tbuckley/cabot-search huggingface dataset:
Drug-Induced Autoimmunity
Authors: Martin H. Flax
Journal: New England Journal of Medicine (1974)

Allergic reactions to drugs can be manifested by a bewildering variety of pathological conditions. For the most part, these reactions are initiated by the development of antibodies directed against specific antigenic determinants on the drug. The allergic manifestations result from the interaction of these antibodies with the drug localized in various cells and tissues, with the concomitant activation or release of various allergic mediator substances such as complement or histamine. For example, in sedormid-induced thrombocytopenia, the anti-sedormid antibodies produced by the allergic person react with the drug bound to the platelets.1 The platelet, an "innocent bystander," is indirectly damaged by . . .
Abstract 3696: Pharmacokinetics (PK) of XMT-1001, a novel polymeric prodrug of camptothecin, in mice bearing HT-29 human colon carcinoma xenografts
Authors: Mark D. Walsh, Suzan K. Hanna, Jeremy M. Sen, John D. Benson, Carolina B. Cabral, Alex Yurkovetskiy, Timothy B. Lowinger, Beth A. Zamboni, William C. Zamboni
Journal: Cancer Research (2010)

Abstract Introduction: XMT-1001 is a water soluble macromolecular conjugate of camptothecin (CPT). In this novel CPT prodrug, CPT is conjugated with a ∼60 kDa biodegradable hydrophilic polyacetal, poly (1-hydroxymethylethylene hydroxymethylformal) (PHF). Dual-phase release of CPT from XMT-1001 occurs via lipophilic intermediates, CPT-20-O-(N-succinimido-glycinate) (CPT-SI) and CPT-20-O-(N-succinamidoyl-glycinate) (CPT-SA). Hydrolysis of intermediates results in formation of an active-lactone form of CPT. XMT-1001 is designed to produce a prolonged exposure in plasma and tumor and to improve CPT's therapeutic index. We evaluated plasma, tumor and tissue PK of XMT-1001, CPT-SI, CPT-SA and CPT in mice bearing HT-29 human colon cancer xenografts. Methods: XMT-1001 was administered at 60 mg CPT equivalents/kg IV x 1 via a tail vein. Mice (n = 3) were sacrificed at 0.083 to 24, 48, 72, 168 and 336 h after administration. Plasma, tumor and tissue samples were processed to measure the total (lactone + hydroxy acid) forms of XMT-1001, CPT-SI, CPT-SA and CPT via LC-MS/MS. Area under concentration versus time curves (AUC0-t) and time of last detectable concentration (TLast) were calculated. Results: PlasmaTumorLiver AUC0-t (ng/mL·h)TLast (h)AUC0-t (ng/mL·h)TLast (h)AUC0-t (ng/mL·h)TLast (h)XMT-10013,639,034168138,156336663,493336CPT-SI53,653248,85033613,239336CPT-SA46,010241,59516814,063336CPT8,86024853481,11616 Conclusions: CPT conjugation to the polymer carrier, PHF, provides a water soluble formulation with potential advantages of extended systemic exposure to the conjugated drug XMT-1001, conjugated release products CPT-SI and CPT-SA, and active drug CPT. After XMT-1001 administration, the majority of plasma exposure is accounted for by conjugated CPT. The analysis of XMT-1001 revealed substantial tumor and tissue accumulation and extended exposure of conjugated drug and conjugated release products CPT-SI, CPT-SA and CPT. The improved tumor distribution and extended localized release of small molecule prodrugs and active CPT by XMT-1001 are hypothesized to improve safety and efficacy over existing drugs of the same class. Supported by Mersana Therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3696.
Mother to child transmission of HIV among Zimbabwean women who seroconverted postnatally: prospective cohort study
Authors: J. H. Humphrey, E. Marinda, K. Mutasa, L. H. Moulton, P. J. Iliff, R. Ntozini, H. Chidawanyika, K. J. Nathoo, N. Tavengwa, A. Jenkins, E. G. Piwoz, P. Van de Perre, B. J. Ward
Journal: BMJ (2010)

To estimate the rates and timing of mother to infant transmission of HIV associated with breast feeding in mothers who seroconvert postnatally, and their breast milk and plasma HIV loads during and following seroconversion, compared with women who tested HIV positive at delivery.Prospective cohort study.Urban Zimbabwe.14 110 women and infants enrolled in the Zimbabwe Vitamin A for Mothers and Babies (ZVITAMBO) trial (1997-2001).Mother to child transmission of HIV, and breast milk and maternal plasma HIV load during the postpartum period.Among mothers who tested HIV positive at baseline and whose infant tested HIV negative with polymerase chain reaction (PCR) at six weeks (n=2870), breastfeeding associated transmission was responsible for an average of 8.96 infant infections per 100 child years of breast feeding (95% CI 7.92 to 10.14) and varied little over the breastfeeding period. Breastfeeding associated transmission for mothers who seroconverted postnatally (n=334) averaged 34.56 infant infections per 100 child years (95% CI 26.60 to 44.91) during the first nine months after maternal infection, declined to 9.50 (95% CI 3.07 to 29.47) during the next three months, and was zero thereafter. Among women who seroconverted postnatally and in whom the precise timing of infection was known (≤90 days between last negative and first positive test; n=51), 62% (8/13) of transmissions occurred in the first three months after maternal infection and breastfeeding associated transmission was 4.6 times higher than in mothers who tested HIV positive at baseline and whose infant tested HIV negative with PCR at six weeks. Median plasma HIV concentration in all mothers who seroconverted postnatally declined from 5.0 log(10) copies/mL at the last negative enzyme linked immunosorbent assay (ELISA) to 4.1 log(10) copies/mL at 9-12 months after infection. Breast milk HIV load in this group was 4.3 log(10) copies/mL 0-30 days after infection, but rapidly declined to 2.0 log(10) copies/mL and <1.5 log(10) copies/mL by 31-90 days and more than 90 days, respectively. Among women whose plasma sample collected soon after delivery tested negative for HIV with ELISA but positive with PCR (n=17), 75% of their infants were infected or had died by 12 months. An estimated 18.6% to 20.4% of all breastfeeding associated transmission observed in the ZVITAMBO trial occurred among mothers who seroconverted postnatally.Breastfeeding associated transmission is high during primary maternal HIV infection and is mirrored by a high but transient peak in breast milk HIV load. Around two thirds of breastfeeding associated transmission by women who seroconvert postnatally may occur while the mother is still in the "window period" of an antibody based test, when she would test HIV negative using one of these tests. Trial registration Clinical trials.gov NCT00198718.
Smoking cessation treatment and risk of depression, suicide, and self harm in the Clinical Practice Research Datalink: prospective cohort study
Authors: K. H. Thomas, R. M. Martin, N. M. Davies, C. Metcalfe, F. Windmeijer, D. Gunnell
Journal: BMJ (2013)

<b>Objective</b> To compare the risk of suicide, self harm, and depression in patients prescribed varenicline or bupropion with those prescribed nicotine replacement therapy. <b>Design</b> Prospective cohort study within the Clinical Practice Research Datalink. <b>Setting</b> 349 general practices in England. <b>Participants</b> 119 546 men and women aged 18 years and over who used a smoking cessation product between 1 September 2006 and 31 October 2011. There were 81 545 users of nicotine replacement products (68.2% of all users of smoking cessation medicines), 6741 bupropion (5.6%), and 31 260 varenicline (26.2%) users. <b>Main outcome measures</b> Outcomes were treated depression and fatal and non-fatal self harm within three months of the first smoking cessation prescription, determined from linkage with mortality data from the Office for National Statistics (for suicide) and Hospital Episode Statistics data (for hospital admissions relating to non-fatal self harm). Hazard ratios or risk differences were estimated using Cox multivariable regression models, propensity score matching, and instrumental variable analysis using physicians' prescribing preferences as an instrument. Sensitivity analyses were performed for outcomes at six and nine months. <b>Results</b> We detected 92 cases of fatal and non-fatal self harm (326.5 events per 100 000 person years) and 1094 primary care records of treated depression (6963.3 per 100 000 person years). Cox regression analyses showed no evidence that patients prescribed varenicline had higher risks of fatal or non-fatal self harm (hazard ratio 0.88, 95% confidence interval 0.52 to 1.49) or treated depression (0.75, 0.65 to 0.87) compared with those prescribed nicotine replacement therapy. There was no evidence that patients prescribed bupropion had a higher risk of fatal or non-fatal self harm (0.83, 0.30 to 2.31) or of treated depression (0.63, 0.46 to 0.87) compared with patients prescribed nicotine replacement therapy. Similar findings were obtained using propensity score methods and instrumental variable analyses. <b>Conclusions</b> There is no evidence of an increased risk of suicidal behaviour in patients prescribed varenicline or bupropion compared with those prescribed nicotine replacement therapy. These findings should be reassuring for users and prescribers of smoking cessation medicines.
Diagnostic value of the ratio of recovery systolic blood pressure to peak exercise systolic blood pressure for the detection of coronary artery disease.
Authors: D Acanfora, L De Caprio, S Cuomo, M Papa, N Ferrara, D Leosco, P Abete, F Rengo
Journal: Circulation (1988)

It has been previously reported that at treadmill exercise testing an abnormal ratio of recovery systolic blood pressure (SBP) to peak exercise SBP is more sensitive than exercise-induced angina or ST segment depression for diagnosing coronary artery disease (CAD). To investigate whether the SBP ratio keeps its diagnostic value during upright bicycle exercise, we evaluated the ratio of postexercise SBP to peak SBP in 73 patients with angiographically documented CAD and in 48 patients with normal coronary arteries (OV group) undergoing maximal stress testing on a bicycle ergometer. Three minutes after exercise ended, SBP ratio was significantly higher in the CAD than in the OV group (0.79 +/- 0.1 vs 0.71 +/- 0.08; p less than .001). Setting the upper normal limits of the recovery SBP ratio at 2 SDs from the mean for the OV group (SBP ratio = 0.98 and 0.88 at 1 and 3 min after exercise, respectively), with an increase or no change in SBP ratio at between 1 and 3 min of recovery considered an abnormal response, the sensitivity of SBP ratio was 30%, the specificity was 83%, and the accuracy was 51%. The respective values for ST depression were 81% (p less than .0001 vs SBP ratio), 48% (p less than .001 vs SBP ratio), and 67% (p less than .01 vs SBP ratio). Thus, for bicycle ergometer exercise testing, ST segment depression seems to be more accurate than SBP ratio in diagnosing CAD.
Oral Contraceptives: Turmoil and Aftermath
Authors: C. Alvin Paulsen
Journal: JAMA (1970)

Once again the political arena has provided the ingredients for turmoil in the medical field. Although much has been said and written during and since the recent Senate hearings, it is worthwhile to focus on some of the important issues which are involved. Firstly, medical consensus or "truth" is a precious but fragile state. Generation of new data which revise previously held concepts requires careful attention to experimental design and then hopefully a nonbiased analysis of the results derived. Despite these ideal guidelines, honest and even heated differences of opinion may emerge during the presentation and discussion of these new data at scientific meetings. Fortunately, the glare of the public media is either absent or minor in importance at these deliberations. Therefore, it is usually possible to conduct further work and let the passage of time place new or startling concepts into proper perspective before widespread publicity occurs. On the
TUBERCULOSIS OF THE BREAST
Authors: Gale E. Wilson
Journal: JAMA (1934)

Primary tuberculosis of the breast is still a relatively uncommon pathologic lesion, in spite of the fact that it was first described by Sir Astley Cooper in 1829 in a paper entitled "Scrofulous Swellings of the Breast." A short time later Velpeau mentioned tuberculosis as occurring in the mammary gland, only to be flatly contradicted by Virchow, who wrote in his famous "Treatise on Tumors" that tuberculosis never occurred in the breast. At the close of the nineteenth century, Durbar first demonstrated the tubercle bacillus in breast tissue. In 1902, Bindo de Vecchi was able to find seventy-seven cases reported in the literature and added one of his own. Four years later, Braendle reported eleven additional cases from the Tübingen clinic. In 1913, Powers of Denver reported four cases, bringing the total reported to ninety-three. Da Costa, in the ninth edition of "Modern Surgery," stated that, of the hundred cases
INCREASE IN ENDOTHELIAL PROGENITOR CELLS AFTER ACUTE MYOCARDIAL INFARCTION MAY REDUCE LATE LUMINAL LOSS IN THE STENT DEPLOYED IN INFARC RELATED CORONARY ARTERY
Authors: Motoo Date, Hiroshi Ito, Katsuomi Iwakura, Atsunori Okamura, Yasushi Koyama, Yoshiharu Higuchi, Koichi Inoue, Ryusuke Kimura, Hiroyuki Nagai, Kenshi Fujii
Journal: Journal of the American College of Cardiology (2010)
Phenothiazines in Prevention of Psychiatric Hospitalization
Authors: David M. Engelhardt, Bernard Rosen, Norbert Freedman, David Mann, None Reuben
Journal: JAMA (1963)

The relationship between duration of treatment and incidence of hospitalization was studied on a sample of 173 patients, previously reported, after a 36-months' interval, and on a total sample of 445 chronically schizophrenic outpatients. Subjects were assigned randomly to placebo, chlorpromazine, or promazine therapy and treated under double-blind conditions continuously for periods up to 61 months. Results clearly indicated that the effect of chlorpromazine in reducing incidence of hospitalization is greatest early in treatment but diminishes progressively thereafter. The question is raised whether long-term phenothiazine treatment of outpatient schizophrenics<i>prevents or delays</i>hospitalization.
<i>APOL1</i> Risk Variants, Race, and Progression of Chronic Kidney Disease
Authors: Afshin Parsa, W.H. Linda Kao, Dawei Xie, Brad C. Astor, Man Li, Chi-yuan Hsu, Harold I. Feldman, Rulan S. Parekh, John W. Kusek, Tom H. Greene, Jeffrey C. Fink, Amanda H. Anderson, Michael J. Choi, Jackson T. Wright, James P. Lash, Barry I. Freedman, Akinlolu Ojo, Cheryl A. Winkler, Dominic S. Raj, Jeffrey B. Kopp, Jiang He, Nancy G. Jensvold, Kaixiang Tao, Michael S. Lipkowitz, Lawrence J. Appel
Journal: New England Journal of Medicine (2013)

Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients.In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline.In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons).Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).
Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders
Authors: N. Singewald, C. Schmuckermair, N. Whittle, A. Holmes, K.J. Ressler
Journal: Pharmacology & Therapeutics (2014)

Pathological fear and anxiety are highly debilitating and, despite considerable advances in psychotherapy and pharmacotherapy they remain insufficiently treated in many patients with PTSD, phobias, panic and other anxiety disorders. Increasing preclinical and clinical evidence indicates that pharmacological treatments including cognitive enhancers, when given as adjuncts to psychotherapeutic approaches [cognitive behavioral therapy including extinction-based exposure therapy] enhance treatment efficacy, while using anxiolytics such as benzodiazepines as adjuncts can undermine long-term treatment success. The purpose of this review is to outline the literature showing how pharmacological interventions targeting neurotransmitter systems including serotonin, dopamine, noradrenaline, histamine, glutamate, GABA, cannabinoids, neuropeptides (oxytocin, neuropeptides Y and S, opioids) and other targets (neurotrophins BDNF and FGF2, glucocorticoids, L-type-calcium channels, epigenetic modifications) as well as their downstream signaling pathways, can augment fear extinction and strengthen extinction memory persistently in preclinical models. Particularly promising approaches are discussed in regard to their effects on specific aspects of fear extinction namely, acquisition, consolidation and retrieval, including long-term protection from return of fear (relapse) phenomena like spontaneous recovery, reinstatement and renewal of fear. We also highlight the promising translational value of the preclinial research and the clinical potential of targeting certain neurochemical systems with, for example d-cycloserine, yohimbine, cortisol, and L-DOPA. The current body of research reveals important new insights into the neurobiology and neurochemistry of fear extinction and holds significant promise for pharmacologically-augmented psychotherapy as an improved approach to treat trauma and anxiety-related disorders in a more efficient and persistent way promoting enhanced symptom remission and recovery.
In search of a good death: Law needs to be changed to allow terminally ill people choice of a dignified death
Authors: L. Cook
Journal: BMJ (2003)

EDITOR—I am a 35 year old married mother who has tested positive for the gene for Huntington's disease. Although I am symptom free at present, it is clinically certain that this incurable, degenerative, neurological disorder will manifest itself at some point in the near future. Growing up in a family …
Upper limits of normal for alanine aminotransferase activity in the United States population
Authors: Constance E. Ruhl, James E. Everhart
Journal: Hepatology (2011)

Abstract Alanine aminotransferase (ALT) is an important test for liver disease, yet there is no generally accepted upper limit of normal (ULN) in the United States. Furthermore, the ability of ALT to differentiate persons with and without liver disease is uncertain. We examined cut-offs for ALT for their ability to discriminate between persons with positive hepatitis C virus (HCV) RNA and those at low risk for liver injury in the U.S. population. Among adult participants in the 1999-2008 U.S. National Health and Nutrition Examination Survey, 259 were positive for serum HCV RNA and 3,747 were at low risk for liver injury (i.e., negative HCV RNA and hepatitis B surface antigen, low alcohol consumption, no evidence of diabetes, and normal body mass index and waist circumference). Serum ALT activity was measured centrally. Maximum correct classification was achieved at ALT = 29 IU/L for men (88% sensitivity, 83% specificity) and 22 IU/L (89% sensitivity, 82% specificity) for women. The cut-off for 95% sensitivity was an ALT = 24 IU/L (70% specificity) for men and 18 IU/L (63% specificity) for women. The cut-off for 95% specificity was ALT = 44 IU/L (64% sensitivity) for men and 32 IU/L (59% sensitivity) for women. The area under the curve was 0.929 for men and 0.915 for women. If the cut-offs with the best correct classification were applied to the entire population, 36.4% of men and 28.3% of women would have had abnormal ALT. Conclusion : ALT discriminates persons infected with HCV from those at low risk of liver disease, but would be considered elevated in a large proportion of the U.S. population. (Hepatology 2012)
Transplantation of an allogeneic vein bioengineered with autologous stem cells: a proof-of-concept study
Authors: Michael Olausson, Pradeep B Patil, Vijay Kumar Kuna, Priti Chougule, Nidia Hernandez, Ketaki Methe, Carola Kullberg-Lindh, Helena Borg, Hasse Ejnell, Suchitra Sumitran-Holgersson
Journal: The Lancet (2012)
Severe Asthma
Authors: Nizar N. Jarjour, Serpil C. Erzurum, Eugene R. Bleecker, William J. Calhoun, Mario Castro, Suzy A. A. Comhair, Kian Fan Chung, Douglas Curran-Everett, Raed A. Dweik, Sean B. Fain, Anne M. Fitzpatrick, Benjamin M. Gaston, Elliot Israel, Annette Hastie, Eric A. Hoffman, Fernando Holguin, Bruce D. Levy, Deborah A. Meyers, Wendy C. Moore, Stephen P. Peters, Ronald L. Sorkness, W. Gerald Teague, Sally E. Wenzel, William W. Busse
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

The National Heart, Lung, and Blood Institute Severe Asthma Research Program (SARP) has characterized over the past 10 years 1,644 patients with asthma, including 583 individuals with severe asthma. SARP collaboration has led to a rapid recruitment of subjects and efficient sharing of samples among participating sites to conduct independent mechanistic investigations of severe asthma. Enrolled SARP subjects underwent detailed clinical, physiologic, genomic, and radiological evaluations. In addition, SARP investigators developed safe procedures for bronchoscopy in participants with asthma, including those with severe disease. SARP studies revealed that severe asthma is a heterogeneous disease with varying molecular, biochemical, and cellular inflammatory features and unique structure-function abnormalities. Priorities for future studies include recruitment of a larger number of subjects with severe asthma, including children, to allow further characterization of anatomic, physiologic, biochemical, and genetic factors related to severe disease in a longitudinal assessment to identify factors that modulate the natural history of severe asthma and provide mechanistic rationale for management strategies.
Endotoxin Exposure, CD14, and Allergic Disease
Authors: Angela Simpson, Sally L. John, Francine Jury, Rob Niven, Ashley Woodcock, William E. R. Ollier, Adnan Custovic
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

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