tbuckley/cabot-search huggingface dataset:
Restriction-Modification Systems as Mobile Genetic Elements in the Evolution of an Intracellular Symbiont
Authors: Hao Zheng, Carsten Dietrich, Yuichi Hongoh, Andreas Brune
Journal: Molecular Biology and Evolution (2015)

Long-term vertical transmission of intracellular bacteria causes massive genomic erosion and results in extremely small genomes, particularly in ancient symbionts. Genome reduction is typically preceded by the accumulation of pseudogenes and proliferation of mobile genetic elements, which are responsible for chromosome rearrangements during the initial stage of endosymbiosis. We compared the genomes of an endosymbiont of termite gut flagellates, "Candidatus Endomicrobium trichonymphae," and its free-living relative Endomicrobium proavitum and discovered many remnants of restriction-modification (R-M) systems that are consistently associated with genome rearrangements in the endosymbiont genome. The rearrangements include apparent insertions, transpositions, and the duplication of a genomic region; there was no evidence of transposon structures or other mobile elements. Our study reveals a so far unrecognized mechanism for genome rearrangements in intracellular symbionts and sheds new light on the general role of R-M systems in genome evolution.
Changes in government spending on healthcare and population mortality in the European union, 1995–2010: a cross-sectional ecological study
Authors: Sanjay Budhdeo, Johnathan Watkins, Rifat Atun, Callum Williams, Thomas Zeltner, Mahiben Maruthappu
Journal: Journal of the Royal Society of Medicine (2015)

Economic measures such as unemployment and gross domestic product are correlated with changes in health outcomes. We aimed to examine the effects of changes in government healthcare spending, an increasingly important measure given constrained government budgets in several European Union countries.Multivariate regression analysis was used to assess the effect of changes in healthcare spending as a proportion of total government expenditure, government healthcare spending as a proportion of gross domestic product and government healthcare spending measured in purchasing power parity per capita, on five mortality indicators. Additional variables were controlled for to ensure robustness of data. One to five year lag analyses were conducted.European Union countries 1995-2010.Neonatal mortality, postneonatal mortality, one to five years of age mortality, under five years of age mortality, adult male mortality, adult female mortality.A 1% decrease in government healthcare spending was associated with significant increase in all mortality metrics: neonatal mortality (coefficient -0.1217, p = 0.0001), postneonatal mortality (coefficient -0.0499, p = 0.0018), one to five years of age mortality (coefficient -0.0185, p = 0.0002), under five years of age mortality (coefficient -0.1897, p = 0.0003), adult male mortality (coefficient -2.5398, p = 0.0000) and adult female mortality (coefficient -1.4492, p = 0.0000). One per cent decrease in healthcare spending, measured as a proportion of gross domestic product and in purchasing power parity, was both associated with significant increases (p < 0.05) in all metrics. Five years after the 1% decrease in healthcare spending, significant increases (p < 0.05) continued to be observed in all mortality metrics.Decreased government healthcare spending is associated with increased population mortality in the short and long term. Policy interventions implemented in response to the financial crisis may be associated with worsening population health.
Visual Processing in Monkey Extrastriate Cortex
Authors: J H R Maunsell, W T Newsome
Journal: Annual Review of Neuroscience (1987)

The neuronal processes that lead to visual perception have attracted intense interest since Kuffier's studies of receptive field organization in cat retinal ganglion cells over three decades ago (Kuffier 1953). A variety of ana­ tomical and physiological approaches have been employed to analyze the organization of thc visual pathway between the retina and striate cortex (VI ) and the transformations of visual information that occur at each stage (see Hubel & Wiesel 1977, Stone 1 983, Shapley & Lennie 1985). The growth in understanding of the retinostriate pathway has been accompanied by increasing interest in visual processing in the expanse of extrastriate cortex beyond V I . Studies of extrastriate cortex in many spec­ ies showed that it comprises a mosaic of visual areas that can be dis­ tinguished by several anatomical and physiological criteria (reviewed by Kaas 1 978, Zeki 1 978, Cowey 1979, Van Essen 1 979, 1985, Wagor et al 1980, Tusa et al 1 98 1) . The literature in this field is large, and we do not attempt to review all relevant studies. Rather, we concern ourselves with three recent devel­ opments that have yielded insight into information processing and flow within extrastriate cortex. The first of these is the convergence of ana tom-
A Phase I Trial of BKM120 (Buparlisib) in Combination with Fulvestrant in Postmenopausal Women with Estrogen Receptor–Positive Metastatic Breast Cancer
Authors: Cynthia X. Ma, Jingqin Luo, Michael Naughton, Foluso Ademuyiwa, Rama Suresh, Malachi Griffith, Obi L. Griffith, Zachary L. Skidmore, Nicholas C. Spies, Avinash Ramu, Lee Trani, Timothy Pluard, Gayathri Nagaraj, Shana Thomas, Zhanfang Guo, Jeremy Hoog, Jing Han, Elaine Mardis, Craig Lockhart, Matthew J. Ellis
Journal: Clinical Cancer Research (2015)

This trial was conducted to determine the maximum tolerated dose (MTD) and preliminary efficacy of buparlisib, an oral pan-class I PI3K inhibitor, plus fulvestrant in postmenopausal women with metastatic estrogen receptor positive (ER(+)) breast cancer.Phase IA employed a 3+3 design to determine the MTD of buparlisib daily plus fulvestrant. Subsequent cohorts (phase IB and cohort C) evaluated intermittent (5/7-day) and continuous dosing of buparlisib (100 mg daily). No more than 3 prior systemic treatments in the metastatic setting were allowed in these subsequent cohorts.Thirty-one patients were enrolled. MTD was defined as buparlisib 100 mg daily plus fulvestrant. Common adverse events (AE) included fatigue (38.7%), transaminases elevation (35.5%), rash (29%), and diarrhea (19.4%). C-peptide was significantly increased during treatment, consistent with on-target effect of buparlisib. Compared with intermittent dosing, daily buparlisib was associated with more frequent early onset AEs and higher buparlisib plasma concentrations. Among the 29 evaluable patients, the clinical benefit rate was 58.6% (95% CI, 40.7%-74.5%). Response was not associated with PIK3CA mutation or treatment cohort; however, loss of PTEN, progesterone receptor (PgR) expression, or mutation in TP53 was most common in resistant cases, and mutations inAKT1 and ESR1 did not exclude treatment response.Buparlisib plus fulvestrant is clinically active with manageable AEs in patients with metastatic ER(+)breast cancer. Weekend breaks in buparlisib dosing reduced toxicity. Patients with PgR negative and TP53 mutation did poorly, suggesting buparlisib plus fulvestrant may not be adequately effective against tumors with these poor prognostic molecular features.
Mesodermal iPSC–derived progenitor cells functionally regenerate cardiac and skeletal muscle
Authors: Mattia Quattrocelli, Melissa Swinnen, Giorgia Giacomazzi, Jordi Camps, Ines Barthélemy, Gabriele Ceccarelli, Ellen Caluwé, Hanne Grosemans, Lieven Thorrez, Gloria Pelizzo, Manja Muijtjens, Catherine M. Verfaillie, Stephane Blot, Stefan Janssens, Maurilio Sampaolesi
Journal: Journal of Clinical Investigation (2015)

Conditions such as muscular dystrophies (MDs) that affect both cardiac and skeletal muscles would benefit from therapeutic strategies that enable regeneration of both of these striated muscle types. Protocols have been developed to promote induced pluripotent stem cells (iPSCs) to differentiate toward cardiac or skeletal muscle; however, there are currently no strategies to simultaneously target both muscle types. Tissues exhibit specific epigenetic alterations; therefore, source-related lineage biases have the potential to improve iPSC-driven multilineage differentiation. Here, we determined that differential myogenic propensity influences the commitment of isogenic iPSCs and a specifically isolated pool of mesodermal iPSC-derived progenitors (MiPs) toward the striated muscle lineages. Differential myogenic propensity did not influence pluripotency, but did selectively enhance chimerism of MiP-derived tissue in both fetal and adult skeletal muscle. When injected into dystrophic mice, MiPs engrafted and repaired both skeletal and cardiac muscle, reducing functional defects. Similarly, engraftment into dystrophic mice of canine MiPs from dystrophic dogs that had undergone TALEN-mediated correction of the MD-associated mutation also resulted in functional striatal muscle regeneration. Moreover, human MiPs exhibited the same capacity for the dual differentiation observed in murine and canine MiPs. The findings of this study suggest that MiPs should be further explored for combined therapy of cardiac and skeletal muscles.
Clonal Expansion Versus Functional Clonal Inactivation: A Costimulatory Signalling Pathway Determines the Outcome of T Cell Antigen Receptor Occupancy
Authors: D L Mueller, M K Jenkins, R H Schwartz
Journal: Annual Review of Immunology (1989)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
Junior doctors' hours
Authors: T. English
Journal: BMJ (1995)

adequate measures to ensure the safety of those who perform abortions or work in facilities where the procedure is performed.Doctors and other health care workers who dedicate their lives to meeting the health care needs of Americans should be ensured the right to work in a safe environment.Violence against health care workers is unacceptable.The American Medical Association has long condemned acts of terrorism against health care workers and will continue to do so.
Antigen Receptors on B Lymphocytes
Authors: Michael Reth
Journal: Annual Review of Immunology (1992)

Recent studies on the structure of the B cell antigen receptor demonstrate that the membrane-bound and antigen-binding immunoglobulin molecules are noncovalently associated with a heterodimer of two novel transmembrane proteins. The B cell antigen receptor is thus a multicomponent receptor complex whose structural features are similar to those of the T cell antigen receptor complex. Cross-linking of the B cell antigen receptor results in rapid tyrosine phosphorylation of substrate proteins. This suggests that the B cell receptor belongs to a subgroup of the tyrosine kinase receptor family with a noncovalently associated src-like tyrosine kinase.
Nebulised therapy in pregnants with acute respiratory virus infections (ARVI)
Authors: Janna Pahomova, Durdona Ashurova, Rustem Hayaliev
Journal: European Respiratory Journal (2012)

In extragenital pathology of pregnants ARVI occupy the first place - more than 2/3 from the general disease with sharp infections. Identical respiratory support is the most important and necessary component of complex therapy. Advisable to combine the lung ventilation with entering the medicinal preparations through nebuliser that allows to perfect mucociliar clirens, decrease inefficient and unproductive cough. In I trimester of pregnancy possible using mucolytics, bronchodilatators, antibiotics. It was analysed medical documentation of 65 pregnants with ARVI. The threat of the interruption of pregnancy developed in 45 (69,23%) cases: in I-st trimester in 27 (41,53%), in II-d - 14 (21,53%), and in III-rd in 4 (6,15%) pregnants. Intrauterine fetal hypoxy developed in 29 (44,61%) cases after carried out ARVI. The delay of development of the fetus was diagnosed in 21 (32,3%) pregnants. In 36 (55,38%) pregnants developed preeclampsy of low degree, in 17 (26,15%) cases of average degree. For reduction of the risk of toxic influences preparation on fetus we recommend active using respiratory therapy in pregnant with ARVI. In 28 pregnants with ARVI since november 2011y to February 2012y broadly used nebulised therapy with different preparation. As a result the more quick regression of viral intoxication, improvement of functions of the external breathing and increasing saturation of the blood oxygen, reduction of the complications was noted: threat of the interruption developed in 9 (32,14%) pregnants, intrauterine fetal hypoxy in 10 (35,7%) pregnants. In 13 (46,42%) pregnants developed preeclampsy of low degree. Preeclampsy of average degree developed in 5 (17,85%) pregnants.
Letrozole, berberine, or a combination for infertility in Chinese women with polycystic ovary syndrome: a multicentre, randomised, double-blind, placebo-controlled trial
Authors: Xiao-Ke Wu, Yong-Yan Wang, Jian-Ping Liu, Li-Hui Hou, Ya-Qin Gao, Shao-Min Du, Ying Yan, Jin-Feng Zhang, Hui-Ying Xue, Wei-Li Li, Rui-Ning Liang, Zhen-Yu Tan, Jin-Ying Fu, Hong-Xia Ma, Xiao-Guang Shao, Feng-Jie He, Mu-Er An, Pei-Lin Li, Cai-Fei Ding, Xiao-Bin Li, Xian-Ji Shen, Guang-Zhu Yu, Feng Tian, Yan-Ming Xie, Robert M Silver, Elisabet Stener-Victorin, Ernest HY Ng
Journal: The Lancet (2015)
Return to sports after anterior cruciate ligament injury: neither surgery nor rehabilitation alone guarantees success—it is much more complicated
Authors: R Thomeé, M Waldén, M Hägglund
Journal: British Journal of Sports Medicine (2015)

Complex factors influence the likelihood of ACL injured athletes to return to sports.For example, a systematic review from 2014 (1), found weak evidence that higher quadriceps strength, less effusion, less pain, greater tibial rotation, higher Marx Activity score, higher athletic confidence, higher preoperative knee self-efficacy, lower kinesiophobia and higher preoperative self-motivation were associated with returning to sport after ACL reconstruction.Another recent systematic review (2), found that hopping performance, younger age, male gender, participation in elite sport, and having a positive psychological response favoured returning to the pre-injury level of sport.Similarly, a systematic review (3) of level II and III studies found that the following factors contributed to better functional outcomes after ACL reconstruction; male gender, age less than 30 years, reconstruction within three months, and high baseline activity level.Outcome after rehabilitation was negatively affected by smoking, high body mass index, low quadriceps strength, and range-of-motion deficits.No evidence was found for preoperative anterior laxity to influence rehabilitation.(3)It is, however, still somewhat unclear if and in what way these factors influence the athlete's ability and/or decision to return to sport, and it is likely that many factors interact in a complex manner.There are thus many questions to be answered regarding what characterizes athletes who successfully will be able to return to sports, as well as those who will not, after ACL injury in terms of physiological, psychological, sociological and other factors.
Adoptive immunotherapy with vaccine-primed lymph node cells secondarily activated with anti-CD3 and interleukin-2.
Authors: A E Chang, A Aruga, M J Cameron, V K Sondak, D P Normolle, B A Fox, S Shu
Journal: Journal of Clinical Oncology (1997)

PURPOSE In preclinical studies, we have reported the ability to induce immune T cells in lymph nodes (LN) primed by in vivo vaccination with tumor cells admixed with a bacterial adjuvant. These LN cells can be activated and expanded ex vivo for the successful immunotherapy of established tumors. We have applied these methods to generate vaccine-primed LN in patients with advanced melanoma and renal cell cancer (RCC) for therapy. MATERIALS AND METHODS Irradiated autologous tumor cells admixed with bacille Calmette-Guérin (BCG) were used to vaccinate patients. Seven days later, draining LN were removed for activation with anti-CD3 monoclonal antibody (mAb) followed by expansion in interleukin-2 (IL-2). Activated LN cells were administered intravenously (IV) with the concomitant administration of IL-2. RESULTS A total of 23 patients were evaluated (11 melanoma and 12 RCC). Vaccine-primed LN were expanded ex vivo with a mean of 8.4 x 10(10) cells administered per patient. Among 20 patients assessed, 15 demonstrated minimal cytotoxicity of autologous tumor cells by the activated LN cells, with the remaining mediating nonspecific cytotoxicity. By contrast, a majority of the activated LN cells showed highly specific release of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon gamma (IFN-gamma) to autologous but not allogeneic tumor stimulation. This tumor-specific cytokine release was found to be major histocompatibility complex (MHC) class I-restricted, which indicates the involvement of CD8+ cells. Among 11 melanoma patients, one had a partial tumor response. Among 12 RCC patients, two had complete and two partial responses. A trend (P = .066) between the enhancement of delayed-type hypersensitivity (DTH) reactivity to autologous tumor after therapy and tumor regression was observed. CONCLUSION Tumor vaccines can be used to induce immunologically specific T-cell responses against melanoma and RCC in draining LN. Anti-CD3/IL-2 activation of primed LN cells can be reliably performed for clinical therapy and appears to have activity in patients with metastatic RCC.
Aggravation of airway inflammation and hyper‐responsiveness following nasal challenge with <i>Dermatophagoides pteronyssinus</i> in perennial allergic rhinitis without symptoms of asthma
Authors: W. Wang, M. Xian, Y. Xie, J. Zheng, J. Li
Journal: Allergy (2015)

House dust mites are the most prevalent allergen causing sensitizations in patients with rhinitis and asthma in China. We aimed to investigate the changes in both upper and lower airway inflammation and responsiveness following Dermatophagoides pteronyssinus (Der-p) nasal provocation test (NPT) in rhinitis patients.Study subjects included 15 nonasthmatic Der-p-sensitized rhinitis (AR) patients with airway hyper-responsiveness (AHR) (AR+AHR+), 15 AR patients without AHR (AR+AHR-), 15 healthy controls (HCs) with Der-p sensitization (HC+DP+), and 15 HC without Der-p sensitization (HC+DP-). All subjects underwent Der-p NPT. Visual analogue scale (VAS) scores of nasal symptoms, nasal lavage and nasal airway resistance (NAR) measurement, sputum induction, and forced expiratory volume in 1 second (FEV1 ) were performed. Airway responsiveness to histamine bronchoprovocation (PD20 -FEV1 ) and exhaled nitric oxide (FeNO) was determined.NAR increased significantly in all subjects with the greatest effect seen in AR+AHR+ individuals. VAS increased in all subjects at 30 min and returned to baseline at 6 h, with significantly higher levels in AR+AHR+ and AR+AHR- subjects (P < 0.05). Eosinophils in nasal lavage fluid and sputum increased significantly after NPT in AR+AHR+ and AR+AHR- subjects (P < 0.001). FEV1 % and PD20 -FEV1 decreased and FeNO increased significantly after NPT only in AR+AHR+ subjects (P < 0.05). Nasal lavage eosinophil count was positively correlated with sputum eosinophil count and the level of FeNO and negatively correlated with FEV1 and PD20 .House dust mite nasal provocation test induces and aggravates both upper and lower airway inflammation and hyper-responsiveness in patients with persistent allergic rhinitis without asthmatic symptoms.
Leukotriene-Receptor Antagonists Versus Placebo in the Treatment of Asthma in Adults and Adolescents
Authors: Michael Miligkos, Raveendhara R. Bannuru, Hadeel Alkofide, Sucharita R. Kher, Christopher H. Schmid, Ethan M. Balk
Journal: Annals of Internal Medicine (2015)

Leukotriene-receptor antagonists (LTRAs) are recommended as an alternative treatment in patients with mild asthma, but their effect compared with placebo is unclear.To determine the benefits and harms of LTRAs as monotherapy or in combination with inhaled corticosteroids compared with placebo in adults and adolescents with asthma.MEDLINE and the Cochrane Central Register of Controlled Trials from inception through June 2015.Peer-reviewed, English-language, randomized, controlled trials in patients with asthma that reported the effect of LTRAs versus placebo on measures of asthma control.Three researchers extracted data on study population, interventions, outcome measures, and adverse events. One researcher assessed risk of bias.Of the 2008 abstracts that were screened, 50 trials met eligibility criteria. Random-effects meta-analyses of 6 trials of LTRA monotherapy showed that LTRAs reduced the risk for an exacerbation (summary risk ratio [RR], 0.60 [95% CI, 0.44 to 0.81]). In 4 trials of LTRAs as add-on therapy to inhaled corticosteroids, the summary RR for exacerbation was 0.80 (CI, 0.60 to 1.07). Leukotriene-receptor antagonists either as monotherapy or as add-on therapy to inhaled corticosteroids increased FEV1, whereas FEV1 percentage of predicted values was improved only in trials of LTRA monotherapy. Adverse event rates were similar in the intervention and comparator groups.Variation in definitions and reporting of outcomes, high risk of bias in some studies, heterogeneity of findings, possible selective outcome reporting bias, and inability to assess the effect of asthma severity on summary estimates.Leukotriene-receptor antagonists as monotherapy improved asthma control compared with placebo, but which patients are most likely to respond to treatment with LTRAs remains unclear.National Institutes of Health.
Development of a high-capacity cell migration/chemotaxis assay for monocytes.
Authors: Lothar Goretzki, Jue Wang, Mo Saedi
Journal: Cancer Research (2008)

1544  Cell migration is crucial for embryonic development, the inflammatory immune response, wound repair, and tumor invasion and metastasis. Monocytes circulate in the blood stream for about one to three days and then typically migrate into tissues throughout the body. In immune responses, monocyte migration is critical for providing immunological defense and eliminating infectious agents. Circulating monocytes have the capacity to differentiate into a variety of phagocytes, including macrophages, dendritic cells, osteoclasts, microglia in the central nervous system, and Kupffer cells in the liver. To facilltate the assessment of the migratory capacity of monocytes against various chemotactic stimuli and the effect of inhibitory compounds on monocyte migration, we developed a convenient high-capacity migration/chemotaxis assay for monocytes.  The Monocyte Cell Migration Assay Kit is based on the widely accepted Boyden Chamber principle and in a 96-well format. The presented assay procedure is convenient and does not require a cell dissociation or cell lysis step. The cells are labeled with the cell-permeable green fluorescent dye calcein-AM, subsequent to a simple centrifugation step.  We validated the assay using THP-1 cells (acute monocytic leukemia) and U937 cells (histiocytic lymphoma). Both cell lines were attracted by serum in a dose-dependent manner; however, the U937 cells displayed a weaker migratory capacity than the THP-1 cells. In addition, we employed monocyte chemotactic protein-1 (MCP-1) as a chemoattractant in the lower chamber. MCP-1 is a member of the small inducible gene (SIG) family, plays a role in the recruitment of monocytes to sites of injury and infection. THP-1 cells migrated towards MCP-1 in a dose-dependent fashion, whereas U937 cells were rather unresponsive. To demonstrate that the assay is also useful for screening of inhibitors we incubated THP-1 cells in the presence of 1μM Latrunculin, a powerful inhibitor of actin polymerization. In the presence of the inhibitor THP-1 cell migration was significantly impeded.  In conclusion, we present a fluorescent, high-capacity cell migration/chemotaxis assay for monocytes useful for screening of potential anti-migratory compounds or pro-migratory substances (chemotactic stimuli), respectively.