tbuckley/cabot-search huggingface dataset:
Essential role of p53 phosphorylation by p38 MAPK in apoptosis induction by the HIV-1 envelope
Authors: Jean-Luc Perfettini, Maria Castedo, Roberta Nardacci, Fabiola Ciccosanti, Patricia Boya, Thomas Roumier, Nathanael Larochette, Mauro Piacentini, Guido Kroemer
Journal: The Journal of Experimental Medicine (2005)

The proapoptotic activity of the transcription factor p53 critically depends on the phosphorylation of serine 46 (p53S46P). Here, we show that syncytia containing p53S46P could be detected in lymph node biopsies from human immunodeficiency virus (HIV)-1 carriers, in the brain of patients with HIV-1–associated dementia and in cocultures of HeLa expressing the HIV-1 envelope glycoprotein complex (Env) with HeLa cells expressing CD4. In this latter model, cell death was the result of a sequential process involving cell fusion, nuclear fusion (karyogamy), phosphorylation of serine 15 (p53S15P), later on serine 46 (p53S46P), and transcription of p53 target genes. Cytoplasmic p38 mitogen-activated protein kinase (MAPK) was found to undergo an activating phosphorylation (p38T180/Y182P [p38 with phosphorylated threonine 180 and tyrosine 182]) before karyogamy and to translocate into karyogamic nuclei. p38T180/Y182P colocalized and coimmunoprecipitated with p53S46P. Recombinant p38 phosphorylated recombinant p53 on serine 46 in vitro. Inhibition of p38 MAPK by pharmacological inhibitors, dominant-negative p38, or small interfering RNA, suppressed p53S46P (but not p53S15P), the expression of p53-inducible genes, the conformational activation of proapoptotic Bax and Bak, the release of cytochrome c from mitochondria, and consequent apoptosis. p38T180/Y182P was also detected in HIV-1–induced syncytia, in vivo, in patients' lymph nodes and brains. Dominant-negative MKK3 or MKK6 inhibited syncytial activation of p38, p53S46P, and apoptosis. Altogether, these findings indicate that p38 MAPK-mediated p53 phosphorylation constitutes a critical step of Env-induced apoptosis.
The heart as a target organ in systemic allergic reactions: comparison of cardiac analphylaxis in vivo and in vitro.
Authors: N Capurro, R Levi
Journal: Circulation Research (1975)

The purpose of this investigation was to define and quantitatively evaluate cardiac anaphylaxis in vivo. Guinea pigs, passively sensitized with graded amounts of rabbit antipenicilloyl antibody, were anesthetized, ventilated, and challenged intravenously with a constant amount of antigen (anaphylaxis in vivo). In other experiments, guinea pig hearts were excised, perfused in a Langendorff apparatus, and challenged (analphylaxis in vitro). During in vivo anaphylaxis, sinus rate increased 10-30 beats/min, conduction arrhythmias occurred in 15 of 22 experiments, and ventricular fibrillation was seen in 8 of 22 experiments. Tachycardia and arrhythmias began approximately 20 seconds after antigen administration and were accompanied, but not preceded, by respiratory and pressor changes. During in vitro anaphylaxis, sinus rate increased 70-110 beats/min, coronary flow rate decreased 2-22%, conduction arrhythmias occurred in 21 of 31 experiments, and ventricular ectopic activity was seen in 13 of 31 experiments. Tachycardia and arrhythmias began approximately 15 seconds after antigen administration. Sinus tachycardia, atrioventricular conduction block, increased ventricular automaticity, and histamine release were characteristic features of cardiac anaphylaxis in vivo and in vitro. Both in vivo and in vitro, the intensity of the cardiac reaction depended on the amount of antibody used in passive sensitization. Our results clearly indicate that the heart reacts as a target organ in systemic anaphylaxis of the guinea pig.
Humoral and cell-mediated immune responses in fully allogeneic bone marrow chimera in mice
Authors: K Onoe, G Fernandes, RA Good
Journal: The Journal of Experimental Medicine (1980)

AKR mice were protected from lethal irradiation and established as long-lived chimeras by transplanting allogeneic C57BL/6 (B6) bone marrow that had been treated in vitro with anti-Thy-1 antiserum without complement. In these chimeras, which were designated [B6 {arrow} AKR], virtually all the thymus and spleen cells were shown to be derived from the B6 donor; several immune functions studied in these chimeras were as follows: (a) The chimeric mice were tolerant of histocompatibility antigens of both donor and recipient strain and nearly fully reactive to antigens of third party, as revealed by Simonsen's splenomegaly assay. The tolerance of these chimeras could not be attributed to suppressor cells but was compatible with clonal depletion. (b) Proliferative responses to concanavalin A, phytohemagglutinin, and lipopolysaccharide as well as natural killer and antibody-dependent cell- mediated cytotoxicity activity of the chimeric mice was normal. (c) Plaque- forming cell (PFC) assays of antibody responses to sheep erythrocytes (SRBC) showed gross deficiency in the primary response of the [B6 {arrow} AKR] and [AKR {arrow} B6] chimeras. By contrast, [B6-H-2(k)(E(k)) {arrow} AKR] H-2-compatible chimeras and [AKR {arrow} AKR] syngeneic marrow transplanted mice had normal primary PFC responses. PFC responses after secondary stimulation with SRBC, however, revealed vigorous direct plaque formation and substantial but somewhat smaller indirect plaque formation in the [B6 {arrow} AKR] chimeras. This observation favors operationally the concept of adaptive differentiation proposed by Katz et al. (44). (d) Analysis of ability of the chimeras to develop and express delayed-type hypersensitivity responses to contact sensitizer (2,4-dinitro-l-fluorobenzene [DNFB]) showed no apparent immunodeficiency of either chimeras to this form of immunization. Development of immunologic tolerance to DNFB, however, was grossly deficient in [B6 {arrow} AKR] chimeras but normal in [AKR {arrow} AKR], [B6 {arrow} B6], and [E(k) {arrow} AKR] chimeras. These findings indicate that full chimeras across major histocompatibility complex have considerable immunologic vigor even though primary immune responses that require histocompatibility between interacting cell types are initially defective.
Sore Finger-tips in Industry: Protection by H2O2
Authors: J. V. Bates
Journal: BMJ (1945)

CommentaryCase II suffered from a severe attack of typhus fever, the diag- nosis of which appears obvious in retrospect but was rendered difficult at the time by the presence of the septic thumb, which dominated the clinical picture.The continued pyrexia was originally attributed to a septicaemia secondary to the septic focus together with a possible concomitant attack of malaria.That death occurred in this man, who was 44 years of age, confirms the recognized fact that the mortality rate from typhus fever increases with the age of the patient (Mackenzie, 1941).Cases I and III had fairly mild but typical attacks of typhus fever, although at no period of their illness was the toxaemia profound.These cases also differ from the classical description of typhus fever in that delirium was not pronounced and cer- tainly was not of the dissociation or occupational type.Citse IV presents several interesting features: (a) The first sign of the disease developed 27 days after thorough disinfestation -i.e., 4 days longer than the recognized limit of the incubation period for this disease (Memo.on Louse-borne Typhus Fever, No. 252, 1941).As already stated, this patient was a fairly close contact of Case I throughout his illness.That Case IV was a secondary infection from Case I is the obvious explanation, but no other secondary cases have occurred either among other patients in the same ward or among the nursing or medical staff.There have been no secondary cases from Cases II and III, which were nursed in different wards from Case I. (b) The attack of typhus fever was of the abortive type, in that the total duration of the illness was only 5 days and in that the classical signs of the disease did not develop as in the other cases.Positive Weil-Felix reactions also occur in undulant fever in titres of 1 in 50 to 1 in 240, but the progressive rise in titre does not (Findlay, 1941).The Weil-Felix reaction in this patient showed a diagnostic rise in titre from 1 in 50 on the 2nd day of the illness to I in 1,000
How Does Proteinuria Cause Progressive Renal Damage?
Authors: Mauro Abbate, Carla Zoja, Giuseppe Remuzzi
Journal: Journal of the American Society of Nephrology (2006)

The possibility that proteinuria may accelerate kidney disease progression to end-stage renal failure has received support from the results of increasing numbers of experimental and clinical studies. Evidence indicating that this process occurs through multiple pathways, including induction of tubular chemokine expression and complement activation that lead to inflammatory cell infiltration in the interstitium and sustained fibrogenesis, is reviewed. Macrophages are prominent in the interstitial inflammatory infiltrate. This cell type mediates progression of renal injury to the extent that macrophage numbers in renal biopsy predict renal survival in patients with chronic renal disease. Chemoattractants and adhesive molecules for inflammatory cells are upregulated by excess ultrafiltered protein load of proximal tubular cells via activation of NF-kappaB-dependent and NF-kappaB-independent pathways. This mechanism is a potential target for therapeutic approaches, as shown by beneficial effects of manipulations with inhibitory molecules of NF-kappaB activation or of chemokine receptors in experimental studies. Targeting complement synthesis or activation in proximal tubule might offer novel therapeutic opportunities. Finally, proximal tubular cell receptors for uptake of plasma proteins that are under investigation may provide activation signals on excess tubular protein handling.
Functional Impairment of Von Willebrand Factor in Hypertrophic Cardiomyopathy
Authors: Thierry Le Tourneau, Sophie Susen, Claudine Caron, Alain Millaire, Sylvestre Maréchaux, Anne-Sophie Polge, André Vincentelli, Frederic Mouquet, Pierre-Vladimir Ennezat, Nicolas Lamblin, Pascal de Groote, Eric Van Belle, Ghislaine Deklunder, Jenny Goudemand, Christophe Bauters, Brigitte Jude
Journal: Circulation (2008)

Hypertrophic obstructive cardiomyopathy submits blood to conditions of high shear stress. High shear stress impairs von Willebrand factor (VWF) and promotes abnormal bleeding in aortic stenosis. We sought to evaluate VWF impairment and its relationships to baseline or exercise obstruction in hypertrophic cardiomyopathy (HCM).Outflow obstruction was evaluated by rest and exercise echocardiography in 62 patients with HCM (age 44+/-16 years, 40 males). HCM was considered obstructive in 28 patients with rest or exercise peak gradient >or=30 mm Hg. Blood was sampled to assess VWF. History of bleeding was recorded. Baseline median (25th to 75th percentile) peak gradient was 11 (5-62) mm Hg. Shear-induced platelet adhesion was impaired in patients with obstructive HCM. The ratio of VWF-collagen-binding activity to antigen and the percentage of high-molecular-weight multimers of VWF were lower in patients with obstructive HCM than in those with nonobstructive HCM (0.49 [0.43 to 0.59] versus 0.82 [0.73 to 1.03] and 5.0% [3.9% to 7.2%] versus 11.7% [10.8% to 12.5%], respectively; both P<0.0001). Platelet adhesion time, VWF-collagen-binding activity-to-antigen ratio, and the percentage of high-molecular-weight multimers correlated closely and independently with peak gradient (r=0.81, r=-0.68, and r=-0.89, respectively; all P<0.0001). According to receiver operating characteristic curves, a peak gradient threshold of 15 mm Hg at rest and 35 mm Hg during exercise was sufficient to impair VWF. Conversely, VWF function tended to improve with a decrease in peak gradient. Obstructive HCM patients had a trend toward abnormal spontaneous bleeding.In obstructive HCM, VWF impairment is frequent and is closely and independently related to the magnitude of outflow obstruction. A resting peak gradient of 15 mm Hg is sufficient to impair VWF. VWF abnormalities might favor abnormal bleeding in this setting.
The long term results of endoscopic surveillance of premalignant gastric lesions
Authors: J L Whiting
Journal: Gut (2002)

Background: A large proportion of patients attending open access endoscopy have histological and gross pathological findings that are potentially premalignant. The proportion of these patients who go on to develop malignancies and the timescale over which this occurs are uncertain. Aims: This study aims to discover the incidence of gastric cancers in this "high risk" group and to examine the potential for their early diagnosis and treatment. Patients: A total of 1753 patients attended open access endoscopy. From these, 166 patients with dysplasia, intestinal metaplasia, atrophic gastritis, foveolar hyperplasia, regenerative changes, polyps, or ulcers who agreed to undergo annual surveillance endoscopy were studied. Methods: Patients were endoscoped annually. Additionally, patients with ulcers were re-examined at two monthly intervals until ulcer healing. Cancers detected were treated by gastrectomy. Results: Twenty two of 1753 patients attending open access endoscopy had gastric cancer (1.3%). In the study population, 14 cancers were detected over 10 years (8.4 %). These were of an earlier stage than those detected at open access (stage I and II 67% <i>v</i> 23%; p&lt;0.05) and five year survival was significantly higher (50% <i>v</i> 10%; p=0.006). In atrophic gastritis and intestinal metaplasia the risk of malignancy was 11%. Conclusions: In patients with atrophic gastritis or intestinal metaplasia, annual surveillance can detect most new tumours at an early stage with a major improvement in survival. Potential benefits of such a surveillance programme are large and warrant further investigation in a multicentre randomised controlled trial.
Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons
Authors: Josh Gregorio, Stephan Meller, Curdin Conrad, Anna Di Nardo, Bernhard Homey, Antti Lauerma, Naoko Arai, Richard L. Gallo, John DiGiovanni, Michel Gilliet
Journal: The Journal of Experimental Medicine (2010)

Plasmacytoid dendritic cells (pDCs) are specialized type I interferon (IFN-α/β)–producing cells that express intracellular toll-like receptor (TLR) 7 and TLR9 and recognize viral nucleic acids in the context of infections. We show that pDCs also have the ability to sense host-derived nucleic acids released in common skin wounds. pDCs were found to rapidly infiltrate both murine and human skin wounds and to transiently produce type I IFNs via TLR7- and TLR9-dependent recognition of nucleic acids. This process was critical for the induction of early inflammatory responses and reepithelization of injured skin. Cathelicidin peptides, which facilitate immune recognition of released nucleic acids by promoting their access to intracellular TLR compartments, were rapidly induced in skin wounds and were sufficient but not necessary to stimulate pDC activation and type I IFN production. These data uncover a new role of pDCs in sensing tissue damage and promoting wound repair at skin surfaces.
The effects of simvastatin in ventilator-induced lung injury
Authors: Nikolaos Manitsopoulos, Christina Magkou, Anastasia Kotanidou, Stylianos Orfanos, Nikolaos Maniatis
Journal: European Respiratory Journal (2013)

Introduction: Ventilator-induced Lung Injury Acute Lung Injury (VILI) is characterized by increased-permeability pulmonary due to excessive alveolar distention by positive-pressure mechanical ventilation. With the exception of lung-protective ventilation, no pharmacologic treatment exists.

Aims: To determine the role of Simvastatin (HMGCoA reductase inhibitor) as a therapeutic agent in VILI.

Methods: Adult male C57BL6 mice (n=10/group) received protective (8mL/kg) or injurious (25mL/kg) ventilation with Simvastatin (20mg/kg) starting 2 days pre- ventilation or saline intraperitoneally (ip) for four hours. Following lung mechanics’ evaluation with a small animal ventilator (FlexiVent, Scireq), animals were sacrificed and bronchoalveolar lavage fluid (BALF), arterial blood and lung tissue, either snap frozen in liquid nitrogen or formalin-fixed, were obtained.

Results: Simvastatin administration prevented lung injury, caused by high tidal volume ventilation (HVt). The untreated group (Un) exhibited at least a 2-fold alteration in lung mechanics values as opposed to the treated group (Tr) which maintained baseline (Bs) values (e.g.Elastance, Tr:35.22 cmH2O/ml, Un: 86.76 cmH2O/ml, Bs: 30 cmH2O/ml). Moreover drug administration attenuated inflammation as pleiocytosis and protein content in BALF were reduced (e.g.%Neutrophils in BALF, Un: 6.8% Tr: 2.7%, Bs:3%). Additionally, levels of cytokines in plasma, such as interleukine-6 and Tumor Necrosis Factor (TNF), were not altered, suggesting maintained lung integrity (TNF Un:92.95 pg/ml, Tr: 25.85 pg/ml, Bs: 30 pg/ml).

Conclusions: HMGCoA reductase inhibition can reverse the pathophysiology of HVt mechanical ventilation, signifying Simvastatin as a restorative agent in VILI.
Value of Adding Single-Nucleotide Polymorphism Genotypes to a Breast Cancer Risk Model
Authors: Mitchell H. Gail
Journal: JNCI Journal of the National Cancer Institute (2009)

Adding genotypes from seven single-nucleotide polymorphisms (SNPs), which had previously been associated with breast cancer, to the National Cancer Institute's Breast Cancer Risk Assessment Tool (BCRAT) increases the area under the receiver operating characteristic curve from 0.607 to 0.632.Criteria that are based on four clinical or public health applications were used to compare BCRAT with BCRATplus7, which includes the seven genotypes. Criteria included number of expected life-threatening events for the decision to take tamoxifen, expected decision losses (in units of the loss from giving a mammogram to a woman without detectable breast cancer) for the decision to have a mammogram, rates of risk reclassification, and number of lives saved by risk-based allocation of screening mammography. For all calculations, the following assumptions were made: Hardy-Weinberg equilibrium, linkage equilibrium across SNPs, additive effects of alleles at each locus, no interactions on the logistic scale among SNPs or with factors in BCRAT, and independence of SNPs from factors in BCRAT.Improvements in expected numbers of life-threatening events were only 0.07% and 0.81% for deciding whether to take tamoxifen to prevent breast cancer for women aged 50-59 and 40-49 years, respectively. For deciding whether to recommend screening mammograms to women aged 50-54 years, the reduction in expected losses was 0.86% if the ideal breast cancer prevalence threshold for recommending mammography was that of women aged 50-54 years. Cross-classification of risks indicated that some women classified by BCRAT would have different classifications with BCRATplus7, which might be useful if BCRATplus7 was well calibrated. Improvements from BCRATplus7 were small for risk-based allocation of mammograms under costs constraints.The gains from BCRATplus7 are small in the applications examined. Models with SNPs, such as BCRATplus7, have not been validated for calibration in independent cohort data. Additional studies are needed to validate a model with SNPs and justify its use.
Narrowing down the role of common variants in the genetic predisposition to obesity
Authors: Melissa A Calton, Christian Vaisse
Journal: Genome Medicine (2009)

The extent to which common variants contribute to common phenotypes and disease in humans has important consequences for the future of medical genomics. Two reports have recently clarified this issue for one of the most pressing public health concerns, obesity. These large and comprehensive genome-wide association studies find that common variants within at least 11 genes are associated with obesity. Interestingly, most of these genes are highly expressed in the central nervous system, further highlighting its role in the pathogenesis of obesity. However, the individual and combined effects of these variants explain only a small fraction of the inherited variability in obesity, suggesting that rare variants may contribute significantly to the genetic predisposition for this condition.
ROLE OF PHOSPHATIDYLINOSITOL-LINKED PROTEINS IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA PATHOGENESIS
Authors: Taroh Kinoshita, M.D, Norimitsu Inoue, M.D, Junji Takeda, M.D
Journal: Annual Review of Medicine (1996)

▪ Abstract Patients with paroxysmal nocturnal hemoglobinuria have one or more mutant hematopoietic stem cell clones deficient in glycosylphosphatidylinositol (GPI)-anchor synthesis owing to somatic mutations in the X-linked gene PIG-A. The progeny of mutant stem cells dominates the peripheral blood. The presence of a large number of GPI-anchor deficient, complement-sensitive erythrocytes leads to hemolytic anemia. The somatic mutations in PIG-A are small, various, and widely distributed in the coding regions and splice sites, indicating they occur randomly. Profiles of the mutations vary geographically, suggesting the presence of mutagen-induced mutations. The clonal dominance by the mutants does not seem to be solely due to the PIG-A mutation but may be caused either by autonomous expansion of the mutants due to a combination of the PIG-A mutation and some other genetic change(s) or by selection that preferentially suppresses normal stem cells.