tbuckley/cabot-search huggingface dataset:
Rapid in vivo measurement of β-amyloid reveals biphasic clearance kinetics in an Alzheimer’s mouse model
Authors: Carla M. Yuede, Hyo Lee, Jessica L. Restivo, Todd A. Davis, Jane C. Hettinger, Clare E. Wallace, Katherine L. Young, Margaret R. Hayne, Guojun Bu, Chen-zhong Li, John R. Cirrito
Journal: The Journal of Experimental Medicine (2016)

Findings from genetic, animal model, and human studies support the observation that accumulation of the β-amyloid (Aβ) peptide in the brain plays a central role in the pathogenic cascade of Alzheimer’s disease (AD). Human studies suggest that one key factor leading to accumulation is a defect in brain Aβ clearance. We have developed a novel microimmunoelectrode (MIE) to study the kinetics of Aβ clearance using an electrochemical approach. This is the first study using MIEs in vivo to measure rapid changes in Aβ levels in the brains of living mice. Extracellular, interstitial fluid (ISF) Aβ levels were measured in the hippocampus of APP/PS1 mice. Baseline levels of Aβ40 in the ISF are relatively stable and begin to decline within minutes of blocking Aβ production with a γ-secretase inhibitor. Pretreatment with a P-glycoprotein inhibitor, which blocks blood–brain barrier transport of Aβ, resulted in significant prolongation of Aβ40 half-life, but only in the latter phase of Aβ clearance from the ISF.
Cardiac Complications in Patients Undergoing Major Noncardiac Surgery
Authors: P.J. Devereaux, Daniel I. Sessler
Journal: New England Journal of Medicine (2015)

Each year, cardiac complications occur within 30 days after major noncardiac surgery in more than 10 million people worldwide; postoperative mortality is 1.5%. Enhanced patient monitoring and measurement of natriuretic hormone and troponin levels may improve outcomes.
Soundings: Gadgets for consultants
Authors: James Owen Drife
Journal: BMJ (2003)

Calling all consultants! We know you don't buy executive toys but just take a look at our 2003 range of useful gadgets.

Blow up chaperone: Remember when clinics had enough nurses? Nowadays the healthcare assistant cannot be in every room at once. So use our blow up chaperone, attached by Velcro to the consultant's side. With caring expression, realistic hand for the patient to hold, and sound system to make reassuring noises. “Better than the real thing!” (Miss A).

Parking preserver: Scared to leave the hospital for fear of losing your parking slot? Now you can boldly go to that midday meeting at the PCT. Simply put our flatpack under your car. On your departure it expands into a cardboard box stamped “Beware MRSA” in luminous letters. Deluxe version oozes slime (refills available).

Hospital positioning system: With constant reorganisations, are you finding yourself lost in your own hospital? Our satellite-based hospital positioning system (HPS) can guide you to within 1 ft (30 cm) of your destination. “I even found the clinical governance office!” (Dr B).

Political corrector: Nothing destroys a consultant's credibility more quickly than referring to doctors as “he” and nurses as “she.” Our voice-activated corrector immediately adds “or she” when you say “he,” “or hers” when you say “his,” and so on. Absolutely undetectable. Includes deactivating button for use in church when the vicar announces the next hymn.

Portable complaints department: Fill those idle moments when your work is cancelled at short notice through lack of beds, juniors, etc. Just carry your latest batch of complaining letters and our individualised portable complaints department. It consists of two rubber stamps. The Standard prints: “And the same to you.” The Super prints two words of your choice.

Serenity suit: Upset by constant criticism? Unsure of your role? Recapture the old certainties by wearing our all-in-one serenity suit. Bright green, it commands instant respect, confers self-assurance, and tells the world that you are a trained professional.

Interested? Gadgets for consultants are classed as “medical equipment” so they cost 20 times as much as identical gadgets sold to the public. But we think you'll agree they're worth it.
Abstract 2618: DNMT1 as a marker of differential sensitivities to epigenetic therapy of a Kras mutant and Kras wild type human non small cell lung cancer cell line
Authors: Zhenzong Du, John Wrangle, Kristen Pelosky, James Harris, James Shin, Frank Vendetti, Alicia Hulbert, Beverley Lee, Cyntia Zahnow, Nita Ahuja, James Herman, Stephen Baylin, Malcolm Brock
Journal: Cancer Research (2011)

Abstract INTRODUCTION: Epigenetic therapy with a demethylating agent and an histone deacetylase inhibitor (HDACi) is now being pursued in hematological as well as solid tumor malignancies. Clinical responses have been varied with complete responses in some patients and no efficacy of the drugs in others. We investigated the effect of this therapy on two targets, DNA methyltransferase1 (DNMT1) and H3K4 modified histones, respectively. METHODS: Two human lung adenocarcinoma cell lines, A549 (Kras mutant) and H838 (Kras wild type) were pre-exposed for 72 hours with daily treatment of 500nM azacitidine alone or 72 hours of daily 500nM azacitidine followed subsequently with 10 nM, 100nM, 1000nM entinostat at 96 hours. DNMT1 and H3K4 protein levels were assayed by Western blot analysis at various time points after treatment. Cells were also re-plated after treatment to assess differential growth characteristics. RESULTS: In vitro growth of H838 cells is sensitive to azacitidine alone and in combination with entinostat whereas growth of the A549 cell line is only sensitive to azacitidine and entinostat in combination. Treatment with azacitidine, severely depleted DNMT1 protein expression in H838 cells both when given alone and in combination with most dose levels of entinostat. This decrease was transient and within 4 days, the protein was fully replenished. Azacitidine alone did not cause an appreciable decrease in DNMT1 protein expression of A549 cells but, when combined with increasing levels of entinostat, DNMT1 levels were significantly depleted and did not replenish for 7 days. Re-plating after treatment showed growth inhibition versus mock of all regimens containing azacitidine in the H838 cell line only whereas growth inhibition in the A549 cells was observed only in the combinatory therapy arms. Furthermore, in the A549 cell line, H3K4 protein levels (a marker of active gene expression) peaked at 7 days after treatment versus a peak in the first 24 hours in the H838 cell line. CONCLUSIONS: Differing sensitivities to epigenetic therapy in lung adenocarcinoma cell lines may reflect underlying differences in molecular phenotypes. Large decreases in DNMT1 expression are associated with sensitivity to azacitidine. In a cell line insensitive to azacidine alone, the addition of entinostat may accentuate DNMT1 protein depletion and delay its reexpression. This effect on DNMT1 may render this latter cancer cell line more sensitive to epigenetic therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2618. doi:10.1158/1538-7445.AM2011-2618
TM-02 * IDENTIFICATION OF THE AZOLE CLASS OF ANTIFUNGALS AS POTENT INHIBITORS OF HEXOKINASE II MEDIATED TUMOUR METABOLISM IN GLIOBLASTOMA
Authors: S. Agnihotri, A. Vartanian, K. Burrell, S. Singh, A. Alamsahebpour, K. Aldape, G. Zadeh
Journal: Neuro-Oncology (2014)

Rapidly proliferating tumour cells preferentially use aerobic glycolysis over oxidative phosphorylation (OXPHOS) to support growth and survive unfavorable microenvironment conditions. This metabolic reprogramming is referred to as the “Warburg effect” and offers a novel way to target cancer cells including glioblastoma (GBM), the most common malignant brain tumor. Here we demonstrate that Hexokinase 2 (HK2) but not HK1 or HK3 is a critical mediator of metabolic reprograming in GBMs and its inhibition is a potential therapeutic strategy for sensitization of GBM tumors to radiation (RAD) and temozolomide (TMZ). In GBM xenografts, conditional HK2 loss sensitizes tumors to concomitant RAD/TMZ and results in a significant survival benefit. Loss of HK2 resulted in increased necrosis, hypoxia, inflammatory infiltration and reduced vascularization. Currently, no direct inhibitor of HK2 exists so we explored whether a system biology approach to identify gene networks associated with HK2 could lead to the identification of HK2 inhibitors. Using HK2 knockdown in established GBM cell lines and primary cultures we established gene signatures and networks associated with HK2 expression. Loss of HK2 led to attenuation of several pro GBM signaling pathways affecting tumour cell invasion, glucose metabolism and proliferation. Using a small drug screen targeting potential HK2 regulated gene expression networks we identified the azole class of antifungals as inhibitors of tumour metabolism by reducing proliferation, lactate production, glucose uptake in GBM cells but not primary normal human astrocytes or normal neural stem cells. Interestingly, several azole compounds were more potent at killing GBM cells in hypoxic conditions. Azoles in combination with further HK2 knockdown, RT or in combination with other metabolic therapeutics including pyruvate kinase M2 (PKM) activators led to synergistic tumour cell death. In summary, the azole class of antifungals may represent a new way of targeting tumour metabolism in tumours dependent on aerobic glycolysis.
Animals in Research: Researchers Must Tell Their Story
Authors: S. Kumar
Journal: JNCI Journal of the National Cancer Institute (1989)

Journal Article Animals in Research: Researchers Must Tell Their Story Get access Seema Kumar Seema Kumar Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 20, 18 October 1989, Pages 1526–1528, https://doi.org/10.1093/jnci/81.20.1526 Published: 18 October 1989
Abstract P1-13-01: Comparing the Effects of Denosumab and Zoledronic Acid on Pain Interference with Daily Functioning in a Randomized Phase 3 Trial of Patients with Breast Cancer and Bone Metastases
Authors: CS Cleeland, DL Patrick, L Fallowfield, M Clemons, A Lipton, N Masuda, Y Qian, A Braun, K. Chung
Journal: Cancer Research (2010)

Abstract In a recently completed trial of breast cancer patients with bone metastases, denosumab, a fully human monoclonal anti-RANKL antibody, was superior to zoledronic acid (ZA) in delaying/preventing skeletal-related events. Between-treatment differences in patient-reported pain interference with daily functioning were assessed. Eligible breast cancer patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg (double-bind, double-dummy design). Patients completed the Brief Pain Inventory (BPI) to assess pain severity and interference with daily functioning (range 0 [does not interfere]-10 [interferes completely]) at baseline (BL), day 8, and before each monthly visit through end of study. The BPI interference scale generated a total interference score as well as an activity subscale (interference with walking, general activity, and work) and an affective subscale (interference with relations with others, enjoyment of life, and mood). Analyses were conducted on all randomized patients with ≥1 PRO assessment and were performed through week 73, when 30% of patients had dropped out due to death, disease progression, or consent withdrawal. Subgroups included patients with no/mild and moderate/severe worst pain at BL. Analyses included time to improvement (≥2-point decrease) or worsening (≥2-point increase) in pain interference, mean change from baseline, and proportion of patients with improving or worsening pain interference scores. Time to improvement in pain interference with activity (PIWA) tended to occur more quickly with denosumab compared with ZA (N=1124; median: 70 days denosumab v 86 days ZA; P=0.09), and time to worsening PIWA tended to be longer with denosumab compared with ZA (N=1676; median: 394 days denosumab v 310 days ZA; P=0.13). In patients with no/mild pain at BL, denosumab also demonstrated a trend for shorter time to improvement in PIWA (N=388; 93 days denosumab v 120 days ZA; P=0.06) and longer time to worsening PIWA (N=755; 369 days denosumab v 232 days ZA; P=0.12). Overall, a greater proportion of patients on denosumab had improvement in PIWA on study than ZA (Figure). Findings were similar with the total interference score and affective subscale. Figure Proportion of Patients With Improvement in Pain Interference With Activity (≥2-point decrease from BL)* Daily functioning (total interference and interference with activity and affect) tended to be less disrupted by pain in patients on denosumab compared with ZA. Decreased pain interference showed a trend to occur more quickly with denosumab. Overall, a greater proportion of denosumab patients reported decreased pain interference than ZA patients. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-01.
P210 Are sputum and blood biomarkers of inflammation repeatable in stable COPD?
Authors: BL Barker, V Mistry, M Pancholi, CE Brightling, M Bafadhel
Journal: Thorax (2012)

<h3>Background</h3> Spirometry is a commonly used end-point in COPD clinical trials and there is evidence that spirometric values are reproducible in COPD patients. COPD is heterogeneous and differences in biomarkers of pulmonary and systemic inflammation between patients can be identified. Currently limited short-term reproducibility is available in stable COPD. <h3>Aims</h3> Assess repeatability of commonly used clinical measures in subjects with stable COPD over 3 and 6 months. <h3>Methods</h3> Subjects with COPD were enrolled into an observational study and were reviewed at stable visits after 3 and 6 months. Spirometry, blood [peripheral blood total white cell and differential cell counts] and sputum [sputum differential cell counts (%)] markers of inflammation were repeated at each visit. Repeatability of these measures was assessed using the intra-class correlation coefficient (Ri) and is expressed below as Ri (95%CI). <h3>Results</h3> 145 subjects were recruited; 101 were male with a mean (SD) FEV1 (L) and FEV1/FVC ratio (%) of 1.34 L (0.57) and 53% (14.6) respectively. Spirometry values showed excellent repeatability; FEV1 [0.93 (0.84 to 0.92) and 0.89 (0.83 to 0.92)] and FVC [0.80 (0.73 to 0.86) and 0.81 (0.72 to 0.87)] after 3 and 6 months respectively. Sputum biomarkers of inflammation showed moderate repeatability at 3 and 6 months respectively; sputum neutrophils (%) [0.59 (0.43 to 0.71) and 0.50 (0.33 to 0.64)] and eosinophils (%) [0.62 (0.48 to 0.73) and 0.32 (0.13 to 0.49)]. The blood biomarkers peripheral blood white cell count (WCC), neutrophil and eosinophil counts demonstrated good repeatability after 3 and 6 month intervals respectively; WCC [0.68 (0.56 to 0.77) and 0.73 (0.62 to 0.81)], neutrophil count [0.66 (0.54 to 0.76) and 0.71 (0.59 to 0.79)] and eosinophil count [0.66 (0.54 to 0.76) and 0.73 (0.63 t o0.81)]. CRP showed fair repeatability [0.34 (0.16 to 0.5) and 0.30 (0.11 to 0.47) at both time intervals. <h3>Discussions</h3> Sputum differential cell counts (%) and peripheral blood differential cell counts are repeatable after 3 and 6 month intervals. These findings may have clinical implications when targeting therapies to sub-groups of COPD patients.
Association between Ambient Air Pollution and Diabetes Mellitus in Europe and North America: Systematic Review and Meta-Analysis
Authors: Ikenna C. Eze, Lars G. Hemkens, Heiner C. Bucher, Barbara Hoffmann, Christian Schindler, Nino Künzli, Tamara Schikowski, Nicole M. Probst-Hensch
Journal: Environmental Health Perspectives (2015)

Air pollution is hypothesized to be a risk factor for diabetes. Epidemiological evidence is inconsistent and has not been systematically evaluated.We systematically reviewed epidemiological evidence on the association between air pollution and diabetes, and synthesized results of studies on type 2 diabetes mellitus (T2DM).We systematically searched electronic literature databases (last search, 29 April 2014) for studies reporting the association between air pollution (particle concentration or traffic exposure) and diabetes (type 1, type 2, or gestational). We systematically evaluated risk of bias and role of potential confounders in all studies. We synthesized reported associations with T2DM in meta-analyses using random-effects models and conducted various sensitivity analyses.We included 13 studies (8 on T2DM, 2 on type 1, 3 on gestational diabetes), all conducted in Europe or North America. Five studies were longitudinal, 5 cross-sectional, 2 case-control, and 1 ecologic. Risk of bias, air pollution assessment, and confounder control varied across studies. Dose-response effects were not reported. Meta-analyses of 3 studies on PM2.5 (particulate matter ≤ 2.5 μm in diameter) and 4 studies on NO2 (nitrogen dioxide) showed increased risk of T2DM by 8-10% per 10-μg/m3 increase in exposure [PM2.5: 1.10 (95% CI: 1.02, 1.18); NO2: 1.08 (95% CI: 1.00, 1.17)]. Associations were stronger in females. Sensitivity analyses showed similar results.Existing evidence indicates a positive association of air pollution and T2DM risk, albeit there is high risk of bias. High-quality studies assessing dose-response effects are needed. Research should be expanded to developing countries where outdoor and indoor air pollution are high.
The Importance of a Name
Authors: Orit Pinhas-Hamiel, Philip Zeitler
Journal: New England Journal of Medicine (1999)

A 16-year-old black girl presented to the emergency room with increased thirst, frequent urination, fatigue, and an 11-kg weight loss in the preceding two to three weeks.The triad of polydipsia, polyuria, and polyphagia with weight loss is a classic presentation of diabetes mellitus. Among adolescents, type 1 (autoimmune) diabetes mellitus is the most probable diagnosis. With these three symptoms, the differential diagnosis is quite limited, but diabetes insipidus, either nephrogenic or central, should also be considered. Diabetes insipidus is characterized by polydipsia, polyuria, and weight loss, but not polyphagia, and the weight loss is due to a . . .
Response to hepatitis B vaccine: Multiple HLA genes are involved
Authors: Isabelle Desombere, Annick Willems, Geert Leroux-Roels
Journal: Hepatology (1998)

The mechanism underlying the impaired immune response to hepatitis B vaccines in up to 10% of healthy subjects is not known. An increased incidence of poor responsiveness in subjects with HLA-DR3+ or -DR7+ haplotypes has been documented, suggesting that HLA-DR-linked genes may regulate the human response to hepatitis B surface antigen. However, not all HLA-DR3+ and/or -DR7+ individuals are poor responders, and subjects with identical HLA-DR haplotypes sometimes display totally divergent antibody responses to vaccination. HLA class II DNA typing was performed in well and poorly responding hepatitis B vaccine recipients and we analyzed the role of the single HLA-DR, -DP, and -DQ molecules and of their associated (interaction) haplotypes in the response to hepatitis B vaccination. Statistical analysis revealed that HLA-DRB1*010*, -DR5, -DPB1*040*, -DQB1*0301, and -DQB1*0501 were more abundant in good responders, whereas HLA-DRB1*07, -DPB1*1101, and -DQB1*020* were associated with poor response, with DQB1*020* showing the strongest association with poor responsiveness. We further investigated whether there were interactions between the HLA factors contributing to poor responsiveness. We show here that HLA-DPB1*02 was negatively associated with responsiveness when it occurred in association with haplotype DRB1*0701/DRB4*0101-DQB1*020*, and DRB4*0101 was negatively associated with responsiveness when it occurred in association with haplotype DRB1*0301/DRB3*0101-DQB1*020*. Our results indicate that the immune response to hepatitis B vaccine is largely determined by HLA-DR, -DP, and -DQ genes and that interaction between HLA molecules that are not in linkage disequilibrium contributes to poor responsiveness.
Heparan Sulfate–Rich Anionic Sites in the Human Glomerular Basement Membrane
Authors: Robert L. Vernier, David J. Klein, Susan P. Sisson, John D. Mahan, Theodore R. Oegema, David M. Brown
Journal: New England Journal of Medicine (1983)

Recent work suggests that the normal barrier to penetration of the renal glomerular basement membrane by anionic plasma proteins may depend in part on the existence of negatively charged sites within the membrane. We describe an in vitro cytochemical method for the quantitative demonstration of anionic sites in the normal human glomerular basement membrane. In five normal subjects, ranging in age from 10 days to 57 years, the sites were distributed at regular intervals in the lamina rara externa, with a frequency of 23.8±6.8 sites per 1000-nm length of membrane. A similar distribution was observed in the basement membranes from three normal human fetuses. Ex vivo perfusion of one cadaver kidney revealed a similar distribution of anionic sites. The number of anionic sites in the glomerular basement membranes of five patients with the congenital nephrotic syndrome was reduced to 8.9±3.7 (P<0.001). Prior incubation of sections of normal kidney in purified heparinase resulted in a marked reduction in the number of anionic sites. We conclude that congenital nephrosis results from failure of heparan sulfate–rich anionic sites to develop in the lamina rara externa of the glomerular basement membrane. (N Engl J Med 1983; 309:1001–9.)
Viral Isolations and Illnesses in Young Infants Attending a Well-Baby Clinic
Authors: Hugh L. Moffet, Henry G. Cramblett
Journal: New England Journal of Medicine (1962)

ROUTINE culturing indicates that viruses are rarely recovered from newborn infants in the hospital nursery,1 , 2 but are frequently recovered from infants older than six months.3 4 5 6 However, few surveys have obtained data on the frequency of viral isolations from infants during the first months after discharge from the hospital nursery.2 , 4 In the reported studies many infants from whom viruses were recovered had minor illnesses. However, the frequency of the minor illnesses in the infants from whom viruses were not recovered was rarely indicated.1 2 3 4 5 6 The present report describes the frequency of viral isolations and minor illnesses of infants one through six months . . .
Powerful societal discourses and vested interests need to be tackled by too much medicine campaign
Authors: J. Boddington
Journal: BMJ (2013)

The too much medicine campaign will need to tackle two issues related to the overmedicalisation of society—public understanding of the value of screening and the private sector’s role.1

Every medical student learns about Wilson’s criteria, yet doctors still ask for screening interventions that fail to make the grade. Some are policy driven, such as the almost certainly …