tbuckley/cabot-search huggingface dataset:
Chronic graft-versus-host disease of the liver: Presentation as an acute hepatitis
Authors: Simone I. Strasser, Howard M. Shulman, Mary E. Flowers, Rajender Reddy, David A. Margolis, Manfred Prumbaum, Stuart E. Seropian, George B. McDonald
Journal: Hepatology (2000)

Chronic graft–versus–host disease (GVHD) of the liver usually presents as an indolent cholestatic disease in patients with skin, mouth, and eye involvement. We observed 14 patients in whom chronic GVHD of the liver presented with marked elevations of serum aminotransferases, clinically resembling acute viral hepatitis. Onset of liver dysfunction was at 294 days (range, 74–747 days) after allogeneic hematopoietic cell transplantation and coincided with a recent cessation or taper of immunosuppressive drugs. Median peak serum alanine transaminase (ALT) was 1,640 U/L (698–2,565 U/L), and median bilirubin was 12.3 mg/dL (0.9–55.9 mg/dL). All biopsies showed characteristic features of GVHD with damaged and degenerative small bile ducts. Other features included a marked lobular hepatitis, moderate to marked amounts of hepatocyte unrest, sinusoidal inflammation with perivenular necroinflammatory foci, and many acidophilic bodies scattered throughout the lobule. When high–dose immunosuppressive therapy was instituted soon after presentation, progressive improvement and eventual normalization of liver enzymes and bilirubin levels were observed. However, in cases in which the diagnosis was not made and therapy was delayed, a progressive cholestatic picture emerged with histologic evidence of loss of small bile ducts and portal fibrosis. We conclude that a distinct syndrome of chronic liver GVHD presenting as an acute hepatitis can be recognized in a patient at risk who is receiving no, or minimal, immunosuppressive medications. Liver biopsy is necessary to exclude viral causes of liver dysfunction and to confirm characteristic abnormalities of small bile ducts. Institution of high–dose immunosuppression can prevent progressive bile duct destruction and effect resolution of jaundice if given early.
Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and meta-analysis
Authors: Anna C Seale, Hannah Blencowe, Alexander A Manu, Harish Nair, Rajiv Bahl, Shamim A Qazi, Anita K Zaidi, James A Berkley, Simon N Cousens, Joy E Lawn
Journal: The Lancet Infectious Diseases (2014)

BackgroundBacterial infections are a leading cause of the 2·9 million annual neonatal deaths. Treatment is usually based on clinical diagnosis of possible severe bacterial infection (pSBI). To guide programme planning, we have undertaken the first estimates of neonatal pSBI, by sex and by region, for sub-Saharan Africa, south Asia, and Latin America.MethodsWe included data for pSBI incidence in neonates of 32 weeks' gestation or more (or birthweight ≥1500 g) with livebirth denominator data, undertaking a systematic review and forming an investigator group to obtain unpublished data. We calculated pooled risk estimates for neonatal pSBI and case fatality risk, by sex and by region. We then applied these risk estimates to estimates of livebirths in sub-Saharan Africa, south Asia, and Latin America to estimate cases and associated deaths in 2012.FindingsWe included data from 22 studies, for 259 944 neonates and 20 196 pSBI cases, with most of the data (18 of the 22 studies) coming from the investigator group. The pooled estimate of pSBI incidence risk was 7·6% (95% CI 6·1–9·2%) and the case-fatality risk associated with pSBI was 9·8% (7·4–12·2). We estimated that in 2012 there were 6·9 million cases (uncertainty range 5·5 million–8·3 million) of pSBI in neonates needing treatment: 3·5 million (2·8 million–4·2 million) in south Asia, 2·6 million (2·1 million–3·1 million) in sub-Saharan Africa, and 0·8 million (0·7 million–1·0 million) in Latin America. The risk of pSBI was greater in boys (risk ratio 1·12, 95% CI 1·06–1·18) than girls. We estimated that there were 0·68 million (0·46 million–0·92 million) neonatal deaths associated with pSBI in 2012.InterpretationThe need-to-treat population for pSBI in these three regions is high, with ten cases of pSBI diagnosed for each associated neonatal death. Deaths and disability can be reduced through improved prevention, detection, and case management.FundingThe Wellcome Trust and the Bill & Melinda Gates Foundation through grants to Child Health Epidemiology Reference Group (CHERG) and Save the Children's Saving Newborn Lives programme.
Howard Eaton Freeman Davies
Authors: A. F. M. Davies
Journal: BMJ (2013)

Howard Eaton Freeman Davies (known affectionately to his friends and colleagues as “HEF”) died after a brief illness, having been frail for some months as a result of worsening cardiac failure. Born in Bargoed in the Welsh valleys, he was the son of a local history master. He was educated at Bridgend Grammar School and was offered a place to read medicine at Cambridge, but a wartime schoolmaster’s salary did not run to the fees so at the age of 17 he entered University College Cardiff, where he gained a first class honours degree in physiology. In his final undergraduate year he had his name on several papers. Howard then won an exhibition scholarship to Guy’s Hospital Medical School in London and graduated with the prize for pathology.

After national service he held various junior posts at Guy’s where his great intellect was noted, then at the Hammersmith …
Application of Cognitive Rehabilitation Theory to the Development of Smart Prompting Technologies
Authors: A. M. Seelye, M. Schmitter-Edgecombe, B. Das, D. J. Cook
Journal: IEEE Reviews in Biomedical Engineering (2012)

Older adults with cognitive impairments often have difficulty performing instrumental activities of daily living (IADLs). Prompting technologies have gained popularity over the last decade and have the potential to assist these individuals with IADLs in order to live independently. Although prompting techniques are routinely used by caregivers and health care providers to aid individuals with cognitive impairment in maintaining their independence with everyday activities, there is no clear consensus or gold standard regarding prompt content, method of instruction, timing of delivery, or interface of prompt delivery in the gerontology or technology literatures. In this paper, we demonstrate how cognitive rehabilitation principles can inform and advance the development of more effective assistive prompting technologies that could be employed in smart environments. We first describe cognitive rehabilitation theory (CRT) and show how it provides a useful theoretical foundation for guiding the development of assistive technologies for IADL completion. We then use the CRT framework to critically review existing smart prompting technologies to answer questions that will be integral to advancing development of effective smart prompting technologies. Finally, we raise questions for future exploration as well as challenges and suggestions for future directions in this area of research.
Subfunctionalization of Expression and Peptide Domains Following the Ancient Duplication of the Proopiomelanocortin Gene in Teleost Fishes
Authors: F. S. J. de Souza
Journal: Molecular Biology and Evolution (2005)

The proopiomelanocortin gene (POMC) encodes several bioactive peptides, including adrenocorticotropin hormone, α-, β-, and γ-melanocyte-stimulating hormone, and the opioid peptide β-endorphin, which play key roles in vertebrate physiology. In the human, mouse, and chicken genomes, there is only one POMC gene. By searching public genome projects, we have found that Tetraodon (Tetraodon nigroviridis), Fugu (Takifugu rubripes), and zebrafish (Danio rerio) possess two POMC genes, which we called POMCα and POMCβ, and we present phylogenetic and mapping evidence that these paralogue genes originated in the whole-genome duplication specific to the teleost lineage over 300 MYA. In addition, we present evidence for two types of subfunction partitioning between the paralogues. First, in situ hybridization experiments indicate that the expression domains of the ancestral POMC gene have been subfunctionalized in Tetraodon, with POMCα expressed in the nucleus lateralis tuberis of the hypothalamus, as well as in the rostral pars distalis and pars intermedia (PI) of the pituitary, whereas POMCβ is expressed in the preoptic area of the brain and weakly in the pituitary PI. Second, POMCβ genes have a β-endorphin segment that lacks the consensus opioid signal and seems to be under neutral evolution in tetraodontids, whereas POMCα genes possess well-conserved peptide regions. Thus, POMC paralogues have experienced subfunctionalization of both expression and peptide domains during teleost evolution. The study of regulatory regions of fish POMC genes might shed light on the mechanisms of enhancer partitioning between duplicate genes, as well as the roles of POMC-derived peptides in fish physiology.
Marginated monocytes play a central role in lung ischaemia-reperfusion injury in mice: Implications for lung transplantation
Authors: Kate Tatham, Hannah Donaldson, Kieran O'Dea, Kenji Wakabayashi, Nandor Marczin, Masao Takata
Journal: European Respiratory Journal (2013)

Background: Lung transplantation success is limited by donor lung inflammation, which exacerbates ischaemia-reperfusion (IR) injury leading to primary graft dysfunction. Alveolar macrophages within the donor lung and recipient neutrophils have been implicated in this process. Recent evidence suggests that lung-marginated inflammatory subset monocytes play a key role in the progression of acute lung injury. We hypothesised that donor lung-marginated monocytes are important contributors to the IR injury in lung transplantation.

Methods: Isolated mouse lungs were flushed for 5min with RPMI/4%BSA buffer, and then underwent 2hrs of ischaemia and 2hrs of recirculating perfusion (40ml/kg/min).

Results: Compared to perfusion-only controls, IR produced much higher levels of BALF protein and lung wet:dry ratios (Table 1). A substantial number of Ly-6Chigh monocytes still remained after reperfusion (4.8 x105) and exhibited activation as measured by L-selectin shedding. Monocyte depletion (by pretreating mice with iv clodronate) resulted in a significant reduction in IR-induced injury (Table 1), with reduced lung neutrophil CD11b expression.

View this table:

Lung Injury





Discussion: We have demonstrated that significant numbers of monocytes are still retained within the buffer-flushed lungs, and that these monocytes play a central role in the evolution of IR injury. Our findings indicate that lung-marginated donor-derived leukocytes, in particular monocytes, can be an important novel target for prevention of post-transplantation lung injury.
Longitudinal analysis of T cell receptor (TCR) gene usage by human immunodeficiency virus 1 envelope-specific cytotoxic T lymphocyte clones reveals a limited TCR repertoire.
Authors: S A Kalams, R P Johnson, A K Trocha, M J Dynan, H S Ngo, R T D'Aquila, J T Kurnick, B D Walker
Journal: The Journal of Experimental Medicine (1994)

Human immunodeficiency virus 1 (HIV-1) infection is associated with a vigorous cellular immune response that allows detection of cytotoxic T lymphocyte (CTL) activity using freshly isolated peripheral blood mononuclear cells (PBMC). Although restricting class I antigens and epitopes recognized by HIV-1-specific CTL have been defined, the effector cells mediating this vigorous response have been characterized less well. Specifically, no studies have addressed the breadth and duration of response to a defined epitope. In the present study, a longitudinal analysis of T cell receptor (TCR) gene usage by CTL clones was performed in a seropositive person using TCR gene sequences as a means of tracking responses to a well-defined epitope in the glycoprotein 41 transmembrane protein. 10 CTL clones specific for this human histocompatibility leukocyte antigen-B14-restricted epitope were isolated at multiple time points over a 31-mo period. All clones were derived from a single asymptomatic HIV-1-infected individual with a vigorous response to this epitope that was detectable using unstimulated PBMC. Polymerase chain reaction amplification using V alpha and V beta family-specific primers was performed on each clone, followed by DNA sequencing of the V-D-J regions. All 10 clones utilized V alpha 14 and V beta 4 genes. Sequence analysis of the TCR revealed the first nine clones isolated to also be identical at the nucleotide level. The TCR-alpha junctional region sequence of the tenth clone was identical to the junctional region sequences of the other nine, but this clone utilized distinct D beta and J beta gene segments. This study provides evidence that the observed high degree of HIV-1-specific CTL activity may be due to monoclonal or oligoclonal expansion of specific effector cells, and that progeny of a particular CTL clone may persist for prolonged periods in vivo in the presence of a chronic productive viral infection. The observed limited TCR diversity against an immunodominant epitope may limit recognition of virus variants with mutations in regions interacting with the TCR, thereby facilitating immune escape.
Prospective Prognostic Assessment of Blood Pressure Response During Exercise in Patients With Hypertrophic Cardiomyopathy
Authors: Nicolas Sadoul, Krishna Prasad, Perry M. Elliott, Soma Bannerjee, Michael P. Frenneaux, William J. McKenna
Journal: Circulation (1997)

Background Previous studies revealed that an abnormal blood pressure response (ABPR) during exercise was common in young hypertrophic cardiomyopathy (HCM) patients and was associated with a family history of premature sudden cardiac death (SCD). This study was performed prospectively to assess the prognostic significance of blood pressure response during exercise in young patients with HCM. Methods and Results Maximum symptom-limited treadmill exercise testing with continuous blood pressure monitoring was performed in 161 consecutive patients 8 to 40 years old (27±9). A normal blood pressure response, defined as an increase in the systolic pressure of at least 20 mm Hg from rest to peak exercise in the absence of a fall of &gt;20 mm Hg from peak pressure, was seen in 101 (63%). In 60 (37%), the blood pressure response was abnormal. There was no significant difference in patients with normal blood pressure response and ABPR in terms of age, sex, follow-up, or recognized risk factors for SCD. During the follow-up period (mean, 44±20 months), SCD occurred in 12 patients: 3 (3%) in the normal blood pressure response group versus 9 (15%) in the ABPR group ( P &lt;.009). ABPR had a sensitivity of 75%, a specificity of 66%, a negative predictive value of 97%, and a positive predictive value of 15% for the prediction of SCD. There was no significant difference in the incidence of other recognized risk factors between patients with SCD and the survivors. Conclusions A normal exercise blood pressure response identifies low-risk young patients with HCM. An ABPR identifies the high-risk cohort; the low positive predictive accuracy, however, indicates that further risk stratification is warranted.
Metabolic surgery profoundly influences gut microbial-host metabolic cross-talk
Authors: J. V. Li, H. Ashrafian, M. Bueter, J. Kinross, C. Sands, C. W. le Roux, S. R. Bloom, A. Darzi, T. Athanasiou, J. R. Marchesi, J. K. Nicholson, E. Holmes
Journal: Gut (2011)

<h3>Abstract</h3> Neuropeptides have been reported to regulate progenitor proliferation and neurogenesis in the central nervous system. However, these studies have typically been conducted using pharmacological agents in <i>ex vivo</i> preparations, and <i>in vivo</i> evidence for their developmental function is generally lacking. Recent scRNA-Seq studies have identified multiple neuropeptides and their receptors as being selectively expressed in neurogenic progenitors of the embryonic mouse and human retina. This includes Sstr2, whose ligand somatostatin is transiently expressed by immature retinal ganglion cells. By analyzing retinal explants treated with selective ligands that target these receptors, we found that Sstr2-dependent somatostatin signaling induces a dose-dependent inhibition of photoreceptor generation while increasing the relative fraction of primary progenitor cells. These effects were confirmed by scRNA-Seq analysis of retinal explants and abolished in <i>Sstr2</i>-deficient retinas. Although no changes in the relative fraction of primary progenitors or photoreceptor precursors were observed in <i>Sstr2</i>-deficient retinas <i>in vivo</i>, scRNA-Seq analysis demonstrated accelerated differentiation of neurogenic progenitors. We conclude that Sstr2 signaling may act to negatively regulate retinal neurogenesis in combination with other retinal ganglion cell-derived secreted factors such as Shh, although <i>in vivo</i> Sstr2 is dispensable for normal retinal development.
Species D Adenoviruses as Oncolytics against B-cell Cancers
Authors: Christopher Y. Chen, Julien S. Senac, Eric A. Weaver, Shannon M. May, Diane F. Jelinek, Philip Greipp, Thomas Witzig, Michael A. Barry
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Oncolytic viruses are self-amplifying anticancer agents that make use of the natural ability of viruses to kill cells. Adenovirus serotype 5 (Ad5) has been extensively tested against solid cancers, but less so against B-cell cancers because these cells do not generally express the coxsackie and adenoviral receptor (CAR). To determine whether other adenoviruses might have better potency, we “mined” the adenovirus virome of 55 serotypes for viruses that could kill B-cell cancers. Experimental Design: Fifteen adenoviruses selected to represent Ad species B, C, D, E, and F were tested in vitro against cell lines and primary patient B-cell cancers for their ability to infect, replicate in, and kill these cells. Select viruses were also tested against B-cell cancer xenografts in immunodeficient mice. Results: Species D adenoviruses mediated most robust killing against a range of B-cell cancer cell lines, against primary patient marginal zone lymphoma cells, and against primary patient CD138+ myeloma cells in vitro. When injected into xenografts in vivo, single treatment with select species D viruses Ad26 and Ad45 delayed lymphoma growth. Conclusions: Relatively unstudied species D adenoviruses have a unique ability to infect and replicate in B-cell cancers as compared with other adenovirus species. These data suggest these viruses have unique biology in B cells and support translation of novel species D adenoviruses as oncolytics against B-cell cancers. Clin Cancer Res; 17(21); 6712–22. ©2011 AACR.
Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphomas: a pooled analysis of 1546 patients
Authors: Stefan K. Barta, Xiaonan Xue, Dan Wang, Roni Tamari, Jeannette Y. Lee, Nicolas Mounier, Lawrence D. Kaplan, Josep-Maria Ribera, Michele Spina, Umberto Tirelli, Rudolf Weiss, Lionel Galicier, Francois Boue, Wyndham H. Wilson, Christoph Wyen, Albert Oriol, José-Tomás Navarro, Kieron Dunleavy, Richard F. Little, Lee Ratner, Olga Garcia, Mireia Morgades, Scot C. Remick, Ariela Noy, Joseph A. Sparano
Journal: Blood (2013)
The wnt-frizzled cascade in cardiovascular disease
Authors: M van Gijn
Journal: Cardiovascular Research (2002)

Time for primary review 31 days. 

Wnt-proteins constitute a family of secreted cystein-rich glycosylated proteins, involved in a variety of modeling and remodeling processes including cell proliferation, differentiation, apoptosis and the control of cell orientation [1–3]. Malfunctioning of the wnt-frizzled pathway has been implied in diseases as divergent as cancer and Alzheimer's disease [1,4]. The wnt-frizzled signal transduction pathway plays an important role during non-vertebrate and vertebrate development [5]. Several studies have shown the importance of wnts in the control of processes such as patterning of the body axis and development of the central nervous system and the limbs [6,7]. Moreover, interventions in wnt signaling have been described to affect cardiac morphogenesis [8,9] and several members of the wnt-frizzled signal transduction pathway were found to be expressed during cardiac development in vertebrates [10–14].

In cardiovascular pathology, re-expression of a fetal gene expression pattern is a generally observed phenomenon [15]. The study of gene expression during development may therefore provide clues about the expression profile during cardiovascular pathology. Recently, considerable progress has been made concerning the role of the wnt-frizzled signal transduction pathway in the development and progression of cardiovascular pathology. This review will focus on the possible role of the wnt-frizzled signal transduction pathway in cardiovascular diseases.

The family of wnt proteins consists of 16 members [5]. These proteins are extremely difficult to purify because they tend to bind to the extracellular matrix [16], which hampers the study of their characteristics. An overview of the wnt proteins and their proposed function during development, derived from the study of null mutants, is provided in Table 1. Based on functional differences, wnt proteins can be divided into two classes, the wnt1 class and the wnt5a class. Members of the wnt1 class are able … 

* Corresponding author. Tel.: +31-43-388-1417; fax: +31-43-388-4149 wm.blankesteijn{at}farmaco.unimaas.nl
PIK3CA Mutation Associates with Improved Outcome in Breast Cancer
Authors: Kevin Kalinsky, Lindsay M. Jacks, Adriana Heguy, Sujata Patil, Marija Drobnjak, Umeshkumar K. Bhanot, Cyrus V. Hedvat, Tiffany A. Traina, David Solit, William Gerald, Mary Ellen Moynahan
Journal: Clinical Cancer Research (2009)

Abstract Purpose: In breast cancer, somatic mutations in the PIK3CA gene are common. The prognostic implication of these activating mutations remains uncertain as moderately sized studies have yielded variable outcomes. Our aim was to determine the prognostic implications of PIK3CA mutations in breast cancer. Experimental Design: Archival formalin-fixed paraffin-embedded primary breast tumors, from 590 patients selected for known vital status with a median follow-up of 12.8 years and a tumor &amp;gt;1 cm, were genotyped for PIK3CA mutations. Mutation rates and associations between mutation site and clinicopathologic characteristics were assessed. Progression-free survival, overall survival, and breast cancer–specific survival were examined using Kaplan-Meier or competing risk methodology. Results: PIK3CA mutation is identified in 32.5% of breast cancers. PIK3CA mutation significantly associates with older age at diagnosis, hormone receptor positivity, HER2 negativity, lower tumor grade and stage, and lymph node negativity. Patients with PIK3CA mutated tumors have significant improvement in overall survival (P = 0.03) and breast cancer–specific survival (P = 0.004). Analysis for PIK3CA mutation site-specific associations reveals that the H1047R kinase domain mutation highly associates with node negativity (P = 0.007), whereas helical domain hotspot mutations associate with older age at diagnosis (P = 0.004). Conclusion: This study defines the positive prognostic significance of PIK3CA mutations. This work is clinically relevant, as it will significantly affect the design of clinical trials planned for phosphatidylinositol 3-kinase–targeted therapy. Future work may define a population of older age breast cancer patients in whom therapy can be minimized. (Clin Cancer Res 2009;15(16):5049–59)