tbuckley/cabot-search huggingface dataset:
Middle-Aged Premenopausal Women With Type 1 Diabetes Have Lower Bone Mineral Density and Calcaneal Quantitative Ultrasound Than Nondiabetic Women
Authors: Elsa S. Strotmeyer, Jane A. Cauley, Trevor J. Orchard, Ann R. Steenkiste, Janice S. Dorman
Journal: Diabetes Care (2006)

OBJECTIVE—To determine whether middle-aged premenopausal women with type 1 diabetes had more self-reported fractures and lower bone mineral density (BMD) compared with nondiabetic women. RESEARCH DESIGN AND METHODS—Participants were premenopausal women aged 35–55 years with type 1 diabetes (n = 67; 32.2 ± 5.3 years duration) and without diabetes (n = 237). Total hip, femoral neck, whole-body, and spine BMD were measured by dual X-ray absorptiometry. Calcaneal broadband ultrasound attenuation (BUA) was assessed with quantitative ultrasound. RESULTS—Women with type 1 diabetes were more likely to report a fracture after age 20 years compared with nondiabetic women (33.3 vs. 22.6%; age-adjusted odds ratio 1.89 [95% CI 1.02–3.49]). Type 1 diabetes was associated with lower total hip BMD (0.890 vs. 0.961 g/cm2; P &amp;lt; 0.001), femoral neck BMD (0.797 vs. 0.847 g/cm2; P = 0.001), whole-body BMD (1.132 vs. 1.165 g/cm2; P &amp;lt; 0.01), and lower calcaneal BUA (71.6 vs. 84.9 dB/MHz; P &amp;lt; 0.001) after multivariate adjustment. BMD was 3–8% lower in type 1 diabetic compared with control women and calcaneal BUA was 15% lower. Spine BMD and biomarkers of bone remodeling were not significantly different between groups. In the type 1 diabetic women, reduced monofilament detection and blindness were both associated with lower BMD. CONCLUSIONS—Lower BMD in premenopausal women with type 1 diabetes may substantially increase their risk of developing osteoporosis after menopause. Type 1 diabetic women should be targeted for osteoporosis screening and possible fracture prevention as they transition through menopause.
New chairmen of NICE and CQC are confirmed
Authors: A. O'Dowd
Journal: BMJ (2012)

The men who will lead two of the most influential and powerful NHS bodies have been confirmed in their posts.

The Department of Health confirmed on 13 December that David Haslam will be the chairman of the drugs watchdog the National Institute for Health and Clinical Excellence and that David Prior will become chairman of the main NHS regulator, the Care Quality Commission.

Both men were selected as the government’s preferred candidates for these posts but had to appear before the parliamentary health select committee recently for pre-appointment scrutiny.1 2

The committee has now approved both men in the …
Sepsis and Acute Kidney Injury
Authors: Abolfazl Zarjou, Anupam Agarwal
Journal: Journal of the American Society of Nephrology (2011)

Sepsis is a severe and dysregulated inflammatory response to infection characterized by end-organ dysfunction distant from the primary site of infection. Development of acute kidney injury (AKI) during sepsis increases patient morbidity, predicts higher mortality, has a significant effect on multiple organ functions, is associated with an increased length of stay in the intensive care unit, and hence consumes considerable healthcare resources. When compared with AKI of nonseptic origin, septic AKI is characterized by a distinct pathophysiology and therefore requires a different approach. Despite impressive advances in several fields of medicine, the pathophysiology, diagnostic procedures, and appropriate therapeutic interventions in sepsis are still highly debatable. Numerous immunomodulatory agents showing promise in preclinical studies fail to reduce the overwhelmingly high mortality rate of sepsis and provoke AKI when compared with other critically ill patients. Major impediments to progress in understanding, early diagnosis, and application of appropriate therapeutic modalities in sepsis-induced AKI include limited histopathologic information, few animal models that closely mimic human sepsis, and a relative shortage of specific diagnostic tools. Here we discuss the most recent advances in understanding the fundamental mechanisms of sepsis-induced AKI, characteristics of relevant animal models available, and potential therapies.
Ineffectiveness of Isoxsuprine on Intermittent Claudication
Authors: D. Eugene Strandness
Journal: JAMA (1970)

The usefulness of isoxsuprine hyldochloride for the treatment of intermittent claudication was studied in 20 patients with arteriosclerosis obliterans. The study consisted of two four-week periods during which the patient was treated with both drug and placebo, the order of which was randomly assigned. The pattern of the postexercise hyperemic response was measured by the ankle systolic blood pressure response to exercise. A comparison of the drug and placebo treatment periods indicated that isoxsuprine did not improve the hyperemic response to exercise. On the basis of these data, it was not possible to demonstrate that isoxsuprine was useful in the treatment of intermittent claudication.
Personalizing Biomaterials for Precision Nanomedicine Considering the Local Tissue Microenvironment
Authors: Nuria Oliva, Shimon Unterman, Yi Zhang, João Conde, Hyun Seok Song, Natalie Artzi
Journal: Advanced Healthcare Materials (2015)

New advances in (nano)biomaterial design coupled with the detailed study of tissue–biomaterial interactions can open a new chapter in personalized medicine, where biomaterials are chosen and designed to match specific tissue types and disease states. The notion of a “one size fits all” biomaterial no longer exists, as growing evidence points to the value of customizing material design to enhance (pre)clinical performance. The complex microenvironment in vivo at different tissue sites exhibits diverse cell types, tissue chemistry, tissue morphology, and mechanical stresses that are further altered by local pathology. This complex and dynamic environment may alter the implanted material's properties and in turn affect its in vivo performance. It is crucial, therefore, to carefully study tissue context and optimize biomaterials considering the implantation conditions. This practice would enable attaining predictable material performance and enhance clinical outcomes.
The Role of the Nonspecific Inflammatory Markers in Determinıing the Anatomic Extent of Venous Thromboembolism
Authors: Eftal Murat Bakirci, Selim Topcu, Kamuran Kalkan, Ibrahim Halil Tanboga, Abdurrezzak Borekci, Serdar Sevimli, Mahmut Acikel
Journal: Journal of the American College of Cardiology (2013)
CHANGES IN THE RESPIRATORY MECHANISM FOLLOWING PHRENICECTOMY
Authors: WALTER I. WERNER
Journal: JAMA (1930)

In the past year the literature has been replete with reports stressing the importance of phrenicectomy in the treatment of pulmonary tuberculosis. It has been observed that phrenic neurectomy is not attended with any great danger in man.  Lemon, 1 in a series of experiments on normal dogs, concluded that either unilateral or bilateral phrenicectomy was attended with slight risk and did not produce demonstrable impairment of function in general or of respiratory function in particular. Compensation was sufficient to overcome the loss in function of half or the whole diaphragm of the dog, and the animal was able to carry on its usual activities without embarrassment or dyspnea.  Andrus 2 made studies of the changes in the cardiorespiratory mechanism in dogs, following hemiparalysis of the diaphragm. The experimental data collected were summarized as follows: 1. The pulse and respiratory rates increased about 10 per cent. 2. There was a
Abstract LB-188: Co-evolution of primary and metastatic colorectal cancer
Authors: Timothy J. Yeatman, Jamie Teer, Danielle Grenawalt, Richard Kim, Michael J. Schell
Journal: Cancer Research (2014)

Abstract Introduction: Metastasis is thought to be a clonal event whereby a single cell initiates the development of a new tumor that reproduces the primary tumor at a distant site. We hypothesized that primary tumors and their derivative metastases might be genetically identical. To test this hypothesis, we used deep nextgen sequencing to assess the molecular composition of primary:metastatic tumor pairs. Methods: Nearly 20,000 tumors were molecularly profiled as part of a large personalized medicine initiative. Of these, 468 colorectal tumor samples were further assessed by targeted exome sequencing of 1321 individual genes. 16 patients produced genomic profiles paired primary:metastatic specimens; 2 patients produced paired metastases. Non-synonymous, deleterious, single nucleotide variants were identified as potential driver or passenger mutations using the BWA/GATK pipeline. Results: An average of 33.3 mutations/tumor was concordant (shared), with common drivers identified (APC, KRAS, TP53). An average of 2.3 mutations/tumor was discordant (unshared) in the paired primary and metastatic sites. Thus, the overall concordance rate for mutations was 93.5%; however, nearly all (17/18 (94.4%)) paired tumors showed at least one mutational discordance: TTN, the largest gene (5 discordant pairs); ADAMTS20, APC, MACF1, RASA1, TP53, and WNT2 (2 discordant pairs); SMAD2, SMAD3, SMAD4, FBXW7, and ∼66 others (1 discordant pair). Conclusions: Primary and metastatic tumors displayed little variance overall supporting clonality; however, in ∼50% of cases, co-evolution produced incremental, potential driver mutations in both. These results suggest analysis of the primary lesion alone may be insufficient to precisely tailor therapy. Citation Format: Timothy J. Yeatman, Jamie Teer, Danielle Grenawalt, Richard Kim, Michael J. Schell. Co-evolution of primary and metastatic colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-188. doi:10.1158/1538-7445.AM2014-LB-188
Rwanda: physician complicity and rebuilding the medical community
Authors: Paul Geltman
Journal: The Lancet (1997)

Three years after the Rwandan genocide, physicians around the world should pause and learn from the Rwandan medical community's failure to act ethically and with respect for basic human rights. Some physicians in Rwanda resisted the wave of killing and refused to execute or turn over patients who were targeted by extremists, but most of these doctors were murdered in the genocide.1Hall P, Carney A. Rwanda 1994: a report of the genocide. Dundee: PHR (UK), 1994.Google Scholar However, notable physicians played key roles in planning the genocide (President Theodore Sindikubwabo, a paediatrician, and Dr Casimir Bizimungu, the Minister of Health), and many others passively cooperated with local acts of genocide, as well as in the identification, torture, and murder of individuals, particularly patients in hospitals.1Hall P, Carney A. Rwanda 1994: a report of the genocide. Dundee: PHR (UK), 1994.Google Scholar In the wake of the genocide, the country's medical infrastructure was completely destroyed. For example, a report by Physicians for Human Rights (USA) on the impact of the genocide on children, noted that fewer than ten trained paediatricians remained in the country.2Geltman P Stover E Letter from Kigali: genocide and the plight of children in Rwanda.JAMA. 1997; 277: 289-294Crossref PubMed Scopus (19) Google Scholar Before 1994, Rwanda had no organised medical society to oversee professional conduct and ethics. Rwandan physicians are now working to create such a professional infrastructure. A Rwandan medical society will help rebuild the compromised medical system, define ethical codes of conduct, and regulate the profession. This process is vital if the medical profession is to gain the confidence of survivors of the genocide. The international medical community should support these efforts and call for the establishment of a permanent international tribunal, whose mandate will include investigation and punishment of physician complicity in human rights abuses.
A Novel Missense Mutation of Wilms’ Tumor 1 Causes Autosomal Dominant FSGS
Authors: Gentzon Hall, Rasheed A. Gbadegesin, Peter Lavin, Guanghong Wu, Yangfan Liu, Edwin C. Oh, Liming Wang, Robert F. Spurney, Jason Eckel, Thomas Lindsey, Alison Homstad, Andrew F. Malone, Paul J. Phelan, Andrey Shaw, David N. Howell, Peter J. Conlon, Nicholas Katsanis, Michelle P. Winn
Journal: Journal of the American Society of Nephrology (2014)

FSGS is a clinical disorder characterized by focal scarring of the glomerular capillary tuft, podocyte injury, and nephrotic syndrome. Although idiopathic forms of FSGS predominate, recent insights into the molecular and genetic causes of FSGS have enhanced our understanding of disease pathogenesis. Here, we report a novel missense mutation of the transcriptional regulator Wilms' Tumor 1 (WT1) as the cause of nonsyndromic, autosomal dominant FSGS in two Northern European kindreds from the United States. We performed sequential genome-wide linkage analysis and whole-exome sequencing to evaluate participants from family DUK6524. Subsequently, whole-exome sequencing and direct sequencing were performed on proband DNA from family DUK6975. We identified multiple suggestive loci on chromosomes 6, 11, and 13 in family DUK6524 and identified a segregating missense mutation (R458Q) in WT1 isoform D as the cause of FSGS in this family. The identical mutation was found in family DUK6975. The R458Q mutation was not found in 1600 control chromosomes and was predicted as damaging by in silico simulation. We depleted wt1a in zebrafish embryos and observed glomerular injury and filtration defects, both of which were rescued with wild-type but not mutant human WT1D mRNA. Finally, we explored the subcellular mechanism of the mutation in vitro. WT1(R458Q) overexpression significantly downregulated nephrin and synaptopodin expression, promoted apoptosis in HEK293 cells and impaired focal contact formation in podocytes. Taken together, these data suggest that the WT1(R458Q) mutation alters the regulation of podocyte homeostasis and causes nonsyndromic FSGS.
Multi-institutional Profile of Adults Admitted to Pediatric Intensive Care Units
Authors: Jeffrey D. Edwards, Amy J. Houtrow, Eduard E. Vasilevskis, R. Adams Dudley, Megumi J. Okumura
Journal: JAMA Pediatrics (2013)

Growing numbers of persons with childhood-onset chronic illnesses are surviving to adulthood. Many use pediatric hospitals for their inpatient needs. To our knowledge, the prevalence and characteristics of adult pediatric intensive care unit patients have not been reported.To estimate the proportion of adults admitted to pediatric intensive care units (PICUs), characterize them, and compare them with older adolescents.One-year cross-sectional analysis.Pediatric intensive care units in the United States that participated in the Virtual Pediatric Intensive Care Unit Systems.Pediatric intensive care unit patients 15 years or older admitted in 2008.We compared adults with adolescents across clinical characteristics and outcomes. Mixed-effects logistic regression was used to estimate the independent association of age with PICU mortality.Seventy PICUs had 67 629 admissions; 1954 admissions (2.7%) were patients 19 years or older; and 9105 admissions (13.5%) were patients aged 15 to 18 years. The proportion of adults (≥19 years) varied considerably by PICU (range, 0%-9.2%). As age increased, the proportion of patients who had a complex chronic condition and planned or perioperative admissions increased; the proportion of trauma-related admissions decreased. Patients aged 21 to 29 years had a 2 times (95% CI, 1.3-3.2; P = .004) greater odds of PICU mortality compared with adolescent patients, after adjusting for Paediatric Index of Mortality score, sex, trauma, and having a complex chronic condition. Being 30 years or older was associated with a 3.5 (95% CI, 1.3-9.7; P = .01) greater odds of mortality.In this multi-institutional study, adults constituted a small but high-risk proportion of patients in some PICUs, suggesting that these PICUs should have plans and protocols specifically focused on this group.
Phenotyping Non-Allergic Rhinitis (NAR) Patients: Application of the Major Non-Allergic Rhinitis (NAR) Triggers under Controlled Conditions of an Environmental Exposure Chamber (EEC) reveal NAR Patient Heterogeneity
Authors: A. Salapatek, D. Wilson, D. Patel, J.A. Bernstein, P. D'Angelo, J.S. Lee
Journal: Journal of Allergy and Clinical Immunology (2010)
A Common Genetic Origin for Early Farmers from Mediterranean Cardial and Central European LBK Cultures
Authors: Iñigo Olalde, Hannes Schroeder, Marcela Sandoval-Velasco, Lasse Vinner, Irene Lobón, Oscar Ramirez, Sergi Civit, Pablo García Borja, Domingo C. Salazar-García, Sahra Talamo, Josep María Fullola, Francesc Xavier Oms, Mireia Pedro, Pablo Martínez, Montserrat Sanz, Joan Daura, João Zilhão, Tomàs Marquès-Bonet, M. Thomas P. Gilbert, Carles Lalueza-Fox
Journal: Molecular Biology and Evolution (2015)

The spread of farming out of the Balkans and into the rest of Europe followed two distinct routes: An initial expansion represented by the Impressa and Cardial traditions, which followed the Northern Mediterranean coastline; and another expansion represented by the LBK (Linearbandkeramik) tradition, which followed the Danube River into Central Europe. Although genomic data now exist from samples representing the second migration, such data have yet to be successfully generated from the initial Mediterranean migration. To address this, we generated the complete genome of a 7,400-year-old Cardial individual (CB13) from Cova Bonica in Vallirana (Barcelona), as well as partial nuclear data from five others excavated from different sites in Spain and Portugal. CB13 clusters with all previously sequenced early European farmers and modern-day Sardinians. Furthermore, our analyses suggest that both Cardial and LBK peoples derived from a common ancient population located in or around the Balkan Peninsula. The Iberian Cardial genome also carries a discernible hunter-gatherer genetic signature that likely was not acquired by admixture with local Iberian foragers. Our results indicate that retrieving ancient genomes from similarly warm Mediterranean environments such as the Near East is technically feasible.
Lifetime Cancer Risks in Individuals with Germline <i>PTEN</i> Mutations
Authors: Min-Han Tan, Jessica L. Mester, Joanne Ngeow, Lisa A. Rybicki, Mohammed S. Orloff, Charis Eng
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Age-adjusted cancer incidence and age-related penetrance studies have helped guide cancer risk assessment and management. PTEN hamartoma tumor syndrome (PHTS) is a term encompassing subsets of several clinical syndromes with germline mutations in the PTEN tumor suppressor gene. We conducted the first prospective study to clarify corresponding cancer risks to shed biologic insights on human germline PTEN mutations, and to better inform current surveillance recommendations on the basis of expert opinion. Experimental Design: A series of 3,399 individuals meeting relaxed International Cowden Consortium PHTS criteria were prospectively recruited; 368 individuals were found to have deleterious germline PTEN mutations. Age-adjusted standardized incidence ratio (SIR) calculations and genotype–phenotype analyses were carried out. Results: Elevated SIRs were found for carcinomas of the breast [25.4, 95% confidence interval (CI), 19.8–32.0], thyroid (51.1, 38.1–67.1), endometrium (42.9, 28.1–62.8), colorectum (10.3, 5.6–17.4), kidney (30.6, 17.8–49.4), and melanoma (8.5, 4.1–15.6). Estimated lifetime risks were, respectively, 85.2% (95% CI, 71.4%–99.1%), 35.2% (19.7%–50.7%), 28.2% (17.1%–39.3%), 9.0% (3.8%–14.1%), 33.6% (10.4%–56.9%), and 6% (1.6%-9.4%). Promoter mutations were associated with breast cancer, whereas colorectal cancer was associated with nonsense mutations. Conclusion: Lifetime risks for a variety of cancers, now extending to colorectal cancer, kidney cancer, and melanoma, are increased in patients with PTEN mutations. The genotype–phenotype associations here may provide new insights on PTEN structure and function. We propose a comprehensive approach to surveillance of patients with PTEN mutations. Clin Cancer Res; 18(2); 400–7. ©2012 AACR.
Effects of large doses of anabolic steroids.
Authors: R. A. Harkness, B. H. Kilshaw, B. M. Hobson
Journal: British Journal of Sports Medicine (1975)

The effects of large doses of anabolic steroids have been difficult to study as these have generally been used therapeutically in doses which are less than those needed for replacement of physiological androgen production.About 15 mg of methandrostenolone a day is required for androgen substitution (Liddle & Burke, 1960) where- as the therapeutic dose is generally 5 mg a day and does not have large observable effects, especially on the self- regulating system of androgen production itself.Al- though it has been alleged that some athletes take large amounts of anabolic steroids, this has been under- standably difficult to study, (Wade, 1973).Large doses of oxymetholone have been used in aplastic anaemia; however, this occurs mainly in childhood, therefore effects on the reproductive system are not detectable (Allen et al., 1968).Marked effects on the testes and accessory sex organs are to be expected in man because anabolic steroids were developed from their preferential effects on the rat 'levator ani' muscle which is part of the male reproductive system in that animal (Hayes, 1965).In the rat,
Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function
Authors: Tanya Ponomaryov, Amnon Peled, Isabelle Petit, Russell S. Taichman, Liliana Habler, Judith Sandbank, Fernando Arenzana-Seisdedos, Aude Magerus, Antonio Caruz, Nobutaka Fujii, Arnon Nagler, Meir Lahav, Martin Szyper-Kravitz, Dov Zipori, Tsvee Lapidot
Journal: Journal of Clinical Investigation (2000)

The chemokine stromal-derived factor-1 (SDF-1) controls many aspects of stem cell function. Details of its regulation and sites of production are currently unknown. We report that in the bone marrow, SDF-1 is produced mainly by immature osteoblasts and endothelial cells. Conditioning with DNA-damaging agents (ionizing irradiation, cyclophosphamide, and 5-fluorouracil) caused an increase in SDF-1 expression and in CXCR4-dependent homing and repopulation by human stem cells transplanted into NOD/SCID mice. Our findings suggest that immature osteoblasts and endothelial cells control stem cell homing, retention, and repopulation by secreting SDF-1, which also participates in host defense responses to DNA damage.
Transcript Length Mediates Developmental Timing of Gene Expression Across Drosophila
Authors: Carlo G. Artieri, Hunter B. Fraser
Journal: Molecular Biology and Evolution (2014)

The time required to transcribe genes with long primary transcripts may limit their ability to be expressed in cells with short mitotic cycles, a phenomenon termed intron delay. As such short cycles are a hallmark of the earliest stages of insect development, we tested the impact of intron delay on the Drosophila developmental transcriptome. We find that long zygotically expressed genes show substantial delay in expression relative to their shorter counterparts, which is not observed for maternally deposited transcripts. Patterns of RNA-seq coverage along transcripts show that this delay is consistent with their inability to completely transcribe long transcripts, but not with transcriptional initiation-based regulatory control. We further show that highly expressed zygotic genes maintain compact transcribed regions across the Drosophila phylogeny, allowing conservation of embryonic expression patterns. We propose that the physical constraints of intron delay affect patterns of expression and the evolution of gene structure of a substantial portion of the Drosophila transcriptome.