tbuckley/cabot-search huggingface dataset:
Cold Urticaria, Immunodeficiency, and Autoimmunity Related to<i>PLCG2</i>Deletions
Authors: Michael J. Ombrello, Elaine F. Remmers, Guangping Sun, Alexandra F. Freeman, Shrimati Datta, Parizad Torabi-Parizi, Naeha Subramanian, Tom D. Bunney, Rhona W. Baxendale, Marta S. Martins, Neil Romberg, Hirsh Komarow, Ivona Aksentijevich, Hun Sik Kim, Jason Ho, Glenn Cruse, Mi-Yeon Jung, Alasdair M. Gilfillan, Dean D. Metcalfe, Celeste Nelson, Michelle O'Brien, Laura Wisch, Kelly Stone, Daniel C. Douek, Chhavi Gandhi, Alan A. Wanderer, Hane Lee, Stanley F. Nelson, Kevin V. Shianna, Elizabeth T. Cirulli, David B. Goldstein, Eric O. Long, Susan Moir, Eric Meffre, Steven M. Holland, Daniel L. Kastner, Matilda Katan, Hal M. Hoffman, Joshua D. Milner
Journal: New England Journal of Medicine (2012)

Mendelian analysis of disorders of immune regulation can provide insight into molecular pathways associated with host defense and immune tolerance.We identified three families with a dominantly inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to infection and autoimmunity. Immunophenotyping methods included flow cytometry, analysis of serum immunoglobulins and autoantibodies, lymphocyte stimulation, and enzymatic assays. Genetic studies included linkage analysis, targeted Sanger sequencing, and next-generation whole-genome sequencing.Cold urticaria occurred in all affected subjects. Other, variable manifestations included atopy, granulomatous rash, autoimmune thyroiditis, the presence of antinuclear antibodies, sinopulmonary infections, and common variable immunodeficiency. Levels of serum IgM and IgA and circulating natural killer cells and class-switched memory B cells were reduced. Linkage analysis showed a 7-Mb candidate interval on chromosome 16q in one family, overlapping by 3.5 Mb a disease-associated haplotype in a smaller family. This interval includes PLCG2, encoding phospholipase Cγ(2) (PLCγ(2)), a signaling molecule expressed in B cells, natural killer cells, and mast cells. Sequencing of complementary DNA revealed heterozygous transcripts lacking exon 19 in two families and lacking exons 20 through 22 in a third family. Genomic sequencing identified three distinct in-frame deletions that cosegregated with disease. These deletions, located within a region encoding an autoinhibitory domain, result in protein products with constitutive phospholipase activity. PLCG2-expressing cells had diminished cellular signaling at 37°C but enhanced signaling at subphysiologic temperatures.Genomic deletions in PLCG2 cause gain of PLCγ(2) function, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype encompassing both excessive and deficient immune function. (Funded by the National Institutes of Health Intramural Research Programs and others.).
Emerging role of LRRK2 in human neural progenitor cell cycle progression, survival and differentiation
Authors: Javorina Milosevic, Sigrid C Schwarz, Vera Ogunlade, Anne K Meyer, Alexander Storch, Johannes Schwarz
Journal: Molecular Neurodegeneration (2009)

Despite a comprehensive mapping of the Parkinson's disease (PD)-related mRNA and protein leucine-rich repeat kinase 2 (LRRK2) in the mammalian brain, its physiological function in healthy individuals remains enigmatic. Based on its structural features and kinase properties, LRRK2 may interact with other proteins involved in signalling pathways. Here, we show a widespread LRRK2 mRNA and/or protein expression in expanded or differentiated human mesencephalic neural progenitor cells (hmNPCs) and in post-mortem substantia nigra PD patients. Using small interfering RNA duplexes targeting LRRK2 in hmNPCs following their differentiation into glia and neurons, we observed a reduced number of dopaminergic neurons due to apoptosis in LRRK2 knockdown samples. LRRK2-deficient hmNPCs exhibited elevated cell cycle- and cell death-related markers. In conclusion, a reduction of LRRK2 expression in hmNPCs severely impaired dopaminergic differentiation and/or survival of dopaminergic neurons most likely via preserving or reactivating the cell cycle.
Recommended Colorectal Cancer Surveillance Guidelines by the American Society of Clinical Oncology
Authors: Christopher E. Desch, Al B. Benson, Thomas J. Smith, Patrick J. Flynn, Carol Krause, Charles L. Loprinzi, Bruce D. Minsky, Nicholas J. Petrelli, David G. Pfister, Mark R. Somerfield
Journal: Journal of Clinical Oncology (1999)

OBJECTIVE: To determine the most effective, evidence-based, postoperative surveillance strategy for the detection of recurrent colon and rectal cancer. Tests are to be recommended only if they have an impact on the outcomes listed below. POTENTIAL INTERVENTION: All tests described in the literature for postoperative monitoring were considered. In addition, the data were critically evaluated to determine the optimal frequency of monitoring. OUTCOMES: Outcomes of interest included overall and disease-free survival, quality of life, toxicity reduction, and cost-effectiveness. The American Society of Clinical Oncology (ASCO) Colorectal Cancer Surveillance Expert Panel was guided by the principle of cost minimization, ie, when two strategies were believed to be equally effective, the least expensive test was recommended. EVIDENCE: A complete MEDLINE search was performed of the past 20 years of the medical literature. Keywords included colorectal cancer, follow-up, and carcinoembryonic antigen, as well as the names of the specific tests. The search was broadened by articlesfrom the tumor marker ASCO panel literature search, as well as from bibliographies of selected articles. VALUES: Levels of evidence and guideline grades were rated by a standard process. More weight was given to studies that tested a hypothesis directly relating testing to one of the primary outcomes in a randomized design. BENEFITS/HARMS/COSTS: The possible consequences of false-positive and false-negative tests were considered in evaluating a preference for one of two tests that provide similar information. Cost alone was not a determining factor. RECOMMENDATIONS: The expert panel's recommended postoperative monitoring schema is discussed in this article. VALIDATION: Five outside reviewers, the ASCO Health Services Research Committee, and the ASCO Board of Directors examined this document. SPONSOR: American Society of Clinical Oncology.
<i>FcγRIIa</i>and<i>Fc<b><i>γ</i></b>RIIIa</i>Polymorphisms and Cetuximab Benefit in the Microscopic Disease
Authors: Francesco Sclafani, David Gonzalez de Castro, David Cunningham, Sanna Hulkki Wilson, Clare Peckitt, Jaume Capdevila, Bengt Glimelius, Susana Roselló Keränen, Andrew Wotherspoon, Gina Brown, Diana Tait, Ruwaida Begum, Janet Thomas, Jacqueline Oates, Ian Chau
Journal: Clinical Cancer Research (2014)

FcγR polymorphisms have been reported to enhance the immune-mediated effects of cetuximab in metastatic colorectal cancer. There are no data on the relationship between these polymorphisms and cetuximab in the early-stage setting. We performed a pharmacogenomic analysis of EXPERT-C, a randomized phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX±cetuximab in high-risk, locally advanced rectal cancer.FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms.Genotyping was successfully performed in 105 of 164 (64%) patients (CAPOX=54, CAPOX-C=51). No deviation from the Hardy-Weinberg equilibrium or association of these polymorphisms with tumor RAS status was observed. FcγRIIa-131R (HR, 0.38; P=0.058) and FcγRIIIa-158F alleles (HR, 0.21; P=0.007) predicted improved progression-free survival (PFS) in patients treated with cetuximab. In the CAPOX-C arm, carriers of both 131R and 158F alleles had a statistically significant improvement in PFS (5 years: 78.4%; HR, 0.22; P=0.002) and overall survival (OS; 5 years: 86.4%; HR, 0.24; P=0.018) when compared with patients homozygous for 131H and/or 158V (5-year PFS: 35.7%; 5-year OS: 57.1%). An interaction between cetuximab benefit and 131R and 158F alleles was found for PFS (P=0.017) and remained significant after adjusting for prognostic variables (P=0.003).This is the first study investigating FcγRIIa and FcγRIIIa polymorphisms in patients with early-stage colorectal cancer treated with cetuximab. We showed an increased clinical benefit from cetuximab in the presence of 131R and 158F alleles.
Ward Rounds with an Acupuncturist
Authors: E. Grey Dimond
Journal: New England Journal of Medicine (1965)

IN September, 1964, a visit to Saigon, Vietnam, was in itself cause for excitement and anticipation. Riot, coup and night-time curfew all made a highly dramatic background for a series of ward rounds and lectures at the University of Saigon Medical School.Before the visit, I had heard that in addition to the regular practice of medicine, there were many active practitioners of acupuncture. Acupuncture and moxa had long intrigued me, and although I had not seen either procedure actually carried out, I had, in previous trips to the Orient, observed patients who received medical care through multiple approaches — . . .
Accuracy of a pulse oximeter in the measurement of the oxyhaemoglobin saturation
Authors: F Chiappini, L Fuso, R Pistelli
Journal: European Respiratory Journal (1998)

The aim of the present study was to evaluate the accuracy, in comparison with a reference method, of the Nellcor N-20P pulse oximeter in the assessment of oxyhaemoglobin saturation (Sa,O2). Sa,O2 was monitored at rest by the Nellcor N-20P pulse oximeter in 100 subjects (82 males, mean age 68+/-12 yrs) consecutively enroled. At the same time, an arterial blood sample was collected for the measurement of Sa,O2, carboxyhaemoglobin, and methaemoglobin by an IL-282 Co-oximeter. A significant difference was found between Sa,O2 values measured with the two methods (t=11.78, p<0.05), but the two series of measurements were significantly correlated (r=0.97). Both the level and the limits of agreement between the two methods were satisfactory when the more appropriate Bland and Altman method was applied. Nevertheless, a lack of accuracy of the pulse oximeter was found, but only for Sa,O2 values <82% and >94%, as demonstrated by the Youden index. In conclusion, these data show that Nellcor N-20P is sufficiently reliable for the assessment and monitoring of oxyhaemoglobin saturation. The lack of accuracy does not seem clinically relevant since it is appreciable only for values at the extremes of the oxyhaemoglobin saturation range.
15-deoxy-Δ12,14-PGJ2 induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats
Authors: Yutaka Kawahito, Motoharu Kondo, Yasunori Tsubouchi, Akira Hashiramoto, David Bishop-Bailey, Ken-ichiro Inoue, Masataka Kohno, Ryoji Yamada, Timothy Hla, Hajime Sano
Journal: Journal of Clinical Investigation (2000)

Peroxisome proliferator–activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and have a dominant regulatory role in adipocyte and monocyte differentiation. PPAR-γ agonists are also negative regulators of macrophage activation and have modulatory effects on tumorigenesis. In this study we demonstrate that synovial tissue localized expression of PPAR-γ in patients with rheumatoid arthritis (RA). We detected markedly enhanced expression of PPAR-γ in macrophages, as well as modestly enhanced expression in the synovial lining layer, fibroblasts, and endothelial cells. Activation of the PPAR-γ by 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and the synthetic PPAR-γ ligand (troglitazone) induced RA synoviocyte apoptosis in vitro. Moreover, intraperitoneal administration of these PPAR-γ ligands ameliorated adjuvant-induced arthritis with suppression of pannus formation and mononuclear cell infiltration in female Lewis rats. Anti-inflammatory effects of 15d-PGJ2 were more potent than troglitazone. These findings suggest that PPAR-γ may be an important immunoinflammatory mediator and its ligands, especially 15d-PGJ2, may be useful in the treatment of RA.
Prognostic Impact of Trisomies of Chromosomes 10, 17, and 5 Among Children With Acute Lymphoblastic Leukemia and High Hyperdiploidy (&gt; 50 Chromosomes)
Authors: Nyla A. Heerema, Harland N. Sather, Martha G. Sensel, Tracy Zhang, Raymond J. Hutchinson, James B. Nachman, Beverly J. Lange, Peter G. Steinherz, Bruce C. Bostrom, Gregory H. Reaman, Paul S. Gaynon, Fatih M. Uckun
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy (&gt; 50 chromosomes) have improved outcome compared with other ALL patients. We sought to identify cytogenetic features that would predict differences in outcome within this low-risk subset of ALL patients. MATERIALS AND METHODS: High-hyperdiploid ALL patients (N = 480) were enrolled between 1988 and 1995 on Children’s Cancer Group (CCG) trials. Karyotypes were determined by conventional banding. Treatment outcome was analyzed by life-table methods. RESULTS: Patients with 54 to 58 chromosomes had better outcome than patients with 51 to 53 or 59 to 68 chromosomes (P = .0002). Patients with a trisomy of chromosome 10 (P &lt; .0001), chromosome 17 (P = .0002), or chromosome 18 (P = .004) had significantly improved outcome compared with their counterparts who lacked the given trisomy. Patients with a trisomy of chromosome 5 had worse outcome than patients lacking this trisomy (P = .02). Patients with trisomies of both chromosomes 10 and 17 had better outcome than those with a trisomy of chromosome 10 (P = .09), a trisomy of chromosome 17 (P = .01), or neither trisomy (P &lt; .0001). Multivariate analysis indicated that trisomy of chromosome 10 (P = .001) was the most significant prognostic factor for high-hyperdiploid patients, yet trisomy of chromosome 17 (P = .02) or chromosome 5 (P = .01) and modal chromosome number (P = .02) also had significant multivariate effects. CONCLUSION: Trisomy of chromosomes 10 and 17 as well as modal chromosome number 54 to 58 identify subgroups of patients with high-hyperdiploid ALL who have a better outcome than high-hyperdiploid patients who lack these cytogenetic features. Trisomy of chromosome 5 confers poorer outcome among high-hyperdiploid patients.
The Regulation of Parathyroid Hormone Secretion and Synthesis
Authors: Rajiv Kumar, James R. Thompson
Journal: Journal of the American Society of Nephrology (2010)

Secondary hyperparathyroidism classically appears during the course of chronic renal failure and sometimes after renal transplantation. Understanding the mechanisms by which parathyroid hormone (PTH) synthesis and secretion are normally regulated is important in devising methods to regulate overactivity and hyperplasia of the parathyroid gland after the onset of renal insufficiency. Rapid regulation of PTH secretion in response to variations in serum calcium is mediated by G-protein coupled, calcium-sensing receptors on parathyroid cells, whereas alterations in the stability of mRNA-encoding PTH by mRNA-binding proteins occur in response to prolonged changes in serum calcium. Independent of changes in intestinal calcium absorption and serum calcium, 1α,25-dihydroxyvitamin D also represses the transcription of PTH by associating with the vitamin D receptor, which heterodimerizes with retinoic acid X receptors to bind vitamin D-response elements within the PTH gene. 1α,25-Dihydroxyvitamin D additionally regulates the expression of calcium-sensing receptors to indirectly alter PTH secretion. In 2°HPT seen in renal failure, reduced concentrations of calcium-sensing and vitamin D receptors, and altered mRNA-binding protein activities within the parathyroid cell, increase PTH secretion in addition to the more widely recognized changes in serum calcium, phosphorus, and 1α,25-dihydroxyvitamin D. The treatment of secondary hyperparathyroidism by correction of serum calcium and phosphorus concentrations and the administration of vitamin D analogs and calcimimetic agents may be augmented in the future by agents that alter the stability of mRNA-encoding PTH.
Physical activity for patients: an exercise prescription
Authors: D Gerrard
Journal: British Journal of Sports Medicine (2003)

Silence on clinical fundamentalsYour point about lifesaving hand washing to prevent diarrhoeal illness 1 is well made.I have found that the inattention you have noted to such clinical fundamentals in textbooks on sports medicine is mirrored by the absence of any notation, affirmative or otherwise, in many textbooks on pain, correlating the symptom (pain) with the physical sign (tenderness), a rudimentary clinical confirmation of the validity of pain, according to my clinical training in Ireland, that could distinguish malingering from a genuine complaint of pain, for example.Perhaps I have received a false impression but, if so, the utility of eliciting tenderness, a longstanding custom during physical examination, seems a mystery.In November 2002, I attended a conference in Florida on prescribing addictive drugs.None of the purportedly expert presenters mentioned the issue spontaneously.When I collared one of them after his lecture and enquired specifically about the point, he claimed that chronic, non-malignant pain and tenderness are usually ''dissociated''that is, a patient can suffer chronic, nonmalignant pain in the absence of tenderness of the painful part, on physical examination.This assertion seemed contrary to my own, admittedly anecdotal, experience over some 24 years.Furthermore, it would seem to (a) render chronic, non-malignant pain, and maybe all pain, unknowable and undetectable (except perhaps to the alleged sufferer, although nobody else can tell), (b) place the assessment of pain in the realm of ''pathological science'', 5 and (c) invalidate the very idea of regulation of narcotic drugs to ensure that the practitioner prescribe one only when it ''corresponds to the ailment''. 5 The silence on the subject in the medical literature seemed anomalous.A Boolean Pubmed search on the keywords ''pain'' and ''tenderness'' revealed no relevant articles.I examined all 114 textbooks on pain in the medical library of the University of Southern California (USC) and found two 2 3 that addressed the issue.
Phase I dose-escalating trial of Escherichia coli purine nucleoside phosphorylase and fludarabine gene therapy for advanced solid tumors
Authors: E.L. Rosenthal, T.K. Chung, W.B. Parker, P.W. Allan, L. Clemons, D. Lowman, J. Hong, F.R. Hunt, J. Richman, R.M. Conry, K. Mannion, W.R. Carroll, L. Nabell, E.J. Sorscher
Journal: Annals of Oncology (2015)
Bone mineral density in professional female dancers.
Authors: N Keay, I Fogelman, G Blake
Journal: British Journal of Sports Medicine (1997)

OBJECTIVES: To measure the long term effects of dance training and the contribution of the timing and duration of any menstrual disruption on bone mineral density (BMD). DESIGN: Measurement of BMD in 57 premenopausal, previously professionally dance trained women and the relationship to menstrual and training history. MAIN OUTCOME MEASURES: Bone density measurements at lumbar spine and femoral neck by dual energy x-ray absorptiometry. RESULTS: The average Z score for BMD at the lumbar spine in the amenorrhoeic dancers was significantly below that for the normal population. The average Z score for BMD at the femoral neck in the eumenorrhoeic dancers was significantly above that for the normal population. There was a significant difference between the average Z score for BMD at both the lumbar spine and femoral neck between the amenorrhoeic and eumenorrhoeic dancers. Significant negative relationships were found between BMD at the lumbar spine and (1) age at menarche, (2) duration of amenorrhoea, (3) BMD at the femoral neck, and (4) the variable of ideal minus lowest weight, which was independent of amenorrhoea. No significant relationships were found between duration of oral contraceptive pill usage and BMD at either the lumbar spine or the femoral neck in eumenorrhoeic or amenorrhoeic dancers. In order to quantify the effect of a combination of these significant factors, a model of BMD was constructed using multiple regression incorporating the variables duration of amenorrhoea, age at menarche, and ideal minus lowest body weight. In this model R2 was 33.6%, in other words 33.6% of the total variation in the Z score for BMD at the lumbar spine could be accounted for by these factors. CONCLUSION: Professional female dancers with a history of delayed menarche and amenorrhoea have been identified as another group of premenopausal women potentially at risk of developing osteoporosis because of a decrease in BMD at the lumbar spine. The femoral neck in dancers with a history of amenorrhoea was partially protected from loss of BMD by virtue of being the major weight bearing site in previous dance training, and in eumenorrhoeic dancers BMD was significantly increased at this site.
Dr. Hennis Green on Inflammation of the Spinal Marrow in Children
Authors: P. H. Green
Journal: BMJ (1841)

<h3>SUMMARY</h3> Temporal identity factors are sufficient to reprogram developmental competence of neural progenitors, but whether they could also reprogram the identity of fully differentiated cells is unknown. To address this question, we designed a conditional gene expression system combined with genetic lineage tracing that allows rapid screening of potential reprogramming factors in the mouse retina. Using this assay, we report that co-expression of the early temporal identity transcription factor Ikzf1, together with Ikzf4, another Ikaros family member, is sufficient to directly convert adult Müller glial cells into neuron-like cells in vivo, without inducing a proliferative progenitor state. scRNA-seq analysis shows that the reprogrammed cells share some transcriptional signatures with both cone photoreceptors and bipolar cells. Furthermore, we show that co-expression of Ikzf1 and Ikzf4 can reprogram mouse embryonic fibroblasts to induced neurons by remodeling chromatin and promoting a neuronal gene expression program. This work uncovers general neuronal reprogramming properties for temporal identity factors in differentiated cells, opening new opportunities for cell therapy development.
ADDITIONAL STUDIES ON THE TRANSFERRINS OF CORD SERUM AND CEREBROSPINAL FLUID
Authors: W. Carey Parker, Jack W. C. Hagstrom, Alexander G. Bearn
Journal: The Journal of Experimental Medicine (1963)

Serum transferrins have been examined in 392 samples from full-term infants and from premature infants at various stages of growth. The characteristic transferrin pattern of the infants by starch gel electrophoresis contained a single prominent iron-binding component accompanied by 4 faint, slower migrating components. An additional faint component was present in the sera of infants heterozygous for a transferrin variant. The faint components migrated slightly more rapidly than the corresponding components in the stepwise pattern produced by the action of neuraminidase in removing sialic acid from transferrin. The interpretation is presented that the faint components may represent the absence of multi-unit carbohydrate prosthetic groups on the transferrin molecule in the infant. A similar interpretation is possible for the slow migrating transferrins of cerebrospinal fluid.