tbuckley/cabot-search huggingface dataset:
Heparan sulfate deficiency leads to Peters anomaly in mice by disturbing neural crest TGF-β2 signaling
Authors: Keiichiro Iwao, Masaru Inatani, Yoshihiro Matsumoto, Minako Ogata-Iwao, Yuji Takihara, Fumitoshi Irie, Yu Yamaguchi, Satoshi Okinami, Hidenobu Tanihara
Journal: Journal of Clinical Investigation (2009)

During human embryogenesis, neural crest cells migrate to the anterior chamber of the eye and then differentiate into the inner layers of the cornea, the iridocorneal angle, and the anterior portion of the iris. When proper development does not occur, this causes iridocorneal angle dysgenesis and intraocular pressure (IOP) elevation, which ultimately results in developmental glaucoma. Here, we show that heparan sulfate (HS) deficiency in mouse neural crest cells causes anterior chamber dysgenesis, including corneal endothelium defects, corneal stroma hypoplasia, and iridocorneal angle dysgenesis. These dysfunctions are phenotypes of the human developmental glaucoma, Peters anomaly. In the neural crest cells of mice embryos, disruption of the gene encoding exostosin 1 (Ext1), which is an indispensable enzyme for HS synthesis, resulted in disturbed TGF-beta2 signaling. This led to reduced phosphorylation of Smad2 and downregulated expression of forkhead box C1 (Foxc1) and paired-like homeodomain transcription factor 2 (Pitx2), transcription factors that have been identified as the causative genes for developmental glaucoma. Furthermore, impaired interactions between HS and TGF-beta2 induced developmental glaucoma, which was manifested as an IOP elevation caused by iridocorneal angle dysgenesis. These findings suggest that HS is necessary for neural crest cells to form the anterior chamber via TGF-beta2 signaling. Disturbances of HS synthesis might therefore contribute to the pathology of developmental glaucoma.
'Scientists' Summer Camp' Turns to Sea for Answers to Human Biologic Questions
Authors: Chris Anne Raymond
Journal: JAMA (1988)

NINE HUNDRED FIFTY BRAINS, 1900 eyes and hands, one common quest: deciphering the intricate symphony of biochemical and electrical signals that is life. The focus is on the cell. How does it become what it is? How does it maintain its identity and recognize its fellows?  The 950 visitors, speaking in many tongues, come from Cyprus and Munich, Argentina and Ottawa. Each summer, they fill close to 9000 m 2 (100 000 sq ft) of laboratory real estate on a campus hard by Buzzards Bay, Mass—the Marine Biological Laboratory at Woods Hole.  They arrive in waves in June to immerse themselves in research or, if they are students in one of the summer courses, to devote countless hours to perfecting the techniques of gene splicing, immunocytochemistry, and video-enhanced light microscopy that will enable them to carry on the tradition of basic research established 100 years ago this summer. It might
Cost-Effectiveness of Microsatellite Instability Screening as a Method for Detecting Hereditary Nonpolyposis Colorectal Cancer
Authors: Scott D. Ramsey, Lauren Clarke, Ruth Etzioni, Mitchell Higashi, Kristin Berry, Nicole Urban
Journal: Annals of Internal Medicine (2001)

Background: The National Cancer Institute has published consensus guidelines for universal screening for hereditary nonpolyposis colorectal cancer (HNPCC) in patients with newly diagnosed colorectal cancer. Objective: To determine the cost-effectiveness of screening compared with standard care in eligible patients with colorectal cancer and their siblings and children. Design: Cost-effectiveness analysis. Data Sources: National colorectal cancer registry data, the Creighton International Hereditary Colorectal Cancer Registry, Medicare claims records, and published literature. Target Population: Patients with newly diagnosed colorectal cancer and their siblings and children. Time Horizon: Lifetime (varies depending on age at screening). Perspective: Societal. Interventions: Initial office-based screening to determine eligibility (based on personal and family cancer history), followed by tumor testing for microsatellite instability. Those with microsatellite instability were offered genetic testing for HNPCC. Siblings and children of patients with cancer and the HNPCC mutation were offered genetic testing, and those who were found to carry the mutation received lifelong colorectal cancer screening. Measurements: Life-years gained. Results of Base-Case Analysis: When only the patients with cancer were considered, cost-effectiveness of screening was $42 210 per life-year gained. When patients with cancer and their siblings and children were considered together, cost-effectiveness increased to $7556 per life-year gained. Results of Sensitivity Analysis: The model was most sensitive to the estimated survival gain from screening siblings and children, to the prevalence of HNPCC mutations among patients with newly diagnosed cancer, and to the discount rate. In probabilistic analysis, the 90% CI for the cost-effectiveness of screening patients with cancer plus their relatives was $4874 to $21 576 per life-year gained. Conclusion: Screening patients with newly diagnosed colorectal cancer for HNPCC is cost-effective, especially if the benefits to their immediate relatives are considered.
Prevalence of Helicobacter pylori infection and its effect on symptoms and non-steroidal anti-inflammatory drug induced gastrointestinal damage in patients with rheumatoid arthritis.
Authors: P M Goggin, D A Collins, R P Jazrawi, P A Jackson, C M Corbishley, B E Bourke, T C Northfield
Journal: Gut (1993)

Non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter (H pylori) are both associated with an increased risk of peptic ulceration and gastropathy. It is not known, however, if there is an interaction between these two agents, and thus whether or not screening for H pylori before NSAID treatment is of value. The aim of this study was to find out if H pylori potentiates the damaging effects of NSAIDs. Fifty two patients with rheumatoid arthritis requiring longterm NSAID treatment were studied. Dyspeptic symptoms were assessed according to a standardised questionnaire. Gastroscopy was performed after a one week washout period during which NSAIDs were discontinued. Gastric and duodenal mucosal damage was graded endoscopically. H pylori was identified by biopsy urease test and by histological tests. Investigations were repeated after one month's treatment with an NSAID. Patients with H pylori infection (n = 26) had a higher dyspeptic symptom score (p < 0.05). One patient with duodenal ulcer (H pylori +ve) and two with endoscopic gastritis (both H pylori +ve) were excluded from further study. Forty two subjects completed the study. After treatment there was a rise in the gastric damage score both in the H pylori +ve (p = 0.06) and the H pylori -ve (p < 0.005) groups. There was no difference in the extent of increase in grade or the final grade at the end of the treatment period between the H pylori +ve and -ve patients. It is concluded that H pylori infection is associated with increased dyspeptic symptoms in patients receiving NSAIDs but that it does not potentiate NSAID gastropathy.
Efficacy of high-dose therapy and hematopoietic stem cell transplantation for mantle cell lymphoma
Authors: Noel Laudi, Mukta Arora, Linda Burns, Philip McGlave, Jeffrey Miller, Gerald Bohac, Tyson Rogers, Juliet Barker, James Coad, Daniel Weisdorf
Journal: American Journal of Hematology (2006)

Conventional treatment of mantle cell lymphoma (MCL) yields modest responses and short remissions. We report 30 hematopoietic stem cell transplants (HSCT) for MCL: 13 autologous, 10 allogeneic myeloablative, and 7 nonablative. After a median 1.2 years from diagnosis (range 0.5 to 4.7) and a median of 2 pre-HSCT chemotherapeutic regimens (range 1 to 5), their median age at HSCT was 52 years (range 37 to 67). Eleven patients (41%) were in first remission, 11 (41%) were in second remission, and 7 (25%) had resistant disease. Four died early. Nineteen achieved CR (83%) and 4 PR (17%). With median 2.7 years of follow-up, 5-year overall survival (OS) was 42% (95% CI 11–73%) after autologous versus allogeneic at 49% (95% CI 22–76%). Five-year progression-free survival (PFS) was 31% (95% CI 3–59%) and 50% (95% CI 24–76%) for autologous and allogeneic HSCT, respectively. Fourteen died: 3 from sepsis, 1 acute GVHD, 10 MCL. No autologous transplant-related deaths occurred. Allogeneic transplant-related mortality was 29% (95% CI 6–52%) at 1 and 5 years. HSCT for MCL can yield extended disease control and long-term survival. Am. J. Hematol. 81:519–524, 2006. © 2006 Wiley-Liss, Inc.
Desensitization to parathyroid hormone in renal cells from aged rats is associated with alterations in G-protein activity.
Authors: H Hanai, C T Liang, L Cheng, B Sacktor
Journal: Journal of Clinical Investigation (1989)

Parathyroid hormone (PTH)-stimulated Na+/Ca2+ exchange activity, but not forskolin-sensitive Na+-dependent Ca2+ efflux, was blunted in renal cortical cells from aged rats. PTH-sensitive adenylate cyclase activity in renal membranes from senescent rats also declined, but forskolin-stimulated activity did not change. In addition, cholera toxin- and pertussis toxin-stimulated Na+-dependent Ca2+ efflux and cAMP formation were blunted in cells from aged animals. Further, cells from aged rats had decreased Gs-alpha and Gi-alpha proteins, as detected by ADP-ribosylation. These findings would be consistent with the proposal of an age-associated heterologous desensitization that involved the G-proteins. Serum concentrations of iPTH were increased in the old rat, suggesting that the desensitization to PTH in the aging rat represented an adaptive response to prolonged stimulation by the hormone. This hypothesis was supported by the findings that the attenuated PTH-sensitive Na+/Ca2+ exchange activity, cAMP formation, and adenylate cyclase activity in cells from old rats could be reversed by parathyroidectomy. The decreased label in cholera toxin-catalyzed ADP-ribosylated Gs-alpha and pertussis toxin catalyzed ADP-ribosylated Gi-alpha found in cells from aged rats was also largely negated by the surgery. In conclusion, the results suggest that the age-related blunting in the responses of renal cells to PTH was associated with a deficit in G-protein function and that this alteration could be reversed by removal of the parathyroid gland.
Deaths from abuse of volatile substances: a national epidemiological study.
Authors: H R Anderson, R S Macnair, J D Ramsey
Journal: BMJ (1985)

A survey of the United Kingdom detected 282 deaths from abuse of volatile substances during 1971-83. Deaths appeared to have increased in the most recent years, reaching 80 in 1983. Age at death ranged from 11 to 76 years but most deaths (72%) occurred under 20 years. Ninety five per cent of the subjects were male, and in 1983 deaths from volatile substance abuse accounted for 2% of all deaths in males aged 10-19. All areas of the United Kingdom were affected, the rates being highest in Scotland and urban areas. All social classes were affected, though rates were highest in social class V and the armed forces. The volatile substances abused were gas fuels (24%), mainly butane; aerosol sprays (17%); solvents in glues (27%); and other volatile substances, such as cleaning agents (31%). In 51% of cases death was attributed to the direct toxic effects of the substance abused, in 21% to plastic bag asphyxia, in 18% to inhalation of stomach contents, and in 11% to trauma. Deaths associated with the abuse of glues were more likely to be traumatic, but all substances appeared capable of killing directly by their toxic effects, probably by a cardiac mechanism. Only a small proportion of deaths (6%) were due to the abuse of glues among children under 16; hence current attempts to limit access of children to glues will probably have little impact on overall mortality.
The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4
Authors: Li Liu, Patrick A. Mayes, Stephen Eastman, Hong Shi, Sapna Yadavilli, Tianqian Zhang, Jingsong Yang, Laura Seestaller-Wehr, Shu-Yun Zhang, Chris Hopson, Lyuben Tsvetkov, Junping Jing, Shu Zhang, James Smothers, Axel Hoos
Journal: Clinical Cancer Research (2015)

Abstract Purpose: To assess the immunologic effects of dabrafenib and trametinib in vitro and to test whether trametinib potentiates or antagonizes the activity of immunomodulatory antibodies in vivo. Experimental Design: Immune effects of dabrafenib and trametinib were evaluated in human CD4+ and CD8+ T cells from healthy volunteers, a panel of human tumor cell lines, and in vivo using a CT26 mouse model. Results: Dabrafenib enhanced pERK expression levels and did not suppress human CD4+ or CD8+ T-cell function. Trametinib reduced pERK levels, and resulted in partial/transient inhibition of T-cell proliferation/expression of a cytokine and immunomodulatory gene subset, which is context dependent. Trametinib effects were partially offset by adding dabrafenib. Dabrafenib and trametinib in BRAF V600E/K, and trametinib in BRAF wild-type tumor cells induced apoptosis markers, upregulated HLA molecule expression, and downregulated certain immunosuppressive factors such as PD-L1, IL1, IL8, NT5E, and VEGFA. PD-L1 expression in tumor cells was upregulated after acquiring resistance to BRAF inhibition in vitro. Combinations of trametinib with immunomodulators targeting PD-1, PD-L1, or CTLA-4 in a CT26 model were more efficacious than any single agent. The combination of trametinib with anti–PD-1 increased tumor-infiltrating CD8+ T cells in CT26 tumors. Concurrent or phased sequential treatment, defined as trametinib lead-in followed by trametinib plus anti–PD-1 antibody, demonstrated superior efficacy compared with anti–PD-1 antibody followed by anti–PD-1 plus trametinib. Conclusion: These findings support the potential for synergy between targeted therapies dabrafenib and trametinib and immunomodulatory antibodies. Clinical exploration of such combination regimens is under way. Clin Cancer Res; 21(7); 1639–51. ©2015 AACR.
T-Lymphocyte Subpopulation Abnormalities in Apparently Healthy Patients with Hemophilia
Authors: JONATHAN C. GOLDSMITH
Journal: Annals of Internal Medicine (1983)

T-lymphocyte populations in 12 apparently healthy heterosexual adult patients with hemophilia have been examined to ascertain if these patients have abnormalities in their lymphocyte subpopulations similar to those in homosexual men, Haitian refugees, and narcotic addicts. A striking reduction in the helper to suppressor cell ratio ([0.86 ± 0.14]:1) was found in 9 of the 12 patients. These abnormalities were similar to those previously described in two patients with hemophilia critically ill with Pneumocystis carinii pneumonia, and in homosexual men. The abnormality in the ratio of helper to suppressor T cells may be related to the continual exposure of patients with hemophilia to commercial clotting factor concentrates. However, these patients with abnormal T-lymphocyte subpopulations remain healthy. At present there is insufficient evidence to advocate a change in therapeutic practices in patients with hemophilia.
Controlled trial of Iodosorb.
Authors: M C Ormiston, J A Fox
Journal: BMJ (1985)

<h3>Objective</h3> Sudden cardiac death (SCD) is a leading cause of death and is more common among males than females. Epidemiological studies of sex differences in SCD cases of all ages are sparse. The aim of this study was to examine differences in incidence rates, clinical characteristics, comorbidities and autopsy findings between male and female SCD cases. <h3>Methods</h3> All deaths in Denmark in 2010 (54 028) were reviewed. Autopsy reports, death certificates, discharge summaries and nationwide health registries were reviewed to identify cases of SCD. Based on the available information, all deaths were subcategorised into definite, probable and possible SCD. <h3>Results</h3> A total of 6867 SCD cases were identified, of which 3859 (56%) were males and 3008 (44%) were females. Incidence rates increased with age and were higher for male population across all age groups in the adult population. Average age at time of SCD was 71 years among males compared with 79 among females (p&lt;0.01). The greatest difference in SCD incidence between males and females was found among the 35–50 years group with an incidence rate ratio of 3.7 (95% CI: 2.8 to 4.8). Compared with female SCD victims, male SCD victims more often had cardiovascular diseases and diabetes mellitus (p&lt;0.01). <h3>Conclusion</h3> This is the first nationwide study of sex differences in SCD across all ages. Differences in incidence rates between males and females were greatest among young adults and the middle-aged. Incidence rates of SCD among older female population approached that of the male population, despite having significantly more cardiovascular disease and diabetes in male SCD cases.
Preterm Birth: Effect of Corticosteroids or Immediate Cord Clamping?
Authors: David Hutchon, Ben Ononeze
Journal: PLoS Medicine (2006)

Joal HillI read with interest the debate about for-profi t versus non-profi t institutional review boards (IRBs) [1], but was disappointed that no one addressed the ability (or inability) of for-profi t IRBs to review studies with the local context of research subjects in mind and then monitor what actually occurs during the consent process throughout the research trial.To my mind the "bigness" of for-profi t IRBs may be more of an impediment in protecting research subjects than their inherent confl ict of interest.Our IRB has reviewed consent forms approved by central/for-profi t IRBs that contained obvious errors such as schemas that did not match protocol narrative and use of eight point font in a study of geriatric subjects.Even when the initial review is outstanding, it seems a practical impossibility for a single IRB to provide meaningful monitoring of the actual consent process and implementation of the protocol at sites throughout the country.The greater "effi ciency" of for-profi t IRBs is only a meaningful benefi t if increased speed can be shown not to occur at the expense of careful review of consent forms, real understanding of the local research context, and a commitment to audit the informed consent process throughout the study for the protection of research subjects, including ongoing education and advice for researchers and their teams.This is not to say that all local IRBs perform this function as they should, but it does seem almost impossible for one IRB to perform local review and oversight for research sites around the nation in a way that really makes a difference for the men, women, and children who give of their time and their bodies so that society can benefi t.
Assessment of Condenser-Humidifiers with Special Reference to a Multiple-gauze Model
Authors: W. W. Mapleson, J. G. Morgan, E. K. Hillard
Journal: BMJ (1963)

HYPERTENSION M3DICTIM;~~.&rON (average 5 months).In 14 of them the blood-pressure was maintained within reasonable limits.Treatment failed to lower the blood-pressure to any significant extent in two in-patients.Three out-patients became rapidly refractory to the hypotensive effect of methyldopa.Methyldopa was shown to be highly effective in the most severe cases of hypertension, but in some cases for only a short time.The average effective dose in moderate and severe hypertension was 1.5 g. of methyldopa.Thiazide diuretics potentiated the hypotensive action.The results obtained with guanethidine and methyldopa in the treatment of seven hypertensive patients are compared.It appeared that both drugs might be considered in the treatment of severe hypertension and that methyldopa was usually better tolerated.Our results as regards the urinary excretion of catecholamines and metanephrine did not show any parallelism between the inhibition of the biosynthesis of noradrenaline and the blood-pressure reduction.We are grateful to Professor A. De Schaepdrijver, of the department of pharmacology, University of Ghent, -for assaying the urinary catecholamines; and to Professor P. Demoor, of the
Association Between Participation in a Multipayer Medical Home Intervention and Changes in Quality, Utilization, and Costs of Care
Authors: Mark W. Friedberg, Eric C. Schneider, Meredith B. Rosenthal, Kevin G. Volpp, Rachel M. Werner
Journal: JAMA (2014)

Interventions to transform primary care practices into medical homes are increasingly common, but their effectiveness in improving quality and containing costs is unclear.To measure associations between participation in the Southeastern Pennsylvania Chronic Care Initiative, one of the earliest and largest multipayer medical home pilots conducted in the United States, and changes in the quality, utilization, and costs of care.Thirty-two volunteering primary care practices participated in the pilot (conducted from June 1, 2008, to May 31, 2011). We surveyed pilot practices to compare their structural capabilities at the pilot's beginning and end. Using claims data from 4 participating health plans, we compared changes (in each year, relative to before the intervention) in the quality, utilization, and costs of care delivered to 64,243 patients who were attributed to pilot practices and 55,959 patients attributed to 29 comparison practices (selected for size, specialty, and location similar to pilot practices) using a difference-in-differences design.Pilot practices received disease registries and technical assistance and could earn bonus payments for achieving patient-centered medical home recognition by the National Committee for Quality Assurance (NCQA).Practice structural capabilities; performance on 11 quality measures for diabetes, asthma, and preventive care; utilization of hospital, emergency department, and ambulatory care; standardized costs of care.Pilot practices successfully achieved NCQA recognition and adopted new structural capabilities such as registries to identify patients overdue for chronic disease services. Pilot participation was associated with statistically significantly greater performance improvement, relative to comparison practices, on 1 of 11 investigated quality measures: nephropathy screening in diabetes (adjusted performance of 82.7% vs 71.7% by year 3, P < .001). Pilot participation was not associated with statistically significant changes in utilization or costs of care. Pilot practices accumulated average bonuses of $92,000 per primary care physician during the 3-year intervention.A multipayer medical home pilot, in which participating practices adopted new structural capabilities and received NCQA certification, was associated with limited improvements in quality and was not associated with reductions in utilization of hospital, emergency department, or ambulatory care services or total costs over 3 years. These findings suggest that medical home interventions may need further refinement.