tbuckley/cabot-search huggingface dataset:
Abstract 19768: eNOS Uncoupling Leads to Endothelial Dysfunction in Clinical Obstructive Sleep Apnea (OSA): Role of BH4 Depletion
Authors: Saradhadevi Varadharaj, Jacob Wannemacher, Brian Patt, Levy Reyes, Zweier L Jay, Rami Khayat
Journal: Circulation (2012)

OSA is increasingly recognized as a cardiovascular risk factor and is a cause of hypertension, worsening coronary disease and heart failure. OSA leads to endothelial dysfunction (ED) and decreased Nitric oxide (NO) availability. The mechanism of ED in OSA remains unknown. We previously found that OSA causes increased peroxynititrite production in the endothelium. We hypothesized that increased peroxynitrite would result in oxidative modification of proteins and decreased BH4 availability. Methods: Participants were 13 patients with recently diagnosed OSA and 10 healthy individuals with low cardiovascular risk. OSA Patients underwent subcutaneous forearm biopsy and doppler measurements of endothelial function by flow mediated dilation (FMD) prior to, and 12 weeks after initiation of treatment. Non-OSA controls also had FMD measurements and biopsies. NO and superoxide ( · O 2 _ ) levels in the microcirculation were determined using fluorescent probes CuFL and DHE respectively in the absence or presence of the NO synthase inhibitor, L-NAME, the NO scavenger, PTIO, and the SOD mimetic, MnTBAP. Results: OSA patients had impaired FMD, compared to non-OSA controls, which decreased after 12 weeks of CPAP treatment. OSA patients had increased endothelial · O 2 _ and decreased NO production compared to controls. CPAP treatment decreased · O 2 _ and increased NO production in OSA patients. Incubation of subcutaneous sections with BH4 resulted in a significant increase in NO and decrease in · O 2 _ production in the endothelial tissue of untreated OSA patients. The BH4 effect on · O 2 _ and NO was more in OSA patients before treatment than after treatment (Figure). This indicates BH4 deficiency is important for VED in OSA patients. Conclusions: Thus BH4 deficiency occurs in VED in OSA and BH 4 supplementation can restore eNOS function conferring protection with reduced oxidative stress. Future clinical studies are warranted to evaluate BH4 supplementation in normalization of ED in OSA.
In-Hospital Prognosis of Patients with Acute Myocardial Infarction Complicated by Primary Ventricular Fibrillation
Authors: Alberto Volpi, Aldo Maggioni, Maria Grazia Franzosi, Sandro Pampallona, Francesco Mauri, Gianni Tognoni
Journal: New England Journal of Medicine (1987)

The in-hospital prognosis of patients with acute myocardial infarction complicated by primary ventricular fibrillation has not been satisfactorily defined. We addressed this question by studying patients with primary ventricular fibrillation derived from a large study (11,712 patients) of intravenous streptokinase in the treatment of acute myocardial infarction. Ventricular fibrillation was considered to be primary when it complicated a first myocardial infarction not associated with heart failure or shock and occurred within 48 hours of hospital admission. The 332 patients with primary ventricular fibrillation represented an overall incidence of 2.8 percent. A significant excess of in-hospital deaths was found in the patients with primary ventricular fibrillation as compared with those in the reference group (10.8 percent vs. 5.9 percent; relative risk, 1.94; 95 percent confidence interval, 1.35 to 2.78). Thrombolytic treatment with intravenous streptokinase did not afford protection against primary ventricular fibrillation. We observed that being over 65 years old had a protective effect against primary ventricular fibrillation (relative risk, 0.6; 95 percent confidence interval, 0.45 to 0.80). Our data do not indicate whether primary ventricular fibrillation is simply a marker for patients at increased risk of death or a direct cause of the increase in mortality. Our results do show, however, that primary ventricular fibrillation occurring in a coronary care unit is a negative predictor of short-term survival in patients with acute myocardial infarction.
Abnormal Endothelium-Dependent Vascular Relaxation in Patients with Essential Hypertension
Authors: Julio A. Panza, Arshed A. Quyyumi, John E. Brush, Stephen E. Epstein
Journal: New England Journal of Medicine (1990)

Endothelium regulates vascular tone by influencing the contractile activity of vascular smooth muscle. This regulatory effect of the endothelium on blood vessels has been shown to be impaired in atherosclerotic arteries in humans and animals and in animal models of hypertension.To determine whether patients with essential hypertension have an endothelium-dependent abnormality in vascular relaxation, we studied the response of the forearm vasculature to acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (a direct dilator of smooth muscle) in 18 hypertensive patients (mean age [+/- SD], 50.7 +/- 10 years; 10 men and 8 women) two weeks after the withdrawal of antihypertensive medications and in 18 normal controls (mean age, 49.9 +/- 9; 9 men and 9 women). The drugs were infused at increasing concentrations into the brachial artery, and the response in forearm blood flow was measured by strain-gauge plethysmography.The basal forearm blood flow was similar in the patients and controls (mean +/- SD, 3.4 +/- 1.3 and 3.7 +/- 0.8 ml per minute per 100 ml of forearm tissue, respectively; P not significant). The responses of blood flow and vascular resistance to acetylcholine were significantly reduced in the hypertensive patients (P less than 0.0001); maximal forearm flow was 9.1 +/- 5 ml per minute per 100 ml in the patients and 20.0 +/- 8 ml per minute per 100 ml in the controls (P less than 0.0002). However, there were no significant differences between groups in the responses of blood flow and vascular resistance to sodium nitroprusside. Because the vasodilator effect of acetylcholine might also be due to presynaptic inhibition of the release of norepinephrine by adrenergic nerve terminals, the effect of acetylcholine was assessed during phentolamine-induced alpha-adrenergic blockade. Under these conditions, it was also evident that the responses to acetylcholine were significantly blunted in the hypertensive patients (P less than 0.03).Endothelium-mediated vasodilation is impaired in patients with essential hypertension. This defect may play an important part in the functional abnormalities of resistance vessels that are observed in hypertensive patients.
Acute plasma separation with hemodialysis equipment.
Authors: R E Gerhardt, K A Ntoso, J D Koethe, S Lodge, C J Wolf
Journal: Journal of the American Society of Nephrology (1992)

Although plasma separation has been reported to have a relatively small complication rate in large series of healthy outpatients, little attention has been directed to the evaluation of the safety and effectiveness of the therapy in acutely ill, hospitalized patients. The experience of using standard hemodialysis equipment and membrane plasma separators with 281 plasma separation treatments in 49 patients over the last 7 yr is reported and analyzed. The data reveal a 1.4% incidence of hypotension and a 0.4% incidence of hematuria in the 281 treatments--rates similar to those reported in outpatients. In addition, analysis of the diseases and patients treated over the 7 yr reported demonstrates a marked shift from immunological and hematological disorders towards neurological disorders. The data suggest that plasma separation may be easily and safely performed by any institution capable of performing acute hemodialysis.
P173 The investigation of patients referred with haemoptysis via the two week wait system in Southmead Hospital, Bristol, UK
Authors: J Harper, J Curran, M Plummeridge
Journal: Thorax (2015)

<h3>Background</h3> Southmead Hospital is a large teaching Hospital in the South West of England. GP two week wait (TWW) referrals to the respiratory department are sent via a standardised proforma with one of a number of reasons for referral selected. We conducted this project both to evaluate how we are currently investigating patients referred with haemoptysis and to identify whether our diagnostic pathway for patients for these patients could be optimised. We were particularly interested as to whether bronchoscopy is diagnostically helpful in this cohort of patients. <h3>Methods</h3> We looked at all TWW referrals between 13/6/13 and 2/4/15 (825 referrals) and selected those who were referred for haemoptysis (110 patients). The clinical course of these patients was tracked retrospectively by looking at our electronic record system and clinical letters. <h3>Results</h3> Overall 109 of the 110 patients identified had a CT scan – this was normal in 31 patients. In the remainder of cases the CT was suggestive of malignancy in 38 of the 78 abnormal scans. The remainder of CT scans had positive findings that were not suggestive of malignancy. Of the 31 patients who had a normal scan, 22 patients underwent bronchoscopy. 40 patients had abnormal CT scan that were not suggestive of malignancy. 25 of these patients went on to have bronchoscopy All bronchoscopies were either normal or showed non specific findings.16 patients who had an eventual diagnosis of lung malignancy had an initial CT scan suggestive of malignancy. <h3>Conclusion</h3> Our project demonstrates that currently 58% of patients referred with haemoptysis via the TWW system go on to have a bonchoscopy. In our cohort of patients all bronchoscopies were either normal or showed non-specific changes. All patients with lung malignancy had a prior CT that was suggestive of malignancy and did not require a bronchoscopy other than as a potential means of obtaining tissue. We suggest that bronchoscopy may not be necessary in patients referred with haemoptysis who have a normal CT scan. We feel this will change our local practice and may enable us to better target this investigation to patients who will benefit from it.
Use of a moving optical gradient to determine <i>ex vivo</i> chemosensitivity of B- cell chronic lymphocytic leukemias (B-CLL)
Authors: I. Kariv, J. Nieva, P. McNeeley, K. Nguyen, M. Nerenberg, J. Diver, K. Bethel, A. Saven
Journal: Journal of Clinical Oncology (2004)

2097 Background: Induction of apoptosis is a foundation of anti-neoplastic therapies. Existing ex vivo techniques to analyze apoptotic responses are limited to a particular biological aspect of the multi-factorial apoptotic cellular machinery. We have developed a cell-based analysis that detects broad cellular changes, based on physical characteristics of the cell, such as morphology, size, refractive index, density and surface properties. This method quantifies cell motion induced by exposure to a moving optical gradient. Cells are analyzed in their native state with no labels required for quantitation of functional responses; nevertheless fluorescent tags may be used to identify cell subpopulations. Only small numbers of cells are needed, from 500 to 2000 per measurement. Methods: Isolated peripheral lymphocytes from B-CLL patients were incubated for 60 hours. Tested drugs included fludarabine, chlorambucil, vincristine, doxorubicin, and others. Dose response curves were generated for each drug. Results: The initial study included 30 patients. Resistance/sensitivity determinations were based on analysis of the distribution of EC50 values. Clinical outcomes were available for 9 of the patients. For eight of these patients, where historical outcomes were available, ex vivo drug sensitivity correlated with clinical response. For the ninth patient, a prospective outcome was established and the ex vivo cell sensitivity was in good correlation. In some cases fluorescent labels were added to quantitate drug-mediated effects in cell subpopulations of interest (CD19 positive cells). We are monitoring outcomes for the rest of the patients, and expanding tested population. Data indicate inter- and intra-individual variability in response to different drugs. For example the median EC50 was 0.7μM and 3.9μM for fludarabine and chlorambucil respectively. Conclusions: A novel ex vivo analysis based on cell behavior within moving optical gradients quantifies pharmacological responses to chemotherapeutic drugs and provides an advantage over other approaches by integrating fluorescent detection of specific cell subpopulations. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genoptix Genoptix Genoptix Genoptix
Sensitization of hepatocellular carcinoma (HCC) to tigatuzumab (CS-1008), a humanized anti-DR5 antibody, by sorafenib and its derivative SC-49.
Authors: Kuen-Feng Chen, Hui-Ling Chen, Chung-Wai Shiau, Chun-Yu Liu, Wei-Tien Tai, Kimihisa Ichikawa, Pei-Jer Chen, Ann-Lii Cheng
Journal: Journal of Clinical Oncology (2012)

e14516 Background: Previously, we have shown that sorafenib sensitizes HCC cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Here, we report the effects of sorafenib and SC-49, a sorafenib analog, on sensitizing HCC cells to tigatuzumab, a novel antihuman death receptor 5 (DR5) antibody. SC-49 is a sorafenib derivative that is devoid of kinase inhibition activity. Methods: HCC cell lines (Huh-7, PLC5, and Hep3B) were treated with tigatuzumab and/or sorafenib or SC-49 and analyzed in terms of apoptosis and signal transducers. Effects of tigatuzumab and SC-49 on HCC xenograft tumor growth were also evaluated. Results: Our data indicated that sorafenib, as well as SC-49, down-regulated the phosphorylation of signal transducers and activators of transcription 3 (p-STAT3) at Tyr 705 and subsequently reduced the protein levels of STAT3-regulated proteins, Mcl-1, survivin and cycin D1, in tigatuzumab-treated HCC cells. Knockdown of STAT3 by RNA-interference overcame apoptotic resistance to tigatuzumab in HCC cells, and ectopic expression of STAT3 in HCC cells abolished the sensitizing effect of sorafenib or SC-49 on tigatuzumab-induced apoptosis, indicating that inhibition of STAT3 mediates the effects of the combination. Importantly, inhibition of SHP-1 by adding a specific SHP-1 inhibitor reduced the effects of SC-49 and tigatuzumab on p-STAT3 and apoptosis, whereas co-treatment of tigatuzumab and SC-49 increased the activity of SHP-1, suggesting that SHP-1 mediated the combinational effect of tigatuzumab and SC-49 in HCC. Moreover, the in vivo combination of tigatuzumab and SC-49 inhibited HCC xenograft tumor growth. Conclusions: Sorafenib, SC-49 and tigatuzumab induce apoptosis and inhibit tumor growth in HCC through SHP-1-dependent STAT3 inactivation.
Recurrent or Persistent Hematuria
Authors: Levinus B. A. van de Putte, Guy Brutel de la Riviere, Peter J. C. van Breda Vriesman
Journal: New England Journal of Medicine (1974)

Renal biopsies were performed on 47 patients with recurrent macroscopic or persistent microscopic hematuria, unexplained by urinary-tract abnormalities or manifest renal disease. Histologic examination showed a mesangial proliferative glomerulonephritis in 34 patients. Granular deposits of immunoglobulins and complement components were present in the glomerular mesangial area in 15 of 24 biopsies examined by immunofluorescence technics. IgM, β1C and C1q were deposited in all patients, IgA in 10 patients, and IgG in only two. The intensity of immunofluorescent staining correlated with the glomerular proliferate reaction as judged by light microscopy. Electron-dense granular deposits in the mesangial area were found exclusively in patients with active disease. Thus, the glomerulonephritis in these patients was caused by an IgM and IgA antibody-associated mesangial immune-complex deposition with activation of the classic complement pathway. Follow-up data in 41 patients and repeated renal biopsies in 11 patients indicate a good prognosis. (N Engl J Med 290:1165–1170, 1974)
S130 Axl receptor tyrosine kinase on airway macrophages has a key role in lung immune homeostasis
Authors: N Denny, AM Grabiec, G Tavernier, S Holden, H Francis, D Ryan, R Niven, SJ Fowler, A Simpson, T Hussell
Journal: Thorax (2015)

<h3>Rationale</h3> Apoptotic cell uptake (efferocytosis) by airway macrophages (AMs) is critical for lung immune homeostasis and is defective in chronic lung diseases, including asthma,<sup>1</sup> although the molecular mechanism behind this remains unknown. The TAM (Tyro3, Axl, MerTK) receptor tyrosine kinases are one of the main receptor classes that mediate efferocytosis but little is known about their regulation and function in inflammatory lung diseases. <h3>Aim</h3> To investigate expression profile of TAM receptors and their ligand Gas6 in human AMs and analyse potential defects in TAM receptor expression in chronic lung inflammation. <h3>Methods</h3> AMs from the sputum of patients with asthma (BTS step 3–5) (n = 30) or healthy donors (HD) (n = 12) were enriched by plastic adhesion. Monocytes were isolated from matched whole blood samples by CD14 positive selection and differentiated into monocyte-derived macrophages (MDMs). Total RNA was extracted from all purified cell populations and mRNA expression analysed by qPCR. HD MDMs were stimulated with Th2 cytokines <i>in vitro</i> and TAM receptor expression was analysed using qPCR and ELISA. <h3>Main results</h3> Axl was the dominant TAM receptor expressed in HD AMs whereas monocytes and MDMs predominantly expressed MerTK. Axl expression was significantly reduced in AMs from patients with asthma compared to HD (p &lt; 0.0001), while mRNA levels of MerTK and Gas6 was similar in both groups. We found no differences in Axl and MerTK expression in monocytes and MDMs from HD and patients with asthma, indicating that the observed differences were restricted to the site of inflammation. <i>In vitro</i>, MDM stimulation with IL-4 or IL-13 downregulated Axl mRNA and protein expression in a time-dependent manner. <h3>Conclusions</h3> We have shown for the first time that Axl is the principal TAM receptor expressed in human AMs. Significant reduction of Axl expression in AMs from patients with asthma might be responsible for inefficient clearance of apoptotic cells from the inflamed airways and contribute to persistent airway inflammation. Strategies aimed at restoration of Axl expression or activity may represent a novel therapeutic strategy in asthma and other chronic lung diseases. <h3>Reference</h3> 1 Simpson JL, Gibson PG, Yang IA <i>et al</i>. Impaired macrophage phagocytosis in non-eosinophilic asthma. <i>Clin Exp Allergy</i>. 2013;<b>43</b>:29–35
Lack of evidence for allelic association between personality traits and the dopamine D4 receptor gene polymorphisms
Authors: E G Jönsson, M M Nöthen, J P Gustavsson, H Neidt, S Brené, A Tylec, P Propping, G C Sedvall
Journal: American Journal of Psychiatry (1997)

Personality traits in human subjects have shown considerable heritable components. Recently, two research groups reported associations between dopamine D4 receptor genotypes and the personality trait known as novelty seeking. This study was an attempt to replicate these findings.Three different exonic dopamine D4 receptor polymorphisms were genotyped in 126 healthy Swedish subjects. Personality traits of the subjects were assessed with the Karolinska Scales of Personality.Although there was a tendency in the direction hypothesized, no significant association between genotype constellations and personality traits was found.The previously reported association between dopamine D4 receptor alleles and novelty seeking was not replicated. Possible reasons for this include differences in personality inventories, ethnicity, and type I or type II errors.
Blockade of Orai1 Store-Operated Calcium Entry Protects against Renal Fibrosis
Authors: Xiaoyi Mai, Jinyan Shang, Sijia Liang, Beixin Yu, Jiani Yuan, Yu Lin, Renfei Luo, Feiran Zhang, Yingying Liu, Xiaofei Lv, Chunling Li, Xinling Liang, Weidong Wang, Jiaguo Zhou
Journal: Journal of the American Society of Nephrology (2016)

Evidence supports an important role of Ca 2+ release-activated Ca 2+ channel protein 1 (Orai1)-mediated Ca 2+ entry in the development of renal fibrosis, a common pathologic feature of CKDs that lead to ESRD, but the molecular mechanisms remain unclear. We determined the role of Orai1 calcium channel in renal fibrosis induced by high-fat diet and by unilateral ureteral obstruction. Mouse kidneys with fibrosis had higher levels of Orai1 protein expression than did kidneys without fibrosis. In vivo knockdown of Orai1 with adenovirus harboring Orai1–short hairpin RNA or inhibition of Orai1 with SKF96365 dramatically prevented renal fibrosis and significantly decreased protein expression of fibronectin, α ‑smooth muscle actin, and TGF‑ β 1 in the kidney cortex of ApoE –/– mice on a high-fat diet and in the obstructed kidneys of mice with unilateral ureteral obstruction. Compared with kidney biopsy specimens of patients with glomerular minimal change disease, those of patients with fibrotic nephropathy had higher expression levels of Orai1. In cultured human proximal tubule epithelial cells (HK2), knockdown of Orai1 Ca 2+ channel with adenovirus–Orai1–short hairpin RNA markedly inhibited TGF- β 1–induced intracellular Ca 2+ influx and phosphorylation of smad2/3. Knockdown or blockade of the Orai1 Ca 2+ channel in HK2 cells also prevented epithelial-to-mesenchymal transition induced by TGF‑ β 1. In conclusion, blockade of the Orai1 Ca 2+ channel prevented progression of renal fibrosis in mice, likely by suppressing smad2/3 phosphorylation and TGF- β 1–induced epithelial-to-mesenchymal transition. These results render the Orai1 Ca 2+ channel a potential therapeutic target against renal fibrosis.
Animal models of schizophrenia
Authors: W T McKinney, E C Moran
Journal: American Journal of Psychiatry (1981)

The authors review some general issues concerning the development and use of animal models of schizophrenia and present a summary of the criteria necessary for validating models. They also describe some of the major attempts at creating animal models of schizophrenia, including drug and nondrug methods. They comment on the etiologic, phenomenologic, and treatment relevance of the various systems and suggest approaches that might produce improved animal models of schizophrenia.
Case 40-2009
Authors: Timothy M. Uyeki, Amita Sharma, John A. Branda
Journal: New England Journal of Medicine (2009)

A 29-year-old man was transferred to this hospital because of fever and respiratory distress. Nine days earlier, fever, a nonproductive cough, and myalgias developed. On admission to this hospital, he was hypoxemic. Computed tomography of the chest revealed diffuse infiltrates. Respiratory failure, renal failure, and hypotension developed. On the sixth hospital day, a diagnostic test result was received.
Case 23-1996
Authors: Richard L. Kradin, Eugene J. Mark
Journal: New England Journal of Medicine (1996)

Presentation of CaseA 62-year-old woman was referred to the hospital because of progressive exertional dyspnea and reticulonodular pulmonary infiltrates.The patient had been well until six years earlier, when progressive exertional dyspnea began, accompanied by pain in the chest and left arm. A diagnosis of angina pectoris was made, and propranolol was prescribed. The pain disappeared, and the dyspnea improved slightly, but the patient could no longer play tennis. During the next six years, the exertional dyspnea gradually worsened, and in the two years before admission she had several bouts of “bronchitis” with wheezing and a productive cough.Seventeen . . .