tbuckley/cabot-search huggingface dataset:
Myocardial Adeno-Associated Virus Serotype 6–βARKct Gene Therapy Improves Cardiac Function and Normalizes the Neurohormonal Axis in Chronic Heart Failure
Authors: Giuseppe Rengo, Anastasios Lymperopoulos, Carmela Zincarelli, Maria Donniacuo, Stephen Soltys, Joseph E. Rabinowitz, Walter J. Koch
Journal: Circulation (2008)

Background— The upregulation of G protein–coupled receptor kinase 2 in failing myocardium appears to contribute to dysfunctional β-adrenergic receptor (βAR) signaling and cardiac function. The peptide βARKct, which can inhibit the activation of G protein–coupled receptor kinase 2 and improve βAR signaling, has been shown in transgenic models and short-term gene transfer experiments to rescue heart failure (HF). This study was designed to evaluate long-term βARKct expression in HF with the use of stable myocardial gene delivery with adeno-associated virus serotype 6 (AAV6). Methods and Results— In HF rats, we delivered βARKct or green fluorescent protein as a control via AAV6-mediated direct intramyocardial injection. We also treated groups with concurrent administration of the β-blocker metoprolol. We found robust and long-term transgene expression in the left ventricle at least 12 weeks after delivery. βARKct significantly improved cardiac contractility and reversed left ventricular remodeling, which was accompanied by a normalization of the neurohormonal (catecholamines and aldosterone) status of the chronic HF animals, including normalization of cardiac βAR signaling. Addition of metoprolol neither enhanced nor decreased βARKct-mediated beneficial effects, although metoprolol alone, despite not improving contractility, prevented further deterioration of the left ventricle. Conclusions— Long-term cardiac AAV6-βARKct gene therapy in HF results in sustained improvement of global cardiac function and reversal of remodeling at least in part as a result of a normalization of the neurohormonal signaling axis. In addition, βARKct alone improves outcomes more than a β-blocker alone, whereas both treatments are compatible. These findings show that βARKct gene therapy can be of long-term therapeutic value in HF.
A little rest and relaxation
Authors: J TACK
Journal: Gut (2000)

See article on page 30 

In healthy subjects and in patients with mild to moderate gastro-oesophageal reflux disease, gastro-oesophageal reflux occurs mainly during transient lower oesophageal sphincter (LOS) relaxations.1-3 Transient LOS relaxations are a neural reflex, organised in the brain stem, with efferent and afferent pathways travelling in the vagus nerve.3 Distention of the proximal stomach is a major trigger for the reflex to occur, although stimulation of the pharynx or the larynx may also contribute.3 It is clear that the initiation of the reflex requires activation of gastric mechanoreceptors.

Because of their pivotal role in the occurrence of gastro-oesophageal reflux, the neurophysiology and pharmacology of transient LOS relaxations are topics of intense ongoing research. Atropine is one of the drugs that were recently shown to inhibit gastro-oesophageal reflux by inhibiting transient LOS relaxations.4 It is unclear if atropine is acting at the level of the stomach, by altering the mechanosensitivity of the proximal stomach, or at the level of the brain stem, by interfering with central integrative processing.

In this issue of Gut , Lidums and colleagues5 used a gastric barostat procedure to study the influence of atropine on proximal gastric tone and on the occurrence of transient LOS relaxations in healthy subjects (see page 30). Atropine caused prolonged relaxation of …
"Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer
Authors: C. Grommes, G. R. Oxnard, M. G. Kris, V. A. Miller, W. Pao, A. I. Holodny, J. L. Clarke, A. B. Lassman
Journal: Neuro-Oncology (2011)

Erlotinib is effective for epidermal growth factor receptor (EGFR) mutant lung cancer, but CNS penetration at standard daily dosing is limited. We previously reported that intermittent "pulsatile" administration of high-dose (1500 mg) erlotinib once weekly was tolerable and achieved concentrations in cerebrospinal fluid exceeding the half maximal inhibitory concentration for EGFR mutant lung cancer cells in a patient with leptomeningeal metastases; we now expand this paradigm to a series of 9 patients. We retrospectively identified patients with EGFR mutant lung cancer treated with pulsatile erlotinib for CNS metastases (brain and/or leptomeningeal) that occurred despite conventional daily erlotinib or other EGFR tyrosine kinase inhibitors. Mutations in available lung and CNS tissue were correlated with efficacy. Erlotinib was administered as monotherapy at a median dose of 1500 mg weekly. Best CNS radiographic response was partial in 67% (6/9, including 2 with isolated leptomeningeal metastases), stable disease in 11% (1/9), and progressive disease in 22% (2/9). Median time to CNS progression was 2.7 months (range, 0.8–14.5 months) and median overall survival was 12 months (range, 2.5 months–not reached). Treatment was well tolerated. No acquired resistance mutations in EGFR were identified in the CNS metastases of 4 patients, including 1 harboring T790M outside the CNS. Pulsatile erlotinib can control CNS metastases from EGFR mutant lung cancer after failure of standard daily dosing. CNS disease may not harbor acquired resistance mutations that develop systemically. A prospective trial is planned.
PMO-129 Relaxin reduces portal hypertension through stimulation of hepatic nitric oxide production
Authors: J Fallowfield, V Snowdon, R Aucott, T Gordon-Walker, A Pellicoro, J Iredale
Journal: Gut (2012)

<h3>Introduction</h3> We have previously reported that the multifunctional hormone relaxin (RLX) downregulated the activation state and contractility of hepatic myofibroblasts and reduced portal hypertension (PHT) in cirrhotic rats (Fallowfield J <i>et al</i> BASL 2010). RLX has been shown to induce a range of haemodynamic effects in different organs and species, largely through effects on nitric oxide (NO). In cirrhosis, there is hepatic NO deficiency and hyporesponsiveness. We postulated that the effects of RLX on PHT were, at least in part, mediated by activation of the NO pathway. <h3>Methods</h3> Cirrhosis and PHT was induced in age-matched male Sprague-Dawley rats by 8 weeks biweekly i.p. CCl4, before randomisation to the following groups: (1) recombinant human H2-relaxin (H2-RLX) s.c. for 72 h; (2) placebo s.c. for 72 h; (3) H2-RLX s.c. + L-NAME p.o. for 72 h; (4) placebo s.c. + L-NAME p.o. for 72 h; <i>n</i>=5–10/group. NO levels in serum were determined by quantitative immunoassay for total nitrite and hepatic NO bioavailability by cGMP immunoassay. Relative levels of Ser<sup>473</sup> phosphorylated Akt (p-Akt) and Ser<sup>1179</sup> phosphorylated eNOS (p-eNOS) protein in whole liver extracts were quantified by Western blotting. Rho-kinase activity was assessed by phosphorylation of the endogenous Rho-kinase substrate moesin (Thr<sup>558</sup>). Portal pressure (PP) and mean arterial pressure (MAP) were measured under general anaesthesia by direct cannulation. <h3>Results</h3> Rats treated with CCl4 for 8 weeks developed micronodular cirrhosis, splenomegaly and PHT. There was no difference in mean serum nitrite levels between H2-RLX and placebo treated rats. However, H2-RLX increased hepatic cGMP production (p&lt;0.01) and upregulated expression of p-Akt (p&lt;0.05) and p-eNOS (p&lt;0.05) protein. In contrast, there was no difference in p-moesin levels. H2-RLX treated animals had a lower mean PP than placebo controls (11.6±0.3 mm Hg [95% CI 10.97 to 12.81] vs 9.2±0.6 mm Hg [7.66 to 10.7]; p=0.008) and decreased spleen size (p=0.01). The portal hypotensive effect of H2-RLX was abrogated by co-administration of the NOS inhibitor L-NAME (11.42±0.35 mm Hg [10.44 to 12.4]; p=0.004 vs H2-RLX). MAP was comparable in RLX and placebo treated animals that also received L-NAME. <h3>Conclusion</h3> A reduction in NO bioavailability is considered to be a major factor increasing intrahepatic vascular tone in cirrhosis. Our data indicate that H2-RLX was capable of stimulating intrinsic (but not systemic) NO generation in fibrotic liver by activating the Akt/eNOS/cGMP pathway. Furthermore, inhibition of this axis with L-NAME ablated the portal hypotensive effect of H2-RLX, suggesting that it could represent a novel liver-specific NO donor in cirrhotic PHT. <h3>Competing interests</h3> None declared.
Asthma severity and medical resource utilisation
Authors: L. Antonicelli, C. Bucca, M. Neri, F. De Benedetto, P. Sabbatani, F. Bonifazi, H‐G. Eichler, Q. Zhang, D.D. Yin
Journal: European Respiratory Journal (2004)

Asthma represents a growing public health problem and the cost of asthma has been rising in many countries. The aim of this study was to estimate the direct and indirect cost of asthma among adult patients in Italy, and to assess the relationship between healthcare resource use and asthma severity according to the Global Initiative for Asthma (GINA) classification system. A multicentre cross-sectional study was conducted in 16 Italian hospital-based specialised asthma clinics. Data collection was based on self-administered questionnaires and took place during the period May 1–November 30, 1999, and 500 consecutive patients with asthma, aged 18–55 yrs, were enrolled during regularly scheduled visits. Direct costs (drugs, physician visits, emergency service use and hospitalisation), indirect costs (loss of paid workdays) and total costs were determined in euros () for 1999. Patients with more severe disease, as classified by the GINA guideline, exhibited more night-time and daytime symptoms and were more limited in performing normal daily activities. The mean total cost of asthma per patient per year was estimated to be 1,260; drug costs accounted for 16%, physician costs 12%, emergency service and hospitalisation costs 20% and indirect costs 52% of the mean cost. Stratified by severity, the total annual cost per patient amounted to 720, 1,046, 1,535 and 3,328 for patients with intermittent, mild persistent, moderate persistent and severe persistent asthma, respectively. Asthma severity, as determined by the Global Initiative for Asthma classification, is significantly associated with symptoms, limitations in normal daily activities, asthma-related medical resource utilisation and both direct and indirect costs. Asthma control is not only a clinical but also an economic imperative.
Lack of detectable allergenicity of transgenic maize and soya samples
Authors: Rita Batista, Baltazar Nunes, Manuela Carmo, Carlos Cardoso, Helena São José, António Bugalho de Almeida, Alda Manique, Leonor Bento, Cândido Pinto Ricardo, Maria Margarida Oliveira
Journal: Journal of Allergy and Clinical Immunology (2005)
Repetitive Traumatic Brain Injury, Psychological Symptoms, and Suicide Risk in a Clinical Sample of Deployed Military Personnel
Authors: Craig J. Bryan, Tracy A. Clemans
Journal: JAMA Psychiatry (2013)

Traumatic brain injury (TBI) is believed to be one factor contributing to rising suicide rates among military personnel and veterans. This study investigated the association of cumulative TBIs with suicide risk in a clinical sample of deployed military personnel referred for a TBI evaluation.To determine whether suicide risk is more frequent and heightened among military personnel with multiple lifetime TBIs than among those with no TBIs or a single TBI.Patients completed standardized self-report measures of depression, posttraumatic stress disorder (PTSD), and suicidal thoughts and behaviors; clinical interview; and physical examination. Group comparisons of symptom scores according to number of lifetime TBIs were made, and generalized regression analyses were used to determine the association of cumulative TBIs with suicide risk.Patients included 161 military personnel referred for evaluation and treatment of suspected head injury at a military hospital's TBI clinic in Iraq.Behavioral Health Measure depression subscale, PTSD Checklist-Military Version, concussion symptoms, and Suicide Behaviors Questionnaire-Revised.Depression, PTSD, and TBI symptom severity significantly increased with the number of TBIs. An increased incidence of lifetime suicidal thoughts or behaviors was associated with the number of TBIs (no TBIs, 0%; single TBI, 6.9%; and multiple TBIs, 21.7%; P = .009), as was suicidal ideation within the past year (0%, 3.4%, and 12.0%, respectively; P = .04). The number of TBIs was associated with greater suicide risk (β [SE] = .214 [.098]; P = .03) when the effects of depression, PTSD, and TBI symptom severity were controlled for. A significant interaction between depression and cumulative TBIs was also found (β = .580 [.283]; P = .04).Suicide risk is higher among military personnel with more lifetime TBIs, even after controlling for clinical symptom severity. Results suggest that multiple TBIs, which are common among military personnel, may contribute to increased risk for suicide.
TRPV1 and cough
Authors: G P Anderson
Journal: Thorax (2004)

Iodo-resiniferatoxin, a new TRPV1 inhibitor, shows promising antitussive activity in an animal model

Cough is one of the most common respiratory complaints and intractable cough remains one of the most distressing and difficult to treat conditions of the lung. It is ironical that the billions of dollars spent worldwide on proprietary over the counter remedies of questionable efficacy1 for cough exceeds, by orders of magnitude, the money spent on basic cough research. It is therefore not surprising that the cough pharmacopoeia has altered little in the last 50 years, with no important advances over opiate based compounds and cromones. However, basic researchers have not been idle. In this issue of Thorax Trevisani and colleagues2 present new information pointing to a causative role for an ion channel called transient receptor potential vanilloid-1 (TRPV1) in cough. They show that the highly selective and potent TRPV1 inhibitor iodo-resiniferatoxin, derived from a plant toxin found in Euphorbia species, strongly suppresses cough induced by inhaled capsaicin or citric acid in conscious guinea pigs, a widely used animal cough model. …
Safety of hypnotics.
Authors: K O'Malley
Journal: BMJ (1971)

stabilized beforehand, because it seems to us to be more desirable clinically to estab- lish the correct anticonvulsant treatment rather than add another therapeutic agent to an already complicated regime in order to achieve the same result.Though only one specimen of blood was taken for estimation of serum folic acid, the estimations were routinely carried out in pairs in order to eliminate experimental error.We do however agree with the increasing evidence that estimation of red cell folate is a more reliable test of folate deficiency; unfortunately, this test could not be carried out as a routine at the onset of the trial.Finally, we certainly agree with Dr.Richens that case reports such as that of Chanarin et al.2 cannot be dismissed and that further work is required.Our con- clusions, we pointed out, are based on obser- vations of people whose epilepsy and related problems are of such severity to require residential treatment for varying periods of time.It seems important to carry out a prospective trial in new cases of epilepsy to determine whether folic acid administration will prevent some of the mental deterioration due to anticonvulsants.-Weare, etc.,
Analysis of dendritic cell populations using a revised histological staging of morphoea
Authors: T.K. Gilmour, B. Wilkinson, S.N. Breit, S. Kossard
Journal: British Journal of Dermatology (2000)

Recent studies have suggested that dermal dendritic cells (DDCs) may play a part in maintaining the structure of the dermis and in dermal immune modulation. Alteration in the population of DDCs has been noted in localized and systemic scleroderma, particularly a decline in the number of CD34+ DDCs. Objectives To define the alteration of the DDC populations with respect to the histological stage of morphoea.We examined 33 biopsies of morphoea, categorized into four histological stages, and examined the DDC population (CD34+ DDCs and factor XIIIa+ DDCs), the lymphocytic infiltrate, and tenascin (extracellular matrix glycoprotein) and transforming growth factor (TGF)-beta1 expression in each biopsy.As the dermis became less inflammatory and more sclerotic, there was a significant decline in the number of CD34+ DDCs and an increase in the number of factor XIIIa+ DDCs. The pan-T-cell infiltrate (UCHL-1/CD45RO) and tenascin deposition exhibited a similar pattern, with elevated expression in inflammatory stages and a decrease in expression as the dermis became sclerotic. TGF-beta1 was significantly elevated in three of the four histological stages of morphoea, in both the inflammatory and sclerotic stages. The proposed four-stage histological analysis of morphoea biopsies was a useful basis for studying dendritic cells and mediators in cutaneous sclerosis.Our study indicates that there is a reciprocal relationship between CD34+ DDCs and factor XIIIa+ DDCs in morphoea that correlates with the relative degrees of inflammation and sclerosis.
Vessels: new targets for asthma treatment
Authors: J W WILSON
Journal: Thorax (2001)

Are airway vessels really important in asthma? This question has become more relevant since the finding of increased vessel numbers and vascularity in the submucosa of patients with relatively mild asthma.1 It has been confirmed again by Salvato in this issue of Thorax .2 The description of asthmatic bronchial vessels has been extended beyond traditional views of vessel function. As well as supplying nutrients to the vessel wall, temperature regulation, and facilitating humidification of the airway environment, vessels have several other important functions in the asthmatic response that may contribute to airflow obstruction. The study by Salvato2 comments on each of these components.

Firstly, angiogenesis has been described in airway sections, identifying more vessels in asthma when anti-collagen IV antibodies were used to detect vascular basement membrane.1 3 4Interestingly, collagen IV has been shown to be essential for the development of new endothelial cell tubes.5 Studies using …
<i>In vivo</i> Color-Coded Imaging of the Interaction of Colon Cancer Cells and Splenocytes in the Formation of Liver Metastases
Authors: Michael Bouvet, Kazuhiko Tsuji, Meng Yang, Ping Jiang, Abdool R. Moossa, Robert M. Hoffman
Journal: Cancer Research (2006)

Abstract The role of host cells in tumor progression and metastasis is critical. Intrasplenic injection of tumor cells has long been known as an effective method of developing liver metastases in nude mice, whereas portal vein (PV) injection of tumor cells can result in rapid death of the tumor cells. Host cells were thought to play a role in these phenomena. We report here that after splenic injection of tumor cells, splenocytes cotraffic with the tumor cells to the liver and facilitate metastatic colony formation. Human colon cancer cells that express green fluorescent protein (GFP) linked to histone H2B in the nucleus and red fluorescent protein (RFP) in the cytoplasm (HCT-116-GFP-RFP) were injected in either the PV or spleen of nude mice and imaged at the subcellular level in vivo. Extensive clasmocytosis (destruction of the cytoplasm) of the cancer cells occurred within 6 hours after PV injection and essentially all the cancer cells died. In contrast, splenic injection of these tumor cells resulted in the aggressive formation of liver and distant metastasis. GFP spleen cells were found in the liver metastases that resulted from intrasplenic injection of the tumor cells in transgenic nude mice ubiquitously expressing GFP. When GFP spleen cells and the RFP cancer cells were coinjected in the PV, liver metastasis resulted that contained GFP spleen cells. These results suggest a novel tumor-host interaction that enables efficient formation of liver metastasis via intrasplenic injection. (Cancer Res 2006; 66(23): 11293-7)
Cytotoxic T-cell responses to H-Y: correlation with the rejection of syngeneic male skin grafts.
Authors: M Hurme, P R Chandler, C M Hetherington, E Simpson
Journal: The Journal of Experimental Medicine (1978)

The ability of female mice to rapidly reject syngenic male skin grafts is largely determined by dominant genes in the IB region of the H-2b halotype, whereas the ability to produce anti-H-Y cytotoxic cells is determined by a dominant gene in the IA region the H-2b halotype, or by complementary genes in the IC region of some other haplotypes. Thus, it seems that H-2-retricted anti-H-Y cytotoxic T cells are not responsible for the rejection of syngeneic male skin grafts.
Evolving Concepts in Human Renal Dysplasia
Authors: Adrian S. Woolf, Karen L. Price, Peter J. Scambler, Paul J.D. Winyard
Journal: Journal of the American Society of Nephrology (2004)

Human renal dysplasia is a collection of disorders in which kidneys begin to form but then fail to differentiate into normal nephrons and collecting ducts. Dysplasia is the principal cause of childhood end-stage renal failure. Two main theories have been considered in its pathogenesis: A primary failure of ureteric bud activity and a disruption produced by fetal urinary flow impairment. Recent studies have documented deregulation of gene expression in human dysplasia, correlating with perturbed cell turnover and maturation. Mutations of nephrogenesis genes have been defined in multiorgan dysmorphic disorders in which renal dysplasia can feature, including Fraser, renal cysts and diabetes, and Kallmann syndromes. Here, it is possible to begin to understand the normal nephrogenic function of the wild-type proteins and understand how mutations might cause aberrant organogenesis.
Immunoglobulin Abnormalities and Current Status of Treatment of Multiple Myeloma
Authors: J. Russell Little
Journal: JAMA (1969)

Dr. Eric Ezekiel, Fellow in Hematology, Jewish Hospital of St. Louis: A 56-year-old white woman was hospitalized because of severe, progressive pain in the right leg of six weeks' duration. The patient had been well until 17 months before admission when she first noted the onset of low back pain radiating to the right buttock and right thigh. There was no history of trauma, fever, chills, or anorexia. Physical examination revealed a thin, middleaged white woman complaining of pain in both legs. Pulse rate was 86 beats per minute and regular; blood pressure, 120/80 mm Hg; and respiration rate, 14 per minute. Results of examination of the head, ears, eyes, nose, throat, chest, and abdomen were unremarkable. There was exquisite lumbosacral tenderness. Pinprick and position sense were diminished in both legs. Laboratory data on admission included a hemoglobin value of 11.9 gm/100 ml and a white blood cell count (WBC)