tbuckley/cabot-search huggingface dataset:
Eight clinical conundrums relating to anterior cruciate ligament (ACL) injury in sport: recent evidence and a personal reflection
Authors: Per A Renström
Journal: British Journal of Sports Medicine (2012)

Over two million anterior cruciate ligament (ACL) injuries occur worldwide annually, and the greater prevalence for ACL injury in young female athletes is one of the major problems in sports medicine. Optimal treatment of ACL injury requires individualised management. Patient selection is of utmost importance, and so is respect for the patient's functional demands and interests. All patients with an ACL tear may not need surgery, however athletes and persons with an active lifestyle with high knee functional demands including cutting motions need and should be offered surgery. In many cases it may not be the choice of graft or technique that is the key for success, but the choice of surgeon. The surgeon should be experienced and use a reconstructive procedure he/she knows very well and is comfortable with. The development of osteoarthritis after an ACL injury depends very much on the injury mechanism and concurrent meniscal injury, as knee articular cartilage continues to heal for 1-2 years after an ACL injury. Therefore the surgeon and rehabilitation team must pay attention to the rehabilitation process and to the decision when to return to sport. Return to sport must be carefully considered, as top-level sport in itself is one main risk factor for osteoarthritis after ACL injury. The present criteria for return to sport need to be revisited, also due to the fact that recurrent injury seems to be an increasing problem. ACL injury prevention programmes are now available in some sports. The key issue for a prevention programme to be successful is proper implementation. Vital factors for success include the individual coaching of the player and well controlled compliance with the training programme. Preventive activities should be more actively supported by the involved athletic community. Despite substantial advances in the field of ACL injury over the past 40 years, substantial management challenges remain.
In vitro analysis of allogeneic lymphocyte interaction. II. I-region control of the activity of a B-cell-derived H-2-restricted allogeneic effect factor and its receptor during B-cell activation.
Authors: T L Delovitch, J Biggin, F Y Fung
Journal: The Journal of Experimental Medicine (1978)

A genetically restricted allogeneic effect factor (AEF) derived from a mixed lymphocyte culture reaction between Ia-negative activated responder cells and irradiated T-cell-depleted stimulator cells was characterized. Restricted AEF is a B-cell-derived soluble helper factor which consists in part of Ia antigens controlled by the I-A subregion of the stimulator haplotype; additional control by the I-B, I-E, and I-C subregions, although unlikely, could not be excluded. This factor helps B cells of only its own haplotype or of haplotypes which carry an I-A and/or I-B subregion identity. Unprimed as well as hapten-primed Ia-positive B cells express a receptor for restricted AEF. The results indicate that the B-cell receptor for AEF is determined by the I-A subregion. Both restricted AEF and its receptor may therefore be products of the same I-region gene(s). The data are compatible with the hypothesis that the AEF Ia antigens serve as a second signal required for B-cell activation to IgG antibody production.
Overexpression of FKBP51 in idiopathic myelofibrosis regulates the growth factor independence of megakaryocyte progenitors
Authors: Stéphane Giraudier, Hédia Chagraoui, Emiko Komura, Stéphane Barnache, Benoit Blanchet, Jean Pierre LeCouedic, David F. Smith, Frédéric Larbret, Anne-Laure Taksin, Françoise Moreau-Gachelin, Nicole Casadevall, Michel Tulliez, Anne Hulin, Najet Debili, William Vainchenker
Journal: Blood (2002)
PTU-139 An Unusual Complication of Myelodysplasia
Authors: A K Gabr
Journal: Gut (2013)

<h3>Introduction</h3> Oesophageal haematoma is a rare clinical entity which is part of the spectrum of oesophageal injuries that includes Mallory-Weiss tear and Boerhave’s syndrome. We present a case of oesophageal haematoma as the only complication of myelodysplasia. <h3>Methods Case presentation</h3> An 81 year old gentleman presented to the emergency department with sudden onset chest pain. He ate a scone and went to bed. Half an hour later, he developed a sharp, retrosternal pain,radiating to the neck. The pain was worse by breathing and swallowing. His past medical history included myelodysplasia and ischemic heart disease. Physical examination was unremarkable. Laboratory investigations showed platelets count of 59 × 10<sup>3</sup>, D. Dimer of 2746 ng/ml. CT pulmonary angiography didn’t show any pulmonary embolus but obstructed oesophagus,filled with food up to the middle part. Gastroscopy showed large bluish red mass extending between 23 cm and 40 cm in the Oesophageal lumen, originating from the submucosa. The mass didn’t look malignant, therefore, biopsies were not taken. Clinical impression was submucosal oesophageal haematoma. Aspirin was stopped and he was treated conservatively, with liquid diet. Dysphagia improved and he was discharged 4 days later. Complete resolution was shown on follow up CT thorax and gastroscopy 6 weeks later. <h3>Results Discussion</h3> The first published report of Oesophageal haemtoma,from Marks and Keat in 1968, described a small mucosal breach as a constant feature. It is a result of haemorrhage within the oesophageal wall, usually in the submucosa and more often in the distal oesophagus as it is least supported by adjacent structures. The pathogenesis is unclear, Criblez and colleagues reviewed 91 patients with submucosal haematoma in literature, Precipitating factors were vomiting in 22% of cases, instrumentation in 17%, haemostasis abnormalities in 21% and spontaneous occurrence in 37%.Acute chest pain is a common presentation that should be differentiated from other causes as myocardial infarction. The typical triad of chest pain, hematemesis and dysphagia occurred only in one third of patients.CT typically, shows symmetric or asymmetric oesophageal thickening with concentric or eccentric oesophageal mass with well-defined borders. Gastroscopy is the diagnostic test of choice. Most cases resolve spontaneously within 1–3 weeks with conservative approach. Surgery is only indicated in complicated cases. Angiography is usually considered when endoscopic therapy failed or when surgery is risky. <h3>Conclusion</h3> Diagnosis of Oesophageal haematoma can be achieved by interpreting symptoms in conjunction with imaging and endoscopy findings at presentation and follow up. Porgnosis is favourable, as it usually resolves with conservative management. <h3>Disclosure of Interest</h3> None Declared
Asymptotic Dental Score and Prevalent Coronary Heart Disease
Authors: Sok-Ja Janket, Markku Qvarnström, Jukka H. Meurman, Alison E. Baird, Pekka Nuutinen, Judith A. Jones
Journal: Circulation (2004)

Oral infections have been postulated to produce cytokines that may contribute to the pathogenesis of coronary heart disease (CHD). We hypothesized that by estimating the combined production of inflammatory mediators attributable to several oral pathologies, we might be able to explain CHD with better precision.A total of 256 consecutive Finnish cardiac patients from Kuopio University Hospital with angiographically confirmed CHD and 250 age-, gender-, and residence-matched noncardiac patients (controls) were recruited. All dental factors expected to generate inflammatory mediators, including pericoronitis, dental caries, dentate status, root remnants, and gingivitis, were examined, and an asymptotic dental score (ADS) was developed by logistic regression analyses with an appropriate weighting scheme according to the likelihood ratio. We validated the explanatory ability of ADS by comparing it to that of the Total Dental Index and examining whether the ADS was associated with known predictors of CHD. A model that included ADS, C-reactive protein, HDL, and fibrinogen offered an explanatory ability that equaled or exceeded that of the Framingham heart score (C statistic=0.82 versus 0.80). When ADS was removed from this model, the C-statistic decreased to 0.77, which indicates that the ADS was a significant contributor to the explanatory ability of a logistic model.ADS may be useful as a prescreening tool to promote proactive cardiac evaluation among individuals without overt symptoms of CHD. However, additional prospective study is needed to validate the use of an oral health score as a predictor of incident CHD.
Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial
Authors: Anna Caroli, Norberto Perico, Annalisa Perna, Luca Antiga, Paolo Brambilla, Antonio Pisani, Bianca Visciano, Massimo Imbriaco, Piergiorgio Messa, Roberta Cerutti, Mauro Dugo, Luca Cancian, Erasmo Buongiorno, Antonio De Pascalis, Flavio Gaspari, Fabiola Carrara, Nadia Rubis, Silvia Prandini, Andrea Remuzzi, Giuseppe Remuzzi, Piero Ruggenenti
Journal: The Lancet (2013)
Phosphatidylinositol 3-Kinase Activity Is Required for Epidermal Growth Factor to Suppress Proteolysis
Authors: Harold A. Franch, Xiaonan Wang, Sira Sooparb, Nikia S. Brown, Jie Du
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Suppression of protein breakdown occurs commonly in cell growth, but the pathways responsible for controlling proteolysis are poorly understood. Protein breakdown in NRK-52E renal epithelial cells treated with epidermal growth factor (EGF) and intracellular signaling inhibitors or dominant negative signaling molecules contained in an adenoviral vector were measured. The tyrosine kinase inhibitor, herbimycin A, eliminated the suppression of proteolysis induced by EGF. In contrast, the Src inhibitor, PP1, had no effect. Expression of dominant negative H-RasY57 blocked the ability of EGF to stimulate downstream targets of Ras and also reduced the ability of EGF to suppress proteolysis. Inhibiting MEK did not influence the ability of EGF to suppress proteolysis, but the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, LY249002, stimulated basal proteolysis and completely eliminated the proteolytic response to EGF. Use of an adenovirus that expresses a dominant negative p85 subunit of class 1 PI 3-kinase completely blocked the ability of EGF to suppress proteolysis, whereas use of an adenovirus expressing a K227E constitutively active p110 subunit reproduced the reduction in protein breakdown. It was concluded that EGF suppresses proteolysis by a mechanism that involves Ras and class 1 PI 3-kinase.
Tim-3 inhibits T helper type 1–mediated auto- and alloimmune responses and promotes immunological tolerance
Authors: Alberto Sánchez-Fueyo, Jane Tian, Dominic Picarella, Christoph Domenig, Xin Xiao Zheng, Catherine A Sabatos, Natasha Manlongat, Orissa Bender, Thomas Kamradt, Vijay K Kuchroo, José-Carlos Gutiérrez-Ramos, Anthony J Coyle, Terry B Strom
Journal: Nature Immunology (2003)
Hospital-acquired pneumonia: microbiological data and potential adequacy of antimicrobial regimens
Authors: O. Leroy, P. Giradie, Y. Yazdanpanah, H. Georges, S. Alfandari, V. Sanders, P. Devos, G. Beaucaire
Journal: European Respiratory Journal (2002)

Adequate antimicrobial therapy is a main approach employed to decrease the mortality associated with hospital-acquired pneumonia (HAP). All methods that optimise empirical treatment without increasing antibiotic selective pressure are relevant. Categorisation of patients according to HAP time of onset, severity and risk factors (American Thoracic Society (ATS) classification) or duration of mechanical ventilation and prior antibiotics (Trouillet's classification) are two such methods. The aim of this study was to catagorise patients with HAP according to these classifications and to determine the frequency of resistant pathogens and the most adequate antimicrobial regimens in each group. A total 124 patients with bacteriologically proven HAP were studied. The ATS classification categorised patients by increasing frequency of resistant pathogens from 0-30.3%. The ATS empirical antibiotic recommendations appeared valid but proposed combinations including vancomycin for 72.5% of patients. Trouillet's classification categorised patients into four groups with a frequency of resistant pathogens from 4.9-35.6%. Vancomycin was proposed for 48.5% of patients. The American Thoracic Society classification appears to be more specific than Trouillet's for predicting the absence of resistant causative pathogens in hospital-acquired pneumonia but could lead to a greater use of vancomycin. Stratification combining the two classifications is an interesting alternative.
REvolver: Modeling Sequence Evolution under Domain Constraints
Authors: Tina Koestler, Arndt von Haeseler, Ingo Ebersberger
Journal: Molecular Biology and Evolution (2012)

Simulating the change of protein sequences over time in a biologically realistic way is fundamental for a broad range of studies with a focus on evolution. It is, thus, problematic that typically simulators evolve individual sites of a sequence identically and independently. More realistic simulations are possible; however, they are often prohibited by limited knowledge concerning site-specific evolutionary constraints or functional dependencies between amino acids. As a consequence, a protein's functional and structural characteristics are rapidly lost in the course of simulated evolution. Here, we present REvolver (www.cibiv.at/software/revolver), a program that simulates protein sequence alteration such that evolutionarily stable sequence characteristics, like functional domains, are maintained. For this purpose, REvolver recruits profile hidden Markov models (pHMMs) for parameterizing site-specific models of sequence evolution in an automated fashion. pHMMs derived from alignments of homologous proteins or protein domains capture information regarding which sequence sites remained conserved over time and where in a sequence insertions or deletions are more likely to occur. Thus, they describe constraints on the evolutionary process acting on these sequences. To demonstrate the performance of REvolver as well as its applicability in large-scale simulation studies, we evolved the entire human proteome up to 1.5 expected substitutions per site. Simultaneously, we analyzed the preservation of Pfam and SMART domains in the simulated sequences over time. REvolver preserved 92% of the Pfam domains originally present in the human sequences. This value drops to 15% when traditional models of amino acid sequence evolution are used. Thus, REvolver represents a significant advance toward a realistic simulation of protein sequence evolution on a proteome-wide scale. Further, REvolver facilitates the simulation of a protein family with a user-defined domain architecture at the root.
Natural variation in Fc glycosylation of HIV-specific antibodies impacts antiviral activity
Authors: Margaret E. Ackerman, Max Crispin, Xiaojie Yu, Kavitha Baruah, Austin W. Boesch, David J. Harvey, Anne-Sophie Dugast, Erin L. Heizen, Altan Ercan, Ickwon Choi, Hendrik Streeck, Peter A. Nigrovic, Chris Bailey-Kellogg, Chris Scanlan, Galit Alter
Journal: Journal of Clinical Investigation (2013)

While the induction of a neutralizing antibody response against HIV remains a daunting goal, data from both natural infection and vaccine-induced immune responses suggest that it may be possible to induce antibodies with enhanced Fc effector activity and improved antiviral control via vaccination. However, the specific features of naturally induced HIV-specific antibodies that allow for the potent recruitment of antiviral activity and the means by which these functions are regulated are poorly defined. Because antibody effector functions are critically dependent on antibody Fc domain glycosylation, we aimed to define the natural glycoforms associated with robust Fc-mediated antiviral activity. We demonstrate that spontaneous control of HIV and improved antiviral activity are associated with a dramatic shift in the global antibody-glycosylation profile toward agalactosylated glycoforms. HIV-specific antibodies exhibited an even greater frequency of agalactosylated, afucosylated, and asialylated glycans. These glycoforms were associated with enhanced Fc-mediated reduction of viral replication and enhanced Fc receptor binding and were consistent with transcriptional profiling of glycosyltransferases in peripheral B cells. These data suggest that B cell programs tune antibody glycosylation actively in an antigen-specific manner, potentially contributing to antiviral control during HIV infection.
Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids
Authors: Stavroula Kousteni, Li Han, Jin-Ran Chen, Maria Almeida, Lilian I. Plotkin, Teresita Bellido, Stavros C. Manolagas
Journal: Journal of Clinical Investigation (2003)

It has been found that 4-estren-3alpha,17beta-diol, a synthetic ligand for the estrogen receptor (ER) or androgen receptor (AR), which does not affect classical transcription, reverses bone loss in ovariectomized females or orchidectomized males without affecting the uterus or seminal vesicles, demonstrating that the classical genotropic actions of sex steroid receptors are dispensable for their bone-protective effects, but indispensable for their effects on reproductive organs. We have now investigated the mechanism of action of this compound. We report that, identically to 17beta-estradiol or dihydrotestosterone, but differently from raloxifene, estren alters the activity of Elk-1, CCAAT enhancer binding protein-beta (C/EBPbeta), and cyclic adenosine monophosphate-response element binding protein (CREB), or c-Jun/c-Fos by an extranuclear action of the ER or AR, resulting in activation of the Src/Shc/ERK pathway or downregulation of JNK, respectively. All of these effects are non-sex specific, require only the ligand-binding domain of the receptor, and are indispensable for the antiapoptotic action of these ligands on osteoblastic and HeLa cells. Moreover, administration of 17beta-estradiol or 4-estren-3alpha,17beta-diol to ovariectomized mice induces phosphorylation of ERKs, Elk-1, and C/EBPbeta, downregulates c-Jun, and upregulates the expression of egr-1, an ERK/SRE target gene. Kinase-initiated regulation of commonly used transcription factors offers a molecular explanation for the profound skeletal effects of sex steroid receptor ligands, including synthetic ones that are devoid of classical transcriptional activity.
Addressing the Ethical Challenges in Genetic Testing and Sequencing of Children
Authors: Ellen Wright Clayton, Laurence B. McCullough, Leslie G. Biesecker, Steven Joffe, Lainie Friedman Ross, Susan M. Wolf, None For the Clinical Sequencing Explora
Journal: The American Journal of Bioethics (2014)

American Academy of Pediatrics (AAP) and American College of Medical Genetics (ACMG) recently provided two recommendations about predictive genetic testing of children. The Clinical Sequencing Exploratory Research Consortium's Pediatrics Working Group compared these recommendations, focusing on operational and ethical issues specific to decision making for children. Content analysis of the statements addresses two issues: (1) how these recommendations characterize and analyze locus of decision making, as well as the risks and benefits of testing, and (2) whether the guidelines conflict or come to different but compatible conclusions because they consider different testing scenarios. These statements differ in ethically significant ways. AAP/ACMG analyzes risks and benefits using best interests of the child and recommends that, absent ameliorative interventions available during childhood, clinicians should generally decline to order testing. Parents authorize focused tests. ACMG analyzes risks and benefits using the interests of the child and other family members and recommends that sequencing results be examined for additional variants that can lead to ameliorative interventions, regardless of age, which laboratories should report to clinicians who should contextualize the results. Parents must accept additional analysis. The ethical arguments in these statements appear to be in tension with each other.
Estrogen Therapy and Noncognitive Psychiatric Signs and Symptoms in Elderly Patients With Dementia
Authors: Helen H Kyomen, John Hennen, Gary L Gottlieb, Jeanne Y Wei
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: This study investigated the efficacy and safety of short-term estrogen therapy in decreasing noncognitive signs and symptoms of dementia in demented elderly patients. METHOD: Sixteen moderately to severely demented elderly patients with aggressive behavioral disturbances were randomly assigned to receive conjugated equine estrogens or placebo in a 4-week clinical trial. Frequency and severity of noncognitive signs and symptoms of dementia, as assessed with the Dementia Signs and Symptoms Scale, were compared between estrogen and placebo groups. Data were analyzed with intent-to-treat and regression modeling methods. RESULTS: Estrogen therapy was associated with a significantly greater improvement on the Dementia Signs and Symptoms Scale total score than placebo. All five Dementia Signs and Symptoms Scale subscale comparisons favored estrogen therapy. No adverse effects were observed. CONCLUSIONS: These preliminary data suggest that short-term estrogen therapy may safely decrease the frequency and severity of noncognitive signs and symptoms of dementia in elderly patients.
Rat hepatocytes attach to laminin present in liver biomatrix proteins by an Mg++-dependent mechanism*1
Authors: M PONCE
Journal: Hepatology (1995)

Laminin belongs to a family of proteins that contains at least seven variants. Together with fibronectin, it is the most important cell-adhesion protein. Recent data from various laboratories have suggested that liver sinusoidal laminins differ from Engelbert-Holmes-Swarm tumor laminin (laminin 1), because the former contain α2 instead of αl chains. Therefore, we compared the adhesion of hepatocytes to laminin 1 and a matrix extracted with dilute acetic acid from liver biomatrix (LBP). We show that LBP contains laminin and that this extracellular matrix protein is the main adhesion protein. Close to 70% of the hepatocytes attach to LBP after 15 minutes of incubation at 37°C. Cell adhesion was Mg++ and Mn++-dependent and Ca+- and insulin-independent. Ethylenediaminetetraacetic acid prevented cell adhesion in the presence of divalent cations. We show that synthetic cell-adhesion peptide sequences present in laminin 1 (RGD and YIGSR) or an antibody to the cell-binding domain (SIKVAV) of the α1 chain do not prevent hepatocyte adhesion to LBP. We also show that LBP has cell specificity; hepatocytes adhere to it preferentially when compared with other epithelial and mesenchymal cell lines. We suggest that because of the differences in chain composition of laminin 1 and liver sinusoidal laminins as well as the described differences in cell adhesion to the two substrata, further studies are needed to determine the actual composition of liver laminin and establish the chains and domains to which hepatocytes adhere.