tbuckley/cabot-search huggingface dataset:
Minocycline for Symptomatic Neurosyphilis in Patients Allergic to Penicillin
Authors: A. De Maria, C. Solaro, M. Abbruzzese, A. Primavera
Journal: New England Journal of Medicine (1997)

To the Editor: Treatment of symptomatic neurosyphilis is an increasingly common clinical problem because of its rising incidence, particularly in patients coinfected with the human immunodeficiency virus type 1 (HIV-1).1 The mainstay of treatment remains intravenous penicillin G at high dosage, ranging from 12 million to 24 million units given six times a day for 10 to 14 days.1 Treatment options for patients with neurosyphilis who are allergic to penicillin are limited. Such patients should undergo a skin test and hospitalization for a penicillin-desensitization protocol before intravenous penicillin administration.2,3 We know little, however, about the outcomes of high-dose penicillin . . .
OC-165 No increase in surgical complication in patients treated with rescue therapy for acute severe ulcerative colitis: data from the UK IBD audit
Authors: R W Lynch, C Down, M Roughton, I D Arnott
Journal: Gut (2012)

Introduction High dose steroids followed by colectomy if required remains the mainstay of treatment for active ulcerative colitis (UC). Recently we have seen the introduction of second-line medical therapies with the hope of avoiding the need for surgery when medical therapy fails. Using a cohort of 2981 and 3049 ulcerative colitis patients from the 2nd and 3rd rounds of the UK IBD audit we aim to assess whether the use of second-line medical therapies has an impact on the need for surgery and complication of surgery when needed. Methods We audited 3049 patients with ulcerative colitis. Median age was 42; there were 1421 females and 1628 males. There were 495 elective admission for surgery and 2504 acute admissions of which 882 were considered to have severe disease. Of the 2504 acute admissions; 157 underwent surgery during their admission. 202 Sites audited a median of 18 UC patients per site that were admitted with IBD between 1 September 2009 and 31 August 2010. The results of this were compared against the results from the 2008 UK IBD audit which collected data on 2981 UC patients of which there were 863 with severe disease. Of the severe patients 163 patients underwent surgery. 209 sites audited a median of 17 UC patients per site that were admitted with IBD between 1 September 2007 and 31 August 2008. Results There was no significant change in the operative rate among ASUC patients, 18.9% (163/863) in 2008 and 17.8% (157/882) in 2010 (p<0.6). Additionally there was no significant change in the mortality within the surgical populations 2.5% (4/163) in 2008 vs1.9% (3/157) in 2010 (p<0.96). There were significantly more patients proceeding to surgery following anti-TNFα therapy in 2010 10.82% (17/157) vs 3.7% (6/163) (p<0.008). Using the Travis criteria we also found that there were significantly less high risk surgical patients in 2010, 67.5% (106/157) compared to 83.4% (136/163) (p<0.002); this was also reflected in a significant reduction in the overall amount of high risk patients in the ASUC population. Post-operative complications are not statistically different between patients who did and did not receive rescue medical therapy 40.0% (26/65) vs 34.8% (32/92) (p<0.8). There was also no statistical difference in complications between rounds, 32.5% (53/163) in 2008 vs 36.9% (58/157) in 2010 (p<0.4). Conclusion The surgical rate has remained the same over the two audit periods; however there has been a significant reduction in the proportion of high risk patients undergoing operations. This could in part be related to the increased use of second line medical therapies between the two audit rounds, with significantly more patients receiving anti-TNFα prior to surgery. The use of second line medical therapies did not increase the risk of surgery. Competing interests None declared.
Tricyclic Antidepressant Cardiotoxicity
Authors: Richard Dorsey
Journal: JAMA (1977)

<h3>To the Editor.—</h3> The article by Robinson and Barker (236:2089, 1976) regarding tricyclic antidepressant (TCA) toxicity has its good and bad features. The good is that the Food and Drug Administration and its advisors are continuing to present their data and views in a general scientific forum. The bad is that this particular article, while providing very useful and timely information, could also mislead the physician on important scientific and regulatory points. In the scientific area, the authors state that "unfortunately, plasma TCA levels are too variable from patient to patient to be of value in defining a safe therapeutic range." Evidence suggests that, in fact, minimum and maximum therapeutic plasma levels for TCAs do exist and are useful guides to therapy.<sup>1,2</sup> In defining "resistant cases of depression" as adults failing to respond to 200 mg imipramine hydrochloride daily, the authors ignore evidence that at least 30% of patients
Modulation of Mitochondrial ATP-Dependent K <sup>+</sup> Channels by Protein Kinase C
Authors: Toshiaki Sato, Brian O’Rourke, Eduardo Marbán
Journal: Circulation Research (1998)

Pharmacological openers of mitochondrial ATP-dependent K+ (mitoKATP) channels mimic ischemic preconditioning, and such cardioprotection can be prevented by mitoKATP channel blockers. It is also known that protein kinase C (PKC) plays a key role in the induction and maintenance of preconditioning. To look for possible mechanistic links between these 2 sets of observations, we measured mitochondrial matrix redox potential as an index of mitoKATP channel activity in rabbit ventricular myocytes. The mitoKATP channel opener diazoxide (100 micromol/L) partially oxidized the matrix redox potential. Exposure to phorbol 12-myristate 13-acetate (PMA, 100 nmol/L) potentiated and accelerated the effect of diazoxide. These effects of PMA were blocked by the mitoKATP channel blocker 5-hydroxydecanoate, which we verified to be a selective blocker of the mitoKATP channel in simultaneous recordings of membrane current and flavoprotein fluorescence. The inactive control compound 4alpha-phorbol (100 nmol/L) did not alter the effects of diazoxide. We conclude that the activity of mitoKATP channels can be regulated by PKC in intact heart cells. Potentiation of mitoKATP channel opening by PKC provides a direct mechanistic link between the signal transduction of ischemic preconditioning and pharmacological cardioprotection targeted at ATP-dependent K+ channels.
Early Activation of Caspases during T Lymphocyte Stimulation Results in Selective Substrate Cleavage in Nonapoptotic Cells
Authors: Antoine Alam, Luchino Y. Cohen, Salah Aouad, Rafick-Pierre Sékaly
Journal: The Journal of Experimental Medicine (1999)

Apoptosis induced by T cell receptor (TCR) triggering in T lymphocytes involves activation of cysteine proteases of the caspase family through their proteolytic processing. Caspase-3 cleavage was also reported during T cell stimulation in the absence of apoptosis, although the physiological relevance of this response remains unclear. We show here that the caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD) blocks proliferation, major histocompatibility complex class II expression, and blastic transformation during stimulation of peripheral blood lymphocytes. Moreover, T cell activation triggers the selective processing and activation of downstream caspases (caspase-3, -6, and -7), but not caspase-1, -2, or -4, as demonstrated even in intact cells using a cell-permeable fluorescent substrate. Caspase-3 processing occurs in different T cell subsets (CD4+, CD8+, CD45RA+, and CD45RO+), and in activated B lymphocytes. The pathway leading to caspase activation involves death receptors and caspase-8, which is also processed after TCR triggering, but not caspase-9, which remains as a proenzyme. Most importantly, caspase activity results in a selective substrate specificity, since poly(ADP-ribose) polymerase (PARP), lamin B, and Wee1 kinase, but not DNA fragmentation factor (DFF45) or replication factor C (RFC140), are processed. Caspase and substrate processing occur in nonapoptotic lymphocytes. Thus, caspase activation is an early and physiological response in viable, stimulated lymphocytes, and appears to be involved in early steps of lymphocyte activation.
CFTR potentiator for cystic fibrosis
Authors: Siu P Cho
Journal: Thorax (2012)

snaring it via the bronchoscope (figure 1E), the Angio-Seal was placed and the collagen plug was directed into the fistula and deployed under bronchoscopic guidance (figure 1F,G).After 2 months, the patient remained well, and the fistulae were clinically closed.
IgE reactivity and cross-reactivity to Japanese cedar (cryptomeria japonica) and cypress (chamaecyparis obtusa) pollen allergens in dogs with atopic dermatitis
Authors: Masahiro Sakaguchi, Kenichi Masuda, Hiroshi Yasueda, Saburo Saito, Douglus J Deboer, Hajime Tsujimoto
Journal: Journal of Allergy and Clinical Immunology (2002)
Stem Cell Collection and Gene Transfer in Fanconi Anemia
Authors: Patrick F Kelly, Susan Radtke, Christof von Kalle, Brenden Balcik, Kimberley Bohn, Robin Mueller, Todd Schuesler, Moira Haren, Lilith Reeves, Jose A Cancelas, Thomas Leemhuis, Richard Harris, Arleen D Auerbach, Franklin O Smith, Stella M Davies, David A Williams
Journal: Molecular Therapy (2006)

Fanconi anemia (FA) is a rare genetic syndrome characterized by progressive bone marrow failure (BMF), congenital anomalies, and a predisposition to malignancy. Successful gene transfer into hematopoietic stem cells (HSCs) could reverse BMF in this disease. We developed clinical trials to determine whether a sufficient number of CD34+ stem cells could be collected for gene modification and to evaluate the safety and efficacy of HSC-corrective gene transfer in FA genotype A (FANCA) patients. Here, we report that FA patients have significant depletion of their BM CD34+ cell compartment even before severe pancytopenia is present. However, oncoretroviral-mediated ex vivo gene transfer was efficient in clinical scale in FA-A cells, leading to reversal of the cellular phenotype in a significant percentage of CD34+ cells. Re-infusion of gene-corrected products in two patients was safe and well tolerated and accompanied by transient improvements in hemoglobin and platelet counts. Gene correction was transient, likely owing to the low dose of gene-corrected cells infused. Our early experience shows that stem cell collection is well tolerated in FA patients and suggests that collection be considered as early as possible in patients who are potential candidates for future gene transfer trials. Fanconi anemia (FA) is a rare genetic syndrome characterized by progressive bone marrow failure (BMF), congenital anomalies, and a predisposition to malignancy. Successful gene transfer into hematopoietic stem cells (HSCs) could reverse BMF in this disease. We developed clinical trials to determine whether a sufficient number of CD34+ stem cells could be collected for gene modification and to evaluate the safety and efficacy of HSC-corrective gene transfer in FA genotype A (FANCA) patients. Here, we report that FA patients have significant depletion of their BM CD34+ cell compartment even before severe pancytopenia is present. However, oncoretroviral-mediated ex vivo gene transfer was efficient in clinical scale in FA-A cells, leading to reversal of the cellular phenotype in a significant percentage of CD34+ cells. Re-infusion of gene-corrected products in two patients was safe and well tolerated and accompanied by transient improvements in hemoglobin and platelet counts. Gene correction was transient, likely owing to the low dose of gene-corrected cells infused. Our early experience shows that stem cell collection is well tolerated in FA patients and suggests that collection be considered as early as possible in patients who are potential candidates for future gene transfer trials.
CELLULAR MECHANISMS OF PROTEIN METABOLISM IN THE NEPHRON
Authors: N. Kretchmer, H. W. Dickerman
Journal: The Journal of Experimental Medicine (1954)

1. Shifts of enzymatic activity have been followed during the formation and evolution of the droplets that form in the cells of the proximal convolution of the nephron of the rat after the injection of a 50 per cent solution of egg white in isotonic saline. 2. Twelve hours after injection there is a 35 to 40 per cent decrease in succinoxidase and cytochrome oxidase activities in the fraction containing the larger particles; i.e. mitochondria and droplets in equal concentration. Although after 30 hours the quantitative proportion of droplets and mitochondria is the same as previously, the activities of the fraction have returned to the normal observed originally in the uninjected rat in a corresponding fraction consisting of mitochondria only. 3. The microsome fraction shows an average increase of 35 per cent in oxidative enzyme activities during the early period following injection, and decreases to the original figure in the later period of droplet formation. 4. It is concluded from the shifting pattern of localization of oxidative enzyme activity within the cell particulates that the absorption droplets arise by the incorporation of the mitochondrial elements, which originally contain the highest enzyme activity, with absorbed protein through the intermediate stage of smaller (microsomal) particles.
Case of salt overdosage.
Authors: R C McGouran
Journal: BMJ (1975)

The results of investigations showed: plasma sodium 130 mmol/l (130 mEq/l); potassium 6-8 mmol/l (6-8 mEq/l); creatinine 274 .mol/l(3-1 mg/100 ml); urea 3 8 mmol/l (23 mg/100 ml); haemoglobin 18 5 g/dl; white cell count 19x109/1 19000/mm3); serum creatine phosphokinase (CKP) 5 000 IU; serum aldolase 182 Sibley Lehninger units!ml; serum glutamic oxaloacetic transaminase (SGOT) 3 330 IU; hepatitis associated antigen positive.Because of the latter muscle and renal biopsies were not done.A skeletal survey and intravenous urogram were normal.Over the first 24 hours he passed 900 ml of dark brown urine.This reacted positively for haem (orthotolidine reaction-Labstix), but contained no red cells or casts.The next day spectrophotometric examination of the urine (pH6) for myoglobin was negative.He developed hypercatabolic ARF requiring peritoneal dialysis.The patient remained oliguric for 15 days and then experienced a profound diuresis with a weight loss of 20 kg.During this period the urinary sodium excretion was 300-400 mmol/24h; potassium excretion 100-150 mmol/24h; calcium excretion 20-22-5 mmol/24h (800- 900 mg/24 h); serum calcium 3-1 mmol/I (12.3 mg/lOml); serum phosphorus 3-0 mmol/l (9 4 mg/100 ml); and serum alkaline phosphatase 65 IU.The swelling and tenderness of his legs resolved leaving severe global wasting.Ten weeks later all biochemical values were normal The paraplegia recovered completely.
Training the Resident to Meet the Detail Man-Reply
Authors: Robert P. Ferguson
Journal: JAMA (1989)

<h3>In Reply. —</h3> I too would expect my physician to prescribe my medications based solely on what he or she felt was best for me. However, detail men often select out data to present to physicians that support the argument that their product is superior. Furthermore, if the pharmaceutical company provides an incentive (economic or otherwise) to use its product, a physician's decision process may be influenced. I agree with Mr Hall's comments that medical schools and residency programs should train physicians to evaluate pharmaceutical products critically. This was the primary motivation behind the development of our recent seminar that dealt with interactions.
EFFECTS OF SWITCHING FROM CARVEDILOL TO BISOPROLOL IN PATIENTS WITH CHRONIC HEART FAILURE
Authors: Tatsunori Taniguchi, Yasuhiro Ichibori, Machiko Matsui Kanzaki, Hitoshi Minamiguchi, Isamu Mizote, Tomohito Ohtani, Yoshihiro Asano, Yasushi Sakata, Issei Komuro
Journal: Journal of the American College of Cardiology (2012)
An Aromatase-Producing Sex-Cord Tumor Resulting in Prepubertal Gynecomastia
Authors: Patricia Coen, Howard Kulin, Thomas Ballantine, Richard Zaino, Elizabeth Frauenhoffer, Danielle Boal, Sandra Inkster, Angela Brodie, Richard Santen
Journal: New England Journal of Medicine (1991)

GYNECOMASTIA in prepubertal children usually results from an increase in endogenous estrogen production. Estrogen biosynthesis involves the transformation of steroid precursors to androgens and then conversion of androgens to estrogens by the enzyme aromatase. Excessive production of estrogen may result from an increase in levels of endogenous substrate, aromatase activity, or both. A model for the isolated increase in aromatase activity is the Sebright Bantam rooster, in which the aromatase activity is increased 100-fold.1 A human counterpart of the Sebright Bantam rooster has also been described in which increased aromatase activity resulted in the overproduction of estradiol and gynecomastia.2 , 3 In . . .
A Trial for My Life
Authors: Patty Delaney Klafehn
Journal: JAMA (1995)

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Some Indications for the Diagnosis and Treatment of Aortic Aneurism
Authors: F. A. Mahomed
Journal: BMJ (1878)

blood-pressure; but I think it is proved that, so far as the kidney is concerned, there is no shutting off of the blood from the glomeruli ; and it is probable that, tbroughout the body, the obstruction is really in the capillary network, though whether that depends on structural alterations in the vessels or altered relations of osmosis be- tween the intravascular and extravascular fluids, I wvill not attempt to decide, although the latter seems to me, in the absence of any anatomical facts, to offer a plausible explanation.
ATP-dependent transport systems for organic anions
Authors: Piotr Zimniak, Yogesh C. Awasthi
Journal: Hepatology (1993)

Biologcal membranes evolved because of the need to define "self" as opposed to "the outside."Living systems cannot, however, function in isolation from their surroundings, and massive amounts of material continually cross membranes.Much of this material is organic: nutrients are taken up by cells, waste products are excreted and metabolites enter and leave numerous cell organelles and intracellular compartments.Except for very hydrophobic compounds, transport is mediated by proteins.In some cases, facilitated (i.e., transportermediated) diffusion of the solute is adequate; for example, this is the case in the uptake of glucose by erythrocytes.The concentration of glucose in serum is high and relatively constant over time, and the modest requirements of the erythrocyte are covered predictably and comfortably by glucose flowing in down its concentration gradient.The situation is quite different in the case of some other tissues (e.g., the intestinal epithelium).These cells are exposed to varying but usually low glucose concentrations in the intestinal lumen, and their function is to take up the nutrient efficiently.In this example, as in many other cases, the uptake is active (i.e., it proceeds against the concentration [or, more generally, electrochemical1 gradient of the solute and requires the expenditure of free energy).In most cases, the active transport of organic compounds is secondary to (or is coupled to) the transport of inorganic cations.An ATP-utilizing pump, usually the Na+,K* -ATPase, establishes an electrochemical ion gradient, in this case Na', which in turn drives the transport of other molecules.This coupling is achieved through the requirement of the transporter for binding of both Na + and the other solute to move both across the membrane simultaneously; binding of either alone does not lead to transport.This scheme, which has been well established for numerous systems, attained a status of near-dogma in the field, not least because of its parsimonious elegance.Just as centrally generated
The role of prostaglandin E and thromboxane-prostanoid receptors in the response to prostaglandin E2 in the aorta of Wistar Kyoto rats and spontaneously hypertensive rats
Authors: Eva H.C. Tang, Boye L. Jensen, Ole Skott, George P.H. Leung, Michel Feletou, Ricky Y.K. Man, Paul M. Vanhoutte
Journal: Cardiovascular Research (2007)

The present study examined the hypothesis that prostaglandin E2 (PGE2) through activation of prostaglandin E (EP) receptor contributes to endothelium-dependent contractions. Western blotting revealed that the protein expression of EP1 receptor was significantly down-regulated in the aorta of the spontaneously hypertensive rat (SHR), but there was no significant difference in the expression of EP2, EP4, and total EP3 receptors between preparations of Wistar Kyoto rats (WKY) and SHR. Isometric tension studies showed that low concentrations of PGE2 caused endothelium-dependent relaxations in WKY but not in aortas of the SHR. High concentrations of PGE2 evoked contractions predominately through the activation of thromboxane-prostanoid (TP) receptors in the WKY, but involves the dual activation EP and TP receptors in the SHR. SQ29,548, BAYu3405 and Terutroban (TP receptor antagonists), and AH6809 (non-selective EP receptor antagonist) abolished, while SC19220 (preferential EP1 receptor antagonist) did not inhibit endothelium-dependent contractions. Both SC19220 and AH6809 significantly inhibited contractions to U46619 (TP receptor agonist). The present study demonstrates that the contraction caused by PGE2 in the SHR aorta is dependent on the activation of EP1 and TP receptors, but that endothelium-dependent contractions do not require the former. Thus, PGE2 is unlikely to be an endothelium-derived contracting factor in this artery. The ability of AH6809 to inhibit endothelium-dependent contractions can be attributed to its partial antagonism at TP receptors. Nevertheless, the impairment of PGE2-mediated relaxation may contribute to endothelial dysfunction in the aorta of the SHR.