tbuckley/cabot-search huggingface dataset:
In Vivo Hepatic Adenoviral Gene Delivery Occurs Independently of the Coxsackievirus–Adenovirus Receptor
Authors: Theodore Smith, Neeraja Idamakanti, Helen Kylefjord, Michele Rollence, Laura King, Michele Kaloss, Michael Kaleko, Susan C. Stevenson
Journal: Molecular Therapy (2002)

Systemic administration of adenoviral vectors leads to a widespread distribution of vector. Therefore, targeting of adenoviral vectors to specific tissues or cell types will require methods to ablate the normal tropism of the vector simultaneously with the introduction of new receptor specificities. To inhibit native receptor binding, we mutated residues in the AB loop of the adenovirus type 5 (Ad5) fiber. We genetically incorporated the S408E-P409A mutation, referred to as KO1, into the adenoviral genome alone or in combination with an RGD-targeting ligand in the HI loop of fiber. Transduction experiments confirmed that the KO1 mutation results in a significant reduction in fiber-dependent gene transfer on A549 and primary fibroblast cells that could be restored via the RGD-targeting ligand. Competition transduction experiments verified the receptor-binding properties of each vector on A549 and hepatocytes in vitro. Unexpectedly, in mice systemic delivery of the vector containing the KO1 mutation resulted in efficient liver transduction that was localized specifically to hepatocytes. We confirmed these results in three different mouse strains, indicating that hepatic adenoviral gene transfer may be independent of the coxsackievirus–adenovirus receptor and that in vivo retargeting will require further viral capsid modifications to generate a fully detargeted adenoviral vector upon which to introduce new tropisms.
435 TREATMENT OF HCV GENOTYPE 3 (GT3)-INFECTION WITH PEG-IFN A-2B AND RIBAVIRIN (RBV): AGE RELATED DIFFERENCES IN SVR AND RELAPSE
Authors: S. Mauss, G. Teuber, E. Zehnter, M.P. Manns, T. Dahhan, U. Meyer, B. Möller, N. Dikopoulos, T. Witthoeft, M. Bilzer, G. Tossing, P. Hüppe
Journal: Journal of Hepatology (2011)
SHOULD THE TUBERCULOUS PATIENT KNOW THE TRUTH REGARDING HIS CONDITION?
Authors: C. P. AMBLER
Journal: JAMA (1903)

All physicians who practice at health resorts frequented by patients suffering from pulmonary tuberculosis find that comparatively few of these patients have any conception of their real condition, and in the rarest instances have they been carefully instructed as to the necessities for recovery. The profession generally seems to be of the opinion that tuberculous patients should not be told the nature of their trouble, but the average tuberculous patient generally finds out the true nature of his disease, and when he does he loses faith in his physicians, and frequently, very justly, will censure them for not telling him the truth. How is it possible to get the coöperation of the patient; to have him use care in the disposal of expectoration; to avoid violence and over-exertion in exercise, and many other things so important in the detail management of the case, if
Pharmacologic Inhibition of RAF→MEK→ERK Signaling Elicits Pancreatic Cancer Cell Cycle Arrest Through Induced Expression of p27Kip1
Authors: Stephan Gysin, Sang-Hyun Lee, Nicholas M. Dean, Martin McMahon
Journal: Cancer Research (2005)

Abstract Expression of mutationally activated RAS is a feature common to the vast majority of human pancreatic adenocarcinomas. RAS elicits its effects through numerous signaling pathways including the RAF→mitogen-activated protein (MAP)/extracellular signal–regulated kinase (ERK) kinase [MEK]→ERK MAP kinase pathway. To assess the role of this pathway in regulating cell proliferation, we tested the effects of pharmacologic inhibition of MEK on human pancreatic cancer cell lines. In eight cell lines tested, MEK inhibition led to a cessation of cell proliferation accompanied by G0-G1 cell cycle arrest. Concomitant with cell cycle arrest, we observed induced expression of p27Kip1, inhibition of cyclin/cyclin-dependent kinase 2 (cdk2) activity, accumulation of hypophosphorylated pRb, and inhibition of E2F activity. Using both antisense and RNA interference techniques, we assessed the role of p27Kip1 in the observed effects of MEK inhibition on pancreatic cancer cell proliferation. Inhibition of p27Kip1 expression in Mia PaCa-2 cells restored the activity of cyclin/cdk2, phosphorylation of pRb, and E2F activity and partially relieved the effects of U0126 on pancreatic cancer cell cycle arrest. Consistent with the effects of p27Kip1 on cyclin/cdk2 activity, inhibition of CDK2 expression by RNA interference also led to G0-G1 cell cycle arrest. These data suggest that the expression of p27Kip1 is downstream of the RAF→MEK→ERK pathway and that the regulated expression of this protein plays an important role in promoting the proliferation of pancreatic cancer cells. Moreover, these data suggest that pharmacologic inhibition of the RAF→MEK→ERK signaling pathway alone might tend to have a cytostatic, as opposed to a cytotoxic, effect on pancreatic cancer cells.
Medical Malpractice Suits and Autopsies-Reply
Authors: Adam O. Goldstein
Journal: JAMA (1991)

In Reply.  —The purpose of my essay was to expose the personal shortcomings in the way our society chooses to handle medical malpractice lawsuits. Such shortcomings manifest themselves for physicians in at least two ways. First, most clinicians, regardless of their specialty or the health care setting, at least think about potential malpractice lawsuits subconsciously and consciously, and probably on at least a weekly if not daily basis, regardless of whether they have personally ever been sued. An aura of silence usually surrounds such thoughts despite the enormous implications for patient care. Second, as clinicians, we somehow often feel immune to the same diseases attacking the immune systems of our patients: stress, anger, hostility, rejection, burnout, disappointment, and more. Medical malpractice lawsuits, regardless of their origin, pathophysiology, or prognosis, negatively affect our personal and our family's health. Our own self-healing process can begin by openly acknowledging and discussing such effects,
Prevention of karate injuries--a progress report.
Authors: G. R. McLatchie, E. W. Morris
Journal: British Journal of Sports Medicine (1977)

Methods of preventing karate injuries are discussed. These fall into three groups:--1. Prevention by control. 2. Prevention by using protective clothing. 3. Pre-fight medical examination. The results of the above methods in reducing the incidence of injury in karate competitions are described. After a follow up one year (1102 fights) it is concluded that the incidence and severity of karate injuries has been reduced significantly thus making the sport safer.
Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis
Authors: G. J. Geersing, N. P. A. Zuithoff, C. Kearon, D. R. Anderson, A. J. ten Cate-Hoek, J. L. Elf, S. M. Bates, A. W. Hoes, R. A. Kraaijenhagen, R. Oudega, R. E. G. Schutgens, S. M. Stevens, S. C. Woller, P. S. Wells, K. G. M. Moons
Journal: BMJ (2014)

<b>Objective</b> To assess the accuracy of the Wells rule for excluding deep vein thrombosis and whether this accuracy applies to different subgroups of patients. <b>Design</b> Meta-analysis of individual patient data. <b>Data sources</b> Authors of 13 studies (n=10 002) provided their datasets, and these individual patient data were merged into one dataset. <b>Eligibility criteria</b> Studies were eligible if they enrolled consecutive outpatients with suspected deep vein thrombosis, scored all variables of the Wells rule, and performed an appropriate reference standard. <b>Main outcome measures</b> Multilevel logistic regression models, including an interaction term for each subgroup, were used to estimate differences in predicted probabilities of deep vein thrombosis by the Wells rule. In addition, D-dimer testing was added to assess differences in the ability to exclude deep vein thrombosis using an unlikely score on the Wells rule combined with a negative D-dimer test result. <b>Results</b> Overall, increasing scores on the Wells rule were associated with an increasing probability of having deep vein thrombosis. Estimated probabilities were almost twofold higher in patients with cancer, in patients with suspected recurrent events, and (to a lesser extent) in males. An unlikely score on the Wells rule (≤1) combined with a negative D-dimer test result was associated with an extremely low probability of deep vein thrombosis (1.2%, 95% confidence interval 0.7% to 1.8%). This combination occurred in 29% (95% confidence interval 20% to 40%) of patients. These findings were consistent in subgroups defined by type of D-dimer assay (quantitative or qualitative), sex, and care setting (primary or hospital care). For patients with cancer, the combination of an unlikely score on the Wells rule and a negative D-dimer test result occurred in only 9% of patients and was associated with a 2.2% probability of deep vein thrombosis being present. In patients with suspected recurrent events, only the modified Wells rule (adding one point for the previous event) is safe. <b>Conclusion</b> Combined with a negative D-dimer test result (both quantitative and qualitative), deep vein thrombosis can be excluded in patients with an unlikely score on the Wells rule. This finding is true for both sexes, as well as for patients presenting in primary and hospital care. In patients with cancer, the combination is neither safe nor efficient. For patients with suspected recurrent disease, one extra point should be added to the rule to enable a safe exclusion.
The effect of several sex steroid hormones on the growth rate of three morris hepatoma tumor lines
Authors: Julius Erdstein, Steven Wisebord, Shaindel Y. Mishkin, Seymour Mishkin
Journal: Hepatology (1989)

Morris hepatoma 44, whose growth is sensitive to thyroid hormones and prolactin, contains specific receptors for these hormones. In the present experiments, male Buffalo rats bearing Morris hepatoma 7787 were studied to determine the effects of several sex steroid hormones. Castration 1 week postimplantation inhibited tumor growth relative to controls (-53%). Replacement with testosterone propionate (1 mg per day s.c. injection) restored tumor growth to control levels, whereas administration of testosterone (2 mg per day s.c. injection) to castrated controls resulted in significant stimulation. Testosterone administered to control animals at a dose of 1 mg per day stimulated tumor growth (62%), whereas 2 mg per day failed to do so. Progesterone (4-pregnon-3,20-dione) at doses of 125 or 250 micrograms per day (Silastic implants) had no effect on tumor growth, whereas 500 micrograms per day stimulated tumor growth relative to controls. Estrogen (17 beta-estradiol) at doses of 6, 12, or 24 micrograms per day (Silastic implants) did not influence tumor growth. Cytoplasmic testosterone receptors have been demonstrated in tumors (2.2 +/- 0.8 fmoles per mg cytoplasm), although specific cytoplasmic estrogen and progesterone receptors could not be identified in this model. In female rats bearing either Morris hepatoma 44, 7787 or 5123-D, testosterone markedly stimulated tumor growth (226, 328 and 58%, respectively, relative to controls). In conclusion, although Morris hepatoma 7787 appears to be androgen (testosterone) dependent and contains cytoplastic androgen receptors, it lacks specific cytoplasmic receptors for estrogen and progesterone and is not influenced by these hormones except at very high doses of progesterone.
STUDIES ON STARLING'S LAW OF THE HEART. I. THE CIRCULATORY RESPONSE TO ACUTE HYPERVOLEMIA AND ITS MODIFICATION BY GANGLIONIC BLOCKADE
Authors: Robert L. Frye, Eugene Braunwald, Estelle R. Cohen
Journal: Journal of Clinical Investigation (1960)

The application of Starling's law of the heart to the circulation of man has been the subject of intensive interest and investigation. Infusions of intravenous fluids have been employed in attempts to simulate in man the increase in venous return to the Starling heart-lung preparation. A variety of fluids has been utilized in such studies in man, including saline (1-4), dextran (4-6), glucose solutions (4), and human serum albumin (2, 7). In general, the results have been conflicting, with a few investigators noting an increase both in filling pressure and cardiac output (1, 5), while in the majority of studies no consistent relationship between these parameters was noted (2-4, 6, 7). Indeed, in most human subjects the augmentation of the total blood volume has failed to be associated with a rise in cardiac output, even in the face of a decline in hematocrit (2-4, 6, 7). The possibility was considered that the presence of an actively functioning autonomic nervous system in the intact state and its absence in the heart-lung preparation accounts for the difference in the cardiac response to infusion in man and increased venous return to the heart-lung preparation. The present study was therefore designed to determine whether the circulatory response to acutely induced hypervolemia is modified by reducing the activity of the autonomic nervous system by means of ganglionic blockade.
SHELL WOUND OF THE PANCREAS CAUSING PANCREATIC PSEUDO-CYST
Authors: J. Morley
Journal: BMJ (1918)

Shell fragment; enitrance wound only, over eighth rib, leff side; abdomen penetrated ; general condition good; severe dyspnoea.Opera- tion: Trans-diaphragmatic route-rib resected anid blood .,wabbedfrom thorax; omentum found protruding through aL wound in the diaphragm, size of a half a crown-enlarged this opening and found injury to spleen and ki-dney; foreign body removed from kidney, the wound being excised and sutured-no treatment of spleen; diaplhragm closed; sudden cardiac failure theni necessitated .nassage of the heart, whichi responded immediately; operation completed.Recovery unteventful.Base
Future Oversight of Recombinant DNA Research
Authors: Lawrence O. Gostin, Bruce M. Altevogt, Andrew M. Pope
Journal: JAMA (2014)

The National Institutes of Health (NIH) established the Recombinant DNA Advisory Committee (RAC) in 1974 in response to public concerns about the safety of manipulating genetic material through recombinant DNA (rDNA).1 Jesse Gelsinger’s death during a genetic therapy trial in 1999 further galvanized societal apprehensions.2 The RAC—a federal advisory committee to the NIH director—performs multiple functions: reviewing all gene transfer protocols, selecting specific protocols for public review, and acting as a national forum for rDNA research.3 Through its Gene Transfer Safety Assessment Board the RAC also surveils, aggregates, and analyzes adverse events across all human gene transfer trials.
Liver-directed gene transfer and prolonged expression of three major human ApoE isoforms in ApoE-deficient mice.
Authors: K Tsukamoto, P Smith, J M Glick, D J Rader
Journal: Journal of Clinical Investigation (1997)

Apolipoprotein E (apoE) plays a key role in lipoprotein metabolism and may have other important biological functions. In humans, there are three common, naturally occurring isoforms of apoE that are associated with differences in lipid levels and atherosclerosis. However, the direct in vivo effects of the apoE isoforms on lipoprotein metabolism and atherosclerosis are not yet fully understood. To investigate the effect of the apoE isoforms in vivo, we constructed second-generation recombinant adenoviruses encoding each of the apoE isoforms. These recombinant adenoviruses were injected intravenously into apoE-deficient mice fed a Western diet (mean baseline cholesterol level 1401 mg/dl) in order to study their effects in the absence of endogenous mouse apoE. Hepatic expression of apoE3 and apoE4 completely normalized the lipoprotein profile; 3 d after injection, mean plasma cholesterol levels were 194 and 217 mg/ dl, respectively, and this effect was maintained for at least 6 wk. Expression of apoE2 had much less effect on lipoprotein levels (mean cholesterol level 752 mg/dl 3 d after injection), despite much higher plasma levels of apoE2 compared with apoE3 and apoE4; by 6 wk after injection the cholesterol levels had returned to baseline levels in the apoE2-expressing mice. Expression of all three isoforms significantly increased HDL cholesterol levels by approximately threefold and was independent of the cholesterol-lowering effect. ApoE transgene expression was substantially prolonged compared with that achieved using a first generation adenovirus and apoE was readily detected in plasma 3 mo after virus injection. These studies demonstrate: (a) prolonged in vivo expression of human apoE isoforms in apoE deficient mice after second-generation recombinant adenovirus-mediated somatic gene transfer; and (b) significantly impaired ability of apoE2 in vivo to mediate clearance of remnant lipoproteins in apoE-deficient mice fed a Western diet compared with apoE3 and apoE4.
Transforming Growth Factor-β Function Blocking Prevents Myocardial Fibrosis and Diastolic Dysfunction in Pressure-Overloaded Rats
Authors: Fumitaka Kuwahara, Hisashi Kai, Keisuke Tokuda, Mamiko Kai, Akira Takeshita, Kensuke Egashira, Tsutomu Imaizumi
Journal: Circulation (2002)

Background — Excessive myocardial fibrosis impairs cardiac function in hypertensive hearts. Roles of transforming growth factor (TGF)-β in myocardial remodeling and cardiac dysfunction were examined in pressure-overloaded rats. Methods and Results — Pressure overload was induced by a suprarenal aortic constriction in Wistar rats. Fibroblast activation (proliferation and phenotype transition to myofibroblasts) was observed after day 3 and peaked at days 3 to 7. Thereafter, myocyte hypertrophy and myocardial fibrosis developed by day 28. At day 28, echocardiography showed normal left ventricular fractional shortening, but the decreased ratio of early to late filling velocity of the transmitral Doppler velocity and hemodynamic measurement revealed left ventricular end-diastolic pressure elevation, indicating normal systolic but abnormal diastolic function. Myocardial TGF-β mRNA expression was induced after day 3, peaked at day 7, and remained modestly increased at day 28. An anti–TGF-β neutralizing antibody, which was administered intraperitoneally daily from 1 day before operation, inhibited fibroblast activation and subsequently prevented collagen mRNA induction and myocardial fibrosis, but not myocyte hypertrophy. Neutralizing antibody reversed diastolic dysfunction without affecting blood pressure and systolic function. Conclusions — TGF-β plays a causal role in myocardial fibrosis and diastolic dysfunction through fibroblast activation in pressure-overloaded hearts. Our findings may provide an insight into a new therapeutic strategy to prevent myocardial fibrosis and diastolic dysfunction in pressure-overloaded hearts.
Ga-67 Scan in Invasive Aspergillosis
Authors: MARIA DEL VAL GÓMEZ, FELIX G. GALLARDO, JUAN BABE, JULIO COBO
Journal: Clinical Nuclear Medicine (2000)

A 38-year-old patient infected with the human immunodeficiency virus (CD4+ < 50 cells/mm3) was examined because of fever of unknown origin. Ga-67 scintigraphy showed tracer uptake in the upper lobe of the right lung. Aspergillus was identified by fine-needle biopsy and treatment with itraconazole was instituted. Two months later, the patient had persistent fever, cough, and dyspnea, and at this time Ga-67 scintigraphy showed that uptake in the upper lobe of the right lung had increased and a new abnormal Ga-67 accumulation had appeared in the right middle lobe, indicating a lack of response. The patient died 15 days later despite treatment with amphotericine B. Invasive aspergillosis was diagnosed at necropsy.
Statistical methods for censored survival data.
Authors: N Breslow
Journal: Environmental Health Perspectives (1979)

Methods of statistical analysis of censored survival times are briefly reviewed and illustrated by application to clinical trials data. These include estimation of the survival curce, nonparametric tests to compare several survival curves, tests for trend, and regression analysis. Extensions of the methodology are made for application to epidemiologic case-control studies. These are used to estimate relative risks for leukemia associated with radiation exposures. A final section provides some annotated references to the recent literature.
Drug points: Generalised chorea due to digoxin toxicity
Authors: L J M M Mulder, R C van der Mast, J D Meerwaldt
Journal: BMJ (1988)

Digoxin is a widely prescribed drug with narrow therapeutic margins, and intoxication is a common complication.We report a case ofsevere generalised chorea, agitation, and emotional disturbance due to digoxin excess.A 63 year old woman with a dissection of the ascending aorta had been treated conservatively for one month with digoxin 250 ig daily, labetalol 100 mg three times a day, dihydralazine 25 mg twice a day,
Role of Vasopressin in Abnormal Water Excretion in Cirrhotic Patients
Authors: DANIEL BICHET
Journal: Annals of Internal Medicine (1982)

Twelve stable cirrhotic patients with ascites received a 20 mL/kg water load. Seven patients had abnormal water excretion (27.3% ± 5.4% of the water load in 5 hours) and a minimal urine osmolality of 262 mosmol/kg water. Five patients excreted 82.6% in 5 hours and had a minimal urine osmolality of 65 mosmol/kg water. Mean plasma arginine vasopressin values after water load were significantly higher in Group 1 (1.34 ± 0.36 pg/mL) than in Group 2 (undetectable). An effective blood volume lower in Group 1 than Group 2 patients was suggested by a lower plasma albumin (2.5 versus 3.3 g/dL, p< 0.02), a higher pulse rate (96 versus 72, p < 0.001), a higher plasma renin activity (7.8 versus 1.5 ng/mL h, p < 0.005), a higher plasma aldosterone (66 versus 21 ng/dL, p < 0.05), and a lower urinary sodium excretion (2.7 versus 14.2 meq Na/5 h, p < 0.005). The results suggest that nonosmotic stimulation of vasopressin secondary to a decrease in effective blood volume is an important factor in the abnormal water excretion of cirrhosis.
Delayed Perforation of a Strangulated Hernia-Reply
Authors: James L. Berk
Journal: JAMA (1978)

<h3>In Reply.—</h3> The recognized clinical findings described in textbooks of surgery of patients with a strangulated hernia are intense abdominal pain, tenderness, a high WBC count, and, if untreated, a progressive downhill course. After transfer to this hospital and treatment of the cardiogenic shock, our patient became asymptomatic and had none of the classic findings of strangulated bowel except occult blood in the stool, which could be otherwise explained: she had no pain, was hungry, took a full diet, and had normal-appearing stools. The minimal tenderness of the hernia was inconstant on admission and disappeared completely within a few hours. The patient stated that the hernia had been present for four years and that she did not think it was any different at this time. The diagnosis at the first hospital was septic shock following a flu-like illness. The hernia was not prominent and did not enter into their differential