tbuckley/cabot-search huggingface dataset:
Tailoring the length of antiviral treatment for hepatitis C
Authors: A. Mangia, A. Andriulli
Journal: Gut (2009)

The effectiveness of interferon in blocking the replication of hepatitis C virus (HCV) in infected cells is enhanced in patients with genotypes 2 and 3 as compared to genotype 1.1 2 The clinical counterpart of these experimental observations is the higher rate of viral clearance in easy-to-cure genotypes, as reported in registration trials on Peg-Interferon (Peg-IFN) and ribavirin therapy.3 4 5 Consequently, so far, HCV genotyping has represented the common approach to tailoring drug dosage and length of therapy. Recently, an innovative concept has emerged which might also govern treatment schedules besides HCV genotypes: in response to a single interferon injection, viral decline in blood differs not only among individual genotypes but also from patient to patient infected by the same viral strain.6 7 8 This evidence has led to the claim that patients with prompt response could benefit from a shorter duration of treatment compared to that which is currently recommended, whereas for slower responders a prolonged course of treatment might be needed to maximise virological response.

How to categorise rapid, slow or null responders according to current antiviral therapy is a matter of intensive investigation.9 10 Past experience has corroborated the usefulness of evaluating serum HCV-RNA at treatment weeks 4, 12 and 24: rapid responders are patients who are non-viraemic at week 4, and non-responders are those still viraemic at week 24; all other patients falling between these two extremes are defined as slow responders.11 12 As the timing and magnitude of virological response are highly variable from one patient to another, slow responders might include several subgroups of patients with differing chances of achieving a sustained virological response (SVR). Indeed, if a subset of patients defined as complete early virological responders shows an absence of HCV-RNA at treatment week 12, it is …
Antigen Spreading Contributes to MAGE Vaccination-Induced Regression of Melanoma Metastases
Authors: Véronique Corbière, Jacques Chapiro, Vincent Stroobant, Wenbin Ma, Christophe Lurquin, Bernard Lethé, Nicolas van Baren, Benoît J. Van den Eynde, Thierry Boon, Pierre G. Coulie
Journal: Cancer Research (2011)

A core challenge in cancer immunotherapy is to understand the basis for efficacious vaccine responses in human patients. In previous work we identified a melanoma patient who displayed a low-level antivaccine cytolytic T-cell (CTL) response in blood with tumor regression after vaccination with melanoma antigens (MAGE). Using a genetic approach including T-cell receptor β (TCRβ) cDNA libraries, we found very few antivaccine CTLs in regressing metastases. However, a far greater number of TCRβ sequences were found with several of these corresponding to CTL clones specific for nonvaccine tumor antigens, suggesting that antigen spreading was occurring in regressing metastases. In this study, we found another TCR belonging to tumor-specific CTL enriched in regressing metastases and detectable in blood only after vaccination. We used the TCRβ sequence to detect and clone the desired T cells from tumor-infiltrating lymphocytes isolated from the patient. This CD8 clone specifically lysed autologous melanoma cells and displayed HLA-A2 restriction. Its target antigen was identified as the mitochondrial enzyme caseinolytic protease. The target antigen gene was mutated in the tumor, resulting in production of a neoantigen. Melanoma cell lysis by the CTL was increased by IFN-γ treatment due to preferential processing of the antigenic peptide by the immunoproteasome. These results argue that tumor rejection effectors in the patient were indeed CTL responding to nonvaccine tumor-specific antigens, further supporting our hypothesis. Among such antigens, the mutated antigen we found is the only antigen against which no T cells could be detected before vaccination. We propose that antigen spreading of an antitumor T-cell response to truly tumor-specific antigens contributes decisively to tumor regression.
Eccentric training in patients with chronic Achilles tendinosis: normalised tendon structure and decreased thickness at follow up
Authors: L Öhberg, R Lorentzon, H Alfredson
Journal: British Journal of Sports Medicine (2004)

Objective: To prospectively investigate tendon thickness and tendon structure by ultrasonography in patients treated with eccentric calf muscle training for painful chronic Achilles tendinosis located at the 2–6 cm level in the tendon. Methods: The patients were examined with grey scale ultrasonography before and 3.8 years (mean) after the 12 week eccentric training regimen. At follow up, a questionnaire assessed present activity level and satisfaction with treatment. Results: Twenty six tendons in twenty five patients (19 men and six women) with a mean age of 50 years were followed for a mean of 3.8 years (range 1.6–7.75). All patients had a long duration of painful symptoms (mean 17.1 months) from chronic Achilles tendinosis before treatment. At follow up, 22 of 25 patients were satisfied with treatment and active in Achilles tendon loading activities at the desired level. Ultrasonography showed that tendon thickness (at the widest part) had decreased significantly (p&lt;0.005) after treatment (7.6 (2.3) v 8.8 (3) mm; mean (SD)). In untreated normal tendons, there was no significant difference in thickness after treatment (5.3 (1.3) mm before and 5.9 (0.8) mm after). All tendons with tendinosis had structural abnormalities (hypoechoic areas and irregular structure) before the start of treatment. After treatment, the structure was normal in 19 of the 26 tendons. Six of the seven patients with remaining structural abnormalities experienced pain in the tendon during loading. Conclusions: Ultrasonographic follow up of patients with mid-portion painful chronic Achilles tendinosis treated with eccentric calf muscle training showed a localised decrease in tendon thickness and a normalised tendon structure in most patients. Remaining structural tendon abnormalities seemed to be associated with residual pain in the tendon.
Elevated adenosine deaminase activity and hereditary hemolytic anemia. Evidence for abnormal translational control of protein synthesis.
Authors: E G Chottiner, H J Cloft, A P Tartaglia, B S Mitchell
Journal: Journal of Clinical Investigation (1987)

We have investigated the molecular basis of the marked elevation in erythrocyte adenosine deaminase (ADA) activity in a kindred with hereditary hemolytic anemia. Red cell ADA-specific activity was verified to be 70- to 100-fold normal levels. Western blots demonstrated a corresponding increase in erythrocyte ADA-specific immunoreactive protein. Analysis of genomic DNA revealed no evidence for amplification or major structural changes in the ADA gene. ADA-specific messenger RNA (mRNA) from proband reticulocytes was comparable in size and amount to mRNA from control reticulocytes. Translation of proband poly A+ reticulocyte mRNA in a rabbit reticulocyte lysate system and immunoprecipitation of 35S-labeled protein products with anti-ADA antibody yielded a band of approximately 42,000 apparent mol wt that was absent in translation products from control reticulocyte mRNAs. These data suggest that the increased ADA activity in red cells in this disorder results from the increased translation of an aberrant ADA mRNA.
Human Non-Germinal Center B Cell Interleukin (IL)-12 Production Is Primarily Regulated by T Cell Signals CD40 Ligand, Interferon γ, and IL-10: Role of B Cells in the Maintenance of T Cell Responses
Authors: Joachim L. Schultze, Sabine Michalak, Joel Lowne, Adam Wong, Maria H. Gilleece, John G. Gribben, Lee M. Nadler
Journal: The Journal of Experimental Medicine (1999)

Interleukin (IL)-12 is expressed mainly in antigen-presenting cells after challenge with microbial material or after CD40 activation. Although IL-12 was cloned from human Epstein-Barr virus (EBV)-transformed B cell lines, surprisingly, CD40 ligation on murine B cells did not lead to IL-12 production, suggesting that murine B cells do not produce IL-12. Here we demonstrate that a subset of human tonsillar B cells can be induced to express and secrete bioactive IL-12. The major stimulus to produce IL-12 in human B cells was CD40 ligation. In contrast, B cell receptor cross-linking did not induce IL-12. Expression of IL-12 after CD40 activation was restricted to CD38−IgD± non-germinal center (non-GC) B cells. CD40 ligation and interferon (IFN)-γ exhibited synergistic effects on IL-12 production, whereas IL-10 abrogated and IL-4 significantly inhibited IL-12 production by these B cells. In contrast to IL-12, production of IL-6 is conversely regulated, leading to significant increase after CD40 ligation in the presence of the T helper type 2 (Th2) cytokine IL-4. Cord blood T cells skewed towards either a Th1 or a Th2 phenotype maintained their cytokine expression pattern when restimulated with allogeneic resting B cells. Blockade of CD40 and/or IL-12 during T–B interaction significantly reduced IFN-γ production by the T cells. This suggests a model whereby B cells produce either IL-12 or IL-6 after contact with T cells previously differentiated towards Th1 or Th2. Furthermore, IL-12 and IL-6 might provide a positive feedback during cognate T–B interactions, thereby maintaining T cells' differentiation pattern during amplification of the immune response.
Modulation of subthalamic T-type Ca2+ channels remedies locomotor deficits in a rat model of Parkinson disease
Authors: Chun-Hwei Tai, Ya-Chin Yang, Ming-Kai Pan, Chen-Syuan Huang, Chung-Chin Kuo
Journal: Journal of Clinical Investigation (2011)

An increase in neuronal burst activities in the subthalamic nucleus (STN) is a well-documented electrophysiological feature of Parkinson disease (PD). However, the causal relationship between subthalamic bursts and PD symptoms and the ionic mechanisms underlying the bursts remain to be established. Here, we have shown that T-type Ca(2+) channels are necessary for subthalamic burst firing and that pharmacological blockade of T-type Ca(2+) channels reduces motor deficits in a rat model of PD. Ni(2+), mibefradil, NNC 55-0396, and efonidipine, which inhibited T-type Ca(2+) currents in acutely dissociated STN neurons, but not Cd(2+) and nifedipine, which preferentially inhibited L-type or the other non–T-type Ca(2+) currents, effectively diminished burst activity in STN slices. Topical administration of inhibitors of T-type Ca(2+) channels decreased in vivo STN burst activity and dramatically reduced the locomotor deficits in a rat model of PD. Cd(2+) and nifedipine showed no such electrophysiological and behavioral effects. While low-frequency deep brain stimulation (DBS) has been considered ineffective in PD, we found that lengthening the duration of the low-frequency depolarizing pulse effectively improved behavioral measures of locomotion in the rat model of PD, presumably by decreasing the availability of T-type Ca(2+) channels. We therefore conclude that modulation of subthalamic T-type Ca(2+) currents and consequent burst discharges may provide new strategies for the treatment of PD.
Prothrombotic Mutations, Hormone Therapy, and Venous Thromboembolism Among Postmenopausal Women
Authors: Céline Straczek, Emmanuel Oger, Marianne Beau Yon de Jonage-Canonico, Geneviève Plu-Bureau, Jacqueline Conard, Guy Meyer, Martine Alhenc-Gelas, Hervé Lévesque, Nathalie Trillot, Marie-Thérèse Barrellier, Denis Wahl, Joseph Emmerich, Pierre-Yves Scarabin
Journal: Circulation (2005)

Background— Oral estrogen increases the risk of venous thromboembolism (VTE) in postmenopausal women, particularly in those with a prothrombotic mutation. Transdermal estrogen may be safe with respect to VTE. We investigated the impact of the route of estrogen administration on the association between a prothrombotic mutation (factor V Leiden or prothrombin G20210A mutation) and VTE risk. Methods and Results— We performed a multicenter case-control study of VTE among postmenopausal women who were enrolled in 1999 through 2004 at 7 clinical centers in France. We recruited 235 consecutive patients with a first documented episode of idiopathic VTE and 554 controls. Factor V Leiden was associated with a 3.4-fold–increased risk of VTE (95% confidence interval [CI], 2.0 to 5.8), and a prothrombin mutation was associated with a 4.8-fold–increased risk of VTE (95% CI, 2.5 to 9.4). Oral but not transdermal estrogen was associated with an increased risk of VTE (odds ratio [OR], 4.3; 95% CI, 2.6 to 7.2; and OR, 1.2; 95% CI, 0.8 to 1.7, respectively). After adjustment for potential confounding factors, the combination of either factor V Leiden or prothrombin G20210A mutation and oral estrogen gave a 25-fold–increased risk of VTE compared with nonusers without mutation (95% CI, 6.9 to 95.0). However, the risk for women with prothrombotic mutation using transdermal estrogen was similar to that of women with a mutation who were not using estrogen (OR, 4.4; 95% CI, 2.0 to 9.9; and OR, 4.1; 95% CI, 2.3 to 7.4, respectively). Conclusions— In contrast to oral estrogen, transdermal estrogen does not confer additional risk on women who carry a prothrombotic mutation. The safety of transdermal estrogen has to be confirmed in randomized trials.
Surveillance of shigellosis by real-time PCR suggests underestimation of shigellosis prevalence by culture-based methods in a population of rural China
Authors: Song-Mei Wang, Jing-Chen Ma, Zhi-Yong Hao, Zhi-Yong Zhang, Carl Mason, Ornthipa Sethabutr, Lorenz von Seidlein, Xuan-Yi Wang, Zhi-Yi Xu
Journal: Journal of Infection (2010)
Initial versus Delayed Acute Renal Failure in the Intensive Care Unit
Authors: CLAUDE GUERIN, RAPHAELE GIRARD, JEAN-MARC SELLI, JEAN-PIERRE PERDRIX, LOUIS AYZAC
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

We performed a prospective study in the 28 multidisciplinary intensive care units (ICUs) in the Rhône-Alpes area in France to investigate the role of initial versus delayed occurrence of acute renal failure (ARF) in patient outcome. ARF was defined as a serum creatinine concentration > 300 micromol/L, urine output < 500 ml/24 h (or < 180 ml/8 h), or hemodialysis requirement. Over the 1-yr study period, 1,086 patients presented with ARF on ICU admission or during the first 2 d of ICU stay (Group A; 736 patients), from Day 3 to Day 6 (Group B; 202 patients), or from Day 7 (Group C; 148 patients). The overall hospital mortality rate was 66% (61% in Group A, 71% in Group B, and 81% in Group C; p < 0.0001). Logistic regression analysis of a random sample of 510 patients showed that SAPS II score on ICU admission, number of ARF episodes, previous health status, absence of oliguria, absence of hemodialysis, and absence of ischemic acute tubular necrosis were predictive of patient survival. This model was tested and validated on the basis of the remaining patients. Thus, in this population, late ARF was not a predictive factor for patient outcome.
Hamstring exercises for track and field athletes: injury and exercise biomechanics, and possible implications for exercise selection and primary prevention
Authors: Nikos Malliaropoulos, Jurdan Mendiguchia, Hercules Pehlivanidis, Sofia Papadopoulou, Xavier Valle, Peter Malliaras, Nicola Maffulli
Journal: British Journal of Sports Medicine (2012)

Hamstring strain injuries are the most prevalent muscle injuries in track and field (TF). These injuries often cause prolonged symptoms and a high risk of re-injury. Strengthening of the hamstring muscles has been recommended for injury prevention. The authors review the possible role of eccentric training in TF hamstring injury prevention and introduce exercise classification criteria to guide clinicians in designing strengthening programmes adapted to TF. The principles exposed may serve as a foundation for future development and application of new eccentric programmes to decrease the high incidence of this type of injury in other sports.
Motivation for Medicine in the Seventies
Authors: JOHN F. MCDERMOTT, WALTER F. CHAR, MARGARET J. HANSEN
Journal: American Journal of Psychiatry (1973)

A department of psychiatry in Hawaii undertook an exploratory study of the motivational patterns of entering freshmen, relating these to problems of selection, performance, and the educational system itself. The authors, noting that the motivations of students seem to be changing and that a different value system is emerging, call for further study to more accurately assess the values and needs of prospective students and to reassess the educational process.
Opioid dysregulation after biliopancreatic diversion: Effect of naloxone on preprandial and postprandial growth hormone (GH)-releasing hormone-induced GH release in surgically induced weight loss
Authors: A. Mancini, A. Bianchi, R.M. Tacchino, M. Perrelli, D. Milardi, R. Gentilella, A. Giampietro, A. Fusco, D. Valle, L. De Marinis
Journal: Metabolism (2001)
Use of a Cytokine Gene Expression Signature in Lung Adenocarcinoma and the Surrounding Tissue as a Prognostic Classifier
Authors: Masahiro Seike, Nozomu Yanaihara, Elise D. Bowman, Krista A. Zanetti, Anuradha Budhu, Kensuke Kumamoto, Leah E. Mechanic, Shingo Matsumoto, Jun Yokota, Tatsuhiro Shibata, Haruhiko Sugimura, Akihiko Gemma, Shoji Kudoh, Xin W. Wang, Curtis C. Harris
Journal: JNCI Journal of the National Cancer Institute (2007)

BackgroundA 17-cytokine gene expression signature in noncancerous hepatic tissue from patients with metastatic hepatocellular carcinoma (HCC) was recently found to predict HCC metastasis and recurrence. We examined whether the cytokine gene expression profile of noncancerous lung tissue could predict the metastatic capability of adjacent lung adenocarcinoma.
Cross-training and injury risk in british olympic distance triathletes
Authors: V Vleck, F Bessone Alves
Journal: British Journal of Sports Medicine (2011)

Background Triathlon injury research is in its early stages- with no consensus on injury definition and recording methods having been reached, and few prospective data yet available. Levy et al ., (1986) suggested that less injury may occur within this sport than in its component disciplines. Massimino et al ., (1988) proposed the opposite. Objective To determine whether swim, cycle and or run training exert a cumulative stress effect on triathlon overuse injury (OU) risk. Design Seven month prospective longitudinal training diary based survey, from the endurance base period up to World Championships. Setting British Olympic distance specialists. Participants Top 50 finishers at their non-drafting National Championships in the year of, or year prior to, the study. Assessment of risk factors Both absolute (ie, duration) and derived training variables were assessed. Derived variables included both training that was weighted for each of five intensity levels it comprised, and combined training for more than one discipline. Log values (% difference from the previous week) and (difference from the previous week) for training variables for 1, 2, 3, and 4 weeks prior to injury were used. Main outcome measurements ‘New OU’ was used as the dependant variable in a binary logistic regression analysis, involving combinations of 1–4 training related variables. Anatomical location, discipline(s) that OU was attributed to (on first and subsequent occurrence(s), and performance decrement (PD) were also assessed. Results Return rates were 43, 38, 33, 26, 21, 14 and 11 for each consecutive month. 60% of athletes reported OU with concomitant PD at least once. New OU was associated with an increase in the log of combined weighted cycle and run training in levels 3, 4 and 5 two weeks prior to onset (p&lt;0.05). Conclusion The extent to which cycle and run training have a cumulative effect on triathlon injury risk deserves further investigation.
Inhibition of eIF2α Dephosphorylation Maximizes Bortezomib Efficiency and Eliminates Quiescent Multiple Myeloma Cells Surviving Proteasome Inhibitor Therapy
Authors: Denis M. Schewe, Julio A. Aguirre-Ghiso
Journal: Cancer Research (2009)

The proteasome inhibitor bortezomib (Velcade) effectively eradicates multiple myeloma (MM) cells, partly by activating endoplasmic reticulum (ER) stress apoptotic signaling. However, MM recurrences in bortezomib-treated patients are invariable. We have shown that ER stress signaling can also induce growth arrest and survival in cancer cells. Thus, we hypothesized that bortezomib therapy could induce quiescence and survival of residual MM cells, contributing to disease recurrence. Here, we report that in MM cells, proteasome inhibition with MG-132 or bortezomib results in a surviving cell fraction that enters a prolonged quiescent state (G(0)-G(1) arrest). Mechanism analysis revealed that bortezomib-surviving quiescent cells attenuate eIF2alpha phosphorylation and induction of the ER stress proapoptotic gene GADD153. This occurs independently of the eIF2alpha upstream kinases PERK, GCN2, and PKR. In contrast, the prosurvival ER-chaperone BiP/Grp78 was persistently induced. The bortezomib-surviving quiescent fraction could be eradicated by a simultaneous or sequential combination therapy with salubrinal, an inhibitor of GADD34-PP1C phosphatase complex, and, in consequence, eIF2alpha dephosphorylation. This effect was mimicked by expression of a phosphorylated mimetic eIF2alpha-S51D mutant. Our data indicate that bortezomib can induce growth arrest in therapy-surviving MM cells and that attenuation of eIF2alpha phosphorylation contributes to this survival. Most importantly, this survival mechanism can be blocked by inhibiting eIF2alpha dephosphorylation. Thus, strategies that maintain eIF2alpha in a hyperphosphorylated state may be a novel therapeutic approach to maximize bortezomib-induced apoptosis and reduce residual disease and recurrences in this type of cancer.
Superiority on the Embedded Figures Test in autism and in normal males: Evidence of an “innate talent”?
Authors: Simon Baron-Cohen
Journal: Behavioral and Brain Sciences (1998)

Howe et al. suggest that most talents can be explained in terms of practice and other environmental effects, and only exceptionally by innate factors. This commentary provides an illustration of one such exception: performance on the Embedded Figures Test by people with autism and their relatives.