tbuckley/cabot-search huggingface dataset:
Alpha-1-antitrypsin deficiency: optimal therapeutic regimen based on population pharmacokinetics
Authors: D Soy, C de la Roza, B Lara, C Esquinas, A Torres, M Miravitlles
Journal: Thorax (2006)

<b>Background:</b> Exogenous doses of 60 mg/kg α<sub>1</sub>-antitrypsin (AAT) every 7 days are recommended in patients with severe AAT deficiency. However, long term administration of weekly doses is not well accepted by patients. Using pharmacokinetic simulations, we evaluated whether steady state minimum concentrations of total AAT can be maintained above the threshold of 0.5 g/l with longer intervals between doses. <b>Methods:</b> Several sets of exogenous AAT versus time simulations were studied using a non-linear mixed effect approach with dosage regimens every 7, 14, 21, and 28 days. For each regimen the mean exogenous AAT trough concentrations and 5/95th percentiles were determined. The results obtained were applied to estimate the individual optimal dose at 7, 14, and 21 days in six patients using Bayesian analysis. <b>Results:</b> The simulations showed that a dose of 50 mg/kg AAT every 7 days was sufficient to obtain nadir concentrations. Doses of 120 and 100 mg/kg every 14 days were also adequate, but 180 mg/kg given every 21 days required total AAT monitoring to avoid underdosage. Longer intervals were inappropriate. Dosage individualisation confirmed that AAT infusions given every 14 days maintained the nadir level of 0.5 g/l without a significant dose increase compared with current practice. When the time span between doses was fixed at 21 days, a mean relative AAT dose enhancement of 91% and 13%, respectively, was required to achieve sustained total AAT concentrations above the target level for 100% and 85% of the interval between doses. <b>Conclusions:</b> It is feasible to extend the interval between doses of AAT to 14 or 21 days to achieve adequate trough total AAT concentrations. This study might be used as a starting point for clinical evaluation of the regimens described.
Validation of a Standardized Method for Enumerating Circulating Endothelial Cells and Progenitors: Flow Cytometry and Molecular and Ultrastructural Analyses
Authors: Patrizia Mancuso, Pierluigi Antoniotti, Jessica Quarna, Angelica Calleri, Cristina Rabascio, Carlo Tacchetti, Paola Braidotti, Hua-Kang Wu, Amado J. Zurita, Luca Saronni, John B. Cheng, David R. Shalinsky, John V. Heymach, Francesco Bertolini
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Antigenic overlap among circulating endothelial cells (CEC) and progenitors (CEP), platelets, and other blood cells led to the need to develop a reliable standardized method for CEC and CEP quantification. These cells are emerging as promising preclinical/clinical tools to define optimal biological doses of antiangiogenic therapies and to help stratify patients in clinical trials. Experimental Design: We report the experimental validation of a novel flow cytometry method that precisely dissects CEC/CEP from platelets and other cell populations and provides information about CEC/CEP viability. Results: Sorted DNA/Syto16+CD45−CD31+CD146+ CECs, investigated by electron microscopy, were found to be bona fide endothelial cells by the presence of Weibel-Palade bodies. More than 75% of the circulating mRNAs of the endothelial-specific gene, VE-cadherin, found in the blood were present in the sorted population. CECs were 140 ± 171/mL in healthy subjects (n = 37) and 951 ± 1,876/mL in cancer patients (n = 78; P &amp;lt; 0.0001). The fraction of apoptotic/necrotic CECs was 77 ± 14% in healthy subjects and 43 ± 23% in cancer patients (P &amp;lt; 0.0001). CEPs were 181 ± 167/mL in healthy donors and 429 ± 507/mL in patients (P = 0.00019). Coefficients of variation were 4 ± 4% (intrareader), 17 ± 4% (interreader), and 17 ± 7% (variability over 0-72 h), respectively. Parallel samples were frozen by a standardized protocol. After thawing, coefficients of variation were 12 ± 8% (intrareader), 16 ± 10% (interreader), and 26 ± 16% (variability over 0-14 days of frozen storage), respectively. Conclusions: This procedure enumerates a truly endothelial cell population with limited intrareader and interreader variability. It appears possible to freeze samples for large-scale CEC enumeration during clinical trials. This approach could be enlarged to investigate other angiogenic cell populations as well.
Phase II Study of Capecitabine in Patients With Fluorouracil-Resistant Metastatic Colorectal Carcinoma
Authors: Paulo M. Hoff, Richard Pazdur, Yvonne Lassere, Susan Carter, Dvorit Samid, Diane Polito, James L. Abbruzzese
Journal: Journal of Clinical Oncology (2004)

Capecitabine is an oral fluoropyrimidine converted to fluourouracil (FU) preferentially in tumor tissue. It has proven clinical activity against colorectal cancer when used as first-line therapy. The objectives of this study were to assess the safety and efficacy of capecitabine in patients with metastatic colorectal carcinoma who progressed despite previous FU therapy.According to the group sequential analysis design of this study, accrual would stop if no responses were observed in the first 20 patients treated. If one or more objective responses were confirmed, the trial would be expanded. Patients received capecitabine 1,250 mg/m(2) twice a day for 14 days, every 3 weeks. Tumor lesions were assessed every 6 weeks, and patients were followed for survival every 3 months after completing treatment.Twenty-three patients were enrolled onto the study; 22 fulfilled all the eligibility criteria. No objective responses were observed among the 22 eligible patients; 11 patients (50%) had stable disease for a median duration of 141 days (range, 88-289 days). The Kaplan-Meier estimate of median time to disease progression was 64 days (95% CI, 41 to 134 days). The median survival time estimate was 389 days (95% CI, 267 to 637 days). The most frequent treatment-related adverse events were hand-foot syndrome, diarrhea, and nausea or vomiting. There were no grade 4 toxicities and no treatment-related deaths.Single-agent capecitabine in patients with metastatic colorectal carcinoma refractory to FU showed no objective responses and clinical benefit that was, at best, modest. The use of capecitabine in combination with other treatments in this patient population is under investigation.
Efficacy of Fulvestrant According to Duration and Type of Adjuvant Endocrine Treatment, in Metastatic Breast Cancer Patients Enrolled in the Confirm Trial
Authors: L. Malorni, C. Biagioni, J. Thirlwell, C. Guarducci, M. Bonechi, Y. Rukazenkov, G. Jerusalem, M. Martin, A. di Leo, I. Migliaccio
Journal: Annals of Oncology (2014)
Hereditary coproporphyria presenting with photosensitivity induced by the contraceptive pill
Authors: D.T. ROBERTS, M.J. BRODIE, M.R. MOORE, G.G. THOMPSON, A. GOLDBERG, R.N.M. MacSWEEN
Journal: British Journal of Dermatology (1977)

A 26‐year‐old woman developed photosensitivity and jaundice after starting on an oral contraceptive agent. She was found to have hereditary coproporphyria. Histological examination of two liver biopsies taken during and after the acute attack did not reveal any changes thought to be due to hereditary coproporphyria. Screening of the patient's family revealed a further six latent cases.
Drug-susceptibility testing in tuberculosis: methods and reliability of results
Authors: S J Kim
Journal: European Respiratory Journal (2005)

The demand for reliable drug-susceptibility testing (DST) increases with the expansion of antituberculosis drug-resistance surveillance, and with the need for an appropriate treatment of multidrug-resistant tuberculosis, whose incidence gradually increases in many parts of the world. However, the reliability of DST results obtained through widely used methods does not meet acceptable levels, except for DST to isoniazid and rifampicin. In general, susceptibility results are highly predictable, while resistance results show low predictive values when the resistance prevalence is <10%. Poor reliability stems from a weak correlation with clinical response and a low reproducibility due to the poor standardisation of the complex and fragile test procedures. Therefore, in vitro criteria of resistance for susceptibility testing should be carefully determined with representative clinical samples of Mycobacterium tuberculosis isolated from patients never treated with any antituberculosis drug, and from patients having failed treatment with a regimen containing the tested drug; DST should then be carefully standardised to obtain reproducible results. The critical concentration of some drugs is close to the minimal inhibitory concentration for wild susceptible strains and, thus, drug-susceptibility testing is prone to yield poorly reproducible results. These issues call for physicians' attention when using the results from drug-susceptibility testing for case management.
Threefold increased risk of infertility: a meta-analysis of infertility after ileal pouch anal anastomosis in ulcerative colitis
Authors: A Waljee, J Waljee, A M Morris, P D R Higgins
Journal: Gut (2006)

Increased infertility in women has been reported after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis but reported infertility rates vary substantially.(1) To perform a systematic review and meta-analysis of the relative risk of infertility post-IPAA compared with medical management; (2) to estimate the rate of infertility post-IPAA; and (3) to identify modifiable risk factors which contribute to infertility.Medline, EMBASE, Current Contents, meeting abstracts, and bibliographies were searched independently by two investigators. The titles and abstracts of 189 potentially relevant studies were reviewed; eight met the criteria and all data were extracted independently. Consensus was achieved on each data point, and fixed effects meta-analyses, a funnel plot, and sensitivity analyses were performed.The initial meta-analysis of eight studies had significant heterogeneity (p = 0.004) due to one study with very high preoperative infertility (38%). When this study was omitted, the relative risk of infertility after IPAA was 3.17 (2.41-4.18), with non-significant heterogeneity. The weighted average infertility rate in medically treated ulcerative colitis was 15% for all seven studies, and the weighted average infertility rate was 48% after IPAA (50% if all eight studies are included). We were unable to identify any procedural factors that consistently affected the risk of infertility.IPAA increases the risk of infertility in women with ulcerative colitis by approximately threefold. Infertility, defined as achieving pregnancy in 12 months of attempting conception, increased from 15% to 48% in women post-IPAA for ulcerative colitis. This provides a basis for counselling patients considering colectomy with IPAA. Further studies of modifiable risk factors are needed.
Achalasia following Gastro-Oesophageal Reflux
Authors: H L Smart, J F Mayberry, M Atkinson
Journal: Journal of the Royal Society of Medicine (1986)

Five patients initially presenting with symptomatic gastro-oesophageal reflux, proven by radiology or pH monitoring, subsequently developed achalasia, confirmed by radiology and manometry, after an interval of 2–10 years. During this period dysphagia, present as a mild and intermittent symptom accompanying the initial reflux in 3 of the 5, became severe and resulted in oesophageal stasis of food in all. Three of the 5 had a demonstrable hiatal hernia. In none was reflux a troublesome symptom after Rider-Moeller dilatation or cardiomyotomy undertaken for the achalasia. Gastro-oesophageal reflux does not protect against the subsequent development of achalasia. It is suggested that the autonomic damage eventually leading to achalasia may in its initial phases cause gastro-oesophageal reflux.
Cross-reactivity of cell-mediated immunity between interstitial (type I) and basement membrane (type IV) collagens.
Authors: A M Mackel, F DeLustro, E C LeRoy
Journal: The Journal of Experimental Medicine (1982)

In the present study, we demonstrate delayed-type hypersensitivity (DTH) to homologous type I collagen that cross-reacts with type IV collagen. Mice immunized with native or denatured type I collagens and challenged with these same antigens or native type IV collagen develop a peak DTH response on day 7. Challenge with denatured type IV collagen or collagenase-treated type IV collagen failed to elicit DTH in type I collagen-sensitized mice. Type I collagen-sensitized spleen cells adoptively transferred DTH to types IV and I collagen to normal recipients; T cell-depleted spleen cells failed to transfer immunity. Periodate-treated type IV collagen did not elicit DTH in mice sensitized to type I collagen; however, mice sensitized with type IV collagen displayed significant DTH when challenged with periodate-treated type IV collagen. Furthermore, treatment of type IV collagen with a mixed glycosidase or alpha-glucosidase before challenge eliminated the DTH response in type I collagen-sensitized mice; beta-galactosidase treatment of type IV collagen had no effect on this response. Mice sensitized with type IV collagen, however, displayed significant DTH when challenged with these glycosidase-treated antigens. Antibodies produced to types I and IV collagen by repeated immunizations were specific for the sensitizing antigen and did not react with other connective tissue antigens. These studies indicate that a CMI response to type I collagen recognizes similar antigenic determinants on the type IV collagen molecule. These cross-reacting determinants are dependent on conformation and contain carbohydrates, particularly glucose residues.
IL-6 Promoter Polymorphism −174 Is Associated with New-Onset Diabetes after Transplantation
Authors: Jamal Bamoulid, Ce[Combining Acute Accent]cile Courivaud, Marina Deschamps, Patricia Mercier, Christophe Ferrand, Alfred Penfornis, Pierre Tiberghien, Jean-Marc Chalopin, Philippe Saas, Didier Ducloux
Journal: Journal of the American Society of Nephrology (2006)

New-onset diabetes after transplantation (NODAT) is a serious complication of transplantation. This study tested whether IL-6 production capacity may influence the development of NODAT in two different groups of patients. The occurrence of NODAT was analyzed with respect to IL-6 gene promoter polymorphism at position -174 (G-->C) and other relevant risk factors retrospectively in 217 renal transplant recipients and prospectively in 132. A linear increase in both circulating IL-6 (P = 0.09) and C-reactive protein (an indicator of basal IL-6 secretion; P = 0.03) concentrations from the CC genotype to the GG genotype was observed. In the multivariate model, the CC genotype was associated with a decreased risk for NODAT compared with the GG genotype in the two cohorts. Homeostasis Model Assessment for Insulin Resistance also revealed lesser insulin sensitivity in the GG carriers than in the CC carriers (2.15 +/- 2 versus 1.32 +/- 1.03; P = 0.03). Subgroup analysis showed that the influence of IL-6 gene promoter polymorphism on the development of NODAT was restricted mostly to overweight patients. These results highly suggest that IL-6 production capacity influences the development of NODAT and that diabetes-inducing drug administration should be limited in overweight patients who carry the GG genotype.
Mutation Rate and the Cost of Complexity
Authors: Ralph Haygood
Journal: Molecular Biology and Evolution (2006)

Two recent theoretical studies of adaptation suggest that more complex organisms tend to adapt more slowly. Specifically, in Fisher's “geometric” model of a finite population where multiple traits are under optimizing selection, the average progress ensuing from a single mutation decreases as the number of traits increases—the “cost of complexity.” Here, I draw on molecular and histological data to assess the extent to which on a large phylogenetic scale, this predicted decrease in the rate of adaptation per mutation is mitigated by an increase in the number of mutations per generation as complexity increases. As an index of complexity for multicellular organisms, I use the number of visibly distinct types of cell in the body. Mutation rate is the product of mutational target size and population mutation rate per unit target. Despite much scatter, genome size appears to be positively correlated with complexity (as indexed by cell-type number), which along with other considerations suggests that mutational target size tends to increase with complexity. In contrast, effective population mutation rate per unit target appears to be negatively correlated with complexity. The net result is that mutation rate probably does tend to increase with complexity, although probably not fast enough to eliminate the cost of complexity.
<i>EGFR/KRAS/BRAF</i> Mutations in Primary Lung Adenocarcinomas and Corresponding Locoregional Lymph Node Metastases
Authors: Katharina Schmid, Natalie Oehl, Fritz Wrba, Robert Pirker, Christine Pirker, Martin Filipits
Journal: Clinical Cancer Research (2009)

The epidermal growth factor receptor (EGFR) and its downstream factors KRAS and BRAF are mutated with different frequencies in non-small cell lung cancer and mutations predict clinical response to EGFR inhibitors. The present study compared the mutational status of EGFR, KRAS, and BRAF in primary tumors with the one in corresponding lymph node metastases.Direct bidirectional sequencing of EGFR gene exons 18 to 21, KRAS gene codons 12/13 and 61 to 68, and BRAF exon 15 was done on 96 paired samples of primary lung adenocarcinomas and corresponding locoregional lymph node metastases. In addition, comparative genomic hybridization analyses in two pairs of corresponding primary and metastatic tumor samples with discordant EGFR mutation status were done.Mutations in EGFR, KRAS, and BRAF were observed in 7 (7%), 36 (38%), and 2 (2%) patients, respectively. Interestingly, KRAS mutations were observed in two patients with an EGFR mutation. Mutations in primary tumors and lymph node metastases were identical in 1 of 7 (14%) patients in case of EGFR and 11 of 36 (31%) patients in case of KRAS. One patient harbored different KRAS mutations in primary and corresponding metastatic tumors. Comparative genomic hybridization analysis revealed similar patterns of chromosomal changes, strongly supporting a common clonal origin of primary tumors and metastases.The possibility of differences in the mutational status of EGFR, KRAS, BRAF between primary tumors and corresponding lymph node metastases should be considered whenever these mutations are used for the selection of patients for EGFR-directed tyrosine kinase inhibitor therapy.
The Social Determinants of Health: Coming of Age
Authors: Paula Braveman, Susan Egerter, David R. Williams
Journal: Annual Review of Public Health (2011)

In the United States, awareness is increasing that medical care alone cannot adequately improve health overall or reduce health disparities without also addressing where and how people live. A critical mass of relevant knowledge has accumulated, documenting associations, exploring pathways and biological mechanisms, and providing a previously unavailable scientific foundation for appreciating the role of social factors in health. We review current knowledge about health effects of social (including economic) factors, knowledge gaps, and research priorities, focusing on upstream social determinants—including economic resources, education, and racial discrimination—that fundamentally shape the downstream determinants, such as behaviors, targeted by most interventions. Research priorities include measuring social factors better, monitoring social factors and health relative to policies, examining health effects of social factors across lifetimes and generations, incrementally elucidating pathways through knowledge linkage, testing multidimensional interventions, and addressing political will as a key barrier to translating knowledge into action.
Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH)
Authors: N. Inoue, T. Izui-Sarumaru, Y. Murakami, Y. Endo, J.-I. Nishimura, K. Kurokawa, M. Kuwayama, H. Shime, T. Machii, Y. Kanakura, G. Meyers, C. Wittwer, Z. Chen, W. Babcock, D. Frei-Lahr, C. J. Parker, T. Kinoshita
Journal: Blood (2006)
Functional Adult Myocardium in the Absence of Na <sup>+</sup> -Ca <sup>2+</sup> Exchange
Authors: Scott A. Henderson, Joshua I. Goldhaber, Jessica M. So, Tieyan Han, Christi Motter, An Ngo, Chana Chantawansri, Matthew R. Ritter, Martin Friedlander, Debora A. Nicoll, Joy S. Frank, Maria C. Jordan, Kenneth P. Roos, Robert S. Ross, Kenneth D. Philipson
Journal: Circulation Research (2004)

The excitation-contraction coupling cycle in cardiac muscle is initiated by an influx of Ca2+ through voltage-dependent Ca2+ channels. Ca2+ influx induces a release of Ca2+ from the sarcoplasmic reticulum and myocyte contraction. To maintain Ca2+ homeostasis, Ca2+ entry is balanced by efflux mediated by the sarcolemmal Na+-Ca2+ exchanger. In the absence of Na+-Ca2+ exchange, it would be expected that cardiac myocytes would overload with Ca2+. Using Cre/loxP technology, we generated mice with a cardiac-specific knockout of the Na+-Ca2+ exchanger, NCX1. The exchanger is completely ablated in 80% to 90% of the cardiomyocytes as determined by immunoblot, immunofluorescence, and exchange function. Surprisingly, the NCX1 knockout mice live to adulthood with only modestly reduced cardiac function as assessed by echocardiography. At 7.5 weeks of age, measures of contractility are decreased by 20% to 30%. We detect no adaptation of the myocardium to the absence of the Na+-Ca2+ exchanger as measured by both immunoblots and microarray analysis. Ca2+ transients of isolated myocytes from knockout mice display normal magnitudes and relaxation kinetics and normal responses to isoproterenol. Under voltage clamp conditions, the current through L-type Ca2+ channels is reduced by 50%, although the number of channels is unchanged. An abbreviated action potential may further reduce Ca2+ influx. Rather than upregulate other Ca2+ efflux mechanisms, the myocardium appears to functionally adapt to the absence of the Na+-Ca2+ exchanger by limiting Ca2+ influx. The magnitude of Ca2+ transients appears to be maintained by an increased gain of sarcoplasmic reticular Ca2+ release. The myocardium of the NCX1 knockout mice undergoes a remarkable adaptation to maintain near normal cardiac function.