tbuckley/cabot-search huggingface dataset:
Hospital trust prosecuted for not supervising junior doctors
Authors: Clare Dyer
Journal: BMJ (2006)

<h3>Abstract</h3> Microtubules (MTs) are polymers of α/β-tubulin heterodimers that stochastically switch between growth and shrinkage phases. This dynamic instability is critically important for MT function. It is believed that GTP hydrolysis within the MT lattice is accompanied by destabilizing conformational changes, and that MT stability depends on a transiently existing GTP cap at the growing MT end. Here we use cryo-EM and TIRF microscopy of GTP hydrolysis-deficient MTs assembled from mutant recombinant human tubulin to investigate the structure of a GTP-bound MT lattice. We find that the GTP-MT lattice of two mutants in which the catalytically active glutamate in α-tubulin was substituted by inactive amino acids (E254A and E254N) is remarkably plastic. Undecorated E254A and E254N MTs with 13 protofilaments both have an expanded lattice, but display opposite protofilament twists, making these lattices distinct from the compacted lattice of wildtype GDP-MTs. End binding proteins of the EB family have the ability to compact both mutant GTP-lattices and to stabilize a negative twist, suggesting that they promote this transition also in the GTP cap of wildtype MTs, thereby contributing to the maturation of the MT structure. We also find that the MT seam appears to be stabilized in mutant GTP-MTs and destabilized in GDP-MTs, supporting the proposal that the seam plays an important role in MT stability. Together, these first high-resolution structures of truly GTP-bound MTs add mechanistic insight to our understanding of MT dynamic instability. <h3>Significance Statement</h3> Microtubules (MTs) are non-equilibrium polymers that switch between states of growth and shrinkage. This property is critical for their function and is a consequence of GTP hydrolysis in the MT. The structure of the stable GTP part of the MT (the GTP cap) has previously been inferred from MTs polymerized with non-hydrolyzable GTP analogs. Here, we report the first high-resolution structures of MTs truly containing GTP, polymerized from mutated, hydrolysis-deficient tubulins. We find that GTP-MTs have an “expanded lattice” and a “closed seam”, structural characteristics possibly responsible for stabilizing the GTP cap. These results provide new insight into the structural transitions at growing MT ends, furthering our understanding of the bistable nature of MTs.
Chromosome translocations and fusion genes in breast cancer.
Authors: KD Howarth, EM Batty, JC Beavis, KA Blood, S Newman, B Ng, JC Pole, Y Chua, K Ichimura, VP Collins, CG Project, S Chin, C Caldas, NP Carter, PA Edwards
Journal: Cancer Research (2009)

Abstract Abstract #2021 Background: Little is known about chromosome translocations in the common epithelial cancers such as breast cancer, in spite of the central role played by translocations and consequent gene fusions in haematopoietic cancers.&amp;#x2028; Methods: We present a comprehensive analysis by array painting of the chromosome translocations of four breast cancer cell lines, DU4475, HCC1806, HCC1187 and ZR-75-30. In array painting chromosomes are isolated by flow cytometry, amplified and hybridized to DNA microarrays. All breakpoints, totalling nearly 250, were mapped to at least 1Mb resolution and most balanced breakpoints were mapped to about 2kb resolution using custom oligonucleotide arrays. The remaining unbalanced breakpoints were mapped to around 20kb by identifying copy number steps in Affymetrix SNP6 array hybrizations obtained by the Sanger Institute's Cancer Genome Project. Breast tumours in parraffin section in tissue microarrays were screened by FISH to see whether selected breakpoints found in the cell lines are present in breast tumours.&amp;#x2028; Results: We found at least 12 reciprocal translocations in the four cell lines, substantially more than expected, and many more rearrangements were balanced for at least one participating chromosome. Many of the breakpoints were within or adjacent to cancer-relevant genes, and three of the translocations have already been shown to form fusion transcripts, RIF1-PKD1L1, PUM1-TRERF1 and TAX1BP1-AHCY. For selected genes targetted by the translocations, about 100 breast tumours were screened for breaks. Breaks were found in two to six cases for several of the genes, confirming that some of them were broken in breast tumours. For example two cases of unbalanced breakage were identified in PKD1L1, and these were confirmed by array-CGH.&amp;#x2028; Discussion: Our results suggest that breast cancers have fusion genes, and support the emerging view that chromosome rearrangements are likely to play a significant role in common epithelial cancers. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2021.
Acute Hemodynamic Effects of Hexamethonium in Normotensive Man
Authors: LOUIS RAKITA, SALVATORE M. SANCETTA, HECKMAN R.N. GLADYS, JANOUSKOVEC, R.Y. HANNA
Journal: Circulation Research (1953)

The effect of intravenous hexamethonium bromide was studied in 10 normotensive human subjects in the steady state. In the absence of over-all change in cardiac output, the variable decrease in arterial pressure is accounted for by decrease in calculated total peripheral resistance.
Abstract 5617: A new alphaV/beta3 integrin selective carrier for nanodrug delivery to tumors based on isoDGR-tagged albumin.
Authors: Flavio Curnis, Angelina Sacchi, Renato Longhi, Barbara Colombo, Anna Gasparri, Angelo Corti
Journal: Cancer Research (2013)

Abstract Albumin is emerging as a versatile drug carrier in a number of applications in cancer therapy and diagnosis. Basically, albumin can be exploited to enhance the tumor uptake of peptides and low molecular-weight compounds, owing its tendency to accumulate in tumors, and for the preparation of nanoparticles that encapsulate anti-cancer drugs or diagnostic agents. We have addressed the hypothesis that coupling albumin with a peptide containing the isoAsp-Gly-Arg (isoDGR) sequence, a tumor-vasculature targeting motif discovered by our group, might enhance its tumor-homing properties. IsoDGR is a mimetic of Arg-Gly-Asp (RGD), an integrin-recognition motif. Accordingly, isoDGR can recognize RGD-dependent integrins with different affinity and selectivity depending on isoDGR conformation and molecular scaffold. To have at hand isoDGR peptides that can be easily coupled to albumin we designed various head-to-tail-cyclized exapeptides containing free thiol groups, to enable chemical coupling to proteins, and analyzed their integrin binding properties before and after coupling to albumin. We have identified a peptide (c(CGisoDGRG)) that, after coupling to human serum albumin, has a very good selectivity for alphaV/beta3 and alphaV/beta5, two integrins overexpressed in the tumor vasculature. In vitro and in vivo studies showed that isoDGR-tagged albumin binds to endothelial cells, inhibits their adhesion properties, homes in on tumor vessels and inhibits tumor growth, with no evidence of toxicity. IsoDGR-tagged albumin was exploited as a carrier for the preparation of a new nano-gold systems capable of delivering tumor necrosis factor α (TNF), a well known vascular damaging agent, to tumor vessels. In vivo studies, performed with mice bearing WEHI-fibrosarcomas, showed that intravenous administration of gold nanoparticles loaded with isoDGR-tagged albumin and TNF (equivalent 5 pg of bioactive TNF/mouse) could induce stronger anti-tumor effects than nanoparticles loaded with albumin and TNF. These findings support the concept that isoDGR-tagged albumin is superior to albumin as a vector system for targeted delivery of nanomedicines to tumor vessels. Because of its good selectivity for tumor vessels and its inherent anticancer activity isoDGR-tagged albumin might be exploited as a novel and versatile material for the preparation of a wide range of tumor vasculature-selective drugs and nanoparticles for cancer therapy and diagnosis. Citation Format: Flavio Curnis, Angelina Sacchi, Renato Longhi, Barbara Colombo, Anna Gasparri, Angelo Corti. A new alphaV/beta3 integrin selective carrier for nanodrug delivery to tumors based on isoDGR-tagged albumin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5617. doi:10.1158/1538-7445.AM2013-5617
"Batch" or "on-line" for child health--a review.
Authors: C H Walker
Journal: BMJ (1980)

The report of the New Charter Working Group' showed that general practitioners have joined most other medical groups in recognising that computer systems will become the principal form of medical record keeping in the future.The debate is, therefore, not whether computers should be used but which type of system is the most appropriate to child care-"batch" processing or "on-line."There have been many articles in the press on the subject.Some have given helpful accurate in- formation but many have contained half truths and emotive statements which have misled medical and lay readers.The essential difference between the two systems is that with batch processing written information is sent to a central service for conversion to computer language for processing, whereas with on-line systems each user enters and retrieves the information using his or her own keyboard and visual display unit.As examples of the two systems I have chosen the Scottish neonatal record batch process system and the Exeter on-line project. Scottish batch processThe purpose of the two systems is broadly the same-that is, to facilitate the accurate recording and retrieval of medical information.But they differ in several important respects.The batch process system, which has been proposed by the DHSS for the child health computing programme, is designed primarily to help in the efficient care of every child from birth.But it is also intended to record a large amount of medical information not only for the benefit of the patient and his attendants but also for the management of community health programmes, for the study of epidemiological trends, and even for a limited amount of clinical research.It has been described as "a remote, centralised, bureaucrat-controlled, administrator-oriented system"'2-"a monster of a computer."'3
P08.24 * PREDICTIVE FACTORS OF PERITUMORAL EDEMA IN BRAIN METASTASES
Authors: A. Marantidou, M. Hou, A. Sacko, J. Doridam, R. Ursu, C. Belin, I. Coman, C. Levy, K. Chouahnia, A. Carpentier
Journal: Neuro-Oncology (2014)

OBJECT: To investigate peritumoral edema and its prognostic factors in brain metastases of lung and breast cancers, and more specifically to evaluate the effect of treatment with angiotensine-II (Ang2) inhibitors. This treatment was shown in a recent study to display a significant effect in primary brain tumor edema. MATERIALS AND METHODS: We retrospectively reviewed the medical files of all patients with newly diagnosed brain metastases consulting in our institution in the years 2012 and 2013. We measured the maximal diameter of lesions DL (contrast enhancement) and peritumoral edema DE (diameter of edema minus contrast enhancement) on the first diagnostic imaging of brain metastasis. Patients under steroids or files with insufficient informations were excluded from analysis. RESULTS: A total of 157 medical files were reviewed from which 54 patients with 170 metastases were selected for analysis. There were 87 metastases of lung adenocarcinomas, 35 of small cell carcinomas, 18 of epidermoiïd lung cancer, 7 of undifferentiated and 23 of breast cancer. Median DL was 9.35mm (1-74.3), median DE was 5,98mm (0-69,5). There was no significant difference in DL or DE between the histology groups. Younger age (<65 years old), female gender and treatment with Ang2 inhibitors seem to be associated with statistically less peritumoral edema (p = 0,005; p = 0,022; p = 0,005, respectively). This finding was persistent even when the 23 metastases of breast cancer were taken out from the analysis. Both DL and DE were smaller in the 25 patients under treatment with Ang2 inhibitors (n = 84 metastases) than in the 29 patients without such treatment (n = 86 metastases) (mean DL: 10.2 vs 13.4 mm, p= 0.036; mean DE 9.5 vs 15.9 mm, p= 0.005, respectively) The delay between the diagnosis of the primary tumors and brain metastases did not have any impact on the peritumoral edema. Moreover, the diameter of edema did not seem to be associated with the location, the size or the number of lesions, neither with the pattern of contrast enhancement (annular, homogenic or necrotic). Different patterns of contrast enhancement and sizes of edema were observed even within the same patient with multiple metastases. From the main 157 files reviewed, multiple metastases were more frequent in breast cancer patients (9 patients out of 10) compared to lung adenocarcinomas (29/81) and other lung cancers (13/25). CONCLUSION: In this series of patients with lung and breast cancer, younger age (<65 years old), female gender and treatment with Ang2 inhibitors seem to be associated with statistically smaller brain metastases and peritumoral edema Peritumoral edema did not seem to be associated with any other factors like histology, delayed brain metastasis diagnosis, size, location, number of lesions or contrast enhancing pattern.
Subspecialist Care Improves Diabetes Outcomes
Authors: Rhoda H. Cobin
Journal: Diabetes Care (2002)

The ultimate goal of the care of diabetic individuals is to reduce complications and prolong high quality of life. In view of the soaring increase in prevalence of this devastating illness, we as a society are obliged to “pull out all the stops” to identify disease early, prevent its progression, and provide the best care for those in need of treatment. It has become axiomatic that the best way to provide care for patients is the team setting, with substantial emphasis on the role and responsibility of the patient himself. The role of the specialist in caring for people with diabetes is a particularly timely issue in view of the rapidly escalating disease prevalence and the shrinking pool of endocrinologists. The solution may be to train more specialists, distribute their services differently, or use new approaches to assist already overworked primary physicians or other health care providers.

The article by Zgibor et al. (1) in this month’s issue of Diabetes Care supports the contention that specialist physicians and clinics contribute to better outcomes for patients with type 1 diabetes. The study demonstrated that in a large population of 429 childhood-onset type 1 diabetic patients who were followed prospectively over a period of 10 years, a longer duration of time spent in specialist care resulted in a reduction in the development of overt nephropathy, neuropathy, and coronary artery disease. Although the study is limited in that some of the information was obtained by patient questionnaire, the information was validated by medical record review, providing reassurance of the accuracy of responses. After correcting for a number of variables that could influence outcome, including patient demographic characteristics, duration of disease, and comorbidties, significant differences in outcomes persisted.

The current work is vital because it reports the result of clinically important long-term disease outcomes. …
Risk factors, prevalence, and treatment of anxiety and depressive disorders in Pakistan: systematic review
Authors: Ilyas Mirza, Rachel Jenkins
Journal: BMJ (2004)

Abstract Objectives To assess the available evidence on the prevalence, aetiology, treatment, and prevention of anxiety and depressive disorders in Pakistan. Design Systematic review of published literature. Studies reviewed 20 studies, of which 17 gave prevalence estimates and 11 discussed risk factors. Main outcome measures Prevalence of anxiety and depressive disorders, risk factors, effects of treatment. Results Factors positively associated with anxiety and depressive disorders were female sex, middle age, low level of education, financial difficulty, being a housewife, and relationship problems. Arguments with husbands and relational problems with in-laws were positively associated in 3/11 studies. Those who had close confiding relationships were less likely to have anxiety and depressive disorders. Mean overall prevalence of anxiety and depressive disorders in the community population was 34% (range 29-66% for women and 10-33% for men). There were no rigorously controlled trials of treatments for these disorders. Conclusions Available evidence suggests a major social cause for anxiety and depressive disorders in Pakistan. This evidence is limited because of methodological problems, so caution must be exercised in generalising this to the whole of the population of Pakistan.
Clinical decision making: from theory to practice. The individual vs society. Is there a conflict?
Authors: D. M. Eddy
Journal: JAMA (1991)

Eddy argues that many medical interventions that make sense from the point of view of the individual patient and his or her physician might not make sense from the point of view of society -- either because they restrict resources available for other needs, or because they drive up the cost of resources. He illustrates his argument with the case of a hypothetical patient with metastatic breast cancer whose physician offers her an expensive investigative treatment that is 5% effective. The cost of the treatment would buy 10 years of mammogram screening for 150 women. Eddy discusses the nature of the conflict between individuals and society when making judgments regarding the value of different health care activities. He will discuss the resolution of the conflict in a future JAMA article.
Dr. Quine on Homeopathy.
Authors: A. C. Simonton
Journal: JAMA (1899)

Seattle, Wash., May 15, 1899. <h3>To the Editor:</h3> —Relative to Dr. Quine's address, in exposition of the tenets of homeopathy (seeJournal, April 29 and May 6), I wish to say that my perusal of it afforded me the greatest pleasure, as well as imparting much information. It was the opportunity of a lifetime—"to beard the lion in his own den." Those homeopaths scarcely realized what the Doctor had in store for them. It is so easy to be deceived and even to deceive oneself when only one side of a proposition is presented or thought upon. Many of those homeopathic students went away from that hall wiser then when they came. If homeopaths everywhere could read that address, it would do more toward the collapse of that "pathy" than anything that has happened since the crazy Hahnemann promulgated his dogmas of "similia similibus, curantur," "potentization," and "infinitesimals." Professor Palmer's
Abstract 3783: An Insulin-independent AMPK-dependent Survival Pathway Is Activated In Glucose-starved Cardiac Myocytes through IRS-1/PI3-kinase and Rictor-mediated Activation of PDK1 and PDK2
Authors: Ines Chopra, Huifang Li, Nanette H Bishopric, Keith A Webster
Journal: Circulation (2008)

INTRODUCTION: Akt (PKB) is the downstream effector of insulin and IGF-1 and regulates multiple targets that control cell survival and growth. Akt is phosphorylated at Thr-308 (activating) and Ser-473 (regulatory) sites by PI3-kinase dependent kinase-1 (PDK1) and TOR2-rictor/PDK2 respectively. When energy is abundant Akt supports cell growth by stimulating TORC1 and inhibiting GSK3β. When energy and insulin are low such as during ischemia, AMPK is activated and depresses TORC1 by activating the repressive TSC1/2 complex. It is not known how AMPK affects TORC2 in this setting. HYPOTHESIS: Under low energy states AMPK promotes survival by differentially regulating TORC1 and 2 thereby maintaining Akt phosphorylation and survival in the absence of insulin. METHODS: Cardiac myocytes (CM) were subjected to glucose and insulin-free incubation for 4h and the activities of insulin signaling components were measured by western blot and co-IP. Survival was measured ± siRNAs by Hoechst/PI staining. RESULTS: After 4h of glucose/insulin deprivation there was increased phosphorylation of Akt-Thr-308 (11.2±2.4; n=6, p&lt;0.001) and Akt-Ser-473 (9.7± 2; n=6, p&lt;0.001). Phosphorylation of GSK-3β (Ser-9) also increased but there was decreased phosphorylation of p70S6-kinase (Thr389) and 4EBP (Ser65) indicating global down-regulation of TORC1. We identified 2 separate pathways for the insulin-independent phosphorylation of Akt at both sites in glucose-depleted CM. Activated AMPK promoted phosphorylation of insulin receptor substrate-1 (IRS-1) on Ser-789. AraA or a Ser-789 decoy peptide blocked this, and IRS-1-P-Ser-789 co-IP’d with PI3-kinase suggesting positive regulation of PDK1. Glucose depletion did not change the levels of rictor or raptor or their relative binding to TOR. However TSC1 and rictor were quantitatively associated with PI3-kinase selectively under glucose/insulin depletion and this correlated with Akt phosphorylation. CM survival under glucose/insulin depletion was impaired by siRNA-mediated knockdown of IRS-1 or rictor (n=3; P&lt;0.05). CONCLUSIONS: AMPK maintains phosphorylation of Akt under low energy states in the absence of insulin. The mechanism involves IRS-1 phosphorylation by AMPK and enhanced binding of rictor and TSC1 to PI3K. This research has received full or partial funding support from the American Heart Association, AHA Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico &amp; Tennessee).
Warfarin After Bioprosthetic Aortic Valve Implantation
Authors: Shamir R. Mehta, Jeffrey I. Weitz
Journal: JAMA (2012)

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Cyclic neutropenia in animals
Authors: Jorge M. Pacheco, Arne Traulsen, Tibor Antal, David Dingli
Journal: American Journal of Hematology (2009)

Cyclic neutropenia in animalsTo the editor: Pacheco et al. [1] recently published in these pages an allometric scaling analysis of cyclic neutropenia (CN) in mammals, using as reference points the hereditary disorders in humans and in gray collie dogs [2].They make a central assumption ''that the biological defect in CN is the same in dogs and in humans.''However, virtually all human cases derive from mutations in the neutrophil elastase (ELA2) gene [3], whereas the disorder in dogs represents a similar hematological phenotype, in association with partial albinism, because of the defects in the adaptor protein complex 3 (AP3) b-subunit, directing trans-Golgi export of transmembrane cargo proteins to lysosomes [4].Thus, the canine disorder better models Hermansky-Pudlak syndrome Type 2, [5] than human CN.Although the genetic defects in man and dog may share common downstream mechanisms involving elastase trafficking or elicitation of the unfolded protein response, the resultant kinetics of apoptosis induction and recovery in myeloid precursors may not be the same, and thus the assumption may not be correct.