tbuckley/cabot-search huggingface dataset:
Abstract 1377: Identification and characterization of small molecule inhibitors of the activator protein-1 pathway
Authors: Nicole R. Miller, Ruili Huang, Menghang Xia
Journal: Cancer Research (2011)

Abstract The activation of transcription factor activator protein-1 (AP-1) plays a critical role in multiple stages associated with carcinogenesis. The AP-1 complex is a dimeric transcription factor typically made up of proteins from JUN, FOS, ATF, and MAF families. Growth factors including EGF activate AP-1 via cell surface receptors such as EGF receptor (EGFR). EGFR activation of MAPK cascades lead to phosphorylation and nuclear translocation of AP-1 subunits. Discovery of selective inhibitors of the AP-1 pathway would lead to invaluable tools in the study, treatment and prevention of multiple cancers. To screen for AP-1 pathway inhibitors, a FRET-based AP-1 β-lactamase reporter was used to measure AP-1 activation in a ME-180 cervical cancer cell line. Approximately 75,000 compounds were screened, each at 7-15 concentrations, in a quantitative high-throughput screening (qHTS) format. Several novel structure series were identified from this screen. Hits selected based on a structure-activity relationship analysis were confirmed and further investigated for mechanism of action because EGF-stimulated AP-1 activation can be inhibited by multiple mechanisms in the pathway. Inhibitors mechanisms of action in the EFGR-mediated pathway were determined in follow-up studies including receptor inhibition, MAPK inhibition, and direct disruption of the AP-1 signaling complex. The identification and characterization of novel AP-1 inhibitors will lead to compounds that serve as probes of the AP-1 pathway and potential candidates for anticancer drug development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1377. doi:10.1158/1538-7445.AM2011-1377
CESAREAN SECTION WITH TOTAL HYSTERECTOMY NECESSITATED BY CONGENITAL MALFORMATION OF VAGINA
Authors: J. E. Countryman
Journal: JAMA (1923)

Miss O., aged 28, was admitted to the Deaconess Hospital, March 19, 1923, having been in labor eighteen hours, with pains on admission at five minute intervals and resembling those of a well advanced second stage. On routine examination it was apparent that an abnormality existed, but the patient was so unruly that an anesthetic was necessary to determine the condition present. The external genital organs had the appearance of virginity; the labia majora were normal, and the space between was covered with mucous membrane. The urethral orifice was markedly dilated, easily admitting the index finger to the interior of the bladder. No vaginal outlet could at that time be determined, and it was supposed that the vagina opened into the bladder. By rectal examination the head could be felt well down in the pelvis and the cervix about two thirds dilated. A cesarean section with hysterectomy was the only
Embryologic Specimens Desired
Authors: F. P. Mall
Journal: JAMA (1910)

To the Editor:—  I wish again to request throughThe Journalthat physicians send me embryologic specimens which are constantly falling into their hands. The collection of such specimens at the Johns Hopkins is now one of the best in existence, has been studied carefully by the staff, and is being used constantly by anatomists at home and abroad. About 100 published studies on human embryology are based on this collection, including the Manual of Human Embryology, in two volumes, published recently by the J. B. Lippincott Co.  Much more material than is now at hand is needed by investigators to further the science of human embryology, as well as to study with greater care the diseases of the ovum and the cause of abortion. To be of most value, the material should be preserved immediately after the abortion in a 10 per cent. dilution of liquor formaldehydi, or by
All a matter of viewpoint
Authors: Rob Doran
Journal: Journal of the Royal Society of Medicine (2010)

I am afraid that the authors have fallen into a common pit for the unwary in diagnosing squint from a single image.1 Every orthoptist knows that in order to diagnose a squint it is necessary to begin with the eyes in primary gaze (straight to the front). Second, one needs to employ the cover test before proceeding to examine alignment in the other cardinal gaze positions. A corneal light reflex, if present, is the most useful marker for ocular alignment, but in portraits may be misleading.

Judging by the self-portrait of Durer in their Figure 2, I contend that he is not displaying a squint at all, divergent or otherwise. Close scrutiny shows the corneal reflex in the right eye implies a convergent deviation, while the lack of visible lateral sclera a pseudo-divergent squint. In art, any apparent deviation of the eyes may be contrived with respect to the position of the observer. In this case, the sitter has his eyes to the right and fixed on an object more distant than the artist. This was historically a very common position adopted for portraiture, for a variety of artistic reasons.

For example, I enclose a photo similar to their portrait (Figure 1). This shows someone gazing to their right and beyond the camera. Despite appearances, the sitter has no squint and excellent stereoacuity – as befits a practising strabismologist!



Figure 1

Apparent exo-deviation of the eyes when the subject’s point of regard is beyond the plane of the observer (camera)
A pilot study of rhuIL-11 treatment of refractory ITP
Authors: James B. Bussel, Robin Mukherjee, Anne J. Stone
Journal: American Journal of Hematology (2001)

The objective of this research was to determine whether rhuIL-11 is an effective treatment in patients with refractory immune thrombocytopenic purpura (ITP). Platelet production is decreased in certain cases of refractory ITP. IL-11 stimulates megakaryocytopoiesis in vitro and was licensed for its clinical effects to ameliorate chemotherapy-induced thrombocytopenia. A pilot study was initiated, intending to enroll 12 patients with ITP. These patients were to receive rhuIL-11 (Neumega) at a dose of 50 μg/kg subcutaneously daily for 21 consecutive days and be observed afterward for 21 additional days. CBC with platelets were obtained twice weekly with visits and physical examinations weekly. The study was terminated after 7 patients were enrolled because of toxicity and lack of efficacy. All 7 patients had had ITP for >9 years and had failed splenectomy, intravenous gammaglobulin, corticosteroids, and a variety of other treatments. The patients at entry all had platelet counts <20,000/μl; 5 of 7 had counts <10,000/μl. The maximal median increase for any day of the study was 6,000/μl. No patient achieved a count of 30,000/μl, and only 3 patients achieved (once each) a platelet count >20,000/μl. Substantial toxicity was seen. The nadir hemoglobin decrease was a mean of 2 g/dl. rhuIL-11 was not effective at increasing the platelet count in any of these patients with refractory ITP. Toxicity was substantial. The lack of platelet response to rhuIL-11 in this study does not exclude the possibility of better effects at other doses and/or in less refractory patients. Am. J. Hematol. 66:172–177, 2001. © 2001 Wiley-Liss, Inc.
234. Polyclonal Insertion Sites in Two Rhesus Macaques after Non-Myeloablative Transplantation with MFGS-gp91phox Transduced Autologous CD34+PBPC
Authors: Sebastian Brenner, Martin F. Ryser, Uimook Choi, Narda Whiting-Theobald, Gilda Linton, Elizabeth Kang, Romy Lehmann, Anne M. Farese, Thomas J. MacVittie, Joachim Roesler, Mitchell E. Horwitz, Harry L. Malech
Journal: Molecular Therapy (2005)

Mutagenesis activation of the LMO-2 gene was observed to be associated with the development of lymphoid leukemia several years after two infants with X-SCID had their immune systems restored by gene therapy with a murine onco-retrovirus vector encoding the human IL2 receptor common gamma chain. Just recently, a third infant treated with the same vector was reported to also have developed T cell leukemia, however, insertion site analysis is pending in this case. These observations highlight the importance of the conductance of large animal marking studies which follow the insertional pattern of vectors planned for human treatments. We have recently reported that a high titer RD114 pseudotyped MFGS-gp91phox vector achieves unprecedented levels of correction of the oxidase defect in CD34+ cells from patients with X-linked chronic granulomatous disease in the xenotransplant NOD/SCID mouse model. In anticipation of considering clinical use of this vector, we transduced G-CSF-FLT3L fusion protein mobilized peripheral blood CD34+ cells (CD34+ PBPC) of two healthy rhesus macaques with the RD114-MFGS-gp91phox. Transduced CD34+PBPC were transplanted on culture day 4 into two non-myeloablative (2|[times]|300 Rads) irradiated animals. The in vivo marking decreased over the first months and stabilized at about 8 months post transplant. Marking for animal J976 and D406 at 15 and 19 months, respectively is 1.3% and 0.3% in B lymphocytes, 0.3% and 0.3% in neutrophils and 0.7% and 0.4% in T lymphocytes at which time the animals remained healthy. Vector insertion analysis was performed using LAM-PCR and gel electrophoresis. Analyses of cloned and sequenced integration sites revealed 44 integrations sites in monkey J976, and 33 integration sites in monkey D406 with no predominant clone seen to emerge over time. 27% (J976) and 12% (D406) of the insertion sites were identified as coding regions (intron or exon). Nested PCR with insertion site specific primers enabled recovery of identified sites from different cell lineages at different time points. In summary, we detected a high number of integration sites in two rhesus macaques transplanted with gene-modified CD34+ cells despite low marking due to non-myeloablative conditioning.
Prevalence of Fasting Hyperglycemia and Known Non-Insulin-Dependent Diabetes Mellitus Classified by Plasma C-Peptide: Fredericia Survey of Subjects 60–74 Yr Old
Authors: Else M Damsgaard, Ole K Faber, Anders Frøland, Anders Green, Mogens Hauge, Niels V Holm, Steffen Iversen
Journal: Diabetes Care (1987)

A Danish population of 5699 individuals (60–74 yr old) was screened by fasting blood glucose (FBG) and interviewed about known diabetes. The distribution of FBG in individuals not known to have diabetes showed no sex difference or significant variation with age. Fasting hyperglycemia (FH), defined as FBG ≥ 7 mM in subjects without a history of diabetes, was found in 1.7% of men and women. Known diabetes (KD) had a prevalence of 3.9 and 5.0% in men and women, respectively. The prevalence rates of FH and KD increased significantly with age. In the two subgroups, plasma C-peptide was measured after overnight fasting and subsequently 6 min after an intravenous injection of glucagon. Based on the distribution of the C-peptide concentrations in non-insulin-treated KD subjects, lower limits for non-insulin-dependent diabetes mellitus (NIDDM) of 0.30 pmol/ml for fasting C-peptide and 0.60 pmol/ml for stimulated C-peptide were arbitrarily chosen. According to these cutoff points, only 38.5% of KD subjects treated with insulin had insulin-dependent diabetes mellitus, corresponding to 9.3% of all KD subjects. After exclusion of these patients, the prevalence of recognized NIDDM was 3.5% in men and 4.5% in women. All FH subjects except one had C-peptide values in the NIDDM interval. A close agreement between fasting and glucagon-stimulated C-peptide was seen. In epidemiological studies with an expected high prevalence of NIDDM, we propose to use fasting C-peptide for classification of patients with insulin-treated diabetes.
Education in Surgery for General Practice
Authors: D. Wilkie
Journal: BMJ (1937)

At the present time there is a somewhat widespread feeling of discontent with the medical curriculum, and various plans are being discussed for its amendment and improve- ment.It is generally conceded that with the immense additions to knowledge in the last two decades, with the development and growth of specialties, and with the wealth of technical detail which e'ach of these involves, the medical student of to-day tends to have brought before him more than he can assimilate, and is thus apt to lose balance and perspective.The need for a thorough grounding in the fundamental sciences has become more and not less neces- sary.
Cardiovascular Effects of Infusions of Epinephrine and Angiotensin Singly and in Combination
Authors: PETER F. BINNION, J. DONALD HATCHER
Journal: Circulation Research (1963)

Angiotensin infused at 0.05 mcg/kg per min for 30 minutes into anesthetized dogs reduces cardiac output, raises arterial blood pressure, increases total peripheral resistance, but does not raise right ventricular pressure nor change left ventricular stroke work. It is suggested that this infusion rate may be comparable to the rate of production under certain conditions. The cardiovascular action of epinephrine given at rates similar to those occurring under stress, namely 0.1 mcg/kg per min and 0.2 mcg/kg per min for 30 minutes, are discussed. In the former dose no cardiovascular effects are seen, but with the latter dose the usual cardiovascular effects were observed. A transient augmentation of effect on cardiac output and stroke work is noted with a combination of epinephrine 0.1 mcg/kg per min and angiotensin 0.05 mcg/kg per min, and of stroke work alone when the dose of each is doubled. It is suggested that the physiological importance of this interaction may be limited to the initial phases of certain stresses in which both these substances are released. The mechanism of this effect is not clear, but may be the result of the interaction of epinephrine, angiotensin and aldosterone.
Association of Periampullary Duodenal Diverticula with Bile Duct Stones and with Technical Success of Endoscopic Retrograde Cholangiopancreatography
Authors: T. C. Tham, M. Kelly
Journal: Endoscopy (2004)

Periampullary diverticula are thought to be associated with bile duct stones. However, studies to date have been inconclusive as they have not taken into account the influence of age. Our study analysed the association of diverticula with bile duct stones and with the technical success of endoscopic retrograde cholangiopancreatography (ERCP).A total of 415 consecutive patients who were undergoing ERCP were prospectively entered into a database. Of these patients, 83 (20 %; mean age 73 years; 34 men, 49 women) were found to have diverticula. The age-matched control group comprised 261 patients (mean age 72 years; 106 men, 155 women). The chi-squared test was used to analyse the results.In the diverticula group, 53 (64 %) had bile duct stones, compared with 86 (33 %) of the controls ( P < 0.0001), with an odds ratio of 3.6. Significantly more patients in the diverticula group had primary bile duct stones; also significantly more of them had stones in both the bile duct and gallbladder. There was no difference between the two groups with regard to previous history of pancreatitis (10 % in the diverticula group vs. 11 % in the control group). There were no significant differences found between the diverticula group and the control group in terms of successful duct cannulation (94 % in both groups), sphincterotomies (96 % vs. 98 %) or stone extraction (94 % vs. 88 %). The incidence of complications was similar in the two groups (diverticula group 5 % vs. control group 3.3 %).Periampullary diverticula are associated with an increased incidence of bile duct stones but not with pancreatitis. Diverticula did not cause any technical difficulties at ERCP or increase the risk of complications.
Reply to the letter of Matsushita et al.
Authors: P. Katsinelos, G. Chatzimavroudis
Journal: Endoscopy (2007)

We appreciate the interest of Matsushita and colleagues in our study which described a novel technique of double injection of dextrose 50 % plus epinephrine (D50+E) solution in the endoscopic hemostasis of post-endoscopic sphincterotomy (ES) hemorrhage [1].
Ketoacidosis at Diagnosis of Type 1 Diabetes in Children in Northern Finland
Authors: Anne Hekkala, Mikael Knip, Riitta Veijola
Journal: Diabetes Care (2007)

To study the frequency of diabetic ketoacidosis (DKA) over a 20-year period among children diagnosed with type 1 diabetes in northern Finland.The study population comprised 585 patients (328 boys) diagnosed with type 1 diabetes aged <15 years in the Department of Pediatrics, Oulu University Hospital, between 1 January 1982 and 31 December 2001. The data for clinical characteristics were collected retrospectively from the patients' case records. The earlier 10-year period (1982-1991) was compared with the later 10-year period (1992-2001). Two definitions for DKA were used: DKA(i) pH <7.30 or DKA(ii) pH <7.30 and/or bicarbonate <15 mmol/l.During the later 10-year period, children less often had DKA at diagnosis [DKA(i) 15.2 vs. 22.4%, P = 0.028, and DKA(ii) 18.9 vs. 29.5%, P = 0.003]. The proportion of young children aged <5 years at diagnosis increased over time, but the frequency of DKA also was lower in this age-group during 1992-2001 compared with the earlier 10-year period [DKA(i) 17.7 vs. 32.1%, P = 0.052, and DKA(ii) 20.3 vs. 42.6%, P = 0.005]. In children aged <2 years at diagnosis, the frequency of DKA remained high during 1992-2001 [DKA(i) 39.1% and DKA(ii) 47.8%].The overall frequency of DKA in children with newly diagnosed type 1 diabetes decreased over a 20-year period in northern Finland. However, children aged <2 years are still at high risk for DKA at diagnosis.
Does long-term oxygen therapy affect quality of life in patients with chronic obstructive pulmonary disease and severe hypoxaemia?
Authors: AA Okubadejo, EA Paul, PW Jones, JA Wedzicha
Journal: European Respiratory Journal (1996)

Long-term oxygen therapy (LTOT) improves survival in patients with hypoxaemic chronic obstructive pulmonary disease (COPD), but previous studies using general health measures have shown no effect on quality of life (QoL). In this study, the effect of LTOT on QoL was assessed using a disease-specific health measure, the St George's Respiratory Questionnaire (SGRQ). Twenty three hypoxaemic COPD patients (15 females and 8 males) were studied before and after starting LTOT: median age 71 (range 47-82) yrs, mean (SD) forced expiratory volume in one second (FEV1) 0.75 (0.22) L, arterial oxygen tension (Pa,O2) 6.95 (0.75) kPa, arterial carbon dioxide tension (Pa,CO2) 6.52 (1.21) kPa. A control group comprised 18 COPD patients (6 females and 12 males) with less severe hypoxaemia: median age 72 (range 58-85) yrs, FEV1 0.94 (0.33) L, Pa,O2 8.17 (0.94) kPa, Pa,CO2 6.02 (0.75) kPa. QoL was measured at baseline, 2 weeks, 3 and 6 months. The LTOT group had higher SGRQ total scores than controls (p<0.05) at all visits, implying lower QoL. Repeated measures analysis of variance showed no effect of LTOT on QoL over 6 months (F=0.43, p=0.79). In this study we detected no change in quality of life using a disease-specific health measure in patients with severe chronic obstructive pulmonary disease using an oxygen concentrator to provide long-term oxygen therapy.
Bupivacaine. A review of 2,077 cases
Authors: D. C. Moore
Journal: JAMA (1970)

Bupivacaine (LAC 43, Marcaine [Sweden]) hydrochloride, a long-acting local anesthetic agent in concentrations of 0.1%, 0.25%, 0.5%, and 0.75% with and without a vasoconstrictor drug, was used in caudal, epidural, and peripheral nerve block. Onset occurred in 4 to 10 minutes and maximum analgesia in 15 to 30 minutes. Concentrations of 0.25%, 0.5%, and 0.75% consistently produced excellent sensory anesthesia, but only 0.75% consistently produced profound motor relaxation needed for intra-abdominal surgery. However, 0.25% and 0.5% were satisfactory in caudal, epidural, and peripheral nerve block for (1) pain relief of labor; (2) vaginal delivery; (3) perineal surgery; and (4) extremity surgery. Two inadvertent intravenous injections of 100 and 120 mg of bupivacaine hydrochloride caused mild systemic toxic reactions but no untoward sequelae. One inadvertent subarachnoid injection of 110 mg resulted in a total spinal block with an uneventful recovery.
Evolution of QRS-T relationship from birth to adolescence in Frank-lead orthogonal electrocardiograms of 1492 normal children.
Authors: P M Rautaharju, A Davignon, F Soumis, E Boiselle, A Choquette
Journal: Circulation (1979)

Patterns of evolution of QRS-T relationship were investigated by determining statistical distributions of QRS and STT integral vectors and the ventricular gradient vector in 1492 normal children divided into 12 age groups from birth to the age of 16 years. From birth to the age of 4 days, the ventricular gradient vector shifts posteriorly and to the left due to posterior shift of the STT integral vector and an increase in the spatial angle between QRS and STT integral vectors to a mean value of 103 degrees. These early neonatal changes in QRS-T relationship probably reflect the sudden reduction of hemodynamic load and the subsequent postnatal atrophy of the right ventricle while the left ventricular load slowly increases. The magnitude of the ventricular gradient vector increases from age 3 weeks until about 7 years. The increase appears to be related to a gradual increase in the magnitude of the QRS and STT integral vectors and a drastic decrease in the spatial angle between them. The spatial angle between QRS and STT integral vectors reaches it minimum (22 degrees) in the age group 1.5--4.5 years, suggesting that at that age the average direction of ventricular excitation and repolarization wavefronts are nearly opposite to each other. In addition to the shifting balance between the left and right ventricular hemodynamic load, other factors, such as the maturation of the sympathetic nervous system, may be important in determining spatial gradients in the duration of action potentials, thus influencing the relationship between ventricular excitation and repolarization.
Child of our time: how childhood now lasts a lifetime
Authors: D. Spence
Journal: BMJ (2011)

<h3>Abstract</h3> <h3>OBJECTIVE</h3> To evaluate the emerging classes of antihyperglycemic agents that target the incretin pathway, including their therapeutic efficacy and side effect profiles, in order to help identify their place among the treatment options for patients with type 2 diabetes. <h3>QUALITY OF EVIDENCE</h3> MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews were searched. Most evidence is level I and II. <h3>MAIN MESSAGE</h3> Two classes of incretin agents are currently available: glucagonlike peptide 1 (GLP1) receptor agonists and dipeptidyl peptidase 4 (DPP4) inhibitors, both of which lower hyperglycemia considerably without increasing the risk of hypoglycemia. The GLP1 receptor agonists have a greater effect on patients’ glycated hemoglobin A<sub>1c</sub> levels and cause sustained weight loss, whereas the DPP4 inhibitors are weight-neutral. <h3>CONCLUSION</h3> The GLP1 and DPP4 incretin agents, promising and versatile antihyperglycemic agents, are finding their way into the therapeutic algorithm for treating type 2 diabetes. They can be used in patients not adequately controlled by metformin monotherapy or as initial therapy in those for whom metformin is contraindicated.