tbuckley/cabot-search huggingface dataset:
Making informed choices on co-sleeping with your baby
Authors: Peter J Fleming, Peter S Blair
Journal: BMJ (2015)

Avoid smoking, alcohol, recreational drugs, and co-sleeping on the sofa

For most of human history, and in most parts of the world today, sharing a sleep surface (“co-sleeping”) with the primary caregiver—almost always the mother—has been the normal experience of most human infants. Such close contact has benefits for the baby, including facilitating breast feeding, and even in modern Western societies infant mortality is significantly lower among breast fed infants.1 Routine co-sleeping is common in Western societies and is thought to be increasing with increased breast feeding; studies have shown a close bidirectional relation between breast feeding and co-sleeping.2 On any given night in the UK, around one quarter of infants under 6 months of age spend part or all of the night sharing a sleep surface with a sleeping parent.3

Against this background is the recognition that, since the large fall in the number of sudden infant deaths that followed the “Back to Sleep” campaign, the proportion of such deaths occurring while co-sleeping has risen.4 In some countries, notably the United States, many professionals have accepted that co-sleeping substantially contributes to unexpected infant deaths and should be discouraged.5

For parents who smoke, …
ADSORPTION OF INFLUENZA VIRUS ON CELLS OF THE RESPIRATORY TRACT
Authors: George K. Hirst
Journal: The Journal of Experimental Medicine (1943)

A study of the reaction between influenza virus and the cells of the excised and perfused ferret lung has yielded the following results: (1) The cells of the lung rapidly adsorbed large amounts of intratracheally inoculated virus. (2) After a short interval the pulmonary cells began spontaneously to release the adsorbed virus, and in the case of influenza B the release was 75 per cent complete after 5 hours. (3) The Lee strain was more completely released from pulmonary cells after 5 hours than was the PR8 strain. (4) After the cells released the adsorbed virus they appeared incapable of adsorbing virus as before. (5) When the mouse-infecting capacity of the virus had been done away with by heat or formalin, the virus was adsorbed by the pulmonary cells but was not released. In all except the last of the characteristics listed the interaction between influenza virus and the pulmonary cells closely resembles that between influenza virus and avian red blood cells. In the living ferret inhaled influenza virus was also rapidly adsorbed by the lung, but in a very short time the adsorbed virus which at first could be readily eluted (after perfusion and excision of the lung) became so much more firmly fixed as not to be released by this method. Free virus could not be demonstrated in the living ferret until 24 hours after the animal had been exposed to the inoculum. On the basis of these and previous experiments it is postulated that the destruction of a specific receptor substance,—which may involve an enzymatic reaction,—may be a necessary preliminary event in the parasitism of susceptible cells by influenza virus.
Different responses are elicited in cytotoxic T lymphocytes by different levels of T cell receptor occupancy.
Authors: S Valitutti, S Müller, M Dessing, A Lanzavecchia
Journal: The Journal of Experimental Medicine (1996)

We have investigated the level of TCR occupancy required to elicit different biological responses in human CTL clones specific for an influenza matrix peptide. Specific cytotoxicity could be detected at extremely low peptide concentrations (10(-12) to 10(-15) M). However, IFN-gamma production, responsiveness to IL-2 and Ca++ fluxes were observed only at peptide concentrations > 10(-9) M, while autonomous proliferation required even higher peptide concentrations. In parallel experiments we measured TCR downregulation to estimate the number of TCRs triggered. We observed that at low peptide concentrations, where only cytotoxicity is triggered, TCR downregulation was hardly detectable. Conversely, induction of IFN-gamma production and proliferation required triggering of at least 20-50% of TCRs. Taken together these results indicate that a single CTL can graduate different biological responses as a function of antigen concentration and that killing of the specific target does not necessarily result in full activation.
Dendritic cells initiate a two-stage mechanism for T lymphocyte proliferation.
Authors: J M Austyn, R M Steinman, D E Weinstein, A Granelli-Piperno, M A Palladino
Journal: The Journal of Experimental Medicine (1983)

T cells oxidized with sodium periodate proliferate polyclonally in response to accessory cells. We confirmed previous work showing that DC are potent stimulators of this response. In addition, the accessory function of unfractionated mouse spleen and spleen adherent cells was markedly reduced after elimination of DC with a specific monoclonal antibody and complement. Therefore oxidative mitogenesis was used as a model to study the mechanism by which DC stimulate T cell proliferative responses. A two-stage mechanism was identified. The first stage occurred during the first 20 h of culture, required live DC, and involved the progressive release of interleukin 2 (IL-2) into the medium and acquisition of responsiveness to this growth factor. The second stage occurred between 20 and 40 h, did not require live DC, and involved DNA synthesis in response to IL-2. Similar events occurred during culture of DC with unmodified T cells (syngeneic MLR) but were quantitatively reduced. The experimental approach was to co-culture DC and T cells for up to 20 h and then kill the DC with specific antibody, or anti-Ia antibody, and complement. Subsequent proliferation was inhibited if the T cells were cultured in fresh medium. However, proliferation was restored when the lymphocytes were cultured in the original DC-T cell medium, or with a crude or a purified preparation of IL-2. IL-2 did not induce the proliferation of T cells that had been cultured in the absence of DC, and did not synergize with viable DC. We conclude that DC induce proliferation by tightly coordinating the release of, and responsiveness to, T cell growth factor or IL-2.
Amniotic mesenchymal stem cells have robust angiogenic properties and are effective in treating hindlimb ischaemia
Authors: Sung-Whan Kim, Hong-Zhe Zhang, Chae Eun Kim, Hyun Sook An, Jong-Min Kim, Moo Hyun Kim
Journal: Cardiovascular Research (2011)

In this study, we aimed to evaluate whether human amniotic mesenchymal stem cells (AMMs) have angio-vasculogenic properties and to determine their therapeutic effects on experimental ischaemia. Although AMMs are a promising source of stem cells, their angio-vasculogenic properties are not fully understood. We have characterized AMMs by quantitative real-time polymerase chain reaction, Matrigel tube formation assays, and various in vitro endothelial differentiation assays. AMMs expressed significantly higher levels of representative proangiogenic genes, vascular endothelial growth factor-A, angiopoietin-1, hepatocyte growth factor, and fibroblast growth factor-2 (FGF-2) than adipose-derived mesenchymal stem cells. In addition, the anti-apoptotic factor Akt-1 was highly expressed in the AMMs. Cells were directly transplanted into the ischaemic hindlimbs of mice to evaluate their angio-vasculogenic and therapeutic effects. They spontaneously differentiate into vascular-like structures and exhibit endothelial-specific genes and proteins. In an in vivo study on hindlimb ischaemia, implantation of AMMS augmented blood perfusion and capillary density, indicating AMM-augmented neovascularization. The engraftment rate of AMMs was high, and the transplanted AMMs showed vasulogenic potential. AMMs are not only markedly angiogenic but also vasculogenic, thus ameliorating hindlimb ischaemia. Our data suggest that AMMs have considerable therapeutic effects on ischaemic hindlimb through high angiogenic and engraftment abilities.
The importance of sports medicine for the Vancouver Olympic Games
Authors: Lars Engebretsen, Kathrin Steffen
Journal: British Journal of Sports Medicine (2009)

I remember Turin well. As the head doctor for Norway I witnessed our best alpine skier injure his knee at the very first vertical in the downhill race. The injury probably prevented him from winning a medal that day. However, he managed to recover incredibly fast and won the Gold medal in Super-G 1 week later. Many have not been as lucky as this! In the current edition of IPHP , Florenes et al describe the injury incidence among World Cup alpine skiers, and their injury rate is indeed high!1 (see page 973) This is the first large cohort study to examine the overall injury risk and detailed injury patterns among World Cup alpine skiers during the competitive season. The main findings reveal that the injury incidence for elite alpine skiers was higher than reported previously, in general higher for men than women, and that the injury rate increased with skiing speed. The knee was the most commonly injured body part, with a majority of severe injuries. Notably, as many as 38% of all time-loss injuries caused an absence of more than 1 month (more than 28 days). …
Hippocampal Morphology and Distinguishing Late-Onset From Early-Onset Elderly Depression
Authors: Martina Ballmaier, Katherine L. Narr, Arthur W. Toga, Virginia Elderkin-Thompson, Paul M. Thompson, Liberty Hamilton, Ebrahim Haroon, Daniel Pham, Andreas Heinz, Anand Kumar
Journal: American Journal of Psychiatry (2007)

Despite evidence for hippocampal abnormalities in elderly depression, it is unknown whether these changes are regionally specific. This study used three-dimensional mapping techniques to identify regional hippocampal abnormalities in early- and late-onset depression. Neuropsychological correlates of hippocampal morphology were also investigated.With high-resolution magnetic resonance imaging, hippocampal morphology was compared among elderly patients with early- (N=24) and late-onset (N=22) depression and comparison subjects (N=34). Regional structural abnormalities were identified by comparing distances, measured from homologous hippocampal surface points to the central core of each individual's hippocampal surface model, between groups.Hippocampal volumes differed between depressed patients and comparison subjects but not between patients with early- and late-onset depression. However, statistical mapping results showed that regional surface contractions were significantly pronounced in late- compared to early-onset depression in the anterior of the subiculum and lateral posterior of the CA1 subfield in the left hemisphere. Significant shape differences were observed bilaterally in anterior CA1-CA3 subfields and the subiculum in patients in relation to comparison subjects. These results were similar when each disease group was separately compared to comparison subjects. Hippocampal surface contractions significantly correlated with memory measures among late- but not early-onset depressed patients or comparison subjects.More pronounced regional volume deficits and their associations with memory in late-onset depression may suggest that these patients are more likely to develop cognitive impairment over time than individuals with early-onset depression. Mapping regional hippocampal abnormalities and their cognitive correlates may help guide research in defining risk profiles and treatment strategies.
Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR
Authors: Makoto Maemondo, Akira Inoue, Kunihiko Kobayashi, Shunichi Sugawara, Satoshi Oizumi, Hiroshi Isobe, Akihiko Gemma, Masao Harada, Hirohisa Yoshizawa, Ichiro Kinoshita, Yuka Fujita, Shoji Okinaga, Haruto Hirano, Kozo Yoshimori, Toshiyuki Harada, Takashi Ogura, Masahiro Ando, Hitoshi Miyazawa, Tomoaki Tanaka, Yasuo Saijo, Koichi Hagiwara, Satoshi Morita, Toshihiro Nukiwa
Journal: New England Journal of Medicine (2010)

Non-small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor (EGFR) is highly responsive to EGFR tyrosine kinase inhibitors such as gefitinib, but little is known about how its efficacy and safety profile compares with that of standard chemotherapy.We randomly assigned 230 patients with metastatic, non-small-cell lung cancer and EGFR mutations who had not previously received chemotherapy to receive gefitinib or carboplatin-paclitaxel. The primary end point was progression-free survival; secondary end points included overall survival, response rate, and toxic effects.In the planned interim analysis of data for the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P<0.001), resulting in early termination of the study. The gefitinib group had a significantly longer median progression-free survival (10.8 months, vs. 5.4 months in the chemotherapy group; hazard ratio, 0.30; 95% confidence interval, 0.22 to 0.41; P<0.001), as well as a higher response rate (73.7% vs. 30.7%, P<0.001). The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P=0.31). The most common adverse events in the gefitinib group were rash (71.1%) and elevated aminotransferase levels (55.3%), and in the chemotherapy group, neutropenia (77.0%), anemia (64.6%), appetite loss (56.6%), and sensory neuropathy (54.9%). One patient receiving gefitinib died from interstitial lung disease.First-line gefitinib for patients with advanced non-small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy. (UMIN-CTR number, C000000376.)
The Cost of Preventing Diabetes
Authors: Steven Teutsch
Journal: Diabetes Care (2003)

The landmark Diabetes Prevention Program (DPP) demonstrated that we can prevent diabetes (1). The DPP study in this issue of Diabetes Care (2) presents the costs of that intervention. The challenge is how to implement those findings in real-world clinical practice settings. I will first provide a framework for thinking about a cost study and then comment more specifically on the findings.

Randomized clinical trials (RCTs) answer the first important question—is an intervention efficacious? That is, can it work? RCTs are carefully structured to optimize the opportunity to demonstrate that an intervention can work; hence, they are conducted in relatively idealized environments. Patients are carefully identified, not only for their clinical characteristics, but also because of their willingness to participate as subjects. Institutions with strong research and clinical support environments are selected to ensure that interventions are delivered as optimally as possible to enhance the likelihood that any real effect will indeed be found. If the trial demonstrates efficacy, we have proof of concept. Yet, we know that simply showing that there is an efficacious strategy is insufficient. Translating those findings into routine practice is a critical and daunting challenge. Only 25% of hypertensive patients have their blood pressure controlled despite over a quarter of a century of concerted effort. Thus, showing that interventions can work is simply not enough.

The questions we really want answered concern not the efficacy of an intervention, but its effectiveness—how well does intervention work in practice? What is the balance between its benefits and harms? These issues require an understanding of the barriers to implementation and the development of appropriate systems and incentives to ensure delivery of and adherence to regimens on the part of providers and patients.

One of …
IL-4 blocks TH1-polarizing/inflammatory cytokine gene expression during monocyte-derived dendritic cell differentiation through histone hypoacetylation
Authors: María López-Bravo, María Minguito de la Escalera, Pilar M. Domínguez, Leticia González-Cintado, Carlos del Fresno, Pilar Martín, Gloria Martínez del Hoyo, Carlos Ardavín
Journal: Journal of Allergy and Clinical Immunology (2013)
Fine mapping and conditional analysis identify a new mutation in the autoimmunity susceptibility gene BLK that leads to reduced half-life of the BLK protein
Authors: Angélica M Delgado-Vega, Mikhail G Dozmorov, Manuel Bernal Quirós, Ying-Yu Wu, Belén Martínez-García, Sergey V Kozyrev, Johan Frostegård, Lennart Truedsson, Enrique de Ramón, María F González-Escribano, Norberto Ortego-Centeno, Bernardo A Pons-Estel, Sandra D'Alfonso, Gian Domenico Sebastiani, Torsten Witte, Bernard R Lauwerys, Emoke Endreffy, László Kovács, Carlos Vasconcelos, Berta Martins da Silva, Jonathan D Wren, Javier Martin, Casimiro Castillejo-López, Marta E Alarcón-Riquelme
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> To perform fine mapping of the autoimmunity susceptibility gene BLK and identify functional variants involved in systemic lupus erythematosus (SLE). <h3>Methods</h3> Genotyping of 1163 European SLE patients and 1482 controls and imputation were performed covering the BLK gene with 158 single-nucleotide polymorphisms. Logistic regression analysis was done using PLINK and conditional analyses using GENABEL9s test score. Transfections of BLK constructs on HEK293 cells containing the novel mutation or the wild type form were analysed for their effect on protein half-life using a protein stability assay, cycloheximide and western blot. CHiP-qPCR for detection of nuclear factor κ B (NFkB) binding. <h3>Results</h3> Fine mapping of BLK identified two independent genetic effects with functional consequences: one represented by two tightly linked associated haplotype blocks significantly enriched for NFκB-binding sites and numerous putative regulatory variants whose risk alleles correlated with low BLK mRNA levels. Binding of NFkBp50 and p65 to an associated 1.2 Kb haplotype segment was confirmed. A second independent genetic effect was represented by an Ala71Thr, low-frequency missense substitution with an OR=2.31 (95% CI 1.38 to 3.86). The 71Thr decreased BLK protein half-life. <h3>Conclusions</h3> These results show that rare and common regulatory variants in BLK are involved in disease susceptibility and both, albeit independently, lead to reduced levels of BLK protein.
Siltuximab, a Novel Anti–Interleukin-6 Monoclonal Antibody, for Castleman's Disease
Authors: Frits van Rhee, Luis Fayad, Peter Voorhees, Richard Furman, Sagar Lonial, Hossein Borghaei, Lubomir Sokol, Julie Crawford, Mark Cornfeld, Ming Qi, Xiang Qin, Jennifer Herring, Corey Casper, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2010)

Interleukin-6 (IL-6) has emerged as a key factor in the pathogenesis of the atypical lymphoproliferative disorder Castleman's disease (CD). Siltuximab is a new anti-IL-6, chimeric monoclonal antibody with potential therapeutic benefit in patients with CD.We report interim results from an open-label, dose-finding, seven-cohort, phase I study in which patients with symptomatic, multicentric or unresectable, unicentric CD received siltuximab at 1-, 2-, or 3-week intervals. The main efficacy end point of clinical benefit response (CBR) was defined as a composite of clinical and laboratory measures relevant to the management of CD. In addition, radiologic response was independently assessed by using modified Cheson criteria.Eighteen (78%) of 23 patients (95% CI, 56% to 93%) achieved CBR, and 12 patients (52%) demonstrated objective tumor response. All 11 patients (95% CI, 72% to 100%) treated with the highest dose of 12 mg/kg achieved CBR, and eight patients (73%) achieved objective tumor response. Overall objective-response duration ranged from 44 to > or = 889 days, and one patient had complete response for > or = 318 days. Hemoglobin increased markedly in 19 patients (median increase, 2.1 g/dL; range, 0.2 to 4.7 g/dL) in the absence of transfusion or erythropoiesis-stimulating agents. No dose-limiting toxicity was reported, and only three patients had grade 3 or higher adverse events after a median exposure of 331 days (range, 1 to 1,148 days).These interim results strongly suggest that siltuximab is an effective treatment with favorable safety for the management of CD. An additional study is planned to fully evaluate safety and efficacy at the recommended dose of 12 mg/kg every 3 weeks.
Pancreatic Lymph Nodes Are Required for Priming of β Cell Reactive T Cells in NOD Mice
Authors: Marie-Claude Gagnerault, Jian Jian Luan, Chantal Lotton, Françoise Lepault
Journal: The Journal of Experimental Medicine (2002)

Nonobese diabetic (NOD) mice develop spontaneous autoimmune diabetes that results from the destruction of insulin secreting β cells by diabetogenic T cells. The time and location of the encounter of autoantigen(s) by naive autoreactive T cells in normal NOD mice are still elusive. To address these issues, we analyzed diabetes development in mice whose spleen or pancreatic lymph nodes (panLNs) had been removed. Excision of panLNs (panLNx) at 3 wk protected mice against insulin autoantibodies (IAAs), insulitis, and diabetes development almost completely, but had no effect when performed at 10 wk. The protection afforded by panLNx at weaning was not due to modifications of the immune system, the absence of autoreactive T cells, or the increase in the potency of regulatory T cells. That panLNs are dispensable during adult life was confirmed by the capacity of 10-wk-old panLNx irradiated recipients to develop diabetes upon transfer of diabetogenic T cells. In contrast, splenectomy had no effect at any age. Partial excision of mesenteric LN at 3 wk did not prevent accelerated diabetes by cyclophosphamide as panLNx did. Thus, in normal NOD mice, autoreactive T cell initial priming occurs in LNs draining the target organ of the disease from 3 wk of age.