tbuckley/cabot-search huggingface dataset:
Does antibiotic treatment increase bacterial virulence in cystic fibrosis?
Authors: A de-Soyza
Journal: Thorax (2005)

<h3>SUMMARY:</h3> Neuroimaging plays a critical role in the evaluation of patients with traumatic brain injury, with NCCT as the first-line of imaging for patients with traumatic brain injury and MR imaging being recommended in specific settings. Advanced neuroimaging techniques, including MR imaging DTI, blood oxygen level\Ndependent fMRI, MR spectroscopy, perfusion imaging, PET/SPECT, and magnetoencephalography, are of particular interest in identifying further injury in patients with traumatic brain injury when conventional NCCT and MR imaging findings are normal, as well as for prognostication in patients with persistent symptoms. These advanced neuroimaging techniques are currently under investigation in an attempt to optimize them and substantiate their clinical relevance in individual patients. However, the data currently available confine their use to the research arena for group comparisons, and there remains insufficient evidence at the time of this writing to conclude that these advanced techniques can be used for routine clinical use at the individual patient level. TBI imaging is a rapidly evolving field, and a number of the recommendations presented will be updated in the future to reflect the advances in medical knowledge.
Immobilisation causes longlasting matrix changes both in the immobilised and contralateral joint cartilage
Authors: M. O Jortikka, R. I Inkinen, M. I Tammi, J. J Parkkinen, J. Haapala, I. Kiviranta, H. J Helminen, M. J Lammi
Journal: Annals of the Rheumatic Diseases (1997)

<h3>OBJECTIVE</h3> The capacity of articular cartilage matrix to recover during 50 weeks of remobilisation after an atrophy caused by 11 weeks of immobilisation of the knee (stifle) joint in 90° flexion starting at the age of 29 weeks, was studied in young beagle dogs. <h3>METHODS</h3> Proteoglycan concentration (uronic acid) and synthesis ([<sup>35</sup>S]sulphate incorporation) were determined in six and three knee joint surface locations, respectively. Proteoglycans extracted from the cartilages were characterised by chemical determinations, gel filtration, and western blotting for chondroitin sulphate epitope 3B3. <h3>RESULTS</h3> The proteoglycan concentrations that were reduced in all sample sites immediately after the immobilisation, remained 14-28% lower than controls after 50 weeks of remobilisation in the patella, the summit of medial femoral condyle, and the superior femoropatellar surface. In the contralateral joint, there was a 49% increase of proteoglycans in the inferior femoropatellar surface after remobilisation, while a 34% decrease was simultaneously noticed on the summit of the medial femoral condyle. Total proteoglycan synthesis was not significantly changed after immobilisation or 50 weeks' remobilisation in the treated or contralateral joint, compared with age matched controls. The chondroitin 6- to 4- sulphate ratio was reduced by immobilisation both in the radioactively labelled and the total tissue proteoglycans. In the remobilised joint, this ratio was restored in femur, while in tibia it remained at a level lower than controls. Neither immobilisation nor remobilisation induced epitopes recognised by the monoclonal antibody 3B3 on native (undigested) proteoglycans. <h3>CONCLUSION</h3> These results show that the depletion of proteoglycans observed after 11 weeks of immobilisation was not completely restored in certain surface sites after 50 weeks of remobilisation. The significant changes that developed in the contralateral joint during the remobilisation period give further support to the idea that a permanent alteration of matrix metabolism results even from a temporary modification of loading pattern in immature joints.
NF-κB regulation of endothelial cell function during LPS-induced toxemia and cancer
Authors: Tatiana Kisseleva, Li Song, Marina Vorontchikhina, Nikki Feirt, Jan Kitajewski, Christian Schindler
Journal: Journal of Clinical Investigation (2006)

The transcription factor NF-kappaB is an important regulator of homeostatic growth and inflammation. Although gene-targeting studies have revealed important roles for NF-kappaB, they have been complicated by component redundancy and lethal phenotypes. To examine the role of NF-kappaB in endothelial tissues, Tie2 promoter/enhancer-IkappaBalpha(S32A/S36A) transgenic mice were generated. These mice grew normally but exhibited enhanced sensitivity to LPS-induced toxemia, notable for an increase in vascular permeability and apoptosis. Moreover, B16-BL6 tumors grew significantly more aggressively in transgenic mice, underscoring a new role for NF-kappaB in the homeostatic response to cancer. Tumor vasculature in transgenic mice was extensive and disorganized. This correlated with a marked loss in tight junction formation and suggests that NF-kappaB plays an important role in the maintenance of vascular integrity and response to stress.
Early aging in adult survivors of childhood medulloblastoma: long-term neurocognitive, functional, and physical outcomes
Authors: K. Edelstein, B. J. Spiegler, S. Fung, T. Panzarella, D. J. Mabbott, N. Jewitt, N. M. D'Agostino, W. P. Mason, E. Bouffet, U. Tabori, N. Laperriere, D. C. Hodgson
Journal: Neuro-Oncology (2011)

Treatment for medulloblastoma during childhood impairs neurocognitive function in survivors. While those diagnosed at younger ages are most vulnerable, little is known about the long-term neurocognitive, functional, and physical outcomes in survivors as they approach middle age. In this retrospective cohort study, we assessed 20 adults who were treated with surgery and radiotherapy for medulloblastoma during childhood (median age at assessment, 21.9 years [range, 18–47 years]; median time since diagnosis, 15.5 years [range, 6.5–42.2 years]). Nine patients also underwent chemotherapy. Cross-sectional analyses of current neurocognitive, functional, and physical status were conducted. Data from prior neuropsychological assessments were available for 18 subjects; longitudinal analyses were used to model individual change over time for those subjects. The group was well below average across multiple neurocognitive domains, and 90% had required accommodations at school for learning disorders. Longer time since diagnosis, but not age at diagnosis, was associated with continued decline in working memory, a common sign of aging. Younger age at diagnosis was associated with lower intelligence quotient and academic achievement scores, even many years after treatment had been completed. The most common health complications in survivors were hearing impairment, second cancers, diabetes, hypertension, and endocrine deficiencies. Adult survivors of childhood medulloblastoma exhibit signs of early aging regardless of how young they were at diagnosis. As survival rates for brain tumors continue to improve, these neurocognitive and physical sequelae may become evident in survivors diagnosed at different ages across the lifespan. It will become increasingly important to identify factors that contribute to risk and resilience in this growing population.
Bradykinin and asthma.
Authors: P J Barnes
Journal: Thorax (1992)

Many mediators have been implicated in the pathophysiology of asthma'2 but the role of individual mediators will become apparent only with the use of potent and selective antagonists or synthesis of inhibitors, which are now becoming available for many mediators.Bradykinin has long been con- sidered to be a mediator concerned in asthma, since the first demonstration of bronchocon- striction after inhaled bradykinin in asthmatic patients.3The recent development of potent bradykinin receptor antagonists' has raised questions about the role of bradykinin in the pathophysiology of asthma and the potential of bradykinin antagonists in the treatment of asthma.
CELL-TO-CELL INTERACTION IN THE IMMUNE RESPONSE
Authors: J. F. A. P. Miller, J. Sprent
Journal: The Journal of Experimental Medicine (1971)

Collaboration between thymus-derived lymphocytes and nonthymus-derived antibody-forming cell precursors occurs in the primary antibody response of mice to heterologous erythrocytes and serum proteins. The purpose of the experiments reported here was to determine whether collaboration took place in an adoptive secondary antibody response. A chimeric population of lymphocytes was produced by reconstituting neonatally thymectomized CBA mice soon after birth with (CBA x C57BL)F(1) thymus lymphocytes. These mice could be effectively primed to fowl immunoglobulin G (FgammaG) and their thoracic duct lymphocytes adoptively transferred memory responses to irradiated mice. The activity of these cells was impaired markedly by preincubation with CBA anti-C57BL serum and to a lesser extent by anti-theta-serum. Reversal of this deficiency was obtained by adding T cells in the form of thoracic duct cells from normal CBA mice. Cells from FgammaG-primed mice were at least 10 times as effective as cells from normal mice or from CBA mice primed to horse erythrocytes. These results were considered to support the concept that memory resides in the T cell population and that collaboration between T and B cells is necessary for an optimal secondary antibody response. Poor antibody responses were obtained in irradiated mice given mixtures of thoracic duct cells from primed mice and of B cells from unprimed mice (in the form of spleen or thoracic duct cells from thymectomized donors). In contrast to the situation with T cells, the deficiency in the B cell population could not be reversed by adding B cells from unprimed mice. It was considered that memory resides in B cells as well as in T cells and that priming probably entails a change in the B cell population which is fundamentally different from that produced in the T cell population.
HLA-B27 associated spondyloarthropathy, an autoimmune disease based on crossreactivity between bacteria and HLA-B27?
Authors: J H Ringrose
Journal: Annals of the Rheumatic Diseases (1999)

Most autoimmune diseases are associated with certain HLA types. Therefore, spondyloarthropathies (SpA) strongly associated with HLA-B27, are also often classified as autoimmune diseases. This study questions whether SpA indeed fulfils the criteria of an autoimmune disease. The Medline database was searched for all reports between 1966 and April 1998 on the presence of autoimmune reactivity in SpA patients. This search yielded 45 articles on this subject. Only eight articles study T cell reactivity. Twelve reports were found on the assessment of antibodies crossreacting between bacteria and HLA-B27. In the 45 studies demonstrating autoimmune reactions in SpA patients proper controls matched for HLA-B27, sex and age were nearly always lacking. Therefore, it is concluded that the frequency of increased autoreactivity in sera from patients and controls is not significantly different, and that this lack of autoreactivity does not justify classification of SpA as an autoimmune disease. As crossreactive antibodies against bacteria and HLA-B27 were equally present in sera from patients and controls, the pathogenetic significance of molecular mimicry between various bacteria and HLA-B27 is questionable. Furthermore, the regions of the B27 molecule that are supposed to be crossreactive with bacteria, differ in one or more amino acids among the distinct B27 subtypes. Although these differences strongly influence the binding of antibodies to the B27 molecule, there was no relation between the degree of crossreactivity of certain subtypes and the association of these subtypes with SpA. In conclusion, there is no evident proof that SpA is an autoimmune disease attributable to crossreactivity between bacteria and HLA-B27.
Biochemical and Genetic Association of Plasma Apolipoprotein A-II Levels With Familial Combined Hyperlipidemia
Authors: Hooman Allayee, Lawrence W. Castellani, Rita M. Cantor, Tjerk W.A. de Bruin, Aldons J. Lusis
Journal: Circulation Research (2003)

Apolipoprotein A-II (apoA-II) is a major protein on high-density lipoprotein (HDL) particles, and in mice, its levels are associated with triglyceride and glucose metabolism. In particular, transgenic mice overexpressing apoA-II exhibit hypertriglyceridemia, increased body fat, and insulin resistance, whereas apoA-II-null mice have decreased triglycerides and increased insulin sensitivity. Given the phenotypic overlap between familial combined hyperlipidemia (FCH) and apoA-II transgenic mice, we investigated the relationship of apoA-II to this disorder. Despite having lower HDL-cholesterol (HDL-C), FCH subjects had higher apoA-II levels compared with unaffected relatives (P<0.00016). Triglyceride and HDL-C levels were significant predictors of apoA-II, demonstrating that apoA-II variation is associated with several FCH-related traits. After adjustment for multiple covariates, there was evidence for the heritability of apoA-II levels (h2=0.15; P<0.02) in this sample. A genome scan for apoA-II levels identified significant evidence (LOD=3.1) for linkage to a locus on chromosome 1q41, coincident with a suggestive linkage for triglycerides (LOD score=1.4). Thus, this locus may have pleiotropic effects on apoA-II and FCH traits. Our results demonstrate that apoA-II is biochemically and genetically associated with FCH and may serve as a useful marker for understanding the mechanism by which FCH develops.
Identification of Polo-like Kinase 1 as a Potential Therapeutic Target in Anaplastic Thyroid Carcinoma
Authors: Tito Claudio Nappi, Paolo Salerno, Horst Zitzelsberger, Francesca Carlomagno, Giuliana Salvatore, Massimo Santoro
Journal: Cancer Research (2009)

Abstract Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and chemoresistant cancers. The serine/threonine kinase Polo-like kinase 1 (PLK1), a key regulator of multiple steps during mitotic progression, is highly expressed in ATC. Here, we used the BI 2536 PLK1 inhibitor on ATC and nontransformed thyroid follicular cell lines. Our data show that ATC cells are addicted to high levels of PLK1 activity for proliferation, survival, anchorage-independent growth, and tumorigenicity. On treatment with nanomolar doses of BI 2536, ATC cells progressed normally through S phase but died thereafter, directly from mitotic arrest. Immunofluorescence microscopy, immunoblot, and flow cytometry analysis showed that, on PLK1 blockade, ATC cells arrested in prometaphase with a 4N DNA content. Treated ATC cells accumulated phosphohistone H3 and displayed characteristic mitotic (Polo) spindle aberrations. Nontransformed thyroid cells were 3.2- to 18.4-fold less susceptible to BI 2536–induced cell cycle effects compared with ATC cells. These findings identify PLK1 as a promising target for the molecular therapy of ATC. [Cancer Res 2009;69(5):1916–23]
Nasal Airway Ion Transport and Lung Function in Young People with Cystic Fibrosis
Authors: Helen L. Wallace, Pierre M. Barker, Kevin W. Southern
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

There is strong evidence that abnormal airway ion transport is the primary defect that initiates the pathophysiology of lung disease in cystic fibrosis (CF). To examine the relationship between airway ion transport abnormality and severity of lung disease, we measured nasal potential difference in 51 young people with CF using a validated modified technique. There was no correlation between any component of the ion transport measurement and clinical condition (respiratory function, chest radiograph score, or Shwachman clinical score). Thirty subjects, homozygous for the DeltaF508 mutation, were divided into those above and those below average respiratory function for their age. There was no significant difference in any of the ion transport parameters between those with above and below average pulmonary function. Of the 51 subjects, 10 had significant hyperpolarization after perfusion with a zero Cl- solution (> 5 mV). This Cl- secretory capacity did not correlate with above average lung function. These data do not support the assertion that the extent of lung disease in CF reflects the degree of ion transport abnormality. We suggest that although an ion transport abnormality initiates lung disease, other factors (e.g., environmental and genetic modifiers) are more influential in determining disease severity.
A male patient with ileitis and a calcifying small bowel lesion
Authors: A Aghdassi, G Richter, P Simon, J Ringel, R Puls, M Evert, U Wahnschaffe
Journal: Gut (2008)

A 70-year-old man presented with a 1 week history of right-sided lower abdominal pain and recurrent episodes of nausea and diarrhoea over at least 3 years. The medical history included anti-neutrophil auto-antibody (ANCA)-positive extracapillary-proliferative glomerulonephritis which was currently …
Temozolomide Pharmacodynamics in Patients with Metastatic Melanoma: DNA Damage and Activity of Repair Enzymes <i>O</i>6-Alkylguanine Alkyltransferase and Poly(ADP-Ribose) Polymerase-1
Authors: E. Ruth Plummer, Mark R. Middleton, Christopher Jones, Anna Olsen, Ian Hickson, Peter McHugh, Geoffrey P. Margison, Gail McGown, Mary Thorncroft, Amanda J. Watson, Alan V. Boddy, A. Hilary Calvert, Adrian L. Harris, David R. Newell, Nicola J. Curtin
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Temozolomide, a DNA methylating agent used to treat melanoma, induces DNA damage, which is repaired by O6-alkylguanine alkyltransferase (ATase) and poly(ADP-ribose) polymerase-1 (PARP-1)–dependent base excision repair. The current study was done to define the effect of temozolomide on DNA integrity and relevant repair enzymes as a prelude to a phase I trial of the combination of temozolomide with a PARP inhibitor. Experimental Design: Temozolomide (200 mg/m2 oral administration) was given to 12 patients with metastatic malignant melanoma. Peripheral blood lymphocytes (PBL) were analyzed for PARP activity, DNA single-strand breakage, ATase levels, and DNA methylation. PARP activity was also measured in tumor biopsies from 9 of 12 patients and in PBLs from healthy volunteers. Results: Temozolomide pharmacokinetics were consistent with previous reports. Temozolomide therapy caused a substantial and sustained elevation of N7-methylguanine levels, a modest and sustained reduction in ATase activity, and a modest and transient increase in DNA strand breaks and PARP activity in PBLs. PARP-1 activity in tumor homogenates was variable (828 ± 599 pmol PAR monomer/mg protein) and was not consistently affected by temozolomide treatment. Conclusions: The effect of temozolomide reported here are consistent with those documented in previous studies with temozolomide and similar drug, dacarbazine, demonstrating that a representative patient population was investigated. Furthermore, PARP activity was not inhibited by temozolomide treatment and this newly validated pharmacodynamic assay is therefore suitable for use in a proof-of-principle phase I trial a PARP-1 inhibitor in combination with temozolomide.
Alterations of the HBP1 Transcriptional Repressor Are Associated with Invasive Breast Cancer
Authors: K. Eric Paulson, Kimberly Rieger-Christ, Michael A. McDevitt, Charlotte Kuperwasser, Jiyoung Kim, Vincent E. Unanue, Xiaowei Zhang, Maowen Hu, Robin Ruthazer, Stephen P. Berasi, Chun-Yin Huang, Dilip Giri, Seth Kaufman, John M. Dugan, Joanne Blum, Georges Netto, David E. Wazer, Ian C. Summerhayes, Amy S. Yee
Journal: Cancer Research (2007)

Abstract Invasive breast cancer has a high risk of recurrence to incurable disease and needs improved prognostic and therapeutic tools. Our work combines clinical and molecular analyses to show that the transcriptional repressor HBP1 may be a new target for invasive breast cancer. Previous work indicated that HBP1 regulated proliferation and senescence and inhibited Wnt signaling. Two of these functions have been associated with invasive breast cancer. In 76 breast tumors, we identified 10 HBP1 mutations/variants that were associated with fully invasive breast cancer. In a separate analysis, we found that a subset of invasive breast cancer specimens also had reduced HBP1 mRNA levels. These clinical correlations suggested that mutation or reduction of HBP1 occurs in invasive breast cancer and that HBP1 might regulate the proliferation and invasiveness of this breast cancer type. Analysis of the HBP1 mutants showed they were functionally defective for suppressing Wnt signaling. To test the consequences of reduced HBP1 levels, we used RNA interference to knock down HBP1 and observed increased Wnt signaling, tumorigenic proliferation, and invasiveness in cell and animal breast cancer models. Lastly, statistical analysis of a breast cancer patient database linked reduced HBP1 expression to breast cancer recurrence. In considering two-gene criteria for relapse potential, reduced expression of HBP1 and SFRP1, which is another Wnt inhibitor that was recently linked to invasive breast cancer, strikingly correlated with recurrence. Together, these data indicate that HBP1 may be a molecularly and clinically relevant regulator of breast cancer transitions that eventually lead to poor prognosis. [Cancer Res 2007;67(13):6136–45]
A systematic review of ultrasonography in gout and asymptomatic hyperuricaemia
Authors: Priya V Chowalloor, Helen Isobel Keen
Journal: Annals of the Rheumatic Diseases (2013)

Gout is one of the most common inflammatory arthritides. The literature reveals that management of this condition is often suboptimal. Imaging techniques, such as ultrasound (US), may assist in the diagnosis and management of gout and asymptomatic hyperuricaemia (AH). To undertake a systematic review evaluating US as an outcome tool in gout and asymptomatic hyperuricaemia, articles published in Medline and PubMed (1975–February 2012) were identified. Data was extracted and categorised into four different groups namely tophi, articular cartilage, soft tissue pathologies and bony changes, with a focus on validity, responsiveness, reproducibility and feasibility. Lesions reported in the literature include tophi, cartilage abnormalities, soft tissue lesions and erosions. US is able to detect tophi, using MRI as the gold standard, and is sensitive to change. The double contour sign seen overlying cartilage is specific to gout and sensitive to change. Synovial pathology is identified in gout, with some reporting intrasynovial hyperechogeneicity is suggestive of gout. US was less sensitive than MRI to cortical erosions in gout, but better than conventional radiography. Interobserver reliability when assessed ranged from fair to substantial agreement for soft tissue changes and was very good for assessing tophi, double contour and erosions. US is a promising tool which could be used in the diagnosis and management of gout. More studies are needed to assess responsiveness, reliability and feasibility.