tbuckley/cabot-search huggingface dataset:
The combination of lenalidomide and dexamethasone reduces bone resorption in responding patients with relapsed/refractory multiple myeloma but has no effect on bone formation: Final results on 205 patients of the Greek myeloma study group
Authors: Evangelos Terpos, Dimitrios Christoulas, Efstathios Kastritis, Eirini Katodritou, Athanasios Papatheodorou, Anastasia Pouli, Marie‐Christine Kyrtsonis, Eurydiki Michalis, Xenophon Papanikolaou, Maria Gkotzamanidou, Efstathios Koulieris, Maria Gavriatopoulou, Konstantinos Zervas, Meletios A. Dimopoulos
Journal: American Journal of Hematology (2013)

The combination of lenalidomide plus dexamethasone (RD) is very effective for patients with relapsed/ refractory myeloma. However, the effect of RD on bone metabolism has not been previously evaluated in these patients. To address this issue, we initially performed a retrospective study in 106 consecutive patients with relapsed or refractory myeloma who received RD. We measured the following bone indices on Cycle 1/Day 1 and then on Cycles 3 and 6/Day 28: dickkopf-1 (Dkk-1), sRANKL, osteoprotegerin (OPG), bone resorption markers (C-telopeptide of collagen type-I, CTX and TRACP-5b) and bone formation markers (bone-specific alkaline phosphatase-bALP and osteocalcin). RD produced a reduction of CTX only in responders, with no effect on bone formation. To validate these results, we then evaluated prospectively 99 patients who received either RD (n550) or VRD (bortezomib + RD, n549). RD reduced CTX, mainly in responders but showed no effect on bone formation, confirming the result of the retrospective study. However, the addition of bortezomib to RD (VRD arm) reduced Dkk-1, sRANKL/OPG, and CTX, while it increased bALP and OC after six cycles of therapy. These changes were irrespective of treatment response, which was similar between treatment arms. No skeletal-related events were observed in the VRD arm while two, nonresponding patients treated with RD developed a vertebral fracture. We conclude that RD reduces bone resorption only in responding patients with relapsed/refractory myeloma but has no effect on bone formation. Combination with bortezomib, which enhances bone formation, seems to be preferred for the management of myeloma patients with osteolytic disease.
Long-term mitral valve replacement in young children. Influence of somatic growth on prosthetic valve adequacy.
Authors: S Friedman, L H Edmunds, C C Cuaso
Journal: Circulation (1978)

Long-term clinical and laboratory findings in three children who required mitral valve replacement below age four years are reported. In each instance a second valve replacement was necessary approximately 8 1/2 years after the initial one, following a two and one-half fold increase in body weight. Inadequate mitral valve orifice size was found in each instance, producing a hemodynamic picture equivalent to mitral stenosis: congestive heart failure, pulmonary hypertension and atrial fibrillation. A second valve was placed without mortality in each instance and relieved the mitral valve obstruction. Pulmonary vascular resistance increased postoperatively in two patients and failed to decrease in the third. Pulmonary arterial hypertension and left ventricular hypertrophy persisted as long as 13 to 37 months after the second valve placement in all patients. The consequences of increasing body size and the long-term interposition of a rigid prosthesis in a growing heart introduce additional complications to mitral valve replacement in childhood. Frequent hemodynamic observations and the use of a prosthesis other than the ball-cage variety is recommended for improved management.
Studying Selective Blockage of Sensation
Authors: Paul Cotton
Journal: JAMA (1990)

CAPSAICIN has a specificity for nociceptive, or pain-transmitting, type C nerve fibers. That, investigators say, is why it can block pain while not affecting sense of touch, pressure, or vibration. And it is why this active agent in Tabasco sauce is becoming a common condiment in many basic science laboratories. Topical application triggers a burst of the neuropeptide substance P from the C fibers, causing an initial burning sensation. Investigators say that unpleasant experience keeps some users from using it long enough to discover its full potential benefit. <h3>Preventing Pain's Return</h3> That benefit comes later because capsaicin also keeps substance P from being replenished, thus blocking further conduction of pain. In one study using 0.075% capsaicin ointment to treat diabetic neuropathy, it took 4 weeks for pain relief to become significant. (See accompanying article.) This delayed benefit is likely due to calcium-mediated structural changes, says James R. Brorson, MD, a
Designing a post-genomics knowledge ecosystem to translate pharmacogenomics into public health action
Authors: Edward S Dove, Samer A Faraj, Eugene Kolker, Vural Özdemir
Journal: Genome Medicine (2012)

Translation of pharmacogenomics to public health action is at the epicenter of the life sciences agenda. Post-genomics knowledge is simultaneously co-produced at multiple scales and locales by scientists, crowd-sourcing and biological citizens. The latter are entrepreneurial citizens who are autonomous, self-governing and increasingly conceptualizing themselves in biological terms, ostensibly taking responsibility for their own health, and engaging in patient advocacy and health activism. By studying these heterogeneous 'scientific cultures', we can locate innovative parameters of collective action to move pharmacogenomics to practice (personalized therapeutics). To this end, we reconceptualize knowledge-based innovation as a complex ecosystem comprising 'actors' and 'narrators'. For robust knowledge translation, we require a nested post-genomics technology governance system composed of first-order narrators (for example, social scientists, philosophers, bioethicists) situated at arm's length from innovation actors (for example, pharmacogenomics scientists). Yet, second-order narrators (for example, an independent and possibly crowd-funded think-tank of citizen scholars, marginalized groups and knowledge end-users) are crucial to prevent first-order narrators from gaining excessive power that can be misused in the course of steering innovations. To operate such 'self-calibrating' and nested innovation ecosystems, we introduce the concept of 'wiki-governance' to enable mutual and iterative learning among innovation actors and first- and second-order narrators. '[A] scientific expert is someone who knows more and more about less and less, until finally knowing (almost) everything about (almost) nothing.' [1] 'Ubuntu: I am because you are.' [2]
Extent of mesorectal spread and involvement of lateral resection margin as prognostic factors after surgery for rectal cancer
Authors: S.J. Cawthorn, S.M. Caffarey, C.I.M. Broughton, C.G. Marks, M. Chir, D.V. Parums, N.M. Gibbs, R.P. A'Hern
Journal: The Lancet (1990)
One novel and one recurrent mutation in the PROS1 gene cause type I protein S deficiency in patients with pulmonary embolism associated with deep vein thrombosis
Authors: Kazuhiro Mizukami, Toru Nakabayashi, Sumiyoshi Naitoh, Mika Takeda, Takashi Tarumi, Itaru Mizoguchi, Masahiro Ieko, Takao Koike
Journal: American Journal of Hematology (2006)

Abstract We investigated the molecular basis of type I protein S (PS) deficiency in two unrelated Japanese families, in which both probands developed pulmonary embolism associated with deep vein thrombosis. Nucleotide sequencing of amplified DNA revealed distinct point mutations in the PROS1 gene of the probands, which were designated protein S Sapporo 1 and protein S Sapporo 2. Additional mutations in the PROS1 gene were excluded by DNA sequencing of all exons and intron/exon boundaries. In the 25‐year‐old Japanese male patient who carried protein S Sapporo 1, we identified a heterozygous A‐to‐T change in the invariant ag dinucleotide of the acceptor splice site of intron f of the PROS1 gene. This mutation is a novel splice site mutation that impairs normal mRNA splicing, leading to exon 7 skipping, which was confirmed by platelet mRNA analysis. Translation of this mutant transcript would result in a truncated protein that lacks the entire epidermal growth factor‐like domain 3 of the PS molecule. In a 31‐year‐old Japanese male and his younger brother who each carried protein S Sapporo 2, we detected a previously described heterozygous T‐to‐C transition at nucleotide position 1147 in exon 10 of the PROS1 gene, which predicts an amino acid substitution of tryptophan by arginine at residue 342 in the laminin G1 domain of the PS molecule. Both mutations would cause misfolding of the PS protein, resulting in the impairment of secretion, which is consistent with the type I PS deficiency phenotype. Am. J. Hematol., 2006. © 2006 Wiley‐Liss, Inc.
Etiology and pathogenesis of uterine leiomyomas: a review.
Authors: Gordon P Flake, Janet Andersen, Darlene Dixon
Journal: Environmental Health Perspectives (2002)

Uterine leiomyomas, or fibroids, represent a major public health problem. It is believed that these tumors develop in the majority of American women and become symptomatic in one-third of these women. They are the most frequent indication for hysterectomy in the United States. Although the initiator or initiators of fibroids are unknown, several predisposing factors have been identified, including age (late reproductive years), African-American ethnicity, nulliparity, and obesity. Nonrandom cytogenetic abnormalities have been found in about 40% of tumors examined. Estrogen and progesterone are recognized as promoters of tumor growth, and the potential role of environmental estrogens has only recently been explored. Growth factors with mitogenic activity, such as transforming growth factor- (subscript)3(/subscript), basic fibroblast growth factor, epidermal growth factor, and insulin-like growth factor-I, are elevated in fibroids and may be the effectors of estrogen and progesterone promotion. These data offer clues to the etiology and pathogenesis of this common condition, which we have analyzed and summarized in this review.
Advances in the Treatment of Localized Prostate Cancer: The Role of Anatomic and Functional Imaging in Men Managed With Radiotherapy
Authors: Joycelyn L. Speight, Mack Roach
Journal: Journal of Clinical Oncology (2007)

Radiation therapy is an active modality in the management of local and regional prostate cancer, but can be curative only if all existing disease is encompassed within the treatment portal. In addition to the ability to deliver sufficient radiation dose, accurate targeting is critical to achieve better treatment outcomes. Failure to accommodate daily variations in setup and organ motion potentially limits the efficacy of sophisticated conformal techniques (three-dimensional conformal radiotherapy and intensity-modulated radiotherapy). Increased use of various online and real-time imaging techniques is an important step toward enhancing treatment accuracy. The incorporation of functional imaging techniques into treatment planning is another important step. The addition of biologic and metabolic information regarding the location and extent of disease combined with real-time online imaging will allow us to better determine where, how, and with what to treat appropriate targets and improve cure rates.
Importance of Sulfadiazine Resistance in Meningococcal Disease in Civilians
Authors: John M. Leedom, Daniel Ivler, Allen W. Mathies, Lauri D. Thrupp, Bernard Portnoy, Paul F. Wehrle
Journal: New England Journal of Medicine (1965)

THE first known concentration of cases of meningitis due to sulfadiazine-resistant strains of meningococci occurred during the spring of 1963 at the United States Naval Training Center in San Diego, California.1 Most of the resistant organisms detected during the Naval Training Center outbreak belonged to serologic Group B, and some were resistant to more than 25 mg. of sulfadiazine per 100 ml.1 Because the patterns of sulfadiazine resistance of meningococci isolated from military recruits might be expected to reflect, perhaps in accentuated form, those in civilians in the region, it seemed desirable to assess the prevalence of resistant strains among . . .
Noxa Up-regulation and Mcl-1 Cleavage Are Associated to Apoptosis Induction by Bortezomib in Multiple Myeloma
Authors: Patricia Gomez-Bougie, Soraya Wuillème-Toumi, Emmanuelle Ménoret, Valérie Trichet, Nelly Robillard, Moreau Philippe, Régis Bataille, Martine Amiot
Journal: Cancer Research (2007)

Abstract Targeting the ubiquitin-proteasome pathway has emerged as a potent anticancer strategy. Bortezomib, a specific proteasome inhibitor, has been approved for the treatment of relapsed or refractory multiple myeloma. Multiple myeloma cell survival is highly dependent on Mcl-1 antiapoptotic molecules. In a recent study, proteasome inhibitors induced Mcl-1 accumulation that slowed down their proapoptotic effects. Consequently, we investigated the role of Bcl-2 family members in bortezomib-induced apoptosis. We found that bortezomib induced apoptosis in five of seven human myeloma cell lines (HMCL). Bortezomib-induced apoptosis was associated with Mcl-1 cleavage regardless of Mcl-1L accumulation. Furthermore, RNA interference mediated Mcl-1 decrease and sensitized RPMI-8226 HMCL to bortezomib, highlighting the contribution of Mcl-1 in bortezomib-induced apoptosis. Interestingly, an important induction of Noxa was found in all sensitive HMCL both at protein and mRNA level. Concomitant to Mcl-1 cleavage and Noxa induction, we also found caspase-3, caspase-8, and caspase-9 activation. Under bortezomib treatment, Mcl-1L/Noxa complexes were highly increased, Mcl-1/Bak complexes were disrupted, and there was an accumulation of free Noxa. Finally, we observed a dissociation of Mcl-1/Bim complexes that may be due to a displacement of Bim induced by Noxa. Thus, in myeloma cells, the mechanistic basis for bortezomib sensitivity can be explained mainly by the model in which the sensitizer Noxa can displace Bim, a BH3-only activator, from Mcl-1, thus leading to Bax/Bak activation. [Cancer Res 2007;67(11):5418–24]
Application to Coronary Arteries of the Basic Principles Governing the Development of Collateral Arterial Channels
Authors: WILLIAM H. SEWELL
Journal: Circulation (1963)

The experiments performed on 350 dogs showed that when certain technical points were observed, a pedicle containing the mammary artery, mammary vein, and surrounding soft tissue consistently contributed large collateral channels which were capable of carrying the entire arterial blood supply to a large portion of the left ventricle of the heart of a dog with experimental chronic coronary arterial hypotension. Original plastic devices were used to produce controlled, gradual, coronary constrictions and occlusions. Direction and velocity of movement and size of the donor arteries, the collateral channels, and the recipient coronary arteries were determined from frame-by-frame analysis of cinearteriograms.
Thiamine-Dependent Beriberi in the “Thiamine-Responsive Anemia Syndrome”
Authors: Hanna Mandel, Moshe Berant, Annie Hazani, Yehezkel Naveh
Journal: New England Journal of Medicine (1984)

IN 1969 Rogers et al. described a case of unexplained anemia in association with diabetes mellitus and sensorineural deafness.1 The anemia responded only to pharmacologic closes of thiamine. Another such case of "thiamine-responsive anemia" was reported by Viana and Carvalho in 1978,2 and two additional cases were presented by Haworth et al. in 1982.3We describe a three-month-old girl who presented with severe anemia, diabetes, and deafness, all of which improved with high-dose thiamine treatment. To our knowledge, our patient is the youngest patient recognized as having this syndrome. In addition to anemia, diabetes, and deafness, she had generalized puffiness, . . .
A Voxel-Based PET Investigation of the Long-Term Effects of “Ecstasy” Consumption on Brain Serotonin Transporters
Authors: Ralph Buchert, Rainer Thomasius, Florian Wilke, Kay Petersen, Bruno Nebeling, Jost Obrocki, Oliver Schulze, Ulrich Schmidt, Malte Clausen
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: Recent functional imaging studies have reported evidence of alterations in the serotonergic system induced by 3,4-methylenedioxymethamphetamine (MDMA), or "Ecstasy." However, these studies have often been limited by small sample size, lack of tracer selectivity, unreliable assessment of MDMA doses, insufficiently matched comparison groups, or region-of-interest analysis. METHOD: Positron emission tomography (PET) using the specific serotonin transporter ligand [11C](+)McN5652 was performed in 117 subjects: 30 current MDMA users, 29 former MDMA users, 29 drug-naive comparison subjects, and 29 users of drugs other than MDMA (polydrug comparison subjects). Self-assessment of drug history was checked by analyzing hair samples. Local serotonin transporter availability was computed by a regularized reference tissue approach. Voxel-based comparison of serotonin transporter availability was performed using statistical parametric mapping (SPM 99). RESULTS: Serotonin transporter availability in current MDMA users was significantly reduced in the mesencephalon, thalamus, left caudate, hippocampus, occipital cortex, temporal lobes, and posterior cingulate gyrus compared with all other groups. Reduction was more pronounced in female than in male subjects. There was no significant difference of serotonin transporter availability among former MDMA users and the drug-naive and polydrug comparison subjects. A negative correlation between serotonin transporter availability and mean MDMA dose was found in occipital visual areas and in the left precentral sulcus of current MDMA users. In addition, there was a significant positive correlation between the serotonin transporter availability and the MDMA abstention period in brainstem and in the basal forebrain in all MDMA users. CONCLUSIONS: These findings support the hypothesis of MDMA-induced protracted alterations of the serotonergic system and indicate that the reduced availability of serotonin transporter, as measured by PET, might be reversible. Women appear to be more susceptible than men to MDMA-induced alterations of the serotonergic system.
Hospital Nurse Staffing and Patient Mortality, Nurse Burnout, and Job Dissatisfaction
Authors: Linda H. Aiken, Sean P. Clarke, Douglas M. Sloane, Julie Sochalski, Jeffrey H. Silber
Journal: JAMA (2002)

ContextThe worsening hospital nurse shortage and recent California legislation mandating minimum hospital patient-to-nurse ratios demand an understanding of how nurse staffing levels affect patient outcomes and nurse retention in hospital practice.ObjectiveTo determine the association between the patient-to-nurse ratio and patient mortality, failure-to-rescue (deaths following complications) among surgical patients, and factors related to nurse retention.Design, Setting, and ParticipantsCross-sectional analyses of linked data from 10 184 staff nurses surveyed, 232 342 general, orthopedic, and vascular surgery patients discharged from the hospital between April 1, 1998, and November 30, 1999, and administrative data from 168 nonfederal adult general hospitals in Pennsylvania.Main Outcome MeasuresRisk-adjusted patient mortality and failure-to-rescue within 30 days of admission, and nurse-reported job dissatisfaction and job-related burnout.ResultsAfter adjusting for patient and hospital characteristics (size, teaching status, and technology), each additional patient per nurse was associated with a 7% (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.03-1.12) increase in the likelihood of dying within 30 days of admission and a 7% (OR, 1.07; 95% CI, 1.02-1.11) increase in the odds of failure-to-rescue. After adjusting for nurse and hospital characteristics, each additional patient per nurse was associated with a 23% (OR, 1.23; 95% CI, 1.13-1.34) increase in the odds of burnout and a 15% (OR, 1.15; 95% CI, 1.07-1.25) increase in the odds of job dissatisfaction.ConclusionsIn hospitals with high patient-to-nurse ratios, surgical patients experience higher risk-adjusted 30-day mortality and failure-to-rescue rates, and nurses are more likely to experience burnout and job dissatisfaction.
Evaluation of a proposed breast cancer screening regimen.
Authors: E. G. Knox
Journal: BMJ (1988)

The Forrest working group on breast cancer screening recommended routine mammography for women in the United Kingdom at ages 50, 53, 56, 59, 62, and 65. Benefits were costed at about 3000 pounds for each life year recovered, but there was no estimate of the cost of each life saved, and the consequent reduction in mortality from breast cancer in the general population of the United Kingdom was not estimated. The present study addressed both of these issues using an interactive computer modelling process. Long term savings were calculated at 900 deaths a year in England and Wales--that is, about 8% of the total deaths from breast cancer--and 9% of life years currently lost. The cost of each death saved from breast cancer was estimated at 39,000 pounds.
Intestinal steroid profiles and microbiota composition in colitic mice
Authors: Steffen Wohlgemuth, Sylvia Keller, Romy Kertscher, Mandy Stadion, Dirk Haller, Sigrid Kisling, Gerhard Jahreis, Michael Blaut, Gunnar Loh
Journal: Gut Microbes (2011)

Reduced gut microbiota diversity in conjunction with a bloom of few bacterial species is a common feature in inflammatory bowel disease (IBD) patients. However, the environmental changes caused by inflammation and their possible impact on the microbiota are largely unknown. Since IBD is associated with an impaired intestinal steroid metabolism, we hypothesized that changes in intestinal steroid and particularly bile acid (BA) concentrations affect microbial communities. We used Interleukin-10 deficient (IL-10-/-) mice as a model for chronic gut inflammation. Healthy wild-type mice served as controls. In these animals, intestinal steroid concentrations and gut microbial diversity were analyzed at 24 weeks of age. The IL 10-/- mice developed moderate inflammation in cecum and colon and colorectal tumor formation was observed in 55 % of the animals. Compared to the healthy conditions, gut inflammation was associated with higher intestinal cholesterol and cholic acid concentrations and a reduced microbial diversity. The latter was accompanied by a proliferation of Robinsoniella peoriensis, Clostridium innocuum, Escherichia coli, and Enterococcus gallinarum. All these species proved to be highly bile acid resistant. We concluded that chronic colitis in IL-10-/- mice is associated with changes in intestinal steroid profiles. These changes may be due to alterations in gut microbiota composition or vice versa. Whether the bacterial sterol and bile acid metabolism is implicated in colitis and colorectal carcinoma etiology remains to be clarified.
Chimeric flagellin expressed by Salmonella typhimurium induces an ESAT-6-specific Th1-type immune response and CTL effects following intranasal immunization
Authors: Hui Zhang, Liu Liu, Ke Wen, Jinlin Huang, Shizhong Geng, Junsong Shen, Zhiming Pan, Xinan Jiao
Journal: Cellular and Molecular Immunology (2011)