tbuckley/cabot-search huggingface dataset:
A Role for Gut Microbiota and the Metabolite‐Sensing Receptor GPR43 in a Murine Model of Gout
Authors: Angélica T. Vieira, Laurence Macia, Izabela Galvão, Flaviano S. Martins, Maria Cecília C. Canesso, Flávio A. Amaral, Cristiana C. Garcia, Kendle M. Maslowski, Ellen De Leon, Doris Shim, Jacques R. Nicoli, Jacquie L. Harper, Mauro M. Teixeira, Charles R. Mackay
Journal: Arthritis & Rheumatology (2015)

Host-microbial interactions are central in health and disease. Monosodium urate monohydrate (MSU) crystals cause gout by activating the NLRP3 inflammasome, leading to interleukin-1β (IL-1β) production and neutrophil recruitment. This study was undertaken to investigate the relevance of gut microbiota, acetate, and the metabolite-sensing receptor GPR43 in regulating inflammation in a murine model of gout.Gout was induced by the injection of MSU crystals into the knee joints of mice. Macrophages from the various animals were stimulated to determine inflammasome activation and production of reactive oxygen species (ROS).Injection of MSU crystals caused joint inflammation, as seen by neutrophil influx, hypernociception, and production of IL-1β and CXCL1. These parameters were greatly decreased in germ-free mice, mice treated with antibiotics, and GPR-43-deficient mice. Recolonization or administration of acetate to germ-free mice restored inflammation in response to injection of MSU crystals. In vitro, macrophages produced ROS and assembled the inflammasome when stimulated with MSU. Macrophages from germ-free animals produced little ROS, and there was little inflammasome assembly. Similar results were observed in macrophages from GPR-43-deficient mice. Treatment of germ-free mice with acetate restored in vitro responsiveness of macrophages to MSU crystals.In the absence of microbiota, there is decreased production of short-chain fatty acids that are necessary for adequate inflammasome assembly and IL-1β production in a manner that is at least partially dependent on GPR43. These results clearly show that the commensal microbiota shapes the host's ability to respond to an inflammasome-dependent acute inflammatory stimulus outside the gut.
Characterization of M1 and M2 macrophages in human lung tissue
Authors: Erica Bazzan, Graziella Turato, Elena Mutti, Eleonora Farinazzo, Marco Damin, Kim Lokar-Oliani, Piero Maestrelli, Simonetta Baraldo, Marina Saetta, Manuel G. Cosio
Journal: European Respiratory Journal (2013)

Background. Alveolar macrophages (AM) in experimental models can express a proinflammatory M1 or an antiinflammatory M2 phenotype. The presence and function of these phenotypes in human disease have not been established.  Aim. To study if the M1 and M2 phenotypes of AM are expressed in humans, in particular in lung tissue of nonsmokers and smokers with and without COPD.  Methods. Alveolar macrophages were immunostained in sequential slides for M1 (iNOS) and M2 (CD206) in lungs of 11 severe COPD, 13 smokers without COPD and 11 nonsmokers. M1 and M2 AM were counted and expressed as percentage of total AM.  Results. In COPD the proportion of M1 [53(16-81)%] and M2 [76(40-98)%] was higher than in nonsmokers: M1 [24(11-44)%] and M2 [44(0-88)%], p  Conclusions. Alveolar macrophages can be present as M0, M1 and M2 in normal and diseased lungs. Nonsmokers have a high proportion of M0 macrophages that decreases markedly in COPD. With the development of the chronic inflammation characteristic of COPD alveolar macrophages express both M1 and M2 markers in high proportion, often simultaneously.
Abstract 206: Distribution of ETCO2 Values in Out-of-Hospital Cardiac Arrest Patients
Authors: Ahamed H Idris, Saeed Babaeizadeh, Mohamud Daya, Dana Edelson, Reza Firoozabadi, Eric Helfenbein, Sophia Zhou
Journal: Circulation (2011)

Background  The American Heart Association 2010 guidelines recommend that capnography be used to verify tracheal tube placement and monitor CPR quality as well as detect ROSC during resuscitation. Capnography has been rapidly adopted by EMS in out-of-hospital CPR. Though capnography has been well understood in hospital patient care, the EtCO2 distribution in the population of interest has not been well studied.   Objective  Determine the distribution of EtCO2 levels during CPR in out-of-hospital cardiac arrest (OHCA) patients.   Methods  Recordings from 107 OHCA patients with capnogram waveforms were collected from 2008 to 2010 in two EMS agencies based in Oregon and Texas. Experts manually annotated all the recordings for breathing cycles and EtCO2 values. The histogram was generated using only the segments with active chest compression (total of 33 hours, 19,444 breath cycles). Each patient had chest compressions for an average of 19.8 ± 14.2 minutes. Chest compressions had an average rate of 108 ± 12 compressions-per-minute and average depth of 3.7 ± 0.7 centimeters.   Results  The figure below shows the distribution of the EtCO2 values in the OHCA patients. EtCO2 values varied from 0.5 to 99 mmHg, had a median value of 26 mmHg, and had an average value of 29 ± 18 mmHg.   Conclusion  In OHCA populations, EtCO2 values during CPR vary widely. EtCO2 values below 10 mmHg occurred in 13% of breaths and almost 60% of values were below 30 mmHg. Recommendations that make use of EtCO2 values in OHCA should consider this distribution.
Abstract 3598: Macrophage-derived reactive oxygen species suppress miR-328 targeting CD44 in gastrointestinal cancer cells and promote redox adaptation
Authors: Takatsugu Ishimoto, Naoya Yoshida, Hidetaka Sugihara, Daisuke Izumi, Keisuke Miyake, Hiroshi Sawayama, Yu Imamura, Shiro Iwagami, Yoshifumi Baba, Hideo Baba
Journal: Cancer Research (2014)

Abstract Background: CD44 has recently been identified as one of the cell surface markers associated with cancer stem cells (CSCs) in several types of tumor. We have reported the functional role of CD44 variant isoform in the maintenance of low reactive oxygen species (ROS) levels in gastrointestinal cancer cells. While, microRNA (miRNA) is involved in the pathogenesis of many cancers and the networks of miRNA regulate CSCs properties. However, the mechanism underlying the miRNA in the regulation of CSC marker is mostly unrevealed. Objectives: The aim of this study was to investigate the regulation of CD44 expression by miRNAs and to develop newmolecular targets in gastrointestinal cancer. Methods and Results: To investigate the mechanism in the regulation of CD44, We performed miRNA screening in six human gastrointestinal cancer cell lines and identified three candidate miRNAs that could regulate CD44 expression in gastrointestinal cancer. Among these, we focused on miR-328 and examined its functional relevance using growth assays and cytotoxicity assays. CD44 expression was reduced in gastrointestinal cancer cell lines forced to express miR-328, leading to inhibition of cancer cell growth in vitro and in vivo, and impaired resistance to chemotherapeutic drugs and reactive oxygen species (ROS). In contrast, induction of CD44 expression by miR-328 inhibitor led to promotion of cancer cell growth. Furthermore, we revealed that ROS produced by macrophages triggered CD44 expression through suppression of miR-328 in gastric cancer cells. Finally, tumor-infiltrating macrophages (CD68 and CD163) were closely related to both miR-328 down-regulation and CD44 up-regulation in 63 patients with surgically-resected gastric cancer. Conclusions: Macrophages in the tumor microenvironment may cause increased CD44 expression through miR-328 suppression, resulting in tumor progression by enhancing ROS defense. miR-328-CD44 signaling mediated by macrophages may thus represent a potential target for the treatment of gastrointestinal cancer. Citation Format: Takatsugu Ishimoto, Naoya Yoshida, Hidetaka Sugihara, Daisuke Izumi, Keisuke Miyake, Hiroshi Sawayama, Yu Imamura, Shiro Iwagami, Yoshifumi Baba, Hideo Baba. Macrophage-derived reactive oxygen species suppress miR-328 targeting CD44 in gastrointestinal cancer cells and promote redox adaptation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3598. doi:10.1158/1538-7445.AM2014-3598
Treatment of syringomyelia.
Authors: P David, M Tadié
Journal: BMJ (1971)

Treatment of syringomyelia utilizes two operative approaches: posterior fossa decompression and syrinx shunting (including subarachnoid, pleural and peritoneal shunting). MRI study is nowadays the indispensable tool for the evaluation of patients with syringomyelia and allows to choose the best therapeutic option. Posterior fossa decompression is regarded as the procedure of choice for syringomyelia with Chiari. After intradural exploration, additional steps may be necessary as excision of the cerebellar tonsils. Other therapeutic alternatives are associated with higher complication rates. Patients with persistent focal syrinxes after PFD respond best to syringoperitoneal shunts. For the management of post-traumatic syringomyelia, a large decompressive laminectomy at the fracture site is recommended; the use of a drain does not offer any long-term therapeutic advantage. Syringoperitoneal shunting is the treatment of post-infection syringomyelia but good long-term result is rare in this type of syrinx.
Abstract 1532: A Microbiomic analysis in African American with colonic lesions reveals bacterial markers with potential diagnostic value
Authors: Hassan Brim, Sudhir Varma, Adeinko Laiyemo, Zaki Sharif, Edward L. Lee, Hassan Ashktorab
Journal: Cancer Research (2015)

Abstract Background: Increasing evidence suggests a role of the gut microbiota in colorectal carcinogenesis. However, no specific bacteria have been unequivocally linked to either initiation or progression of colorectal cancer (CRC). Aim: To analyze the taxonomic composition and functional potential of the gut microbiome in African Americans with colorectal lesions with the goal of detecting markers of diagnostic value. Materials &amp; Methods: DNA extracts from 10 stool samples of colon adenoma patients, 10 healthy subjects’ stool samples and from 10 CRC tumors and their matched normal tissues were analyzed for their microbiota composition and genomic content using Illumina MiSeq. Metagenomic Linkage Groups (MLGs) were established and those with high discriminative power between healthy and neoplastic specimens were analyzed for their genetic content. Metagenomic reads from stool samples were mapped against bacterial genes from tissues and vice-versa to identify common markers with discriminative power. Results: The microbiota in both cancer vs. normal tissues and adenoma vs. normal stool samples were different at the 16S rRNA gene level. The metagenomic analysis led to 5 statistically significant MLGs in each set of samples. There was little overlap between the stool-based and tissue-based significant MLGs. Mapping stools reads to annotated tissue genes and vice-versa revealed a panel of 9 bacterial markers with statistically significant discriminative power between normal and adenoma in the stool dataset and visually striking (though non-significant) discriminative power between normal and tumor samples in the tissue dataset. Conclusion: We defined MLGs with discriminative power among cancers vs. normal and adenomas vs. normals and identified 9 bacterial markers that can potentially be used as a panel for non-invasive colorectal cancer screening tests. These findings will need to be validated in a larger population of patients at different stages of the carcinogenic process and from different ethnic/racial backgrounds. Citation Format: Hassan Brim, Sudhir Varma, Adeinko Laiyemo, Zaki Sharif, Edward L. Lee, Hassan Ashktorab. A Microbiomic analysis in African American with colonic lesions reveals bacterial markers with potential diagnostic value. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1532. doi:10.1158/1538-7445.AM2015-1532
Rising trend may be due to "pathoenvironment"
Authors: E. Ravussin
Journal: BMJ (1995)

EDITOR,--The prevalence of obesity has reached epidemic proportions in the United States and many European countries. Andrew M Prentice and Susan A Jebb provide convincing evidence that “simple gluttony” cannot account for this increased prevalence since over the past 20 years food intake has decreased whereas body mass index has continued to increase in Britain.1 The authors conclude that physical activity has decreased even faster over the same period and so obesity can be blamed on “sloth.” …
Management skills need to be systematically learnt
Authors: Sean W O'Kelly
Journal: BMJ (2007)

I share Nicholson's belief that NHS organisations will have an improved chance of dealing successfully with the complex challenges they face if led by people who have substantial personal experience of providing clinical care to patients.1

However, management skills are not necessarily intuitive. Currently, too many clinicians with management roles rely on innate instinct and gut feeling, honed by variable …
Influence of Mast Cells on Structural and Functional Manifestations of Radiation-Induced Heart Disease
Authors: Marjan Boerma, Junru Wang, Jan Wondergem, Jacob Joseph, Xiaohua Qiu, Richard H. Kennedy, Martin Hauer-Jensen
Journal: Cancer Research (2005)

Abstract Radiation-induced heart disease (RIHD), characterized by accelerated atherosclerosis and adverse tissue remodeling, is a serious sequelae after radiotherapy of thoracic and chest wall tumors. Adverse cardiac remodeling in RIHD and other cardiac disorders is frequently accompanied by mast cell hyperplasia, suggesting that mast cells may affect the development of cardiac fibrosis. This study used a mast cell–deficient rat model to define the role of mast cells in RIHD. Mast cell–deficient rats (Ws/Ws) and mast cell–competent littermate controls (+/+) were exposed to 18 Gy localized single-dose irradiation of the heart. Six months after irradiation, cardiac function was examined by echocardiography and Langendorff-perfused isolated heart preparation, whereas structural changes were assessed using quantitative histology and immunohistochemical analysis. Mast cell–deficient rats exhibited more severe postradiation changes than mast cell–competent littermates. Hence, mast cell–deficient rats exhibited a greater upward/leftward shift in the left ventricular (LV) diastolic pressure-volume relationship (P = 0.001), a greater reduction in in vivo LV diastolic area (from 0.50 ± 0.024 cm in age-matched controls to 0.24 ± 0.032 cm after irradiation; P = 0.006), and a greater increase in LV posterior wall thickness (from 0.13 ± 0.003 cm in age-matched controls to 0.15 ± 0.003 cm after irradiation; P = 0.04). Structural analysis revealed more pronounced postradiation accumulation of interstitial collagen III but less myocardial degeneration in hearts from mast cell–deficient rats. These data show that the absence of mast cells accelerates the development of functional changes in the irradiated heart, particularly diastolic dysfunction, and suggest that, in contrast to what has been the prevailing assumption, the role of mast cells in RIHD is predominantly protective.
Abstract 17966: A Near-infrared Fluorescent Voltage-sensitive Dye Allows for Moderate-throughput Electrophysiological Analyses of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes
Authors: Angelica Lopez-Izquierdo, Mark Warren, Michael Riedel, Scott Cho, Shuping Lai, Robert Lux, Kennith W Spitzer, Ivor Benjamin, Martin Tristani-Firouzi, Chuanchau J Jou
Journal: Circulation (2014)

Introduction: Recent advances now allow for the routine derivation of patient- and disease-specific human iPSC cardiomyocyte (iPSC-CM) models. However, a major impediment to the widespread use of iPSC-CM assays is the low throughput of the currently available electrophysiological tools. The patch clamp technique is too laborious and the inherent phototoxicity of most voltage-sensitive dyes limits their use in single cells.

Hypothesis: We tested the hypothesis that near-infrared fluorescent voltage-sensitive dye di-4-ANBDQBS exhibits minimal phototoxicity and high precision to allow for moderate-throughput analysis of human iPSC-CMs.

Methods: We compared simultaneous electrical and optical action potential (AP) recordings in human iPSC-CM loaded with di-4-ANBDQBS.

Results: Optical APs tracked electrical APs with high precision, generating nearly identical values of action potential duration (APD10, APD50 and APD90) for atrial- and ventricular-like CMs (Table). Fluorescence from a single CM yielded interpretable optical APs (Fig A-C). CMs tolerated repeated laser exposure, with stable optical AP parameters recorded over a 30 min study period. Optical AP recordings appropriately tracked changes in repolarization induced by pharmacological manipulation. Finally, di-4-ANBDQBS allowed for moderate-throughput analyses that facilitated the distinction between atrial- and ventricular-like CM. APD50 values (n=208) were best fit to a Gaussian function with 2 distinct peaks that effectively discriminated atrial- and ventricular-like CMs (Fig D). Overall throughput was increased >10-fold over traditional patch clamp technique.

Conclusions: We conclude that the voltage-sensitive dye di-4-ANBDQBS allows for high precision optical AP measurements that markedly increase the throughput for electrophysiological characterization of human iPSC-CMs. Optical APD50 may be useful to discriminate between atrial- and ventricular-like phenotypes.

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Love and Dementia
Authors: Fernando Santiago
Journal: JAMA (2015)

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Trastuzumab-Auristatin immunoconjugates inhibit growth and induce apoptosis in human breast cancer cells in vitro
Authors: Guangmin Li, Peter Senter, Gail D. Lewis Phillips
Journal: Cancer Research (2005)

6184  Trastuzumab (Herceptin ®) is a humanized anti-HER2 antibody approved for use in the treatment of women with HER2-overexpressing metastatic breast cancer. There is great interest in using MAbs as vehicles for the selective delivery of cytotoxic agents to tumor cells. Linking a cytotoxic agent to an antibody that recognizes a tumor-associated antigen may improve the therapeutic index of the drug. We demonstrate in vitro activity of antibody-drug conjugates consisting of a potent antimitotic agent monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF, an acidic MMAE analogue) linked to trastuzumab. The conjugate trastuzumab-vc-MMAE or trastuzumab-vc-MMAF is internalized and trafficked to lysosomes in HER2-overexpressing cells, where drug is released after hydrolysis of the valine-citrulline (vc) peptide linker. Trastuzumab-vc-MMAE or trastuzumab-vc-MMAF selectively and potently inhibited the growth of SK-BR-3 and BT-474 cells that overexpress HER2. In contrast, the conjugates did not affect MCF-7 cells, which express normal/low amounts of HER2, or MDA-MB-468 cells, which lack HER2 expression. Short (10 min) exposure to the conjugates produced long-lasting (at least 72 h) inhibition of SK-BR-3 and BT-474 cell proliferation in culture. Treatment of SK-BR-3 or BT-474 cells with the conjugates resulted in a dose-dependent growth arrest at the G2/M phase of the cell cycle after 48 hours. Exposure to the conjugates induced apoptosis as demonstrated by activation of caspase 3/7 and processing of caspases 8 and 9. Apoptosis induction was confirmed by release of cytochrome c from the mitochondria into the cytosol, and degradation of poly (ADP-ribose) polymerase (PARP). In addition, trastuzumab conjugates induced bcl-2 hyperphosphorylation in MCF-7/HER2-18 cells (engineered to overexpress HER2) in a dose dependent manner. These data suggest that trastuzumab-auristatin immunoconjugates may be a highly effective and selective therapy for the treatment of HER2-overexpressing breast cancer.
Visual hallucinations in patients with macular degeneration
Authors: S Holroyd, P V Rabins, D Finkelstein, M C Nicholson, G A Chase, S C Wisniewski
Journal: American Journal of Psychiatry (1992)

This study was undertaken to determine the prevalence of visual hallucinations in patients with macular degeneration, describe such hallucinations phenomenologically, and possibly determine factors predisposing to their development.Using a case-control design, the authors screened 100 consecutive patients with age-related macular degeneration for visual hallucinations. Each patient with visual hallucinations was matched to the next three patients without hallucinations. The patients and comparison subjects were compared in terms of scores on the Beck Depression Inventory, Eysenck Personality Questionnaire, Telephone Interview for Cognitive Status, and a structured questionnaire including demographic characteristics, family history, and medical and psychiatric history. Ophthalmologic data were obtained by chart review.Of the 100 patients, 13 experienced visual hallucinations. Four variables were significantly associated with having hallucinations: living alone, lower cognition score, history of stroke, and bilaterally worse visual acuity. Hallucinations were not associated with family or personal history of psychiatric disorder or with personality traits. In 11 (84.6%) of the 13 patients, the hallucinations had begun in association with an acute change in vision.These results indicate that visual hallucinations are prevalent among patients with macular degeneration. They appear unrelated to primary psychiatric disorder. The predisposing factors of bilaterally worse vision and living alone support an association with sensory deprivation, while history of stroke and worse cognition support a decreased cortical inhibition theory.