tbuckley/cabot-search huggingface dataset:
Nitric oxide potentiates hydrogen peroxide-induced killing of Escherichia coli.
Authors: R Pacelli, D A Wink, J A Cook, M C Krishna, W DeGraff, N Friedman, M Tsokos, A Samuni, J B Mitchell
Journal: The Journal of Experimental Medicine (1995)

Previously, we reported that nitric oxide (NO) provides significant protection to mammalian cells from the cytotoxic effects of hydrogen peroxide (H2O2). Murine neutrophils and activated macrophages, however, produce NO, H2O2, and other reactive oxygen species to kill microorganisms, which suggests a paradox. In this study, we treated bacteria (Escherichia coli) with NO and H2O2 for 30 min and found that exposure to NO resulted in minimal toxicity, but greatly potentiated (up to 1,000-fold) H2O2-mediated killing, as evaluated by a clonogenic assay. The combination of NO/H2O2 induced DNA double strand breaks in the bacterial genome, as shown by field-inverted gel electrophoresis, and this increased DNA damage may correlate with cell killing. NO was also shown to alter cellular respiration and decrease the concentration of the antioxidant glutathione to a residual level of 15-20% in bacterial cells. The iron chelator desferrioxamine did not stop the action of NO on respiration and glutathione decrease, yet it prevented the NO/H2O2 synergistic cytotoxicity, implicating metal ions as critical participants in the NO/H2O2 cytocidal mechanism. Our results suggest a possible mechanism of modulation of H2O2-mediated toxicity, and we propose a new key role in the antimicrobial macrophagic response for NO.
Methacholine inhalation challenge: a shorter, cheaper and safe approach
Authors: G. Izbicki, E. Bar-Yishay
Journal: European Respiratory Journal (2001)

Increased nonspecific bronchial hyperresponsiveness to pharmacological agents such as histamine or methacholine (MCh) is a hallmark of asthma. The measurement of airway reactivity is quite sensitive but testing is tedious, and time and money consuming. The present aim was, therefore, to design the shortest possible, yet safe inhalation challenge protocol applicable for a lung function referral centre. All records of studies performed in our institution during 1996 were analyzed retrospectively with a baseline ratio (bl) of forced expiratory volume in one second/forced vital capacity (FEV 1 /FVC) ≥0.7 (n=449). It was questioned what the initial dose should be, and whether some inhalation steps could have been skipped without losing pertinent information and/or causing an adverse response (a fall in FEV 1 &gt;40%). When unavailable, provocative dose causing a 20% fall in FEV 1 (PD 20 ) values were obtained by linear inter- or extrapolation of the existing data. The present study showed that three-fold concentration steps could have been employed with minimal change in outcome. Only 15/449 patients (3.3%) would have experienced a severe response. Five subjects (of 169, 3.0%) with FEV 1 /FVC bl 0.7–0.8 reacted to inhalation up to 0.073 µmol. Four subjects (of 280, 1.4%) with FEV 1 /FVC bl ≥0.8 reacted to inhalation up to 0.219 µmol. The authors suggest that: 1) an initial dose of 0.219 µmol (initial concentration=0.21 mg·mL −1 ) may be used when the baseline ratio of forced expiratory volume in one second to forced vital capacity ≥0.8 and 0.073 µmol (initial concentration=0.07 mg·mL −1 ) when the baseline ratio is &lt;0.8; 2) a tripling dose protocol is easier to perform, cheaper and 30.2% faster, yet just as safe; and 3) other abbreviated protocols used in epidemiologic settings may not be applicable in a referral centre setting.
Modulation of bleomycin-induced lung fibrosis by serotonin receptor antagonists in mice
Authors: A Fabre, J Marchal-Sommé, S Marchand-Adam, C Quesnel, R Borie, M Dehoux, C Ruffié, J Callebert, J-M Launay, D Hénin, P Soler, B Crestani
Journal: European Respiratory Journal (2008)

Serotonin (5-hydroxytryptamine; 5-HT) is known to increase proliferation and collagen synthesis by fibroblasts. Two receptor subtypes, 5-HT2A and 5-HT2B, have been shown to play the most important roles in the lung. In the present study, the role of serotonin in lung fibrosis was investigated using the bleomycin mouse model. Serotonin concentrations in lung homogenates increased significantly over the time course of bleomycin-induced fibrosis, with a maximum at day seven. The expression of serotonin receptors 5-HT2A and 5-HT2B increased in the lung after bleomycin treatment, as assessed by PCR, specific binding and immunohistochemistry. Blockage of 5-HT2A receptors by ketanserin and 5-HT2B receptors by SB215505 reduced bleomycin-induced lung fibrosis, as demonstrated by reduced lung collagen content and reduced procollagen 1 and procollagen 3 mRNA expression. Serotonin antagonists promoted an antifibrotic environment by decreasing the lung mRNA levels of transforming growth factor-β1, connective growth factor and plasminogen activator inhibitor-1 mRNA, but had minimal effects on lung inflammation as assessed by bronchoalveolar lavage cytology analysis. Interestingly, the 5-HT2B receptor was strongly expressed by fibroblasts in the fibroblastic foci in human idiopathic pulmonary fibrosis samples. In conclusion, the present study showed involvement of serotonin in the pathophysiology of bleomycin-induced lung fibrosis in mice and identified it as a potential therapeutic target in lung fibrotic disorders.
Alternation of the Heart
Authors: DAVID LITTMANN
Journal: Circulation (1963)

Alteration of the heart occurs whenever any of its tissues, contractile or conductive, fail to function during alternate beats. This results in a diversity of 2:1 conduction blocks with electrical alternation and myocardial blocks that produce alternation of the pulse. In a general way, the more distal blocks, involving bundle branches, arborization, and myocardium are the more ominous, implying serious underlying heart disease. They can occur normally, however, at rapid heart rates. Another type of alternation involving atrial as well as ventricular waves is sometimes seen in serious pericardial disease with effusion. It is believed to be due to an unusual rotary oscillation of the heart released from its normal inhibitory mediastinal restraints by the surrounding effusion. This is an anatomic rather than a cellular form of alternation and can exhibit other mechanical disorders such as alternating friction sounds.
Phase I/II Trial of Epratuzumab (Humanized Anti-CD22 Antibody) in Indolent Non-Hodgkin’s Lymphoma
Authors: John P. Leonard, Morton Coleman, Jamie C. Ketas, Amy Chadburn, Scott Ely, Richard R. Furman, William A. Wegener, Hans J. Hansen, Heather Ziccardi, Michael Eschenberg, Urte Gayko, Alessandra Cesano, David M. Goldenberg
Journal: Journal of Clinical Oncology (2003)

This single-center, dose-escalation study examines the safety, efficacy, and pharmacokinetics of epratuzumab (anti-CD22 humanized monoclonal antibody) in patients with recurrent indolent non-Hodgkin's lymphoma (NHL).Patients had indolent NHL and recurrent disease after at least one chemotherapy regimen. Epratuzumab was administered intravenously at 120 to 1,000 mg/m2 over 30 to 60 minutes weekly for four treatments.Fifty-five patients received epratuzumab and were assessable for safety; 51 patients were assessable for response. Patients were heavily pretreated (50% had at least four prior regimens) and 49% had bulky disease (> or = 5 cm). Epratuzumab was well tolerated, with no dose-limiting toxicity. Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. More than 95% of infusions were completed in approximately 1 hour. Mean serum half-life was 23 days. Across all dose levels and histologies, nine patients (18%; 95% confidence interval, 8% to 31%) achieved objective response, including three complete responses (CRs). All responses were in patients with follicular NHL: 24% of these patients responded, including 43% in the 360 mg/m2 dose group and 27% in the 480 mg/m2 dose group. No responses were observed in other indolent histologies. Median duration of objective response was 79.3 weeks (range, 11.1 to 143.3 weeks), with median time to progression for responders of 86.6 weeks by Kaplan-Meier estimate.Epratuzumab was well tolerated at up to 1,000 mg/m2/wk (for 4 weeks) and had clinical activity. One third of responding patients achieved CR. A 43% objective response rate in follicular NHL patients treated at 360 mg/m2/wk indicates that this dose should be explored in additional studies.
Combination Immunotherapy for Cancer:Synergistic Antitumor Interactions of Interleukin-2, Alfa Interferon, and Tumor-Infiltrating Lymphocytes
Authors: S. A. Rosenberg, S. L. Schwarz, P. J. Spiess
Journal: JNCI Journal of the National Cancer Institute (1988)

Attempts have been made to design optimal strategies for the immunotherapy of established tumors. In micebearing pulmonary metastases from sarcomas, a substantial therapeutic synergy was seen when bothinterleukin-2(IL-2) and alfa interferon(α-IFN) were administered compared with the effect of either agentgiven alone. This synergy was dependent on Lyt-2+T cells, since therapeutic effects were abrogated in Lyt-2 depleted mice. The αIFN and IL-2 combination was also synergistic with tumor-infiltrating lymphocytes inmediating the reduction of established lung metastases. These experiments demonstrate that combination immunotherapy can result in substantial reduction of established metastatic deposits and provide a rationale for the application of this treatment to patients with advanced cancer. [J National Cancer Inst 1988;80:1393–1397]
Muscle-specific knockout of PKC-λ impairs glucose transport and induces metabolic and diabetic syndromes
Authors: Robert V. Farese, Mini P. Sajan, Hong Yang, Pengfei Li, Steven Mastorides, William R. Gower, Sonali Nimal, Cheol Soo Choi, Sheene Kim, Gerald I. Shulman, C. Ronald Kahn, Ursula Braun, Michael Leitges
Journal: Journal of Clinical Investigation (2007)

Obesity, the metabolic syndrome, and type 2 diabetes mellitus (T2DM) are major global health problems. Insulin resistance is frequently present in these disorders, but the causes and effects of such resistance are unknown. Here, we generated mice with muscle-specific knockout of the major murine atypical PKC (aPKC), PKC-λ, a postulated mediator for insulin-stimulated glucose transport. Glucose transport and translocation of glucose transporter 4 (GLUT4) to the plasma membrane were diminished in muscles of both homozygous and heterozygous PKC-λ knockout mice and were accompanied by systemic insulin resistance; impaired glucose tolerance or diabetes; islet β cell hyperplasia; abdominal adiposity; hepatosteatosis; elevated serum triglycerides, FFAs, and LDL-cholesterol; and diminished HDL-cholesterol. In contrast to the defective activation of muscle aPKC, insulin signaling and actions were intact in muscle, liver, and adipocytes. These findings demonstrate the importance of aPKC in insulin-stimulated glucose transport in muscles of intact mice and show that insulin resistance and resultant hyperinsulinemia owing to a specific defect in muscle aPKC is sufficient to induce abdominal obesity and other lipid abnormalities of the metabolic syndrome and T2DM. These findings are particularly relevant because humans who have obesity, impaired glucose tolerance, and T2DM reportedly have defective activation and/or diminished levels of muscle aPKC.
Left Main Coronary Artery to Left Atrial Fistula Causing Mild Pulmonary Hypertension
Authors: Dimitris Tousoulis, Stella Brilli, Konstantina Aggelli, Costas Tentolouris, Christodoulos Stefanadis, Kostantinos Toutouzas, Alexandra Frogoudaki, Pavlos Toutouzas
Journal: Circulation (2001)
A Novel Isoform of TUCAN Is Overexpressed in Human Cancer Tissues and Suppresses Both Caspase-8– and Caspase-9–Mediated Apoptosis
Authors: Masaaki Yamamoto, Toshihiko Torigoe, Kenjiro Kamiguchi, Yoshihiko Hirohashi, Katsuya Nakanishi, Chika Nabeta, Hiroko Asanuma, Tetsuhiro Tsuruma, Takashi Sato, Fumitake Hata, Tousei Ohmura, Koji Yamaguchi, Takehiro Kurotaki, Koichi Hirata, Noriyuki Sato
Journal: Cancer Research (2005)

Abstract Caspase-associated recruitment domains (CARD) are protein-protein interaction modules found extensively in proteins that play important roles in apoptosis. One of the CARD-containing proteins, TUCAN (CARD8), was reported previously as an antiapoptotic protein with a molecular weight of 48 kDa, which was up-regulated in colon cancer cells. We identified a novel isoform of TUCAN with a molecular weight of 54 kDa. The new variant of TUCAN, termed TUCAN-54, was expressed in gastric, colon, and breast cancer tissues but was barely detected in normal noncancerous tissues, whereas 48-kDa TUCAN was detected in tumor tissues and noncancerous tissues. To know the function of TUCAN-54 in the apoptosis of cancer cells, TUCAN-54 was overexpressed in tumor cells by gene transfection. Its overexpression inhibited pro-caspase-9 activation, leading to the suppression of the cell death induced by a protein kinase inhibitor, staurosporine, or a chemotherapeutic reagent, etoposide (VP-16). In contrast, specific small interfering RNA–mediated suppression of TUCAN-54 expression in tumor cells increased the VP-16–induced cell death rate, indicating that expression of TUCAN-54 might be associated with chemoresistance of tumor cells. In addition, it inhibited caspase-8 activation as well, thereby suppressing Fas-induced cell death. It was revealed that Fas-associated death domain was physically associated with TUCAN-54 but not with 48-kDa TUCAN. Thus, TUCAN-54 might be a novel tumor-specific antiapoptotic molecule expressed in a variety of human cancer tissues, which might aggravate malignant potential of cancer cells, such as chemoresistance and immunoresistance.
Evidence for the roles of histamine and prostaglandins as mediators in exercise-induced asthma: the inhibitory effect of terfenadine and flurbiprofen alone and in combination
Authors: JP Finnerty, ST Holgate
Journal: European Respiratory Journal (1990)

We investigated the effects of terfenadine, a histamine H1-receptor antagonist, and flurbiprofen, a cyclooxygenase inhibitor, on exercise-induced bronchoconstriction to assess the contribution of the mast cell products histamine and prostaglandins. Eight asthmatics were studied on 4 occasions with treadmill exercise tests. Terfenadine or placebo was administered 3 h prior to exercise, and flurbiprofen or placebo was administered 2 h prior to exercise, in a double-blind randomized trial. Airway calibre was determined by measurement of the forced expiratory volume in one second (FEV1) immediately prior to exercise challenge, and over 30 min post-exercise. Following placebo, the mean maximum percentage fall in FEV1 was 39%. This fell to 25% after terfenadine (p less than 0.05), 27% after flurbiprofen (p less than 0.05), and 30% after the active combination (NS). Analysis of the areas under curves of percentage falls in FEV1 over 30 min showed significant inhibition on all 3 active drug days (p less than 0.05). We conclude that histamine release and prostaglandin generation contribute to exercise-induced bronchoconstriction, although the interaction between these mediators appears complex.
Airway Responsiveness in Early Infancy Predicts Asthma, Lung Function, and Respiratory Symptoms by School Age
Authors: LYLE J. PALMER, PETER J. RYE, NEIL A. GIBSON, PAUL R. BURTON, LOUIS I. LANDAU, PETER N. LeSOUËF
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Asthma is the most common chronic childhood disease in developed nations. Little is known about the relationship between airway responsiveness in infancy and the development of asthma later in life. The relationship of airway responsiveness at 1 mo with asthma, atopy, lower respiratory symptoms, and lung function at 6 yr of age was investigated prospectively in 95 white children from a randomly ascertained birth cohort. Baseline spirometry, airway responsiveness to histamine, and skin reactivity to common allergens were assessed at the age of 1 mo and 6 yr. Total serum immunoglobulin E (IgE) was measured from cord blood and at 6 yr. Blood eosinophil counts were measured at 6 yr only. Family, symptom, and exposure histories at both time points were derived from questionnaire data. Independently of the other factors assessed, increased airway responsiveness at 1 mo was significantly associated with the following parameters measured at six yr: decreased FEV1 (p < 0.001); decreased FVC (p < 0.001); physician-diagnosed asthma (p < 0.001); and lower respiratory tract symptoms (p < 0.05). None of the other physiologic factors measured in infancy showed such consistent associations with important clinical and physiologic outcomes at age 6. These data suggest that airway responsiveness in early life defines a functional state that is associated with abnormal airway function, lower respiratory symptoms, and the emergence of asthma by 6 yr of age.
Transition From Chronic Compensated to Acute Decompensated Heart Failure
Authors: Michael R. Zile, Tom D. Bennett, Martin St. John Sutton, Yong K. Cho, Philip B. Adamson, Mark F. Aaron, Juan M. Aranda, William T. Abraham, Frank W. Smart, Lynne Warner Stevenson, Fred J. Kueffer, Robert C. Bourge
Journal: Circulation (2008)

Background— Approximately half of all patients with chronic heart failure (HF) have a decreased ejection fraction (EF) (systolic HF [SHF]); the other half have HF with a normal EF (diastolic HF [DHF]). However, the underlying pathophysiological differences between DHF and SHF patients are incompletely defined. The purpose of this study was to use echocardiographic and implantable hemodynamic monitor data to examine the pathophysiology of chronic compensated and acute decompensated HF in SHF versus DHF patients. Methods and Results— Patients were divided into 2 subgroups: 204 had EF &lt;50% (SHF) and 70 had EF ≥50% (DHF). DHF patients had EF of 58±8%, end-diastolic dimension of 50±10 mm, estimated resting pulmonary artery diastolic pressure (ePAD) of 16±9 mm Hg, and diastolic distensibility index (ratio of ePAD to end-diastolic volume) of 0.11±0.06 mm Hg/mL. In contrast, SHF patients had EF of 24±10%, end-diastolic dimension of 68±11 mm, ePAD of 18±7 mm Hg, and diastolic distensibility index of 0.06±0.04 mm Hg/mL ( P &lt;0.05 versus DHF for all variables except ePAD). In SHF and DHF patients who developed acute decompensated HF, these events were associated with a significant increase in ePAD, from 17±7 to 22±7 mm Hg ( P &lt;0.05) in DHF and from 21±9 to 24±8 mm Hg ( P &lt;0.05) in SHF. As a group, patients who did not have acute decompensated HF events had no significant changes in ePAD. Conclusions— Significant structural and functional differences were found between patients with SHF and those with DHF; however, elevated diastolic pressures play a pivotal role in the underlying pathophysiology of chronic compensated and acute decompensated HF in both SHF and DHF.
The natural immune barrier to xenotransplantation.
Authors: R L Geller, M A Turman, A P Dalmasso, J L Platt
Journal: Journal of the American Society of Nephrology (1992)

As the shortage of available organs for transplantation becomes critical, many investigators have turned to the possibility of using animals as a source of donor organs. Although there have been several attempts to use organs from closely related species for transplantation into human, there is relatively little experience in the use of nonprimate animals as clinical donor animals. The major problem in transplants between widely disparate species is hyperacute rejection, a rapid and violent rejection reaction that leads to the destruction of the graft within minutes or hours. Hyperacute rejection appears to be triggered by components of natural immunity, most notably natural antibodies and complement. Recent data suggest that hyperacute rejection may not represent an insurmountable barrier to discordant xenotransplantation. There have recently been several examples of survival of grafts in recipients in the face of antigraft antibodies and an intact complement system referred to as accommodation. Once hyperacute rejection can be averted, it becomes necessary to consider elicited cellular responses. There are a number of issues to be considered in the clinically relevant model of porcine to primate xenografts. These include the size of the responding T-cell repertoire and the extent to which the cell adhesion molecules and cytokines of the donor will be able to stimulate recipient immune responses. Finally, the interactions between T cells and the cells forming the inner layer of blood vessels may have profound effects on the outcome of the graft.
Living with vitiligo: development of a new vitiligo burden questionnaire is a step forward for outcomes consensus
Authors: V. Eleftheriadou
Journal: British Journal of Dermatology (2015)

ORIGINAL ARTICLE, p 607 Vitiligo is the most common depigmentation disorder, affecting around 0·5% of the population worldwide.1 It is a cosmetically and psychologically devastating disease.2 Therefore, one would expect that patients' views on the effectiveness of a treatment would be considered important. However, patient‐centred outcomes have rarely been measured in vitiligo trials, despite previous recommendations.1 3 4 In this issue of the BJD, Ezzedine et al.5 report a cross‐sectional study with the aim of developing a new questionnaire specific to vitiligo burden. The burden of vitiligo was evaluated in 300 patients, using the new conceptual vitiligo‐burden‐specific questionnaire alongside several validated assessment tools including the Dermatology Life Quality Index.6 The study demonstrated that regardless of skin phototype, patients with vitiligo experience disease‐related burden and self‐perceived stress. This new questionnaire identified several factors that occurred more or less frequently in patients with dark skin types than in fair‐skinned individuals. In particular, patients with fair skin types were more worried about skin cancer than patients with dark skin types, who were more worried about the visibility and burden of vitiligo.