tbuckley/cabot-search huggingface dataset:
HLA-B*5701 Screening for Hypersensitivity to Abacavir
Authors: Simon Mallal, Elizabeth Phillips, Giampiero Carosi, Jean-Michel Molina, Cassy Workman, Janez Tomažič, Eva Jägel-Guedes, Sorin Rugina, Oleg Kozyrev, Juan Flores Cid, Phillip Hay, David Nolan, Sara Hughes, Arlene Hughes, Susanna Ryan, Nicholas Fitch, Daren Thorborn, Alastair Benbow
Journal: New England Journal of Medicine (2008)

Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele. This study was designed to establish the effectiveness of prospective HLA-B*5701 screening to prevent the hypersensitivity reaction to abacavir.This double-blind, prospective, randomized study involved 1956 patients from 19 countries, who were infected with human immunodeficiency virus type 1 and who had not previously received abacavir. We randomly assigned patients to undergo prospective HLA-B*5701 screening, with exclusion of HLA-B*5701-positive patients from abacavir treatment (prospective-screening group), or to undergo a standard-of-care approach of abacavir use without prospective HLA-B*5701 screening (control group). All patients who started abacavir were observed for 6 weeks. To immunologically confirm, and enhance the specificity of, the clinical diagnosis of hypersensitivity reaction to abacavir, we performed epicutaneous patch testing with the use of abacavir.The prevalence of HLA-B*5701 was 5.6% (109 of 1956 patients). Of the patients receiving abacavir, 72% were men, 84% were white, and 18% had not previously received antiretroviral therapy. Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients, with a significantly lower incidence in the prospective-screening group (3.4%) than in the control group (7.8%) (P<0.001).HLA-B*5701 screening reduced the risk of hypersensitivity reaction to abacavir. In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B*5701 allele and are at low risk for hypersensitivity reaction to abacavir. Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug. (ClinicalTrials.gov number, NCT00340080.)
Multicentre phase II study of oxaliplatin as a single-agent in cisplatin/carboplatin ± taxane-pretreated ovarian cancer patients
Authors: V. Dieras, P. Bougnoux, T. Petit, P. Chollet, P. Beuzeboc, C. Borel, F. Husseini, A. Goupil, P. Kerbrat, J.L. Misset, M.A. Bensmaïne, I. Tabah-Fisch, P. Pouillart
Journal: Annals of Oncology (2002)
Evolution of the Insect Yellow Gene Family
Authors: L. C. Ferguson, J. Green, A. Surridge, C. D. Jiggins
Journal: Molecular Biology and Evolution (2010)

The yellow gene family is intriguing for a number of reasons. To date, yellow-like genes have only been identified in insect species and a number of bacteria. The function of the yellows is largely unknown, although a few have been associated with melanization and behavior in Drosophila, and a unique clade of genes from Apis mellifera may be involved in caste specification. Here, we show that yellow-like sequences are present in bacteria, insects, and fungi but absent from other eukaryotes apart from isolated putative sequences in Amphioxus, the Salmon Louse, and Naegleria. The yellow-like family forms a discrete gene class characterized by the presence of a major royal jelly protein domain, but eukaryote yellow-like proteins are not monophyletic. The unusual phylogenetic distribution of yellow-like sequences suggests either multiple horizontal transfer from bacteria into eukaryotes or extensive gene loss in eukaryote lineages. Comparative analysis of yellow family synteny and gene order demonstrates that a highly conserved block of three to five genes has been maintained throughout insect diversification despite extensive genome rearrangements. We show strong purifying selection on seven yellow genes over approximately 100 My separating the silkmoth and Heliconius butterflies and an association between spatial regulation of gene expression and distribution of melanic pigment in the developing butterfly wing. A single ancestral yellow-like gene has therefore undergone multiple rounds of duplication within the insects accompanied by functional constraint on both genomic location and protein evolution.
Prevention of falls through podiatry care
Authors: W. Vernon
Journal: BMJ (2011)

Consider foot pain, footwear, and orthoses



Jose Oto/SPL

In the linked randomised controlled trial (doi:10.1136/bmj.d3411), Spink and colleagues report a parallel group randomised controlled trial with 12 months of follow-up in 305 older people. The trial assessed the effectiveness of a multifaceted podiatry intervention for preventing falls.1 The intervention included the use of foot orthoses, footwear advice supported by a voucher scheme, a foot and ankle exercise programme, falls prevention education, and routine podiatry care. The intervention significantly reduced the incidence of falls compared with routine care (incidence rate ratio 0.64, 95% confidence interval 0.45 to 0.91). No significant differences were seen between the groups in the proportion of fallers or multiple fallers⇑.

Because the intervention reduced the incidence of falls in people with foot pain and should be inexpensive and simple to implement, the authors concluded that the programme could be used in routine podiatry practice …
ASSOCIATION OF "NATURAL" ANTIBODIES TO GRAM-NEGATIVE BACTERIA WITH THE γ1-MACROGLOBULINS
Authors: J. Gabriel Michael, Fred S. Rosen
Journal: The Journal of Experimental Medicine (1963)

"Natural" antibodies to representative species of Enterobacteriaceae were found to be principally associated with the gamma(1)-macroglobulin prepared from Cohn fraction III-I of pooled human plasma. The amount of antibodies present was estimated by measuring the bactericidal, hemagglutinating, mouse-protective, and opsonophagocytic activities of this fraction. Comparison with the antibody activity of gamma(2)-globulin of Cohn fraction II showed that up to 100 times more antibody activity on a weight basis was present in the macroglobulin fraction. These findings suggest that differences between natural and immune antibody result from the physicochemical properties of 2 different classes of immune globulin.
Prognostic Significance and Tumor Biology of Regional Lymph Node Disease in Patients With Rhabdomyosarcoma: A Report From the Children's Oncology Group
Authors: David A. Rodeberg, Norbert Garcia-Henriquez, Elizabeth R. Lyden, Elai Davicioni, David M. Parham, Stephen X. Skapek, Andrea A. Hayes-Jordan, Sarah S. Donaldson, Kenneth L. Brown, Timothy J. Triche, William H. Meyer, Douglas S. Hawkins
Journal: Journal of Clinical Oncology (2011)

Regional lymph node disease (RLND) is a component of the risk-based treatment stratification in rhabdomyosarcoma (RMS). The purpose of this study was to determine the contribution of RLND to prognosis for patients with RMS.Patient characteristics and survival outcomes for patients enrolled onto Intergroup Rhabdomyosarcoma Study IV (N = 898, 1991 to 1997) were evaluated among the following three patient groups: nonmetastatic patients with clinical or pathologic negative nodes (N0, 696 patients); patients with clinical or pathologic positive nodes (N1, 125 patients); and patients with a single site of metastatic disease (77 patients).Outcomes for patients with nonmetastatic alveolar N0 RMS were significantly better than for patients with N1 RMS (5-year failure-free survival [FFS], 73% v 43%, respectively; 5-year overall survival [OS], 80% v 46%, respectively; P < .001). Patients with a single site of alveolar metastasis had even worse FFS and OS (23% FFS and OS, P = .01) when compared with patients with N1 RMS; however, the differences was not as large as the differences between patients with N0 RMS and N1 RMS. For embryonal RMS, there was no statistically significant difference in FFS or OS (P = .41 and P = .77, respectively) for patients with N1 versus N0 RMS. Gene array analysis of primary tumor specimens identified that genes associated with the immune system and antigen presentation were significantly increased in N1 versus N0 alveolar RMS.RLND alters prognosis for alveolar but not embryonal RMS. For patients with N1 disease and alveolar histology, outcomes were more similar to distant metastatic disease rather than local disease. Current data suggest that more aggressive therapy for patients with alveolar N1 RMS may be warranted.
The Application of the Diabetes Prevention Trial–Type 1 Risk Score for Identifying a Preclinical State of Type 1 Diabetes
Authors: Jay M. Sosenko, Jay S. Skyler, Jeffrey Mahon, Jeffrey P. Krischer, Craig A. Beam, David C. Boulware, Carla J. Greenbaum, Lisa E. Rafkin, Catherine Cowie, David Cuthbertson, Jerry P. Palmer
Journal: Diabetes Care (2012)

We assessed the utility of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) for identifying individuals who are highly likely to progress to type 1 diabetes (T1D) within 2 years.The DPTRS was previously developed from Diabetes Prevention Trial-Type 1 (DPT-1) data and was subsequently validated in the TrialNet Natural History Study (TNNHS). DPTRS components included C-peptide and glucose indexes from oral glucose tolerance testing, along with age and BMI. The cumulative incidence of T1D was determined after DPTRS thresholds were first exceeded and after the first occurrences of glucose abnormalities.The 2-year risks after the 9.00 DPTRS threshold was exceeded were 0.88 and 0.77 in DPT-1 (n = 90) and the TNNHS (n = 69), respectively. In DPT-1, the 2-year risks were much lower after dysglycemia first occurred (0.37; n = 306) and after a 2-h glucose value between 190 and 199 mg/dL was first reached (0.64; n = 59). Among those who developed T1D in DPT-1, the 9.00 threshold was exceeded 0.81 ± 0.53 years prior to the conventional diagnosis. Postchallenge C-peptide levels were substantially higher (P = 0.001 for 30 min; P < 0.001 for other time points) when the 9.00 threshold was first exceeded compared with the levels at diagnosis.A DPTRS threshold of 9.00 identifies individuals who are very highly likely to progress to the conventional diagnosis of T1D within 2 years and, thus, are essentially in a preclinical diabetic state. The 9.00 threshold is exceeded well before diagnosis, when stimulated C-peptide levels are substantially higher.
Insulin Sensitivity and Insulin Secretion Determined by Homeostasis Model Assessment and Risk of Diabetes in a Multiethnic Cohort of Women
Authors: Yiqing Song, JoAnn E. Manson, Lesley Tinker, Barbara V. Howard, Lewis H. Kuller, Lauren Nathan, Nader Rifai, Simin Liu
Journal: Diabetes Care (2007)

OBJECTIVE— The homeostasis model assessment (HOMA), based on plasma levels of fasting glucose and insulin, has been widely validated and applied for quantifying insulin resistance and β-cell function. However, prospective data regarding its relation to diabetes risk in ethnically diverse populations are limited. RESEARCH DESIGN AND METHODS— Among 82,069 women who were aged 50–79 years, free of cardiovascular disease or diabetes, and participating in the Women's Health Initiative Observational Study, we conducted a nested case-control study to prospectively examine the relations of HOMA of insulin resistance (HOMA-IR) and β-cell function (HOMA-B) with diabetes risk. During a median follow-up period of 5.9 years, 1,584 diabetic patients were matched with 2,198 control subjects by age, ethnicity, clinical center, time of blood draw, and follow-up time. RESULTS— Baseline levels of fasting glucose, insulin, and HOMA-IR were each significantly higher among case compared with control subjects, while HOMA-B was lower (all P values &amp;lt;0.0001). After adjustment for matching factors and diabetes risk factors, all four markers were significantly associated with diabetes risk; the estimated relative risks per SD increment were 3.54 (95% CI 3.02–4.13) for fasting glucose, 2.25 (1.99–2.54) for fasting insulin, 3.40 (2.95–3.92) for HOMA-IR, and 0.57(0.51–0.63) for HOMA-B. While no statistically significant multiplicative interactions were observed between these markers and ethnicity, the associations of both HOMA-IR and HOMA-B with diabetes risk remained significant and robust in each ethnic group, including whites, blacks, Hispanics, and Asians/Pacific Islanders. When evaluated jointly, the relations of HOMA-IR and HOMA-B with diabetes risk appeared to be independent and additive. HOMA-IR was more strongly associated with an increased risk than were other markers after we excluded those with fasting glucose ≥126 mg/dl at baseline. CONCLUSIONS— High HOMA-IR and low HOMA-B were independently and consistently associated with an increased diabetes risk in a multiethnic cohort of U.S. postmenopausal women. These data suggest the value of HOMA indexes for diabetes risk in epidemiologic studies.
Pulmonary hypertension in smoking mice over-expressing protease-activated receptor-2
Authors: G. De Cunto, S. Cardini, G. Cirino, P. Geppetti, G. Lungarella, M. Lucattelli
Journal: European Respiratory Journal (2010)

The mechanism(s) involved in the development of pulmonary hypertension (PH) in COPD is still the object of investigation. Cigarette smoke (CS) may lead to remodelling of intrapulmonary vessels and dynamic changes in vascular function, at least in some smokers. A role for proteases in PH has been recently put forward. We investigated, in smoking mice, the role of protease-activated receptor (PAR)-2 in the pathogenesis of PH associated with emphysema. We demonstrated that CS exposure can modulate PAR-2 expression in mouse lung. Acute CS exposure induces in wildtype (WT) and in transgenic mice over-expressing PAR-2 (FVB(PAR-2-TgN)) a similar degree of neutrophil influx in bronchoalveolar lavage fluids. After chronic CS exposure WT and FVB(PAR-2-TgN) mice show emphysema, but only transgenic mice develop muscularisation of small intrapulmonary vessels that precedes the development of PH (~45% increase) and right ventricular hypertrophy. Smoking in FVB(PAR-2-TgN) mice results in an imbalance between vasoconstrictors (especially endothelin-1) and vasodilators (i.e. vascular endothelial growth factor, endothelial nitric oxide synthase and inducible nitric oxide synthase) and enhanced production of growth factors involved both in fibroblast-smooth muscle cell transaction (i.e. platelet-derived growth factor (PDGF) and transforming growth factor β) and vascular cell proliferation (PDGF). PAR-2 signalling can influence the production and release of many factors, which may play a role in the development of PH in smokers.
Use of Insulin Pump Therapy in the Pediatric Age-Group
Authors: Moshe Phillip, Tadej Battelino, Henry Rodriguez, Thomas Danne, Francine Kaufman
Journal: Diabetes Care (2007)

Young patients with diabetes, their families, and their diabetes care providers continue to be faced with the challenge of striving to maintain blood glucose levels in the near-normal range. High blood glucose levels with elevated A1C levels are associated with long-term microvascular and macrovascular complications. Recurrent episodes of hypoglycemia, especially at young ages, may cause short- and long-term adverse effects on cognitive function and lead to hypoglycemia unawareness and may be associated with significant emotional morbidity for the child and parents. Fear of hypoglycemia, especially during the night, may compromise quality of life (QOL) for the family and jeopardize efforts to achieve optimal metabolic control.

Over the past decade, continuous subcutaneous insulin infusion (CSII) has gained increasing popularity among patients with diabetes. CSII is the most physiologic method of insulin delivery currently available. It is able to closely simulate the normal pattern of insulin secretion, namely continuous 24-h adjustable “basal” delivery of insulin upon which are superimposed prandial “boluses.” In addition, CSII offers the possibility of more flexibility and more precise insulin delivery than multiple daily injection (MDI). However, there is still debate among diabetes care practitioners around the world as to whether CSII has advantages over MDI in terms of reduction in A1C levels, occurrence of severe hypoglycemic events, episodes of diabetic ketoacidosis (DKA), and frequency of hospitalizations in young patients. Furthermore, no clear criteria have been established to help the physician choose the “appropriate” patient for CSII therapy.

To address these issues, the European Society for Pediatric Endocrinology (ESPE), the Lawson Wilkins Pediatric Endocrine Society (LWPES), and the International Society for Pediatric and Adolescent Diabetes (ISPAD) convened a panel of expert physicians for a consensus conference endorsed by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).

For each major topic area, …
The Ethics of Organ Donation by Living Donors
Authors: Robert D Truog
Journal: New England Journal of Medicine (2005)

Interview with Robert Truog and Jeremiah Lowney on the ethics of organ donation by living donors. (08:42)Download Most organs for transplantation come from cadavers, but as these have failed to meet the growing need for organs, attention has turned to organs from living donors. Organ donation by living donors presents a unique ethical dilemma, in that physicians must risk the life of a healthy person to save or improve the life of a patient. Transplantation surgeons have therefore been cautious in tapping this source. As surgical techniques and outcomes have improved, however, this practice has slowly expanded. Today, according to the United Network for Organ Sharing (UNOS), almost half of all kidney donors in the United States . . .
Fibroblast-Derived Dermal Matrix Drives Development of Aggressive Cutaneous Squamous Cell Carcinoma in Patients with Recessive Dystrophic Epidermolysis Bullosa
Authors: Yi-Zhen Ng, Celine Pourreyron, Julio C. Salas-Alanis, Jasbani H.S. Dayal, Rodrigo Cepeda-Valdes, Wenfei Yan, Sheila Wright, Mei Chen, Jo-David Fine, Fiona J. Hogg, John A. McGrath, Dedee F. Murrell, Irene M. Leigh, E. Birgit Lane, Andrew P. South
Journal: Cancer Research (2012)

Patients with the genetic skin blistering disease recessive dystrophic epidermolysis bullosa (RDEB) develop aggressive cutaneous squamous cell carcinoma (cSCC). Metastasis leading to mortality is greater in RDEB than in other patient groups with cSCC. Here we investigate the dermal component in RDEB using mRNA expression profiling to compare cultured fibroblasts isolated from individuals without cSCC and directly from tumor matrix in RDEB and non-RDEB samples. Although gene expression of RDEB normal skin fibroblasts resembled that of cancer-associated fibroblasts, RDEB cancer-associated fibroblasts exhibited a distinct and divergent gene expression profile, with a large proportion of the differentially expressed genes involved in matrix and cell adhesion. RDEB cancer-associated fibroblasts conferred increased adhesion and invasion to tumor and nontumor keratinocytes. Reduction of COL7A1, the defective gene in RDEB, in normal dermal fibroblasts led to increased type XII collagen, thrombospondin-1, and Wnt-5A, while reexpression of wild type COL7A1 in RDEB fibroblasts decreased type XII collagen, thrombospondin-1, and Wnt-5A expression, reduced tumor cell invasion in organotypic culture, and restricted tumor growth in vivo. Overall, our findings show that matrix composition in patients with RDEB is a permissive environment for tumor development, and type VII collagen directly regulates the composition of matrix proteins secreted by dermal and cancer-associated fibroblasts.
The Future of the Profession and of the Association
Authors: S. W. Mac Ilwaine
Journal: BMJ (1900)

¢tion to -the time that elapses between the earliest manifeeta- Cion of the disease, and the time the patient is brought under appropriate treatment.In this connection it is impossible to avoid reference to the unsatisfactory state of the law as it affects medical practi- tioners and the signing of lunacy certificates.In theory, in their action in such cases-in bond fide-they are safeguarded -against loss or injury resulting from legal proceedings.In practice it is not so.The present state of affairs is very largely rcsponsible for the difficulty that exists-in bringing many cases of insanity under treatment in the early stages of ,the disease.-.
Multifactorial Analysis of Differences Between Sporadic Breast Cancers and Cancers Involving BRCA1 and BRCA2 Mutations
Authors: S. R. Lakhani, J. Jacquemier, J. P. Sloane, B. A. Gusterson, T. J. Anderson, M. J. van de Vijver, L. M. Farid, D. Venter, A. Antoniou, A. Storfer-Isser, E. Smyth, C. M. Steel, N. Haites, R. J. Scott,, D. Goldgar, S. Neuhausen, P. A. Daly, W. Ormiston, R. McManus, S. Scherneck, B. A. J. Ponder, D. Ford, J. Peto, D. Stoppa-Lyonnet, Y.-J. Bignon, J. P. Struewing, N. K. Spurr, D. T. Bishop, J. G. M. Klijn, P. Devilee, C. J. Cornelisse, C. Lasset, G. Lenoir, R. B. Barkardottir, V. Egilsson, U. Hamann, J. Chang-Claude, H. Sobol, B. Weber, M. R. Stratton, D. F. Easton
Journal: JNCI Journal of the National Cancer Institute (1998)

Background : We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. Methods : Specimens of tumor tissue (5-µm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. Results: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. Conclusions : Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients. [J Natl Cancer Inst 1998;90:1138–45]