tbuckley/cabot-search huggingface dataset:
Risk factors for mortality from imported falciparum malaria in the United Kingdom over 20 years: an observational study
Authors: A. M. Checkley, A. Smith, V. Smith, M. Blaze, D. Bradley, P. L. Chiodini, C. J. M. Whitty
Journal: BMJ (2012)

<b>Objectives</b> To determine which travellers with malaria are at greatest risk of dying, highlighting factors which can be used to target health messages to travellers. <b>Design</b> Observational study based on 20 years of UK national data. <b>Setting </b>National register of malaria cases. <b>Participants</b> 25 054 patients notified with <i>Plasmodium falciparum </i>malaria, of whom 184 died, between 1987 and 2006. <b>Main outcome measures</b> Comparison between those with falciparum malaria who died and non-fatal cases, including age, reason for travel, country of birth, time of year diagnosed, malaria prophylaxis used. <b>Results</b> Mortality increased steadily with age, with a case fatality of 25/548 (4.6%) in people aged &gt;65 years, adjusted odds ratio 10.68 (95% confidence interval 6.4 to 17.8), P&lt;0.001 compared with 18–35 year olds. There were no deaths in the ≤5 year age group. Case fatality was 3.0% (81/2740 cases) in tourists compared with 0.32% (26/8077) in travellers visiting friends and relatives (adjusted odds ratio 8.2 (5.1 to 13.3), P&lt;0.001). Those born in African countries with endemic malaria had a case fatality of 0.4% (36/8937) compared with 2.4% (142/5849) in others (adjusted odds ratio 4.6 (3.1 to 9.9), P&lt;0.001). Case fatality was particularly high from the Gambia. There was an inverse correlation in mortality between region of presentation and number of cases seen in the region (R<sup>2</sup>=0.72, P&lt;0.001). Most delay in fatal cases was in seeking care. <b>Conclusions</b> Most travellers acquiring malaria are of African heritage visiting friends and relatives. In contrast the risks of dying from malaria once acquired are highest in the elderly, tourists, and those presenting in areas in which malaria is seldom seen. Doctors often do not think of these as high risk groups for malaria; for this reason they are important groups to target in pre-travel advice.
Optic Nerve Decompression Surgery for Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) Is Not Effective and May Be Harmful
Authors: Kay Dickersin
Journal: JAMA (1995)

<h3>Objective.</h3> —To assess the safety and efficacy of optic nerve decompression surgery compared with careful follow-up alone in patients with nonarteritic anterior ischemic optic neuropathy (NAION). <h3>Design.</h3> —The Ischemic Optic Neuropathy Decompression Trial (IONDT) is a randomized, single-masked, multicenter trial. <h3>Setting.</h3> —Twenty-five US clinical centers. <h3>Participants.</h3> —The IONDT ceased recruitment on October 20, 1994, on the recommendation of its Data and Safety Monitoring Committee. The preliminary results presented herein are based on data as of September 8,1994, from 244 patients with NAION and visual acuity of 20/64 or worse. One hundred twenty-five patients had been randomized to careful follow-up, and 119 had been randomized to surgery, with 91 and 95, respectively, having completed 6 months of follow-up. <h3>Intervention.</h3> —Patients in the surgery group received optic nerve decompression surgery and follow-up ophthalmologic examinations; those in the careful follow-up group received ophthalmologic examinations at the same times as the surgery group. <h3>Main Outcome Measures.</h3> —Gain or loss of three or more lines of visual acuity on the New York Lighthouse chart at 6 months after randomization, as measured by a technician masked to treatment assignment. <h3>Results.</h3> —Patients assigned to surgery did no better when compared with patients assigned to careful follow-up regarding improved visual acuity of three or more lines at 6 months: 32.6% of the surgery group improved compared with 42.7% of the careful follow-up group. The odds ratio (OR) for three or more lines better, adjusted for baseline visual acuity and diabetes, was 0.74 (95% confidence interval [CI], 0.39 to 1.38). Patients receiving surgery had a significantly greater risk of losing three or more lines of vision at 6 months: 23.9% in the surgery group worsened compared with 12.4% in the careful follow-up group. The 6-month adjusted OR for three or more lines worse was 1.96 (95% CI, 0.87 to 4.41). No difference in treatment effect was observed between patients with progressive NAION and all others. <h3>Conclusion.</h3> —Results from the IONDT indicate that optic nerve decompression surgery for NAION is not effective, may be harmful, and should be abandoned. The spontaneous improvement rate is better than previously reported. (<i>JAMA</i>. 1995;273:625-632)
Maternal and Paternal Lineages in Cross-Breeding Bovine Species. Has Wisent a Hybrid Origin?
Authors: Edward L. C. Verkaar, Isaäc J. Nijman, Maurice Beeke, Eline Hanekamp, Johannes A. Lenstra
Journal: Molecular Biology and Evolution (2004)

The tribe Bovini comprises cattle and cattle-like species. Reconstructions of their phylogeny have so far been incomplete and have yielded conflicting conclusions about the relationship of American bison and wisent (European bison). We have compared the sequences of three mitochondrial and two Y-chromosomal DNA segments. Mitochondrial DNA indicates that four distinct maternal lineages diverged after an early split-off of the buffalo species, leading to (1) taurine cattle and zebu, (2) wisent, (3) American bison and yak, and (4) banteng, gaur, and gayal, respectively. At a higher level, lineages (1) and (2) and lineages (3) and (4) are probably associated. In contrast, Y-chromosomal sequences indicate a close association of American and European bison, which is in agreement with their morphological similarity, complete fertility of hybrid offspring, and amplified fragment length polymorphism (AFLP) fingerprints of nuclear DNA. One explanation for the anomalous divergence of the mitochondrial DNA from the two bison species is lineage sorting, which implies that two distinct mitochondrial lineages coexisted in the bison-yak branch until the recent divergence of American bison and wisent. Alternatively, the wisent may have emerged by species hybridization initiated by introgression of bison bulls in another ancestral species. This "transpatric" mode of species formation would be consistent with the recent appearance of the wisent in the fossil record without clearly identifiable ancestors.
mTOR Inhibition Ameliorates Cognitive and Affective Deficits Caused by Disc1 Knockdown in Adult-Born Dentate Granule Neurons
Authors: Miou Zhou, Weidong Li, Shan Huang, Juan Song, Ju Young Kim, Xiaoli Tian, Eunchai Kang, Yoshitake Sano, Cindy Liu, J. Balaji, Shumin Wu, Yu Zhou, Ying Zhou, Sherveen N. Parivash, Dan Ehninger, Lin He, Hongjun Song, Guo-li Ming, Alcino J. Silva
Journal: Neuron (2013)
Teaching Primary Care in Community Health Centers: Addressing the Workforce Crisis for the Underserved
Authors: Richard E. Rieselbach
Journal: Annals of Internal Medicine (2010)

Universal coverage and multiple initiatives to improve health care delivery are crucial components of health care reform. However, the missing link has been a plan to rapidly address the primary care workforce crisis for the underserved. The authors propose a link between primary care graduate medical education and care for the underserved in community health centers, where expansion will be necessary for the anticipated increase in Medicaid and insured patients. This can be achieved by establishing primary care teaching health centers in expanded community health centers, which have established a patient-centered medical home practice environment. Residents would receive their final year of training in these centers, and then have the incentive of National Health Service Corps debt repayment if they subsequently practice in an underserved area. Primary care residents being trained in this setting would immediately increase the clinical capacity of community health centers and ultimately expand the primary care physician workforce. This proposal addresses the primary care physician workforce crisis and the associated key problems of limited access for the underserved and suboptimal primary care graduate medical education.
Molecular pathogenesis of iron overload
Authors: D Trinder, C Fox, G Vautier, J K Olynyk
Journal: Gut (2002)

Our current understanding of iron absorption under normal conditions is presented, together with an overview of the clinical disorders of iron overload and the molecular processes that contribute to increased iron deposition in iron overload. Recently, a number of new genes involved in iron metabolism have been identified which is allowing the molecular mechanisms of iron absorption to be elucidated.
Experimental Pseudomonas aeruginosa pneumonia: evaluation of the associated inflammatory response
Authors: O Sibila, C Agustí, A Torres, S Baquero, S Gando, J R Patrón, J G Morato, D H Goffredo, N Bassi, C M Luna
Journal: European Respiratory Journal (2007)

An abnormal inflammatory response (IR) in pneumonia is associated with poor outcomes and high mortality. Animal models could help to better understand the relationship between the pulmonary infection and the associated IR. The aims of the present study were to validate an experimental model of pneumonia induced by the inoculation of <i>Pseudomonas aeruginosa</i> in ventilated piglets and to study the associated IR over a long period of time (96 h). Five Lagerwhite–Landrace piglets were ventilated for 4 days. After intubation, a solution containing 75 mL of <i>P. aeruginosa</i> (10<sup>6</sup> colony-forming units·mL<sup>−1</sup>) was bronchoscopically inoculated. Physiological and laboratory parameters were monitored throughout the study. Pro-inflammatory cytokines were measured in serum and in bronchoalveolar lavage (BAL). Histopathology of the lungs and cultures from blood, BAL and lungs were performed. All the animals developed histopathological evidence of pneumonia. Microbiological studies of both BAL and lung confirmed the presence of <i>P. aeruginosa</i> in all the samples. Throughout the study, an increase in interleukin-6 was observed in serum and in BAL. In conclusion, the experimental model of pneumonia induced by the inoculation of high concentrations of <i>Pseudomonas aeruginosa</i> in ventilated piglets is feasible and could be appropriate for the evaluation of different aspects of the associated inflammatory response.
Specific IgE and IgG Responses in Atopic versus Nonatopic Subjects
Authors: ROB C. AALBERSE
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

It is becoming increasingly clear that the asthmatic reaction is the common end point of different processes. These processes all appear to be multi-step reactions. Several of these reaction steps are known (or expected) to be under genetic control. This meeting is concerned with one step in one of these pathways: the development of IgE antibodies to airborne allergens. The rationale for this focus is that this is likely to be an important (if not essential) step in most cases of asthma in the 4to 40-yr age group. It is obviously not the only step, because most subjects who become so sensitized do not develop asthmatic symptoms on allergen exposure. Factors that contribute to the localization and severity of the subsequent reaction include the following: the extent of the activation of inflammatory helper T type 2 (Th2) cells and eosinophils, the migration into and retention inside the lung tissue of these activated cells, and the induction and repair of the tissue reaction.
Lipid vs Protein Theories of Alcohol Action in the Nervous System
Authors: R W Peoples, L Chaoying, F F Weight
Journal: The Annual Review of Pharmacology and Toxicology (1996)

There has been a long-standing debate concerning whether alcohols produce their effects in the central nervous system (CNS) by acting on lipids or proteins. Lipid theories postulate that alcohols act via some perturbation of the membrane lipids of CNS neurons, whereas protein theories propose that alcohols act by interacting with a neuronal protein site. Although the primary site of action differs in the two theories, both theories postulate that the CNS effects of alcohols ultimately result from alterations in protein function. This review discusses lipid and protein theories of alcohol action and the evidence supporting these theories. In addition, the effects of alcohols on the function of neurotransmitter-gated ion channels are discussed, as several types of these receptor-ion channels have been found to be sensitive to the actions of alcohols, and recent studies on those actions have yielded new insights into the question of whether the primary action of alcohols involves lipids or proteins.
TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections
Authors: Sakiko Inamoto, Callie S. Kwartler, Andrea L. Lafont, Yao Yun Liang, Van Tran Fadulu, Senthil Duraisamy, Marcia Willing, Anthony Estrera, Hazim Safi, Mark C. Hannibal, John Carey, John Wiktorowicz, Filemon K. Tan, Xin-Hua Feng, Hariyadarshi Pannu, Dianna M. Milewicz
Journal: Cardiovascular Research (2010)

Transforming growth factor-β (TGF-β) signaling is critical for the differentiation of smooth muscle cells (SMCs) into quiescent cells expressing a full repertoire of contractile proteins. Heterozygous mutations in TGF-β receptor type II (TGFBR2) disrupt TGF-β signaling and lead to genetic conditions that predispose to thoracic aortic aneurysms and dissections (TAADs). The aim of this study is to determine the molecular mechanism by which TGFBR2 mutations cause TAADs.Using aortic SMCs explanted from patients with TGFBR2 mutations, we show decreased expression of SMC contractile proteins compared with controls. Exposure to TGF-β1 fails to increase expression of contractile genes in mutant SMCs, whereas control cells further increase expression of these genes. Analysis of fixed and frozen aortas from patients with TGFBR2 mutations confirms decreased in vivo expression of contractile proteins relative to unaffected aortas. Fibroblasts explanted from patients with TGFBR2 mutations fail to transform into mature myofibroblasts with TGF-β1 stimulation as assessed by expression of contractile proteins.These data support the conclusion that heterozygous TGFBR2 mutations lead to decreased expression of SMC contractile protein in both SMCs and myofibroblasts. The failure of TGFBR2-mutant SMCs to fully express SMC contractile proteins predicts defective contractile function in these cells and aligns with a hypothesis that defective SMC contractile function contributes to the pathogenesis of TAAD.
Rifampicin as an Oral Angiogenesis Inhibitor Targeting Hepatic Cancers
Authors: Masayoshi Shichiri, Nozomi Fukai, Yutaka Kono, Yujiro Tanaka
Journal: Cancer Research (2009)

Angiogenesis is an important therapeutic target in cancer, and to fully exploit its therapeutic potential, combination chemotherapeutic/antiangiogenic regimens should be optimized and delivered earlier to more patients. Ideally, this could be done by a single potent oral agent with established safety. Rifampicin, a semisynthetic antibiotic derived from the rifamycins, is one of the most commonly used pharmaceutical compounds worldwide in the treatment of tuberculosis. Here, we present the effects of oral rifampicin on human cancer progression and its antiangiogenic properties, which were comparable to the angiogenesis inhibitor endostatin. Clinically, low-dose p.o. administration of rifampicin to six high-risk patients with hepatitis C virus-related liver cirrhosis resulted in a single occurrence of hepatocellular carcinoma during the follow-up period of 97.3 +/- 29.1 (mean +/- SD) months. Experimentally, rifampicin rapidly and markedly down-regulated the expression of a wide spectrum of angiogenesis-associated genes in growing human microvascular endothelial cells, thereby suppressing endothelial cell proliferation and migration. Rifampicin, at higher concentrations, also directly inhibited the growth of a variety of human cancer cells. P.o. administration of rifampicin significantly inhibited in vivo growth and metastases of subcutaneous human cancer xenografts. Thus, the potent antiangiogenic properties of oral rifampicin therapy were effective in suppressing cancer progression. It provides a promising new addition to antiangiogenic strategies for designing human cancer therapies. Considering the clinical pharmacokinetics of rifampicin, which enters the enterohepatic circulation and undergoes subsequent hepatic accumulation, it may be especially beneficial as an antitumor agent targeting hepatobiliary tumors.
Transcutaneous immunization induces mucosal CTLs and protective immunity by migration of primed skin dendritic cells
Authors: Igor M. Belyakov, Scott A. Hammond, Jeffrey D. Ahlers, Gregory M. Glenn, Jay A. Berzofsky
Journal: Journal of Clinical Investigation (2004)

Transcutaneous immunization (TCI), the application of vaccines on the skin, induces robust systemic and mucosal antibodies in animal models and in humans. The means by which mucosal immune responses to vaccine antigens are elicited by TCI has not been well characterized. We examined the effect of TCI with an HIV peptide vaccine on the induction of mucosal and systemic CTL responses and protective immunity against mucosal challenge with live virus in mice. Robust HIV-specific CTL responses in the spleen and in the gut mucosa were detected after TCI. The responses were dependent upon the addition of an adjuvant and resulted in protection against mucosal challenge with recombinant vaccinia virus encoding HIV gp160. Although it is clear that adjuvant-activated DCs migrated mainly to draining lymph nodes, coculture with specific T cells and flow cytometry studies with DCs isolated from Peyer's patches after TCI suggested that activated DCs carrying skin-derived antigen also migrated from the skin to immune-inductive sites in gut mucosa and presented antigen directly to resident lymphocytes. These results and previous clinical trial results support the observation that TCI is a safe and effective strategy for inducing strong mucosal antibody and CTL responses.
Induction of cytotoxic T lymphocytes against I-region-coded determinants: in vitro evidence for a third histocompatibility locus in the mouse.
Authors: H Wagner, D Götze, L Ptschelinzew, M Röllinghoff
Journal: The Journal of Experimental Medicine (1975)

Determinants controlled by the I region of the murine H-2 complex provoked the generation of cytotoxic T lymphocytes (CTL) in both a secondary and primary mixed lymphocyte culture. The stimulating determinants appeared to be controlled by loci within the I-A subregion. The target antigens of the CTL generated were present on both lipopolysaccharide- and concanavalin-induced blast lymphocytes, but were barely detectable on phytohemagglutinin-induced blast cells. The stimulating capacity for CTL induction of a complete H-2 complex incompatibility by far exceeded the sum of H-2D/K-region and I-region incompatibility, respectively.
Bronchial stump recurrence after surgery for bronchial carcinoma
Authors: G Verleden, G Deneffe, M Demedts
Journal: European Respiratory Journal (1990)

In 10 out of 295 patients (3.4%), followed-up after radical resection for non-small cell bronchial carcinoma in the period from 1980 until 1986, bronchial stump recurrence developed. A good relationship was found between relapse time (4-52 months) and distance between the primary tumour and bronchial resection line (1-7 cm) (i.e. 5-8 months.cm-1) in 8 of the patients (p less than 0.01). The mean survival time after detection of the recurrence was 10 months (range 1-15 months), and was not clearly influenced by the therapy applied (resurgery, chemotherapy, radiation), nor by the TNM stage of the bronchial stump recurrence.
Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function
Authors: Madhusudhanan Sukumar, Jie Liu, Yun Ji, Murugan Subramanian, Joseph G. Crompton, Zhiya Yu, Rahul Roychoudhuri, Douglas C. Palmer, Pawel Muranski, Edward D. Karoly, Robert P. Mohney, Christopher A. Klebanoff, Ashish Lal, Toren Finkel, Nicholas P. Restifo, Luca Gattinoni
Journal: Journal of Clinical Investigation (2013)

Naive CD8+ T cells rely upon oxidation of fatty acids as a primary source of energy. After antigen encounter, T cells shift to a glycolytic metabolism to sustain effector function. It is unclear, however, whether changes in glucose metabolism ultimately influence the ability of activated T cells to become long-lived memory cells. We used a fluorescent glucose analog, 2-NBDG, to quantify glucose uptake in activated CD8+ T cells. We found that cells exhibiting limited glucose incorporation had a molecular profile characteristic of memory precursor cells and an increased capacity to enter the memory pool compared with cells taking up high amounts of glucose. Accordingly, enforcing glycolytic metabolism by overexpressing the glycolytic enzyme phosphoglycerate mutase-1 severely impaired the ability of CD8+ T cells to form long-term memory. Conversely, activation of CD8+ T cells in the presence of an inhibitor of glycolysis, 2-deoxyglucose, enhanced the generation of memory cells and antitumor functionality. Our data indicate that augmenting glycolytic flux drives CD8+ T cells toward a terminally differentiated state, while its inhibition preserves the formation of long-lived memory CD8+ T cells. These results have important implications for improving the efficacy of T cell-based therapies against chronic infectious diseases and cancer.
TGFBI expression is associated with a better response to chemotherapy in NSCLC
Authors: Marta Irigoyen, María J Pajares, Jackeline Agorreta, Mariano Ponz-Sarvisé, Elisabeth Salvo, María D Lozano, Ruben Pío, Ignacio Gil-Bazo, Ana Rouzaut
Journal: Molecular Cancer (2010)

Abstract Background Lung cancer is one of the most prevalent neoplasias in developed countries. Advances in patient survival have been limited and the identification of prognostic molecules is needed. Resistance to treatment is strongly related to tumor cell adhesion to the extracellular matrix and alterations in the quantity and nature of molecules constituting the tumor cell niche. Recently, transforming growth factor beta-induced protein (TGFBI), an extracellular matrix adaptor protein, has been reported to be differentially expressed in transformed tissues. Loss of TGFBI expression has been described in several cancers including lung carcinoma, and it has been suggested to act as a tumor suppressor gene. Results To address the importance of TGFBI expression in cancer progression, we determined its expression in NSCLC clinical samples using immunohistochemistry. We identified a strong association between elevated TGFBI expression and the response to chemotherapy. Furthermore, we transiently over-expressed and silenced TGFBI in human NSCLC cell lines. Cells over-expressing TGFBI displayed increased sensitivity to etoposide, paclitaxel, cisplatin and gemcitabine. We observed that TGFBI-mediated induction of apoptosis occurred through its binding to αvβ3 integrin. We also determined that full-length TGFBI did not induce caspase 3/7 activation but its proteolytic fragments that were &lt; 3 kDa in size, were able to activate caspase 3, 7 and 8. This pro-apoptotic effect was blocked by anti-αvβ3 integrin antibodies. Conclusions The results shown here indicate that TGFBI is a predictive factor of the response to chemotherapy, and suggest the use of TGFBI-derived peptides as possible therapeutic adjuvants for the enhancement of responses to chemotherapy.