tbuckley/cabot-search huggingface dataset:
Advances in Molecular and Cellular Therapies for Hearing Loss
Authors: Michael S Hildebrand, Stephen S Newton, Samuel P Gubbels, Abraham M Sheffield, Amit Kochhar, Michelle G de Silva, Hans-Henrik M Dahl, Scott D Rose, Mark A Behlke, Richard JH Smith
Journal: Molecular Therapy (2008)

Development of effective therapeutics for hearing loss has proven to be a slow and difficult process, evidenced by the lack of restorative medicines and technologies currently available to the otolaryngologist. In large part this is attributable to the limited regenerative potential in cochlear cells and the secondary degeneration of the cochlear architecture that commonly follows sensorineural hearing impairment. Therapeutic advances have been made using animal models, particularly in regeneration and remodeling of spiral ganglion neurons, which retract and die following hair cell loss. Natural regeneration in avian and reptilian systems provides hope that replacement of hair cells is achievable in humans. The most exciting recent advancements in this field have been made in the relatively new areas of cellular replacement and gene therapy. In this review we discuss recent developments in gene- and cell-based therapy for hearing loss, including detailed analysis of therapeutic mechanisms such as RNA interference and stem cell transplantation, as well as in utero delivery to the mammalian inner ear. We explore the advantages and limitations associated with the use of these strategies for inner ear restoration. Development of effective therapeutics for hearing loss has proven to be a slow and difficult process, evidenced by the lack of restorative medicines and technologies currently available to the otolaryngologist. In large part this is attributable to the limited regenerative potential in cochlear cells and the secondary degeneration of the cochlear architecture that commonly follows sensorineural hearing impairment. Therapeutic advances have been made using animal models, particularly in regeneration and remodeling of spiral ganglion neurons, which retract and die following hair cell loss. Natural regeneration in avian and reptilian systems provides hope that replacement of hair cells is achievable in humans. The most exciting recent advancements in this field have been made in the relatively new areas of cellular replacement and gene therapy. In this review we discuss recent developments in gene- and cell-based therapy for hearing loss, including detailed analysis of therapeutic mechanisms such as RNA interference and stem cell transplantation, as well as in utero delivery to the mammalian inner ear. We explore the advantages and limitations associated with the use of these strategies for inner ear restoration.
Ferritin functions as a proinflammatory cytokine via iron‐independent protein kinase C zeta/nuclear factor kappaB–regulated signaling in rat hepatic stellate cells†
Authors: Richard G. Ruddell, Diem Hoang‐Le, Joanne M. Barwood, Paul S. Rutherford, Terrance J. Piva, Dianne J. Watters, Paolo Santambrogio, Paolo Arosio, Grant A. Ramm
Journal: Hepatology (2008)

Circulating ferritin levels reflect body iron stores and are elevated with inflammation in chronic liver injury. H-ferritin exhibits a number of extrahepatic immunomodulatory properties, although its role in hepatic inflammation and fibrogenesis is unknown. Hepatic stellate cells respond to liver injury through production of proinflammatory mediators that drive fibrogenesis. A specific receptor for ferritin has been demonstrated on activated hepatic stellate cells, although its identity and its role in stellate cell activation is unclear. We propose that ferritin acts as a cytokine regulating proinflammatory function via nuclear factor kappaB (NF-kappaB)-regulated signaling in hepatic stellate cell biology. Hepatic stellate cells were treated with tissue ferritin and iron-free apoferritin, recombinant H-ferritins and L-ferritins, to assess the role of ferritin versus ferritin-bound iron in the production of proinflammatory mediators of fibrogenesis, and to determine whether signaling pathways act via a proposed H-ferritin endocytosis receptor, T cell immunoglobulin-domain and mucin-domain 2 (Tim-2). This study demonstrated that ferritin activates an iron-independent signaling cascade, involving Tim-2 independent phosphoinositide 3 (PI3)-kinase phosphorylation, protein kinase C zeta (PKCzeta) and p44/p42-mitogen-activated protein kinase, resulting in p50/p65-NF-kappaB activation and markedly enhanced expression of hepatic proinflammatory mediators interleukin-1beta (IL-1beta), inducible nitric oxide synthase (iNOS), regulated on activation normal T cell expressed and secreted (RANTES), inhibitor of kappa Balpha (IkappaBalpha), and intercellular adhesion molecule 1 (ICAM1). This study has defined the role of ferritin as a proinflammatory mediator of hepatic stellate cell biology acting through the NF-kappaB signaling pathway, and suggests a potential role in the inflammatory processes associated with hepatic fibrogenesis.
Report on Vaccination as Practised at the Liverpool Station of the National Vaccine Establishment
Authors: A. B. Steele
Journal: BMJ (1862)

remarkably free from this the bane of surgery.And for this improvement, there is no doubt that we are mainly indebted to our convalescent wards, the large, well-aired rooms which have lately been built at the top of the hospital.These convalescent wards I con- sider to be of the utmost use, not only to the pa- tients who are thus enabled, in all weathers, to get out of their own wards; but also to the patients who
OPERATING TEST CHARACTERISTICS OF PEAK OXYGEN PULSE COMBINED WITH OXYGEN PULSE CURVE PATTERN IN DIAGNOSIS OF CARDIAC VERSUS NONCARDIAC CAUSES OF DYSPNEA
Authors: Mirza Nubair Ahmad, Syed Hasan Yusuf, Mary K. Ellis, Haroon Yousaf, Timothy E. Paterick, Khawaja Afzal Ammar
Journal: Journal of the American College of Cardiology (2014)
The stem cell organisation, and the proliferative and gene expression profile of Barrett's epithelium, replicates pyloric-type gastric glands
Authors: Danielle L Lavery, Anna M Nicholson, Richard Poulsom, Rosemary Jeffery, Alia Hussain, Laura J Gay, Janusz A Jankowski, Sebastian S Zeki, Hugh Barr, Rebecca Harrison, James Going, Sritharan Kadirkamanathan, Peter Davis, Timothy Underwood, Marco R Novelli, Manuel Rodriguez–Justo, Neil Shepherd, Marnix Jansen, Nicholas A Wright, Stuart A C McDonald
Journal: Gut (2014)

<h3>Objective</h3> Barrett9s oesophagus shows appearances described as 'intestinal metaplasia', in structures called 'crypts' but do not typically display crypt architecture. Here, we investigate their relationship to gastric glands. <h3>Methods</h3> Cell proliferation and migration within Barrett9s glands was assessed by Ki67 and iododeoxyuridine (IdU) labelling. Expression of mucin core proteins (MUC), trefoil family factor (TFF) peptides and <i>LGR5</i> mRNA was determined by immunohistochemistry or by in situ hybridisation, and clonality was elucidated using mitochondrial DNA (mtDNA) mutations combined with mucin histochemistry. <h3>Results</h3> Proliferation predominantly occurs in the middle of Barrett9s glands, diminishing towards the surface and the base: IdU dynamics demonstrate bidirectional migration, similar to gastric glands. Distribution of MUC5AC, TFF1, MUC6 and TFF2 in Barrett9s mirrors pyloric glands and is preserved in Barrett9s dysplasia. MUC2-positive goblet cells are localised above the neck in Barrett9s glands, and TFF3 is concentrated in the same region. <i>LGR5</i> mRNA is detected in the middle of Barrett9s glands suggesting a stem cell niche in this locale, similar to that in the gastric pylorus, and distinct from gastric intestinal metaplasia. Gastric and intestinal cell lineages within Barrett9s glands are clonal, indicating derivation from a single stem cell. <h3>Conclusions</h3> Barrett9s shows the proliferative and stem cell architecture, and pattern of gene expression of pyloric gastric glands, maintained by stem cells showing gastric and intestinal differentiation: neutral drift may suggest that intestinal differentiation advances with time, a concept critical for the understanding of the origin and development of Barrett9s oesophagus.
Ventricular Arrhythmia and Stokes-Adams Syndrome
Authors: DONALD A. DUPLER
Journal: Circulation (1953)

An unusual case of ventricular arrhythmia is reported with electrocardiograms showing complete attacks of ventricular tachycardia, ventricular flutter and ventricular fibrillation. The etiologyis unknown. Large doses of quinidine, to the point of toxicity, seemed to halt the arrhythmia but did not prevent its recurrence. Ephedrine was given with resulting immediate improvement and no recurrence of the arrhythmia. It is suggested that ephedrine may be of value in treating Stokes-Adams attacks due to ventricular arrhythmia in which there is no heart block but an underlying bradycardia.
Genomic and stem cell policy issues: more alike than different?
Authors: Mary A Majumder
Journal: Genome Medicine (2011)

In a comparison of policy issues related to genomics and stem cells, initially, the differences seem to occupy the foreground. After all, no one is seeking to criminalize the conduct of genomic research, whereas researchers working with human embryonic stem cells face the prospect of criminal penalties in certain jurisdictions. And, in the USA, a polarized political climate, and twists and turns in litigation centering on a statutory provision that prohibits federal funding of ‘research in which a human embryo or embryos are destroyed’ [1], have heightened a sense of insecurity in the stem cell field [2]. However, stem cell policy concerns have always extended beyond the embryo. Furthermore, with the expansion of work using human induced pluripotent stem cells, created without embryo destruction, it is becoming increasingly likely
Harnessing Mother Nature against your fellow humans
Authors: Geoff Watts
Journal: BMJ (2005)

How prepared is Britain for terrorist attempts to use zoonoses as weapons? Geoff Watts reports 

Anthrax, plague, tularaemia, and the haemorrhagic fevers—these are four of the six microbes or groups of microbes classed by the US Centers for Disease Control and Prevention (CDC) as being of greatest potential value to would be bioterrorists. These “category A” agents, as they're known, are all easily disseminated or transmitted from person to person, cause high mortality, and are likely to engender social chaos. The four also have one other feature in common. All are zoonoses: the meeting point between human and veterinary medicine.

Bioterrorists need not, of course, rely on zoonoses. Attacking a nation's agriculture can by itself create mayhem. The economic and social damage caused in the United Kingdom by the entirely natural outbreak of foot and mouth disease in 2001 is testament to that.

But, naturally enough, it is bioterrorism involving human disease that prompts the sharpest fear. “It's corny and it's a cliche, but Mother Nature is the world's worst bioterrorist,” says Paul Gibbs of the University of Florida's College of Veterinary Medicine. Hence the widely held view that if you prepare for natural zoonotic epidemics you're probably well prepared to face an intentional …
Megaloblastic Anaemia Due to Anticonvulsants
Authors: M. Volterra, G. Romualdi
Journal: BMJ (1957)

Dengue virus (DENV) infection disrupts host innate immune signaling at various checkpoints. Cellular levels and stability of intermediate signaling molecules are a crucial hijacking point for a successful viral pathogenesis. Stability and turnover of all the cellular proteins including intermediate signaling molecules are principally regulated by proteasomal degradation pathway. In this study, we show that how DENV infection and particularly DENV-NS1 can modulate the host extracellular vesicle (EV) cargo to manipulate the deubiquitination machinery of the human microglial cell (CHME3). We have performed EV harvesting, size analysis by nanoparticle tracking analysis, identification of cargo microRNA via quantitative PCR, microRNA target validation by overexpression, and knockdown via mimics and anti-miRs, immunoblotting, dual luciferase reporter assay, in vivo ubiquitination assay, chase assay, and promoter activity assay to reach the conclusion. In this study, we show that DENV-infected monocytes and DENV-NS1–transfected cells release high amounts of EVs loaded with miR-148a. These EVs get internalized by human microglial cells, and miR-148a suppresses the ubiquitin-specific peptidase 33 (USP33) protein expression levels via binding to its 3′ untranslated region. Reduced USP33 in turn decreases the stability of cellular ATF3 protein via deubiquitylation. ATF3 acts as a suppressor of major proinflammatory gene expression pathways of TNF-α, NF-κB, and IFN-β. Our mechanistic model explains how DENV uses the EV pathway to transfer miR-148a for modulating USP33 and downstream ATF3 levels in human microglial cells and contributes in neuroinflammation within the CNS.
Mediators of histamine release from human platelets, lymphocytes, and granulocytes
Authors: Michael T. Kelly, R. Russell Martin, Arthur White
Journal: Journal of Clinical Investigation (1971)

Lysates of mixed human leukocyte suspensions released histamine from intact human leukocytes in vitro. Microgram quantities of leukocyte lysate protein released up to 90% of the total available histamine. The mixed leukocyte lysates were separated by differential centrifugation into nuclear (800 g pellet), lysosomal (25,000 g pellet), and postlysosomal supernatant (25,000 g supernatant) fractions. The degree of separation of the lysosomal from the other two fractions was assessed by measuring the relative activities of four lysosomal enzymes. The average distribution of enzyme activity was 11 ±2% (mean ±1 SD), 72 ±10%, and 17 ±8% for the nuclear, lysosomal, and supernatant fractions respectively. The histamine-releasing activity was equally distributed between the lysosomal and supernatant fractions, each of which had 5-fold greater activity than the nuclear fraction.
In vitro cytotoxicity and transplantation protection by autologous natural and activated killer cells against an in vitro transformed tumorigenic fibroblast line. A case study.
Authors: S A Wilhelm, B Mukherji
Journal: Journal of Clinical Investigation (1985)

Cytotoxic immune response by autologous natural killer (NK) cells against a spontaneous in vitro transformed tumorigenic fibroblast line, VIP-F:T, was studied in a 4 h 51Cr-release microcytotoxicity assay and in a tumor cell neutralization technique in vivo in nude mice. Although highly cytotoxic against the NK prototype target K562, the autologous NK cells in their nascent state were only marginally cytotoxic against VIP-F:T and unreactive against the autologous normal fibroblasts, Pen-F2. Autologous NK activity against VIP-F:T could, however, be induced by 2-16-h treatment of the NK cells with several species of interferon and by interferon-free interleukin 2 (IL-2). In vitro co-culture (IVC) in IL-2 of autologous peripheral blood lymphocytes (PBL) against VIP-F:T was shown by fluorescence activated cell sorting and by cold target competition experiments to generate almost exclusively an effector population bearing HNK-1 and Leu-11a phenotypes which exhibited receptor specificity for VIP-F:T distinct from receptors on Pen-F2 or K562 cells. PBL, co-cultured in IL-2 against Pen-F2 or K562, or cultured in IL-2 alone, generated high levels of nonspecific killing and showed no receptor specificity. Identical IVC in IL-2 of autologous PBL against a melanoma line, VIP (PBL and the VIP line derived from the same patient from whom the VIP-F:T line was also derived), and similar IVC in IL-2 of several other autologous PBL against their corresponding target cell lines (established from surgical specimens) generated cytotoxic responses involving cytotoxic populations bearing T8 as well as HNK-1 phenotypes; but the cytotoxic activities in none of these systems showed target receptor specificity. Autologous PBL, co-cultured against VIP-F:T in IL-2, were shown to be capable of rejecting tumorigenic challenge with VIP-F:T.3 (a clone of VIP-F:T) in nude mice at effector to VIP-F:T ratio of 10:1. The protective effect of the co-culture activated PBL was abrogated if the HNK-1+ cells were depleted from the effector population. Our data, thus, demonstrate specificity of cytotoxic reactivity which, by phenotypic markers, can be characterized as HNK-1 and Leu 11a+ cells under these experimental conditions against this particular in vitro transformed VIP-F:T line. In addition, this study shows that similar studies of cytotoxic autologous reactivities against in vitro transformed target cell lines will provide valuable information on the subject of NK-mediated surveillance against human neoplasia.
New issues in tuberculosis
Authors: S H E Kaufmann
Journal: Annals of the Rheumatic Diseases (2004)

Evidence for effects of air pollution exposure on lung function growth into adolescence is scarce. We investigated associations of air pollution exposure with lung function and lung function growth until age 16. We conducted longitudinal (N=915) and cross-sectional analyses (N=721) of associations of air pollution exposure with forced expiratory volume in 1 s (FEV<sub>1</sub>) and forced vital capacity (FVC) growth from ages 8 to 16 and FEV<sub>1</sub> and FVC at age 16. We estimated residential concentrations of nitrogen dioxide (NO<sub>2</sub>), "soot", and particulate matter with diameters &lt;2.5 (PM<sub>2.5</sub>), &lt;10 (PM<sub>10</sub>), and 2.5–10 µm (PM<sub>coarse</sub>) during the preschool, primary school and secondary school time windows by land use regression models and analysed associations with (growth in) FEV<sub>1</sub> and FVC by linear (mixed effects) regression. Higher air pollution exposure was associated with reduced FEV<sub>1</sub> growth, [<i>e.g.</i> adjusted difference (95% confidence interval) −0.26% (−0.49 to −0.03%) per interquartile range increase in secondary school PM<sub>2.5</sub>] and lower FEV<sub>1</sub> [−2.36% (−3.76 to −0.94%)], but was not adversely associated with FVC. Associations with FEV<sub>1</sub> were stronger in boys than girls and were not modified by asthma status. Higher air pollution exposure may lead to increased airway obstruction, but not reduced lung volume in adolescence.
A case of haematuria.
Authors: R T Prentice, J D Fergusson
Journal: BMJ (1977)

closed treatment and not a justifiable substitute for the latter method. Rigid internal fixation of the tibia should be regarded as an elective operation-to be done by the experienced fracture surgeon using an atraumatic technique. The immediate internal fixation of a fresh tibial shaft fracture should not be routine; early internal fixation delays healing and is surgically unsafe. The risk of serious infection is unacceptably high. Closed treat ment is therefore the method of choice for most of these injuries. Reference
Abstract 3168: An antioxidant and DNA repair gene expression pattern associated with lung cancer risk is also associated with COPD risk
Authors: James C. Willey
Journal: Cancer Research (2011)

Abstract Lung cancer and Chronic Obstructive Pulmonary Disease (COPD) are leading causes of morbidity and mortality both in the United States and worldwide. Inhalation of cigarette smoke is the primary known and preventable cause but only 10-15% of heavy smokers develop these diseases. This suggests that cigarette smoke exposure interacts with inherited susceptibility factors to determine risk. While some susceptibility genes are known, they account for less than 5% of risk for either disease. There is urgent need to identify additional heritable susceptibility factors for these diseases that explain the majority of COPD and lung cancer risk. For example, the National Lung Screening Trial (NLST) recently reported a 20% reduction in mortality from lung cancer. Because there are over 50 million individuals in the US who meet the criteria for the NLST, at a cost of $400/CT scan, the yearly cost of screening could be $20 billion. The objective in this study is to determine the role of inter-individual variation in antioxidant and DNA repair gene transcript regulation in conferring risk for both COPD and lung cancer. The central hypothesis is that inherited DNA variants are associated with increased risk for both COPD and lung cancer and that many of these manifest as increased transcript abundance dispersion in key antioxidant, DNA repair, and transcription factor genes. In support of our hypothesis, we recently identified a lung cancer risk test (LCRT) that comprises transcript abundance values of 14 genes, including nine anti-oxidant, three DNA repair, and two transcription factor genes. For each of these genes, transcript abundance values were dispersed over a greater range in lung cancer compared to matched controls (Blomquist et al, 2009). In addition, inherited DNA variation causes variation in transcript regulation of genes comprised by the LCRT (Crawford et al, 2007;Blomquist et al, 2010). Here we report that in a small number of non-lung cancer cases studied thus far N=13), a subject with positive LCRT value has a 6.7-fold increased likelihood of having COPD (defined by FEV1/FVC&amp;lt;0.7). Development of biomarkers for lung cancer and/or COPD risk will enable prioritization for screening and/or chemoprevention trials and provide drug targets for development of chemo-preventative and therapeutic pharmaceuticals. These developments are expected to reduce mortality and health care costs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3168. doi:10.1158/1538-7445.AM2011-3168
Retinal degeneration caused by dominant rhodopsin mutations in Drosophila
Authors: Phani Kurada, Joseph E O'Tousa
Journal: Neuron (1995)

Dominant mutations of the Drosophila ninaE-encoded rhodopsin are described that reduce the expression of wild-type rhodopsin and cause a slow, age-dependent form of retinal degeneration. A posttranslational event subsequent to the requirement for the ninaA-encoded cyclophilin is disrupted by the dominant mutations. Most of these dominant mutations are missense mutations that affect the physical properties of one of the seven transmembrane domains; another affects the cysteine involved in a disulfide linkage. The results indicate that misfolded or unstable mutant rhodopsin can interfere with maturation of wild-type rhodopsin, and that these cellular conditions may trigger retinal degeneration. In addition, these dominant rhodopsin mutations suppress the rapid degeneration seen in rdgC and norpA flies, indicating that high levels of rhodopsin are required.
Cincinnati Phenylketonuria Detection Program—A Progress Note
Authors: Helen K. Berry
Journal: JAMA (1961)

A STUDY was undertaken in 1958 to find a suitable method for obtaining urine specimens from infants during a large scale program for detection of phenylketonuria (PKU).<sup>1</sup>Filter paper urine test kits were used. These kits contained several pieces of absorbent paper which were placed in the baby's diaper to become wet with urine. The paper was dried and mailed to Children's Hospital, where it was tested for phenylpyruvic acid. The value of the program was demonstrated recently when, after testing more than 10,500 negative specimens, a positive test was obtained on a urine specimen from a 5-week-old infant, a first-born child. The diagnosis of phenylketonuria was confirmed by finding a serum phenylalanine concentration of 45 mg. per 100 ml. (Normal concentration is 1 to 4 mg. per 100 ml.). Treatment with a protein hydrolysate (Lofenalac) was begun promptly. At age 9 months the child appears to be developing