tbuckley/cabot-search huggingface dataset:
Levothyroxine dose and risk of fractures in older adults: nested case-control study
Authors: M. R. Turner, X. Camacho, H. D. Fischer, P. C. Austin, G. M. Anderson, P. A. Rochon, L. L. Lipscombe
Journal: BMJ (2011)

<b>Objective</b> To quantify the effect of levothyroxine dose on risk of fractures in older adults. <b>Design</b> Nested case-control study. <b>Setting</b> Population based health databases, Ontario, Canada. <b>Participants</b> Adults aged 70 or more prescribed levothyroxine between 1 April 2002 and 31 March 2007 and followed for fractures until 31 March 2008. Cases were cohort members admitted to hospital for any fracture, matched with up to five controls from within the cohort who had not yet had a fracture. <b>Main outcome measure</b> Primary outcome was fracture (wrist or forearm, shoulder or upper arm, thoracic spine, lumbar spine and pelvis, hip or femur, or lower leg or ankle) in relation to levothyroxine use (current, recent past, remote). Risk among current users was compared between those prescribed high, medium, and low cumulative levothyroxine doses in the year before fracture. <b>Results</b> Of 213 511 prevalent levothyroxine users identified, 22 236 (10.4%) experienced a fracture over a mean 3.8 years of follow-up, 18 108 (88%) of whom were women. Compared with remote levothyroxine use, current use was associated with a significantly higher risk of fracture (adjusted odds ratio 1.88, 95% confidence interval 1.71 to 2.05), despite adjustment for numerous risk factors. Among current users, high and medium cumulative doses (&gt;0.093 mg/day and 0.044-0.093 mg/day) were associated with a significantly increased risk of fracture compared with low cumulative doses (&lt;0.044 mg/day): 3.45 (3.27 to 3.65) and 2.62 (2.50 to 2.76), respectively. <b>Conclusion</b> Among adults aged 70 or more, current levothyroxine treatment was associated with a significantly increased risk of fracture, with a strong dose-response relation. Ongoing monitoring of levothyroxine dose is important to avoid overtreatment in this population.
Long term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid arthritis: ARMADA 4 year extended study
Authors: M E Weinblatt
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To evaluate the efficacy and safety of adalimumab plus methotrexate (MTX) given for up to 4 years in patients with active, longstanding rheumatoid arthritis. <b>Methods:</b> Patients responding inadequately to MTX were entered into a 24 week, controlled study (ARMADA) with adalimumab plus MTX or placebo plus MTX, and some were enrolled in a subsequent open label extension. The efficacy and safety of treatment were evaluated. Additional analyses were made for those patients whose corticosteroid and/or MTX dosages were adjusted during the extension. <b>Results:</b> Of 271 patients in the original ARMADA trial, 262 received at least one dose of adalimumab and were evaluated. At the time of analysis, 162/262 (62%) patients had remained in the study and received treatment for a mean of 3.4 years. Withdrawals were for lack of efficacy (8%), adverse events (12%), and other reasons (18%). In 147 patients who completed 4 years' treatment, efficacy achieved at 6 months was maintained. At 4 years, 78%, 57%, and 31% had achieved ACR20/50/70; 43% achieved clinical remission (DAS28 &lt;2.6); and 22% had no physical function abnormalities (HAQ = 0). Results were similar for 196 patients who received treatment for 2–4 years. Efficacy was maintained in many patients when dosages were decreased (corticosteroids (51/81 (63%) patients), MTX (92/217 (42%)), or both (25/217 (12%))). Serious adverse events were comparable during open label treatment and the controlled phase. Serious infections occurring during open label treatment and the blinded period were similar (2.03 <i>v</i> 2.30 events per 100 patient-years, respectively). <b>Conclusions:</b> Adalimumab plus MTX sustained clinical response and remission in patients with RA during 4 years. The safety profile during the first 6 months was similar to that after 4 years' follow up. Reduction of corticosteroid and/or MTX dosages did not adversely affect long term efficacy.
Modulation by the thyroid state of intracellular calcium and contractility in ferret ventricular muscle.
Authors: R MacKinnon, J K Gwathmey, P D Allen, G M Briggs, J P Morgan
Journal: Circulation Research (1988)

The purpose of this study was to determine whether the cardiac contractile abnormalities induced by hyperthyroidism or hypothyroidism are caused by changes in intracellular Ca2+ handling or by alterations in the distribution of isoenzymes of ventricular myosin. Right ventricular papillary muscles obtained from euthyroid ferrets and ferrets treated with L-thyroxine (hyperthyroid) or methimazole (hypothyroid) were loaded with the calcium indicator aequorin for recording intracellular Ca2+ levels during isometric contraction. In muscles from the hypothyroid ferrets, peak tension was reduced and the duration of contraction prolonged compared to the controls; these changes were associated with a Ca2+ transient of decreased amplitude and prolonged duration. Hyperthyroidism produced opposite changes in the time course of the Ca2+ transient and the associated isometric contraction. Native polyacrylamide gel electrophoresis was performed on myosin extracted from the right ventricular free wall of control and treated ferrets. The hyperthyroid state was associated with new myosin formation as indicated by the appearance of three myosin bands on the pyrophosphate gel. Gels of myosin from hypothyroid and euthyroid ferrets showed a single band that migrated with the slowest of the three bands from the hyperthyroid ferrets. These results suggest that changes in both Ca2+ handling and myosin isoenzymes may contribute to the contractile abnormalities observed in hyperthyroidism. Alterations in intracellular Ca2+ handling alone may account for the contractile changes induced by hypothyroidism.
Human Papillomaviruses As Therapeutic Targets in Human Cancer
Authors: Karin Hellner, Karl Münger
Journal: Journal of Clinical Oncology (2011)

Cervical carcinomas are almost universally associated with high-risk human papillomavirus (HPV) infections, and are a leading cause of cancer death in women worldwide. HPV oncoproteins contribute to cancer initiation and progression and their expression is necessary for the maintenance of the transformed state. The fact that the initiating oncogenic insult, infection with a high-risk HPV and viral oncoprotein expression, is common to almost all cervical cancers offers unique opportunities for prevention, early detection, and therapy. The potential for prevention has been realized by introduction of prophylactic vaccines that are to prevent transmission of specific high-risk HPVs. Given, however, that these vaccines have no therapeutic efficacy and HPV-associated cervical cancers arise years if not decades after the initial infection, it has been estimated that there will be no measurable decline of HPV-associated tumors before 2040. Cervical cancer alone will be diagnosed in more than 375,000 US women between now and 2040. Other HPV-associated anogenital and head and neck cancers are predicted to afflict another 700,000 men and women over this time period. Hence, therapeutic efforts to combat high-risk HPV-associated disease remain of critical importance.
The phenotype and genotype of adult obstructive sleep apnoea/hypopnoea syndrome
Authors: R L Riha, T Gislasson, K Diefenbach
Journal: European Respiratory Journal (2009)

Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is a common condition affecting ∼2–4% of the middle-aged population. A hereditary component to the condition has long been recognised but its genetic basis has been difficult to elucidate. Progress in determining the genotype of OSAHS is hampered by the lack of a consistent definition of phenotype and the large environmental influences on its expression. “Intermediate phenotypes”, such as craniofacial structure, obesity and upper airway control, have been utilised. Multiple gene polymorphisms have been explored in association with the latter, as well as with the sequelae of OSAHS, such as hypertension and increased insulin resistance. To date, two genome-wide scans have identified potential regions that may be of interest in further defining the intermediate phenotypes. The present paper focuses on human studies with an update of the most recent work in the area, including a short discussion on methods of genetic studies.
The doctor--patient relationship in US primary care
Authors: Pam Lings, Philip Evans, David Seamark, Clare Seamark, Kieran Sweeney, Michael Dixon, Denis Pereira Gray
Journal: Journal of the Royal Society of Medicine (2003)

Changes in the organization of primary care in the UK are driven by a need to improve access and availability, but doctor-patient relationships may suffer. To investigate the importance of such relationships in a different setting, we analysed focus-group data obtained in a primary care facility in the USA (Rochester, NY). The findings pointed to three key factors in these relationships-namely, an asymmetry of perceptions on the two sides, belying the notion of a meeting of experts; the importance on both sides of 'liking'; and the value set by both parties on development of trust. The last two of these factors are probably related to continuity of care, now under threat.
Fixed ratio or lower limit of normal for the FEV1/VC ratio: Relation to symptoms and extended lung function tests
Authors: Sophia Frantz, Per Wollmer, Gunnar Engström, Magnus Dencker, Claes-Göran Löfdahl, Ulf Nihlén
Journal: European Respiratory Journal (2013)

There is no generally accepted agreement on the spirometric definition of chronic obstructive pulmonary disease (COPD). A fixed ratio FEV1/VC <0.7 (FR) or a use of the age-related lower limit of normal for FEV1/VC (LLN) are the most common definitions. We analysed respiratory symptoms and extensive lung function in groups of subjects fulfilling none, either or both of the spirometric criteria for COPD.

The study population comprised 450 subjects from a random population sample, who answered a questionnaire on respiratory symptom, underwent spirometry, body plethysmography, measurements of pulmonary reactance (AX) and diffusing capacity for CO (DL,CO).

Results:

View this table:

Symptoms and lung function





For symptoms, there was a significant (p<0.05) difference between groups.

For FEV1, RV/TLC and DL,CO there was a significant difference between FR+LLN+ and FR+ and between FR+ and normal ever-smokers.

Conlusion: Subjects with FEV1/VC LLN.
Tumor Microenvironment of Metastasis in Human Breast Carcinoma: A Potential Prognostic Marker Linked to Hematogenous Dissemination
Authors: Brian D. Robinson, Gabriel L. Sica, Yi-Fang Liu, Thomas E. Rohan, Frank B. Gertler, John S. Condeelis, Joan G. Jones
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Multiphoton-based intravital imaging has shown that invasive carcinoma cells in mouse and rat mammary tumors intravasate when associated with perivascular macrophages, identifying a potential tumor microenvironment of metastasis (TMEM). We define TMEM as the tripartite arrangement of an invasive carcinoma cell, a macrophage, and an endothelial cell. The aim of this study was to determine if TMEM density in human breast carcinoma samples predicts the development of systemic, hematogenous metastases. Experimental Design: A case-control study of 30 patients who developed metastatic breast cancer and 30 patients without metastatic disease was done. Cases were matched to controls based on currently used prognostic criteria. Paraffin-embedded primary breast cancer samples were stained using a triple immunohistochemical method allowing simultaneous identification of carcinoma cells, macrophages, and endothelial cells. Two pathologists, blinded to outcome, evaluated the number of TMEM per 20 high-power fields. Results: No association was seen between TMEM density and tumor size or grade, lymph node metastasis, lymphovascular invasion, or hormone receptor status. TMEM density was greater in the group of patients who developed systemic metastases compared with the patients with only localized breast cancer (median, 105 versus 50, respectively; P = 0.00006). For every 10-unit increase in TMEM density, the odds ratio for systemic metastasis was 1.9 (95% confidence interval, 1.1-3.4). Conclusions: TMEM density predicted the development of systemic, hematogenous metastases. The ability of TMEM to predict distant metastasis was independent of lymph node status and other currently used prognosticators. Quantitation of TMEM may be a useful new prognostic marker for breast cancer patients.
Costimulation improves the killing capability of T cells redirected to tumor cells expressing low levels of CD33: description of a novel modular targeting system
Authors: C Arndt, A Feldmann, M von Bonin, M Cartellieri, E-M Ewen, S Koristka, I Michalk, S Stamova, N Berndt, A Gocht, M Bornhäuser, G Ehninger, M Schmitz, M Bachmann
Journal: Leukemia (2013)
Inhibitory Effect of Silibinin against Azoxymethane-Induced Colon Tumorigenesis in A/J Mice
Authors: Kameswaran Ravichandran, Balaiya Velmurugan, Mallikarjuna Gu, Rana P. Singh, Rajesh Agarwal
Journal: Clinical Cancer Research (2010)

Colorectal cancer is the second leading cause of cancer-associated deaths, which suggests that more effort is needed to prevent/control this disease. Herein, for the first time, we investigate in vivo the efficacy of silibinin against azoxymethane-induced colon tumorigenesis in A/J mice.Five-week-old male mice were gavaged with vehicle or silibinin (250 and 750 mg/kg) for 25 weeks starting 2 weeks before initiation with azoxymethane (pretreatment regime) or for 16 weeks starting 2 weeks after the last azoxymethane injection (posttreatment regime). The mice were then sacrificed, and colon tissues were examined for tumor multiplicity and size, and molecular markers for proliferation, apoptosis, inflammation, and angiogenesis.Silibinin feeding showed a dose-dependent decrease in azoxymethane-induced colon tumorigenesis with stronger efficacy in pretreatment versus posttreatment regimen. Mechanistic studies in tissue samples showed that silibinin inhibits cell proliferation as evident by a decrease (P < 0.001) in proliferating cell nuclear antigen and cyclin D1, and increased Cip1/p21 levels. Silibinin also decreased (P < 0.001) the levels of inducible nitric oxide synthase, cyclooxygenase-2, and vascular endothelial growth factor, suggesting its anti-inflammatory and antiangiogenic potential in this model. Further, silibinin increased cleaved caspase-3 and poly(ADP-ribose) polymerase levels, indicating its apoptotic effect. In other studies, colonic mucosa and tumors expressed high levels of β-catenin, insulin-like growth factor-1 receptorβ, phospho Glycogen synthase kinase-3β, and phospho protein kinase B/pAkt proteins in azoxymethane-treated mice, which were strongly lowered (P < 0.001) by silibinin treatment. Moreover, azoxymethane reduced insulin-like growth factor binding protein-3 protein level, which was enhanced by silibinin.Silibinin targets β-catenin and IGF-1Rβ pathways for its chemopreventive efficacy against azoxymethane-induced colon carcinogenesis in A/J mice. Overall, these results support the translational potential of silibinin in colorectal cancer chemoprevention.
ABO Blood Group, Helicobacter pylori Seropositivity, and Risk of Pancreatic Cancer: A Case-Control Study
Authors: H. A. Risch, H. Yu, L. Lu, M. S. Kidd
Journal: JNCI Journal of the National Cancer Institute (2010)

Carriage of a non–O ABO blood group and colonization by Helicobacter pylori are thought to be risk factors for pancreatic cancer. We examined these associations in a population-based case–control study of 373 case patients and 690 control subjects frequency matched on sex and age. Control subjects were selected by random-digit dialing. Seropositivity for H pylori and its virulence protein CagA was determined by enzyme-linked immunosorbent assay (ELISA). Increased risk of pancreatic cancer was associated with non–O blood group (adjusted odds ratio [OR] = 1.37, 95% confidence interval [CI] = 1.02 to 1.83, P = .034) and CagA-negative H pylori seropositivity (OR = 1.68, 95% CI = 1.07 to 2.66, P = .025), but no association was observed for CagA seropositivity (OR = 0.77, 95% CI = 0.52 to 1.16). An association between pancreatic cancer risk and CagA-negative H pylori seropositivity was found among individuals with non–O blood type but not among those with O blood type (OR = 2.78, 95% CI = 1.49 to 5.20, P = .0014; OR = 1.28, 95% CI = 0.62 to 2.64, P = .51, respectively). This study demonstrates an association between pancreatic cancer and H pylori colonization, particularly for individuals with non–O blood types.
Visual Attention Circuitry in Schizophrenia Investigated With Oddball Event-Related Functional Magnetic Resonance Imaging
Authors: Raquel E. Gur, Bruce I. Turetsky, James Loughead, Wendy Snyder, Christian Kohler, Mark Elliott, Ramapriyan Pratiwadi, J. Daniel Ragland, Warren B. Bilker, Steven J. Siegel, Stephen J. Kanes, Steven E. Arnold, Ruben C. Gur
Journal: American Journal of Psychiatry (2007)

Objective: Schizophrenia patients have problems directing attention. Sustained attention requires ensuring that brain resources are focused on a selected target (top-down task) while ignoring irrelevant distractors (bottom-up interference). Whether patients have too little ability to focus or too much interference from distraction has not been clarified. The oddball paradigm embeds infrequent targets and distractors into the stimulus train, and schizophrenia deficits have been linked to diminished responses to both. Cerebral activity underlying abnormal attention can be examined with event-related functional magnetic resonance imaging. Method: A visual oddball task was presented to 22 patients with schizophrenia and 28 comparison subjects. Statistical probability maps reflecting blood-oxygenation-level-dependent changes were generated for infrequent targets and novel distractors relative to frequent standard stimuli. Activation was related to performance and symptoms. Results: Activation specific to targets and distractors was associated with faster performance. For targets, patients had diminished activation in superior temporal and frontal gyri, cingulate, thalamus, and basal ganglia. They had increased activation in right insula, mid-frontal gyrus, posterior cingulate, and left inferior parietal lobule. For distractors, patients showed less activation in occipital regions and left inferior parietal lobule but increased activation in parietal-occipital, right mid-frontal, and left inferior frontal gyri. Abnormal activation correlated with positive and negative symptoms. Conclusions: Abnormal activation in schizophrenia in response to attentional demands reflects both insufficient recruitment of brain systems required for target detection and overcommitment of resources for processing irrelevant distractors. Schizophrenia patients appear to have an inability both to focus on targets and ignore distraction.
Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach
Authors: C Manichanh
Journal: Gut (2005)

<b>Background and aim:</b> A role for the intestinal microbial community (microbiota) in the onset and chronicity of Crohn's disease (CD) is strongly suspected. However, investigation of such a complex ecosystem is difficult, even with culture independent molecular approaches. <b>Methods:</b> We used, for the first time, a comprehensive metagenomic approach to investigate the full range of intestinal microbial diversity. We used a fosmid vector to construct two libraries of genomic DNA isolated directly from faecal samples of six healthy donors and six patients with CD. Bacterial diversity was analysed by screening the two DNA libraries, each composed of 25 000 clones, for the 16S rRNA gene by DNA hybridisation. <b>Results:</b> Among 1190 selected clones, we identified 125 non-redundant ribotypes mainly represented by the phyla Bacteroidetes and Firmicutes. Among the Firmicutes, 43 distinct ribotypes were identified in the healthy microbiota, compared with only 13 in CD (p&lt;0.025). Fluorescent in situ hybridisation directly targeting 16S rRNA in faecal samples analysed individually (n = 12) confirmed the significant reduction in the proportion of bacteria belonging to this phylum in CD patients (p&lt;0.02). <b>Conclusion:</b> The metagenomic approach allowed us to detect a reduced complexity of the bacterial phylum Firmicutes as a signature of the faecal microbiota in patients with CD. It also indicated the presence of new bacterial species.
Japanese β°-thalassemia: Molecular characterization of a novel insertion causing a stop codon
Authors: Kazuko Oshima, Teruo Harano, Keiko Harano
Journal: American Journal of Hematology (1996)

During a physical checkup, a 42-year-old Japanese man with liver dysfunction was diagnosed as having beta-thalassemia. Using molecular biological techniques including PCR, we investigated the chemical basis of the hematological disorder. We found that a frameshift attributable to the insertion of a thymidine into or following the TTT sequence of codon 42 transformed codon 43 (GAG) into a stop codon (TGA). We believe that this mutation has not been previously reported.
Parent Reports of Quality of Life for Pediatric Patients With Cancer With No Realistic Chance of Cure
Authors: Deborah Tomlinson, Pamela S. Hinds, Ute Bartels, Eleanor Hendershot, Lillian Sung
Journal: Journal of Clinical Oncology (2011)

Purpose To compare quality of life of children with cancer with no reasonable chance of cure reported by parents 6 months or fewer versus more than 6 months before death. Patients and Methods This cross-sectional study included children between the ages of 2 and 18 years with cancer and no reasonable chance of cure at The Hospital for Sick Children, Toronto, Ontario, Canada. Parents reported quality of life on behalf of their children. Outcomes were the PedsQL 4.0 Generic Core Scales, Acute Cancer Module, and Multidimensional Fatigue Scale. Results Seventy-three parents of children participated. Compared with children who survived more than 6 months (n = 43), those who died at 6 months or fewer (n = 30) had significantly worse physical health (mean difference, 15.9; 95% CI, 1.8 to 30.0; P = .028), more pain and hurt (mean difference, 15.5; 95% CI, 0.9 to 30.0; P = .037), and worse general fatigue (mean difference, 15.8; 95% CI, 2.4 to 29.1; P = .021) and sleep/rest fatigue (mean difference, 16.0; 95% CI, 3.5 to 28.5; P = .013). Among the entire cohort, those with leukemia/lymphoma had worse physical and psychosocial quality of life compared with those with solid or brain tumors. Recent stem-cell transplantation was associated with worse psychosocial health. Conclusion Parents of children with cancer reported worse physical health, pain, and fatigue proximal to death. Those with leukemia/lymphoma were at higher risk for impaired quality of life. This knowledge can help in the design of targeted interventions to improve quality of life for children dying as a result of cancer.