tbuckley/cabot-search huggingface dataset:
An 82-Year-Old Woman With Cataracts, 1 Year Later
Authors: Thomas L. Delbanco
Journal: JAMA (1997)

In February 1996, at the combined Ophthalmology/Gerontology Grand Rounds of the Beth Israel Hospital, Dr Stephen Obstbaum discussed an 82-year-old woman from Haiti whose vision was worsening secondary to bilateral cataracts. She lived with her daughter and extended family in a suburb of Boston, Mass, spoke only Haitian Creole, and had a history of cataracts for at least 20 years. Her vision had become increasingly poor throughout the years, but she had accepted only medicines prescribed for her during her frequent trips back to Haiti. When examined in 1996, she had 20/200 vision at distance in both eyes, with near vision in the 20/50 to 20/70 range. Her ophthalmologist suggested cataract surgery but she declined. Generally well, with a history of reasonably controlled hypertension and mild adult-onset diabetes, Mrs K was cared for by her grandson and a visiting nurse at home. Herbal teas and oils were her principal source
Destruction of nonimmunogenic mammary tumor cells by a fusogenic oncolytic herpes simplex virus induces potent antitumor immunity
Authors: Mikihito Nakamori, Xinping Fu, Raphael Rousseau, Si-Yi Chen, Xiaoliu Zhang
Journal: Molecular Therapy (2004)

In principle, destruction of tumor cells in vivo by oncolytic agents would release the entire repertoire of tumor antigens in their natural forms, leading to effective antitumor immunity. This goal has been elusive despite extensive testing of numerous strategies. We developed a doubly fusogenic oncolytic herpes simplex virus (Synco-2D) that kills tumor cells by a unique dual mechanism combining direct cytolysis with syncytial formation induced by cell membrane fusion. A single intratumor injection of Synco-2D induced strong antitumor immunity against an otherwise nonimmunogenic murine mammary tumor growing in immune-competent mice. CD8+ T cells were the primary mediators of immunity, contributing to the destruction of both primary and metastatic tumors. We conclude that the fusogenic capacity of Synco-2D enables it to elicit antitumor immunity exceeding that induced by more conventional oncolytic viruses.
The Poly(I:C)-induced maternal immune activation model in preclinical neuropsychiatric drug discovery
Authors: Sonali Reisinger, Deeba Khan, Eryan Kong, Angelika Berger, Arnold Pollak, Daniela D Pollak
Journal: Pharmacology & Therapeutics (2015)

Increasing epidemiological and experimental evidence implicates gestational infections as one important factor involved in the pathogenesis of several neuropsychiatric disorders. Corresponding preclinical model systems based upon maternal immune activation (MIA) by treatment of the pregnant female have been developed. These MIA animal model systems have been successfully used in basic and translational research approaches, contributing to the investigation of the underlying pathophysiological mechanisms at the molecular, cellular and behavioral levels. The present article focuses on the application of a specific MIA rodent paradigm, based upon treatment of the gestating dam with the viral mimic polyinosinic-polycytidilic acid (Poly(I:C)), a synthetic analog of double-stranded RNA (dsRNA) which activates the Toll-like receptor 3 (TLR3) pathway. Important advantages and constraints of this animal model will be discussed, specifically in light of gestational infection as one vulnerability factor contributing to the complex etiology of mood and psychotic disorders, which are likely the result of intricate multi-level gene×environment interactions. Improving our currently incomplete understanding of the molecular pathomechanistic principles underlying these disorders is a prerequisite for the development of alternative therapeutic approaches which are critically needed in light of the important drawbacks and limitations of currently available pharmacological treatment options regarding efficacy and side effects. The particular relevance of the Poly(I:C) MIA model for the discovery of novel drug targets for symptomatic and preventive therapeutic strategies in mood and psychotic disorders is highlighted in this review article.
AMP-activated protein kinase confers protection against TNF-α-induced cardiac cell death
Authors: Girish Kewalramani, Prasanth Puthanveetil, Fang Wang, Min Suk Kim, Sylvia Deppe, Ashraf Abrahani, Dan S. Luciani, James D. Johnson, Brian Rodrigues
Journal: Cardiovascular Research (2009)

Although a substantial role for 5′ adenosine monophosphate-activated protein kinase (AMPK) has been established in regulating cardiac metabolism, a less studied action of AMPK is its ability to prevent cardiac cell death. Using established AMPK activators like dexamethasone (DEX) or metformin (MET), the objective of the present study was to determine whether AMPK activation prevents tumour necrosis factor-alpha (TNF-α) induced apoptosis in adult rat ventricular cardiomyocytes. Cardiomyocytes were incubated with DEX, MET, or TNF-α for varying durations (0–12 h). TNF-α-induced cell damage was evaluated by measuring caspase-3 activity and Hoechst staining. Protein and gene estimation techniques were employed to determine the mechanisms mediating the effects of AMPK activators on TNF-α-induced cardiomyocyte apoptosis. Incubation of myocytes with TNF-α for 8 h has increased caspase-3 activation and apoptotic cell death, an effect that was abrogated by DEX and MET. The beneficial effect of DEX and MET was associated with stimulation of AMPK, which led to a rapid and sustained increase in Bad phosphorylation. This event reduced the interaction between Bad and Bcl-xL, limiting cytochrome c release and caspase-3 activation. Addition of Compound C to inhibit AMPK reduced Bad phosphorylation and prevented the beneficial effects of AMPK against TNF-α-induced cytotoxicity. Our data demonstrate that although DEX and MET are used as anti-inflammatory agents or insulin sensitizers, respectively, their common property to phosphorylate AMPK promotes cardiomyocyte cell survival through its regulation of Bad and the mitochondrial apoptotic mechanism.
Modified Extrafascial Radical Retropubic Prostatectomy Technique Decreases Frequency of Positive Surgical Margins in T2 Cancers &amp;lt;2 cm&lt;sup&gt;3&lt;/sup&gt;
Authors: Arnauld Villers, Thomas A. Stamey, Cheryl Yemoto, Pascal Rischmann, John E. McNeal
Journal: European Urology (2000)
Use of recombinant activated factor VII for treatment of a retropharyngeal hemorrhage in a hemophilic patient with a high titer inhibitor
Authors: B. Gail Macik, John Hohneker, H. R. Roberts, Anne M. Griffin
Journal: American Journal of Hematology (1989)

Abstract Treatment options during an acute hemorrhage for a hemophilic patient who has an inhibitor (antibody) to factor VIII (FVIII) are limited. If the inhibitor titer is high, even massive doses of FVIII are not sufficient to neutralize the antibody. Likewise, immunoadsorption techniques or plasmapheresis cannot remove enough antibody to permit treatment with FVIII. Allergic reactions and cross‐reacting inhibitors complicate therapy with porcine FVIII. Prothrombin complex concentrates (PCC) may be effective but the mechanism is unclear. The theory that activated factor VII (FVII a ) is the active principle in PCC prompted our treatment of a patient with a recombinant FVII a (rFVII a ) product (NOVO Industries). The patient presented with a large retropharyngeal hemorrhage and an initial inhibitor titer of 129 Bethesda units (BU). Despite Autoplex therapy (100U/kg), tracheal compression by the hematoma increased and asphyxiation was imminent. RFVII a therapy (60 μg/kg) was substituted for Autoplex and nine doses were given without complication. The hemorrhage was controlled. By 18 hr breathing was normal and swallowing and speech were greatly improved. Clinically, the patient dramatically responded to rFVII a . In addition, the purity, the lack of known infectious agents, and the ease of administration make rFVII a a potentially attractive new therapy. Use of this product also promises to further our understanding of in vivo hemostasis.
Bayesian Analysis and the GUSTO Trial-Reply
Authors: James M. Brophy
Journal: JAMA (1995)

In Reply.  —We agree with Dr Avins that clinical significance is far more relevant to the interpretation of clinical trial results than statistical significance. However, it must be emphasized that our Figure 4 displays the posterior probability density for the difference in mortality rates between t-PA and SK, assuming no prior information is available, so that the area under the curve between two points represents the probability that the rate difference is in that range. This is unrelated to aPvalue, which only provides the probability of getting data more extreme than that actually observed in the trial, given that the null hypothesis is exactly true.  Of course, we also agree with Dr Browne that the misuse and misinterpretation ofPvalues is not the answer to the question of how to best analyze clinical trials. We see little difference between the use of Bayes' theorem in assigning a
Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine
Authors: Kara Gross Margolis, Korey Stevanovic, Zhishan Li, Qi Melissa Yang, Tamas Oravecz, Brian Zambrowicz, Kanchan G Jhaver, Alexander Diacou, Michael D Gershon
Journal: Gut (2013)

<h3>Objective</h3> Enterochromaffin cell-derived serotonin (5-HT) promotes intestinal inflammation. We tested hypotheses that peripheral tryptophan hydroxylase (TPH) inhibitors, administered orally, block 5-HT biosynthesis and deplete 5-HT from enterochromaffin cells sufficiently to ameliorate intestinal inflammation; moreover, peripheral TPH inhibitors fail to enter the murine enteric nervous system (ENS) or central nervous systems and thus do not affect constitutive gastrointestinal motility. <h3>Design</h3> Two peripheral TPH inhibitors, LP-920540 and telotristat etiprate (LX1032; LX1606) were given orally to mice. Effects were measured on 5-HT levels in the gut, blood and brain, 5-HT immunoreactivity in the ENS, gastrointestinal motility and severity of trinitrobenzene sulfonic acid (TNBS)-induced colitis. Quantitation of clinical scores, histological damage and intestinal expression of inflammation-associated cytokines and chemokines with focused microarrays and real-time reverse transcriptase PCR were employed to evaluate the severity of intestinal inflammation. <h3>Results</h3> LP-920540 and LX1032 reduced 5-HT significantly in the gut and blood but not in the brain. Neither LP-920540 nor LX1032 decreased 5-HT immunoreactive neurons or fibres in the myenteric plexus and neither altered total gastrointestinal transit time, colonic motility or gastric emptying in mice. In contrast, oral LP-920540 and LX1032 reduced the severity of TNBS-induced colitis; the expression of 24% of 84 genes encoding inflammation-related cytokines and chemokines was lowered at least fourfold and the reduced expression of 17% was statistically significant. <h3>Conclusions</h3> Observations suggest that that peripheral TPH inhibitors uncouple the positive linkage of enterochromaffin cell-derived 5-HT to intestinal inflammation. Because peripheral TPH inhibitors evidently do not enter the murine ENS, they lack deleterious effects on constitutive intestinal motility in mice.
Aspirin use to be banned in under 16 year olds
Authors: S. Macdonald
Journal: BMJ (2002)

The UK Medicines Control Agency has recommended that children under 16 should not be given aspirin, because of its links with Reye’s syndrome, the rare but potentially fatal disorder found almost exclusively in children and adolescents.

The use of aspirin in children under 12 has been banned in the United Kingdom since 1986, and in April this year the Committee on Safety of Medicines warned that it should also be avoided in children up to 15 if they were feverish.

But at its October meeting …
Disparities in Children's Oral Health and Access to Dental Care
Authors: Wendy E. Mouradian
Journal: JAMA (2000)

Dental caries can be prevented by a combination of community, professional, and individual measures including water fluoridation, professionally applied topical fluorides and dental sealants, and use of fluoride toothpastes. Yet, tooth decay is the most common chronic disease of childhood. Dental care is the most prevalent unmet health need in US children with wide disparities existing in oral health and access to care. Only 1 in 5 children covered by Medicaid received preventive oral care for which they are eligible. Children from low income and minority families have poorer oral health outcomes, fewer dental visits, and fewer protective sealants. Water fluoridation is the most effective measure in preventing caries, but only 62% of water supplies are fluoridated, and lack of fluoridation may disproportionately affect poor and minority children. Childhood oral disease has significant medical and financial consequences that may not be appreciated because of the separation of medicine and dentistry. The infectious nature of dental caries, its early onset, and the potential of early interventions require an emphasis on preventive oral care in primary pediatric care to complement existing dental services. However, many pediatricians lack critical knowledge to promote oral health. We recommend financial incentives for prioritizing Medicaid Early and Periodic Screening, Diagnostic, and Treatment dental services; managed care accountability; integration of medical and dental professional training, clinical care, and research; and national leadership. JAMA. 2000;284:2625-2631.
Histamine release from human leukocytes: studies with deuterium oxide, colchicine, and cytochalasin B
Authors: Elizabeth Gillespie, Lawrence M. Lichtenstein
Journal: Journal of Clinical Investigation (1972)

Agents known to interact with either microtubules or microfilaments influenced the antigen-induced release of histamine from the leukocytes of allergic individuals. Deuterium oxide (D(2)O) which stabilizes microtubules and thereby favors their formation enhanced histamine release markedly. Concentrations as low as 5% increased antigen-induced release somewhat while concentrations as high as 75% had no effect on release in the absence of antigen. Enhancement occurred over a wide range of antigen concentrations and was also seen when release was initiated by antibody to IgE or IgG. When the release process was divided into two stages a D(2)O activity could be demonstrated only in the second stage. However, when D(2)O was present in the first stage together with agents which raise cyclic AMP levels and thereby inhibit release it partially reversed this inhibition. Colchicine, demecolcine, and vinblastine, compounds known to disaggregate microtubules, i.e., have an effect opposite to that of D(2)O, inhibited the release of histamine and counteracted the effects of D(2)O. The inhibitory action of colchicine was greater if cells were treated with colchicine before rather than after activation with antigen. Cytochalasin B, a compound which causes the disappearance of microfilaments, had variable effects on histamine release. The most frequently seen response was slight enhancement. Neither D(2)O nor cytochalasin B altered cyclic AMP levels in leukocytes. These observations support and strengthen the view that an intact and functioning microtubule system is directly important for the secretion of histamine from leukocytes and suggest that microfilaments might have multiple indirect effects.
Cancer mortality in U.S. counties with plastics and related industries.
Authors: T J Mason
Journal: Environmental Health Perspectives (1975)

Counties in the United States have been identified with chemical establishments whose primary manufacturing processes use vinyl chloride. Site-specific cancer mortality comparisons have revealed an excess of multiple myeloma in males associated with two of the manufacturing categories, synthetic rubber and synthetic fibers. A causal relationship between these manufacturing categories and multiple myeloma could not be established. An industry-based assessment of the occupational contribution to this excess is needed to evaluate the etiologic importance of this relationship.
Meningococcal carriage in adolescents in the United Kingdom to inform timing of an adolescent vaccination strategy
Authors: Catherine A. Jeppesen, Matthew D. Snape, Hannah Robinson, Nicoletta Gossger, Tessa M. John, Merryn Voysey, Shamez Ladhani, Ifeanyichukwu O. Okike, Clarissa Oeser, Alison Kent, Jennifer Oliver, Pippa Taylor, Begonia Morales-Aza, Stuart C. Clarke, Michelle Casey, Filipa Martins, Nicholas R.E. Kitchin, Annaliesa S. Anderson, Hal Jones, Kathrin U. Jansen, Joseph Eiden, Louise Pedneault, Paul T. Heath, Adam Finn, Saul N. Faust, Andrew J. Pollard
Journal: Journal of Infection (2015)

Recent development of serogroup B meningococcal (MenB) vaccines highlights the importance of pharyngeal carriage data, particularly in adolescents and young adults, to inform implementation strategies. We describe current UK carriage prevalence in this high risk population and compare methods of carriage detection.In this multisite study, pharyngeal swabs were collected on 3-4 occasions over 6-12 months, from 1040 school and university students, aged 10-25 years. Meningococcal carriage was detected by standard culture combined with seroagglutination or PCR of cultured isolates, or by direct PCR from swab. The factor H binding protein (fHBP) variants present in meningococcal isolates were determined.Meningococcal serogroups B and Y were most common, with carriage up to 6.5% and 5.5% respectively, increasing throughout adolescence. Identification by seroagglutination was often unreliable, and the sensitivity of direct PCR detection was 66% compared to culture combined with PCR. Of MenB isolates, 89.1% had subfamily A variants of fHBP. The acquisition rate of MenB carriage was estimated at 2.8 per 1000 person-months.If vaccination is to precede the adolescent rise in MenB carriage, these data suggest it should take place in early adolescence. Studies assessing vaccine impact should use molecular methods to detect carriage.
Adeno-associated virus 2-mediated high efficiency gene transfer into immature and mature subsets of hematopoietic progenitor cells in human umbilical cord blood.
Authors: S Z Zhou, S Cooper, L Y Kang, L Ruggieri, S Heimfeld, A Srivastava, H E Broxmeyer
Journal: The Journal of Experimental Medicine (1994)

Recombinant adeno-associated virus 2 (AAV) virions were constructed containing a gene for resistance to neomycin (neoR), under the control of either the herpesvirus thymidine kinase (TK) gene promoter (vTK-Neo), or the human parvovirus B19 p6 promoter (vB19-Neo), as well as those containing an upstream erythroid cell-specific enhancer (HS-2) from the locus control region of the human beta-globin gene cluster (vHS2-TK-Neo; vHS2-B19-Neo). These recombinant virions were used to infect either low density or highly enriched populations of CD34+ cells isolated from human umbilical cord blood. In clonogenic assays initiated with cells infected with the different recombinant AAV-Neo virions, equivalent high frequency transduction of the neoR gene into slow-cycling multipotential, erythroid, and granulocyte/macrophage (GM) progenitor cells, including those with high proliferative potential, was obtained without prestimulation with growth factors, indicating that these immature and mature hematopoietic progenitor cells were susceptible to infection by the recombinant AAV virions. Successful transduction did not require and was not enhanced by prestimulation of these cell populations with cytokines. The functional activity of the transduced neo gene was evident by the development of resistance to the drug G418, a neomycin analogue. Individual high and low proliferative colony-forming unit (CFU)-GM, burst-forming unit-erythroid, and CFU-granulocyte erythroid macrophage megakaryocyte colonies from mock-infected, or the recombinant virus-infected cultures were subjected to polymerase chain reaction analysis using a neo-specific synthetic oligonucleotide primer pair. A 276-bp DNA fragment that hybridized with a neo-specific DNA probe on Southern blots was only detected in those colonies cloned from the recombinant virus-infected cells, indicating stable integration of the transduced neo gene. These studies suggest that parvovirus-based vectors may prove to be a useful alternative to the more commonly used retroviral vectors for high efficiency gene transfer into slow or noncycling primitive hematopoietic progenitor cells, without the need for growth factor stimulation, which could potentially lead to differentiation of these cells before transplantation.
Mutation causing severe myasthenia reveals functional asymmetry of AChR signature cystine loops in agonist binding and gating
Authors: Xin-Ming Shen, Kinji Ohno, Akira Tsujino, Joan M. Brengman, Monique Gingold, Steven M. Sine, Andrew G. Engel
Journal: Journal of Clinical Investigation (2003)

We describe a highly disabling congenital myasthenic syndrome (CMS) associated with rapidly decaying, low-amplitude synaptic currents, and trace its cause to a valine to leucine mutation in the signature cystine loop (cys-loop) of the AChR α subunit. The recently solved crystal structure of an ACh-binding protein places the cys-loop at the junction between the extracellular ligand-binding and transmembrane domains where it may couple agonist binding to channel gating. We therefore analyzed the kinetics of ACh-induced single-channel currents to identify elementary steps in the receptor activation mechanism altered by the αV132L mutation. The analysis reveals that αV132L markedly impairs ACh binding to receptors in the resting closed state, decreasing binding affinity for the second binding step 30-fold, but attenuates gating efficiency only about twofold. By contrast, mutation of the equivalent valine residue in the δ subunit impairs channel gating approximately fourfold with little effect on ACh binding, while corresponding mutations in the β and ε subunits are without effect. The unique functional contribution of the α subunit cys-loop likely owes to its direct connection via a β strand to αW149 at the center of the ligand-binding domain. The overall findings reveal functional asymmetry between cys-loops of the different AChR subunits in contributing to ACh binding and channel gating.
Antipneumolysin Antibody Titers in HIV-Seropositive Injection Drug Users before and after Pneumococcal Bacteremia
Authors: JEFFREY H. SULLIVAN, TIMOTHY J. MITCHELL, MARK C. STEINHOFF
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Lower baseline antipneumolysin antibody ( α -PLY) levels have been found in populations with a higher incidence of pneumococcal infections. To determine whether predisease α -PLY titer is associated with invasive pneumococcal disease in HIV-seropositive injection drug users (IDU), we utilized a prospective cohort of IDU in Baltimore to compare α -PLY titers before bacteremia in 28 HIV- seropositive IDU cases with α -PLY titers in 56 matched (CD4 and seroconversion date) HIV-seropositive IDU control subjects and 28 matched (calendar time) HIV-seronegative IDU control subjects remaining free of pneumococcal disease. We also compared the postinfection fold-rise of α -PLY titers in cases relative to the change in α -PLY titers in control subjects during the same interval; α -PLY titers were measured using quantitative ELISA, and functional activity was assessed using antihemolysin assays. Predisease α -PLY titer did not differ between cases (66 units) and HIV-seropositive control subjects (70 units, p = 0.56) or HIV-seronegative control subjects (80 units, p = 0.10). There was a significant difference in fold-rise of α -PLY titers postdisease between cases (1.18) and HIV-seronegative control subjects (0.76), p = 0.03. Baseline α -PLY titers do not differ significantly between HIV-seropositive IDU who develop pneumococcal bacteremia from HIV-seropositive and HIV-seronegative IDU control subjects remaining free of severe pneumococcal disease.