already within the control limits at 30 days post injury and demonstrated little change with recovery.Functional recovery of multiple variables has been modelled. In the early phase of post injury, gait velocity seems to be the most useful variable to measure improvement. Recovery of more challenging activities appears to take an average of 5 months. Therefore, patients may need to be monitored in physiotherapy until this time and advised not to return to sport until sufficient recovery is demonstrated on activities such as distance hopping.
Microcyst Formation and HIV-1 Gene Expression Occur in Multiple Nephron Segments in HIV-Associated Nephropathy
Authors: Michael J. Ross, Leslie A. Bruggeman, Patricia D. Wilson, Paul E. Klotman
Journal: Journal of the American Society of Nephrology (2001)

ABSTRACT. Tubular microcyst formation is a prominent histopathologic feature of HIV-associated nephropathy (HIVAN), but its pathogenesis is unknown. HIV-1 has recently been shown to infect renal tubular epithelial cells in patients with HIVAN. In addition, HIV-1 gene expression in renal epithelial cells has been shown to cause a renal disease that is identical to HIVAN in HIV-1 transgenic mice. In these studies, immunohistochemistry for tubular segment-specific markers and mRNA in situ hybridization for HIV-1 was used to determine which tubular segments develop microcysts and which segments express HIV-1 in the kidneys of transgenic mice and patients with HIVAN. It was found that microcysts involve multiple nephron segments in both patients with HIVAN and HIV-1 transgenic mice. Furthermore, HIV-1 infection in HIVAN and HIV-1 transgene expression also occurs in multiple segments of the nephron. These data support a direct role for HIV-1 infection of renal epithelial cells in the pathogenesis of microcyst formation in patients with HIVAN.
Regulation of transforming growth factor expression in rat intestinal epithelial cell lines.
Authors: S Suemori, C Ciacci, D K Podolsky
Journal: Journal of Clinical Investigation (1991)

Autocrine and paracrine modulation of transforming growth factor expression was assessed in rat intestinal epithelial cell lines designated IEC-6 and IEC-7. Addition of the transforming growth factor alpha (TGF alpha) homologue epidermal growth factor (EGF) to media of subconfluent IEC-6 cells led to autocrine stimulation of TGF alpha expression as well as increased expression of the transforming growth factor beta 1 (TGF beta 1). Increased expression of TGF alpha was maximal between 3 and 6 h after addition of EGF and subsequently declined coincident with increasing level of expression of TGF beta 1, which achieved maximal levels 6 h after addition of EGF and was sustained for more than 12 h. Addition of TGF beta 1 also led to autocrine induction of its own expression coincident with suppression of TGF alpha expression. Addition of TGF beta 1 was associated with increased expression of beta-actin when standardized to a constitutive transcript (GAPDH). Similar responses to addition of EGF and TGF beta 1, were observed in another intestinal epithelial cell line, designated IEC-17. Modulation of expression of TGFs was attenuated when cells were grown on the complex extracellular matrix produced by the Engelbreth-Holm-Swarm tumor (Matrigel), reflecting the baseline induction of TGF beta 1 expression when compared to IEC-6 and IEC-17 cells maintained on plastic. These observations suggest that expression of TGFs is controlled by autocrine mechanisms in intestinal epithelial cell lines and proliferation stimulated by TGF alpha may be initially self-reinforcing but ultimately downregulated by induction of TGF beta 1.
Examination of transepithelial exchange of water and solute in the rat renal pelvis.
Authors: J Bargman, S L Leonard, E McNeely, C Robertson, R L Jamison
Journal: Journal of Clinical Investigation (1984)

Severance of the ureter beyond the renal papilla causes a fall in urinary osmolality, which suggests that exchange of water or solute between urine and renal parenchyma normally occurs in the intact renal pelvis. We examined water and solute flux in the renal pelvis with micropuncture and microcatheterization techniques. Four groups of antidiuretic rats were studied. Group I (n = 17) underwent micropuncture through the intact contracting ureter. Urine samples were obtained at the papillary tip, and in the pelvis beside the base of the extrarenal papilla. Urinary osmolality at the base, 880 +/- 97 mosmol/kg H2O (mean +/- SE), was less than that at the tip, 1,425 +/- 104 mosmol/kg H2O (P less than 0.005). In group II (n = 24), samples were analyzed for inulin and osmolality. In 15 rats (group IIA), comparison was made between base and tip samples. In the other nine animals (group IIB), comparisons were made among base, tip, and bladder samples and urea was also measured. In group II (A and B combined) urine-to-plasma (U/P) osmolality was lower at the base, 4.31 +/- 0.27, than at the tip, 6.08 +/- 0.23 (P less than 0.001), and U/P inulin was lower at the base, 192 +/- 25, than at the tip, 306 +/- 16 (P less than 0.001). In group IIB, the bladder urine had a lower U/P osmolality, 5.27 +/- 0.25, than the tip, 6.01 +/- 0.31 (P less than 0.02). The U/P urea was 59 +/- 10.6 (base), 98 +/- 9.4 (tip) (base vs. tip, P less than 0.05), and 81 +/- 6.5 (bladder, P less than 0.005, compared with tip). In group III (n = 8), samples were obtained by microcatheter from the fornices, the deepest intrarenal extensions of the pelvis, and compared with samples at the tip. Urinary osmolality was lower in the fornix, 646 +/- 106 mosmol/kg H2O, than at the tip, 1,296 +/- 99 mosmol/kg H2O (P less than 0.001). Similarly, U/P inulin was lower in the fornix, 48 +/- 14, than at the tip, 128 +/- 12 (P less than 0.001). The lower U/P inulin in the pelvic urine is the result of either the addition of fluid to the pelvis, or the backleak of inulin across the epithelium lining the pelvis. To verify that the pelvic epithelium was impermeable to inulin, in group IVA (n = 4) the left renal pelvis was superfused with a solution of chemical inulin. Cumulative absorption of inulin from the left kidney was 0.15 +/- 0.08% of that superfused. Using [14C]inulin in group IVB (n= 3), similar results were obtained (0.05 +/- 0.02%). These findings indicate that in the renal pelvis, fluid is added to urine after it emerges from the collecting ducts. We suggest that reflux of hyperosmotic urine over the renal papilla creates a transepithelial gradient for the flux of water into the pelvis. A model that incorporates diffusive and convective forces for water and solute transport is proposed to account for these findings.
Immediate Utility of Two Approved Agents to Target Both the Metabolic Mevalonate Pathway and Its Restorative Feedback Loop
Authors: Aleksandra Pandyra, Peter J. Mullen, Manpreet Kalkat, Rosemary Yu, Janice T. Pong, Zhihua Li, Suzanne Trudel, Karl S. Lang, Mark D. Minden, Aaron D. Schimmer, Linda Z. Penn
Journal: Cancer Research (2014)

New therapies are urgently needed for hematologic malignancies, especially in patients with relapsed acute myelogenous leukemia (AML) and multiple myeloma. We and others have previously shown that FDA-approved statins, which are used to control hypercholesterolemia and target the mevalonate pathway (MVA), can trigger tumor-selective apoptosis. Our goal was to identify other FDA-approved drugs that synergize with statins to further enhance the anticancer activity of statins in vivo. Using a screen composed of other FDA approved drugs, we identified dipyridamole, used for the prevention of cerebral ischemia, as a potentiator of statin anticancer activity. The statin-dipyridamole combination was synergistic and induced apoptosis in multiple myeloma and AML cell lines and primary patient samples, whereas normal peripheral blood mononuclear cells were not affected. This novel combination also decreased tumor growth in vivo. Statins block HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the MVA pathway. Dipyridamole blunted the feedback response, which upregulates HMGCR and HMG-CoA synthase 1 (HMGCS1) following statin treatment. We further show that dipyridamole inhibited the cleavage of the transcription factor required for this feedback regulation, sterol regulatory element-binding transcription factor 2 (SREBF2, SREBP2). Simultaneously targeting the MVA pathway and its restorative feedback loop is preclinically effective against hematologic malignancies. This work provides strong evidence for the immediate evaluation of this novel combination of FDA-approved drugs in clinical trials.
Pathogenesis of Abdominal Aortic Aneurysms: MicroRNAs, Proteases, Genetic Associations
Authors: Lars Maegdefessel, Ronald L. Dalman, Philip S. Tsao
Journal: Annual Review of Medicine (2013)

Abdominal aortic aneurysm (AAA) disease is a common, morbid, and highly lethal pathology. Extraordinary efforts have been launched to determine the molecular and pathophysiological characteristics of AAAs. Although surgery is highly effective in preventing death by rupture for larger AAAs, no guidance or preventive therapy is currently available for the &gt;90% of patients whose aneurysms are below the surgical threshold. Predictive animal models of AAA as well as human pathological samples have revealed a complex circuit of AAA formation and progression. The proteolytic destruction of matrix components of the aorta by different proteases has been extensively studied over many years. Recently, a novel class of small noncoding RNAs, called microRNAs, was identified as “fine-tuners” of the translational output of target genes; they act by promoting mRNA degradation. Their therapeutic potential in limiting AAA development appears very intriguing. Further, current studies assessing genetic and heritable associations for AAA disease have provided great insight into its pathogenesis, potentially enabling us to better clinically manage affected patients.
Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection
Authors: Mette D. Hazenberg, Sigrid A. Otto, James W.T. Cohen Stuart, Martie C.M. Verschuren, Jan C.C. Borleffs, Charles A.B. Boucher, Roel A. Coutinho, Joep M.A. Lange, Tobias F. Rinke de Wit, Aster Tsegaye, Jacques J.M. van Dongen, Dörte Hamann, Rob J. de Boer, Frank Miedema
Journal: Nature Medicine (2000)
Age, Breast Cancer Subtype Approximation, and Local Recurrence After Breast-Conserving Therapy
Authors: Nils D. Arvold, Alphonse G. Taghian, Andrzej Niemierko, Rita F. Abi Raad, Meera Sreedhara, Paul L. Nguyen, Jennifer R. Bellon, Julia S. Wong, Barbara L. Smith, Jay R. Harris
Journal: Journal of Clinical Oncology (2011)

Prior results of breast-conserving therapy (BCT) have shown substantial rates of local recurrence (LR) in young patients with breast cancer (BC).We studied 1,434 consecutive patients with invasive BC who received BCT from December 1997 to July 2006. Ninety-one percent received adjuvant systemic therapy; no patients received trastuzumab. Five BC subtypes were approximated: estrogen receptor (ER) or progesterone receptor (PR) positive, HER2 negative, and grades 1 to 2 (ie, luminal A); ER positive or PR positive, HER2 negative, and grade 3 (ie, luminal B); ER or PR positive, and HER2 positive (ie, luminal HER2); ER negative, PR negative, and HER2 positive (ie, HER2); and ER negative, PR negative, and HER2 negative (ie, triple negative). Actuarial rates of LR were calculated by using the Kaplan-Meier method.Median follow-up was 85 months. Overall 5-year cumulative incidence of LR was 2.1% (95% CI, 1.4% to 3.0%). The 5-year cumulative incidence of LR was 5.0% (95% CI, 3.0% to 8.3%) for age quartile 23 to 46 years; 2.2% (95% CI, 1.0% to 4.6%) for ages 47 to 54 years; 0.9% (95% CI, 0.3% to 2.6%) for ages 55 to 63 years; and 0.6% (95% CI, 0.1% to 2.2%) for ages 64 to 88 years. The 5-year cumulative incidence of LR was 0.8% (95% CI, 0.4% to 1.8%) for luminal A; 2.3% (95% CI, 0.8% to 5.9%) for luminal B; 1.1% (95% CI, 0.2% 7.4%) for luminal HER2; 10.8% (95% CI, 4.6% to 24.4%) for HER2; and 6.7% (95% CI, 3.6% to 12.2%) for triple negative. On multivariable analysis, increasing age was associated with decreased risk of LR (adjusted hazard ratio, 0.97; 95% CI, 0.94 to 0.99; P = .009).In the era of systemic therapy and BC subtyping, age remains an independent prognostic factor after BCT. However, the risk of LR for young women appears acceptably low.