tbuckley/cabot-search huggingface dataset:
Identification of a severe bleeding disorder in humans caused by a mutation in CalDAG-GEFI
Authors: William A. Muller
Journal: The Journal of Experimental Medicine (2014)

In this issue, Canault et al. report for the first time a point mutation in the RAS guanyl-releasing protein 2 (RASGRP2) gene that results in a severe bleeding defect in humans.The study of inherited platelet disorders has shed light on the molecular mechanisms of physiologic thrombosis and hemostasis and led to the development of several therapies to prevent pathologic clotting.The RASGRP2 gene encodes the guanine nucleotide exchange factor (GEF) calcium-and DAG-regulated GEF 1 (CalDAG-GEFI), which is crucial for activation of Rap1, a small GTPase that regulates integrin-mediated activation and granule secretion in platelets and other cells.The function of CalDAG-GEFI has been studied in vitro and in mice-mice lacking CalDAG-GEFI have impaired thrombi formation by platelets as well as a defect in neutrophil function-but to date, no pathological RASGRP2 mutations have been identified in humans.Now, Canault et al. have investigated the cause of an inherited platelet disorder in three siblings from a consanguineous marriage that are all affected by a severe bleeding disorder.Whole genome sequencing was used to identify a mutation (cG742T) in the RASGRP2 gene.This mutation reduces Rac1 GTP binding (secondary to decreased Rap1 activation), impairing the ability of platelets to aggregate in response to a variety of stimuli, to form thrombi under flow, and to undergo normal spreading.Heterozygotes also have platelets that fail to adhere normally under flow and have a spreading defect (see figure) but they do not suffer from bleeding because their platelets aggregate normally.The functional deficiency induced by the mutation was confined to platelets and megakaryocytes with no obvious alteration in leukocytes.This is probably because other GEFs in leukocytes are able to activate Rap1 or, as the authors speculate, that CalDAG-GEFI with this point mutation is still able to function in leukocytes.In fact, even in platelets, the aggregation defects can be overcome by high doses of agonists in vitro, so while CalDAG-GEFI may be the preferred way for platelets to activate Rap1, it is clearly not the only way.Mutations in CalDAG-GEFI had previously been reported to be responsible for leukocyte adhesion deficiency type III, which was later found to be caused by the absence of kindlin-3.To demonstrate that the mutation in CalDAG-GEFI is truly responsible for the phenotype, the authors showed that cells transfected with wild-type RASGRP2 can activate Rap1, whereas those transfected with the mutation found in the affected siblings cannot.Looking at these data from a different perspective, the presence of a single normal allele is sufficient to prevent bleeding, but not platelet adhesion to collagen.This suggests that partial inhibition of CalDAG-GEFI might be a novel and potentially safe therapeutic target to prevent thrombosis without causing bleeding-a holy grail of vascular medicine and surgery.
SIX1 Promotes Tumor Lymphangiogenesis by Coordinating TGFβ Signals That Increase Expression of VEGF-C
Authors: Dan Liu, Li Li, Xiao-Xue Zhang, Dong-Yi Wan, Bi-Xin Xi, Zheng Hu, Wen-Cheng Ding, Da Zhu, Xiao-Li Wang, Wei Wang, Zuo-Hua Feng, Hui Wang, Ding Ma, Qing-Lei Gao
Journal: Cancer Research (2014)

Lymphatic vessels are one of the major routes for the dissemination of cancer cells. Malignant tumors release growth factors such as VEGF-C to induce lymphangiogenesis, thereby promoting lymph node metastasis. Here, we report that sine oculis homeobox homolog 1 (SIX1), expressed in tumor cells, can promote tumor lymphangiogenesis and lymph node metastasis by coordinating with TGFβ to increase the expression of VEGF-C. Lymphangiogenesis and lymph node metastasis in cervical cancer were closely correlated with higher expression of SIX1 in tumor cells. By enhancing VEGF-C expression in tumor cells, SIX1 could augment the promoting effect of tumor cells on the migration and tube formation of lymphatic endothelial cells (LEC) in vitro and lymphangiogenesis in vivo. SIX1 enhanced TGFβ-induced activation of SMAD2/3 and coordinated with the SMAD pathway to modulate VEGF-C expression. Together, SIX1 and TGFβ induced much higher expression of VEGF-C in tumor cells than each of them alone. Despite its effect in promoting VEGF-C expression, TGFβ could inhibit lymphangiogenesis by directly inhibiting tube formation by LECs. However, the increased production of VEGF-C not only directly promoted migration and tube formation of LECs but also thwarted the inhibitory effect of TGFβ on LECs. That is, tumor cells that expressed high levels of SIX1 could promote lymphangiogenesis and counteract the negative effects of TGFβ on lymphangiogenesis by increasing the expression of VEGF-C. These findings provide new insights into tumor lymphangiogenesis and the various roles of TGFβ signaling in tumor regulation. Our results also suggest that SIX1/TGFβ might be a potential therapeutic target for preventing lymph node metastasis of tumor.
Screening for Lung Cancer
Authors: David M. Eddy
Journal: Annals of Internal Medicine (1989)

Lung cancer is the commonest cause of death from cancer in both men and women, with approximately 152 000 new cases and 139 000 deaths in 1988. The incidence and mortality rates are increasing rapidly in women. Two main tests have been used to screen for lung cancer: chest roentgenography and sputum cytology. Four recent controlled trials and one case-control study failed, however, to show that screening reduces lung cancer mortality even in high-risk persons (smokers). In the Mayo Lung Project, for example, the lung cancer death rate in high-risk men offered sputum cytology and chest roentgenogram every 4 months was 3.1 per 1000 person-years, compared with 3.0 per 1000 person-years in a control group. Chest roentgenograms and sputum cytology lead to false-positive test results in smokers of approximately 5% and 0.5%, respectively. Because of the lack of evidence of benefit and because of its potential harms and costs, screening for lung cancer is not recommended.
Comparison of the Intravascular Mixing and Disappearance of Radiosodium, Radiopotassiuin and T-1824
Authors: GEORGE BARLOW, HELMER P. K. AGERSBORG, RICHARD R. OVERMAN
Journal: Circulation Research (1957)

A method is presented utilizing the rapid intravenous injection of a dye-isotope mixture and rapid, serial arterial sampling which permits the determination of rates of disappearance of these materials from the vascular system. Since K + traverses capillary endothelial walls at about twice the rate of Na + it appears that these two ions, while being about the same size and having the same charge, are handled in different manners by the capillaries. Other variables obtainable from the T-1824 isotope time-concentration curves such as plasma volume, circulation time, cardiac output and isotope distribution volumes are also presented.
THE RELATIONS OF HUMAN AND VETERINARY PARASITOLOGY
Authors: MAURICE C. HALL
Journal: JAMA (1930)

Human parasitology concerns itself with the parasites of man. Veterinary parasitology concerns itself with a much larger field, one so large that it is a bit difficult to delimit it. For the most part, veterinarians deal with the diseases of domesticated animals, and even these constitute a much larger group of animals than one might assume on first thought. They include not only the horse, ass, mule, cow (<i>Bos taurus</i>), sheep, goat, pig, dog, cat, chicken, turkey, guinea fowl, pea fowl, duck, goose, swan and pigeon, but also the water buffalo (<i>Bos bubalis</i>), Indian cattle (<i>Bos indicus</i>), reindeer, musk ox, yak, camel, dromedary, llama, elephant and ostrich. In addition to these domesticated animals there are the semidomesticated ones, especially the large group of fur-bearers, such as the fox, otter, muskrat, mink and seal, the large group of game animals, such as bear, deer, bison, elk and antelope, and the game
Differences in serum IgE antibody activity to benzylpenicillin and amoxicillin measured by RAST in a group of penicillin allergic patients
Authors: M. Blanca, C. Mayorga, F. Sanchez, J. M. Vega, J. Fernandez, C. Juarez, R. Suau, E. Perez
Journal: Allergy (1991)

To determine the influence of the acyl side chain on the IgE antibody specificity of the two most common penicillins inducing allergic reactions in our community, benzylpenicillin (BP) and amoxicillin (AX), IgE positive sera from a group of 24 patients allergic to penicillin were studied. RAST was determined in parallel to benzyl penicilloyl-polylysine (BPO-PLL) and amoxicilloyl-polylysine (AX-PLL) in each serum, and values greater than an established coefficient of variation of 15% were considered as different for either of the haptens used (BP and AX). 16 sera proved to be more positive to BP (Group A), six to AX (Group B) and in two IgE was positive to both haptens with a similar value (Group C). RAST titration concentration effect curves and RAST inhibition studies with a pool of sera from each group (A, B, C) and individual sera showed that most of them were more specific for either BPO or AX, a minority being of similar value to both. These findings indicate that the side chain structure of penicillins is relevant in the constitution of the antigenic determinant, although in some instances the common chemical structure of betalactam is recognised mainly by the IgE antibodies. The clinical relevance of these data needs to be established.
Antibiotics may be linked to risk of cancer
Authors: R. Dobson
Journal: BMJ (2008)

The risk of developing prostate, breast, lung, and colon cancer rises with use of antibiotics, a large observational study has found ( International Journal of Cancer 2008 Aug 14, doi: 10.1002/ijc.23622).

The risk of less common cancer has also been linked with antibiotic use. The study shows that the risk of being diagnosed with non-melanoma skin, duodenum, pancreas, kidney, bladder, male genitals (excluding prostate), and thyroid cancers as well as myeloma and leukaemia, was more than 1.5 times more among participants with six or more antibiotic prescriptions, compared with the group with lowest exposure.

“Findings suggest that antibiotic use, especially …
Phase III Open-Label Randomized Study of Cytarabine in Combination With Amonafide L-Malate or Daunorubicin As Induction Therapy for Patients With Secondary Acute Myeloid Leukemia
Authors: Richard M. Stone, Emanuele Mazzola, Donna Neuberg, Steven L. Allen, Arnaud Pigneux, Robert K. Stuart, Meir Wetzler, David Rizzieri, Harry P. Erba, Lloyd Damon, Jun-Ho Jang, Martin S. Tallman, Krzysztof Warzocha, Tamás Masszi, Mikkael A. Sekeres, Miklos Egyed, Heinz-August Horst, Dominik Selleslag, Scott R. Solomon, Parameswaran Venugopal, Ante S. Lundberg, Bayard Powell
Journal: Journal of Clinical Oncology (2015)

Purpose Secondary acute myeloid leukemia (sAML), defined as AML arising after a prior myelodysplastic syndrome or after antineoplastic therapy, responds poorly to current therapies. It is often associated with adverse karyotypic abnormalities and overexpression of proteins that mediate drug resistance. We performed a phase III trial to determine whether induction therapy with cytarabine and amonafide L-malate, a DNA intercalator and non–ATP-dependent topoisomerase II inhibitor that evades drug resistance mechanisms, yielded a superior complete remission rate than standard therapy with cytarabine and daunorubicin in sAML. Patients and Methods Patients with previously untreated sAML were randomly assigned at a one-to-one ratio to cytarabine 200 mg/m 2 continuous intravenous (IV) infusion once per day on days 1 to 7 plus either amonafide 600 mg/m 2 IV over 4 hours on days 1 to 5 (A + C arm) or daunorubicin 45 mg/m 2 IV over 30 minutes once per day on days 1 to 3 (D + C arm). Results The complete remission (CR) rate was 46% (99 of 216 patients) in A + C arm and 45% (97 of 217 patients) in D + C arm (P = .81). The 30- and 60-day mortality rates were 19% and 28% in A + C arm and 13% and 21% in D + C arm, respectively. Conclusion Induction treatment with A + C did not improve the CR rate compared with D + C in patients with sAML.
On-Pump Versus Off-Pump Coronary Artery Bypass Surgery in a Matched Sample of Women
Authors: Michael J. Mack, Phillip Brown, Frank Houser, Mark Katz, Aaron Kugelmass, April Simon, Salvatore Battaglia, Lynn Tarkington, Steven Culler, Edmund Becker
Journal: Circulation (2004)

Women have consistently higher mortality and morbidity than men after coronary artery bypass grafting (CABG). Whether elimination of cardiopulmonary bypass and performance of coronary artery bypass grafting off-pump (OPCAB) have a beneficial effect specifically in women has not been defined.From January 1998 through March 2002, 21 902 consecutive female patients at 82 hospitals underwent isolated CABG, as reported in an administrative database. Propensity score computer matching was performed based on 13 variables representing patient characteristics and preoperative risk factors to correct for and minimize selection bias. A total of 7376 (3688 pairs) women undergoing CABG surgery were able to be successfully matched. In a propensity score computer-matched cohort, multivariate logistic regression (odds ratio) revealed that women undergoing on-pump surgery had a 73.3% higher mortality (P=0.002) and a 47.2% higher risk of bleeding complications (P=0.019).In a retrospective analysis of women undergoing CABG, computer-matched to minimize selection bias, off-pump surgery led to decreased mortality and morbidity including bleeding complications.
ABC or colorectal disease. Constipation.
Authors: K. J. Moriarty, M. H. Irving
Journal: BMJ (1992)

There is considerable geographical and racial variation in bowel habit.Constipation is largely a subjective sensation and it has no universally accepted definition.A reasonable working definition is straining at passing stools for morp than 25% of bowel movements.The graph shows the relation between fibre intake in three populations, transit time., and stool weight.The function of the colon is to mix and -7 4~~propel its contents and to absorb water and .t~~~~~~Uelectrolytes.Colonic and rectal motilities are regulated by the sympathetic, parasympathetic, and enteric nervous systems-, and thus lesions of these pathways will influence stool frequency.Colonic motility is stimulated by factors such as food and emotion.The presence of sufficient faeces in the rectum to cause distension leads to reflex contraction of rectal smooth muscle and relaxation of the internal anal sphincter.By contracting the diaphragm and abdominal muscles and relaxing the striated muscles of the puborectalis and external 'anal sphincter the stool can be expelled. Causes of constipation
IGF-I binding proteins, IGF-I binding protein mRNA and IGF-I receptor mRNA in rats with acute renal failure given IGF-I
Authors: Julien BohÉ, Hu Ding, David P. Qing, Kyungwoo Yoon, Raimund Hirschberg, Grushenka H.I. Wolfgang, Joel D. Kopple
Journal: Kidney International (1998)
The polycomb group gene product Ezh2 regulates proliferation and differentiation of murine hepatic stem/progenitor cells
Authors: Ryutaro Aoki, Tetsuhiro Chiba, Satoru Miyagi, Masamitsu Negishi, Takaaki Konuma, Hideki Taniguchi, Makoto Ogawa, Osamu Yokosuka, Atsushi Iwama
Journal: Journal of Hepatology (2010)
Assessment of Nutritional Status
Authors: Derrick B. Jelliffe
Journal: JAMA (1975)

<h3>To the Editor.—</h3> The recent article by Dr. Bruce Bistrian et al (230:858, 1974) and the editorial by Dr. Butterworth (230:879, 1974) were of considerable interest to us. In brief, because the nutritional situation is so much worse and because resources are in all ways inadequate, the assessment of nutritional status using lowcost, simple methods has been tried out in less-developed countries for years. The arm muscle circumference measurement was first used as a community indicator of protein-calorie malnutrition in a nationwide survey in the Republic of Haiti in 1958 (<i>Acta Trop</i>18:1, 1961). Since then, it has been used widely in many different parts of the world and has the advantage of being a reliable method of screening in preschool children, even when the precise age is not known, as is the case in most of the world (<i>J Trop Pediatr</i>15:177, 1969). In addition, investigations have shown that
Physiotherapist-Directed Exercise, Advice, or Both for Subacute Low Back Pain
Authors: Liset H.M. Pengel, Kathryn M. Refshauge, Christopher G. Maher, Michael K. Nicholas, Robert D. Herbert, Peter McNair
Journal: Annals of Internal Medicine (2007)

Advice and exercise are widely recommended for subacute low back pain, but the effectiveness of these interventions is unclear.To investigate the effectiveness of physiotherapist-prescribed exercise, advice, or both for subacute low back pain.Factorial randomized, placebo-controlled trial.7 university hospitals and primary care clinics in Australia and New Zealand.259 persons with subacute low back pain (>6 weeks and <3 months in duration).Participants received 12 physiotherapist-directed exercise or sham exercise sessions and 3 physiotherapist-directed advice or sham advice sessions over 6 weeks.Primary outcomes were average pain over the past week (scale, 0 to 10), function (Patient-Specific Functional Scale), and global perceived effect (11-point scale) at 6 weeks and 12 months. Secondary outcomes were disability (Roland-Morris Disability Questionnaire), number of health care contacts, and depression (Depression Anxiety Stress Scales-21).Exercise and advice were each slightly more effective than placebo at 6 weeks but not at 12 months. The effect of advice on the pain scale was -0.7 point (95% CI, -1.2 to -0.2 point; P = 0.011) at 6 weeks and -0.4 point (CI, -1.0 to 0.3 point; P = 0.27) at 12 months, whereras the effect of exercise was -0.8 point (CI, -1.3 to -0.3 point; P = 0.004) at 6 weeks and -0.5 point (CI, -1.1 to 0.2 point; P = 0.14) at 12 months. The effect of advice on the function scale was 0.7 point (CI, 0.1 to 1.3 points; P = 0.014) at 6 weeks and 0.6 point (CI, 0.1 to 1.2 points; P = 0.023) at 12 months, and the effect of exercise was 0.4 point (CI, -0.2 to 1.0 point; P = 0.174) at 6 weeks and 0.5 point (CI, -0.1 to 1.0 point; P = 0.094) at 12 months. The effect of advice on the global perceived effect scale was 0.8 point (CI, 0.3 to 1.2 points; P < 0.001) at 6 weeks and 0.3 point (CI, -0.2 to 0.9 point; P = 0.24) at 12 months, and the effect of exercise was 0.5 point (CI, 0.1 to 1.0 point; P = 0.017) at 6 weeks and 0.4 point (CI, -0.1 to 1.0 point; P = 0.134) at 12 months. When administered together, exercise and advice had larger effects on all outcomes at 6 weeks (effect on pain, -1.5 [CI -2.2 to -0.7 point; P = 0.001], with similar results for other primary outcomes); however, by 12 months, there was a statistically significant effect only for function (effect, 1.1 points [CI, 0.3 to 1.8 points]; P = 0.005).Physiotherapists were not blinded.In participants with subacute low back pain, physiotherapist-directed exercise and advice were each slightly more effective than placebo at 6 weeks. The effect was greatest when the interventions were combined. At 12 months, the only effect that persisted was a small effect on participant-reported function. AUSTRALIAN CLINICAL TRIALS REGISTRY REGISTRATION NUMBER: 12605000039684.
Sensitivity and Specificity of the Suspected Blood Identification System in Video Capsule Enteroscopy
Authors: C. Signorelli, F. Villa, E. Rondonotti, C. Abbiati, G. Beccari, R. De Franchis
Journal: Endoscopy (2005)

Background and Study Aims: Capsule enteroscopy has become a standard tool for the evaluation of obscure gastrointestinal bleeding. Reviewing the video recordings of capsule examinations is time-consuming and requires prolonged attention. Recently, software that can recognize the frames containing “red spots”, the Suspected Blood Identification system (SBIS), has been developed with the aim of assisting in the analysis of video recordings. We assessed the sensitivity and specificity of the SBIS in patients undergoing capsule enteroscopy. Patients and Methods: 100 consecutive patients underwent capsule enteroscopy at our tertiary referral center, for the following indications: obscure gastrointestinal bleeding (75 patients), metastatic carcinoid (7 patients) known or suspected Crohn’s disease (5 patients), miscellaneous (13 patients). Capsule endoscopy was carried out by the standard method. Four gastroenterologists, experienced in capsule endoscopy, reviewed the recordings. Results: Small-bowel visualization was obtained in 95 cases. The physicians identified 209 “red spots”, 54 of which (25.8 %) were also identified by the SBIS. The overall sensitivity, specificity, and positive and negative predictive values of the SBIS, calculated on the number of true-positive, true-negative, false-positive and false-negative results, were 40.9 %, 70.7 %, 69.2 % and 42.6 %, respectively. Sensitivity was higher for the identification of red blood (60.9 %) than for nonbleeding ”red” lesions such as arteriovenous malformations (25.8 %). Conclusions: The SBIS has low sensitivity and specificity. It can be used as a complementary and rapid screening tool, but complete review of the recordings is still necessary.
Efficacy and Specificity of Chenodeoxycholic Acid Therapy for Dissolving Gallstones
Authors: Johnson L. Thistle, Alan F. Hofmann
Journal: New England Journal of Medicine (1973)

In a controlled trial, 53 patients with asymptomatic radiolucent gallstones in functioning gallbladders were treated with chenodeoxycholic acid, cholic acid or placebo. At six months, 11 of 18 patients receiving chenodeoxycholic acid had a decrease in gallstone size or number, but no response was observed in the 17 treated with cholic acid or in the 18 receiving placebo. Of seven others on chenodeoxycholic acid for two to three years, three had no gallstones, and three had continuing reduction in gallstone size. Of 13 patients with radiopaque gallstones only two responded to chenodeoxycholic acid. About one quarter of those ingesting chenodeoxycholic acid had transiently elevated serum glutamic oxalacetic transaminase, but no other abnormalities in liver function. Liver biopsies from eight patients were normal; three patients had minor changes. Chenodeoxycholic acid continues to appear to offer a specific medical treatment for asymptomatic radiolucent gallstones in functioning gallbladders. (N Engl J Med 289:655–659, 1973)
Shift Work as a Risk Factor for Future Type 2 Diabetes: Evidence, Mechanisms, Implications, and Future Research Directions
Authors: Mika Kivimäki, G. David Batty, Christer Hublin
Journal: PLoS Medicine (2011)

An Pan and colleagues examined data from two Nurses Health Studies and found that extended periods of rotating night shift work were associated with a modestly increased risk of type 2 diabetes, partly mediated through body weight.