tbuckley/cabot-search huggingface dataset:
490. Successful Readministration of AAV8 Following Administration of Nondepleting CD4 Antibody at the Time of Vector Administration
Authors: JennyH. McIntosh, Melanie Cochrane, Arnold Prizzey, Herman Waldmann, Andrew M. Davidoff, Amit C. Nathwani
Journal: Molecular Therapy (2006)

Transgene expression from the liver following recombinant adeno- associated viral vector (rAAV) gene transfer is mediated mainly by episomally maintained genomes. For chronic disorders such as haemophilia this raises concerns that transgene expression will decline to subtherapeutic levels over time with the natural turnover of hepatocytes in humans. Neutralising antibodies that develop at the time of primary vector administration will however prevent readministration of the same serotype. Therefore strategies that allow repeated administration of the optimal vector system may be required to maintain transgene expression at therapeutic levels. We have used a non-depleting CD4 antibody (NDCD4) in conjunction with other immunosuppressive agents in an attempt to attenuate the primary immune response to AAV. Cohorts of male C57BL/6 mice (n= 7-8) were treated with NDCD4 (0.5mg/mouse) alone, or in combination with cyclosporine (CyA) 25mg/kg or mycophenolate mofetil (MMF) 20mg/kg on days -1, 0, +1, 3, 6, 8 after tail vein administration of a pseudotype 8 vector encoding human factor IX. Additional cohorts received CyA or MMF alone and one group received no treatment. CD4 T lymphocyte analysis by FACs with an antibody against CD4 epitope B over 56 days, showed a moderate decline in the NDCD4 treated cohorts (34%) compared to naïve mice (sham treated). At day 98 anti-AAV8 antibody titers were reduced in cohorts receiving NDCD4 alone (11.3±3.5) or in combination with MMF (12.3±5.5). However, the humoral response in CyA+NDCD4 was undetectable. Secondary challenge with a low titer (5x1010) of AAV8 encoding human β interferon (hβIFN) resulted in serum hβIFN levels of 7.3±3.9 ng/mL in the CyA+NDCD4 cohort. These levels were comparable (9.0±5.2 ng/mL) to those in animals receiving only AAV8 hβIFN. Hence treatment with NDCD4 antibody and cyclosporine at the time of vector administration can substantially attenuate the immune response to primary immunisation with AAV, enabling repeat administration and efficient transduction with vectors based on the same serotype. Unlike previously used strategies our approach offers significant safety advances and will have widespread appeal.
Altered minimal coronary resistance to antegrade reflow after chronic coronary artery occlusion in swine.
Authors: D M Roth, F C White, C M Bloor
Journal: Circulation Research (1988)

We examined coronary pressure-flow relations after chronic coronary artery occlusion induced by placement of an ameroid occluder on the left circumflex coronary artery in swine. An acute open-chest procedure was performed in nine pigs 27 +/- 2 days (mean +/- SEM) after surgical placement of the ameroid occluder, and in eight nonoperated control pigs. Coronary vascular resistances were measured during maximal coronary vasodilation with adenosine. Minimal coronary resistance was assessed before and after cannulation and extracorporeal perfusion of the left circumflex coronary artery distal to the site of the ameroid occluder in pigs from the ameroid group and in a similar site in control pigs. Minimal coronary resistance to antegrade reflow in the left circumflex region was decreased significantly in ameroid pigs compared with control pigs (0.06 +/- 0.01 vs. 0.26 +/- 0.03 mm Hg.min.100 g/ml, p less than 0.001, respectively). Decreased minimal coronary vascular resistance was present transmurally in the left circumflex region of ameroid pigs. Altered vascular resistance occurred only in myocardium distal to the ameroid occluder since the nonoccluded left anterior descending region in ameroid pigs had minimal coronary resistance similar to that of the same region from control pigs (0.23 +/- 0.03 vs. 0.19 +/- 0.02 mm Hg.min.100 g/ml). Thus altered minimal coronary vascular resistance occurs and probably reflects vascular proliferation and/or vascular alterations which result in an increased total cross-sectional area of the vasculature in the myocardium distal to the occlusion.
Law and Ethics: A Guide for the Health Professional
Authors: Michael Schwarz
Journal: JAMA (1986)

Dr Sidley has put together a book based on a series of essays on law and ethics. The book is more for classroom use than for reading on one's own. Teachers of nursing, medicine, or hospital administration will find the book a good background text for lectures in a course on medicine and the law. Oftentimes, textbooks seem to control the lectures to such an extent that the student can cut class. This is not true with this book. The text lends itself to good classroom discussion. The book, save the first chapter, is in sentence-outline form, providing the reader with principles of law or ethics followed by short narratives explaining the principles. It is not an easy book to understand; it requires the reader to think and reflect. This is not to say that the book is poorly written or poorly organized. It is succinctly written and indeed well
Abstract LB-437: Co-amplification of ALK and c-MET in a subset of pulmonary sarcomatoid carcinoma (PSC)
Authors: Patrizia Gasparini, Gabriella Sozzi, Alberto Cavazza, Giulio Rossi, Mauro Papotti, Ugo Pastorino, Paolo Scanagatta, Yukio Nakatani, Giuseppe Pelosi
Journal: Cancer Research (2012)

Abstract The prevalence of ALK gene alterations for targeted therapy with specific inhibitors is a largely unexplored issue in pulmonary sarcomatoid carcinoma (PSC), a life-threatening tumor subset whose treatment still is disappointing. ALK gene status by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry (IHC) were carried out on formalin-fixed, paraffin-embedded material from 34 PSC. Fifty-one consecutive metastatic lung adenocarcinomas (MELAD) were also assessed in parallel for ALK with both FISH and IHC. While no rearrangements of ALK gene were detected in PSC, relevant amplification was identified in 6/34 (18%) tumors, while other genes known to behave as driver mutations according to an oncogene addiction criterion, such as EGFR, KRAS, HER2, BRAF, PIK3CA and CTNNB1, were consistently lacking. The percentage of amplified tumor cells ranged from 11% to 43%, with a mean gene copy gain (GCG) ± standard deviation (SD) of 7.5 ± 1.5. We have also investigated 51 MELAD observing that, while 10 of them showed the expected ALK rearrangement (p=0.012), only 1/51 showed the gene amplification (p=0.015). No cases of ALK-amplified tumors, either PSC or adenocarcinoma, expressed the relevant protein, whereas it was otherwise detectable in all ALK-rearranged adenocarcinomas. Interestingly all ALK-amplified tumors, either PSC or adenocarcinoma, showed also c-MET amplification consisting of variably sized clusters of specific signals, whereas negative tumors, regardless of histology, and ALK-rearranged adenocarcinomas did not show c-MET alteration. ALK and c-MET gene amplification clustered into a significant subset of elderly, smoking, predominantly male PSC patients, revealing significant differences with lung adenocarcinoma These encouraging data, however, need to be reinforced on a wider series of tumors in order to elucidate this issue, which could potentially lead to a truly effective treatment of these so life-threatening tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-437. doi:1538-7445.AM2012-LB-437
TV: We all fall down: could smallpox return?
Authors: A. Tonks
Journal: BMJ (2002)

Smallpox 2002 — Silent Weapon , BBC2, Tuesday 5 February, 9 pm

The world has been free from smallpox since 1980. The last outbreak occurred in 1977, it was successfully contained, and the eradication campaign passed into the history books as one of the 20th century's greatest achievements. Governments then wound down their vaccination programmes, and the human race moved on, untroubled by Variola major but also increasingly defenceless against it as the immune populations died out. Last Tuesday, a BBC broadcast dramatised what would happen if a terrorist deliberately unleashed a virulent strain of smallpox on a now virgin population.

Smallpox 2002 — Silent Weapon is a fictional account of a smallpox pandemic in which …
<i>TMPRSS2:ERG</i> Fusion by Translocation or Interstitial Deletion Is Highly Relevant in Androgen-Dependent Prostate Cancer, But Is Bypassed in Late-Stage Androgen Receptor–Negative Prostate Cancer
Authors: Karin G. Hermans, Ronald van Marion, Herman van Dekken, Guido Jenster, Wytske M. van Weerden, Jan Trapman
Journal: Cancer Research (2006)

Recently, a unique fusion between the prostate-specific, androgen-regulated TMPRSS2 gene and the ETS genes ERG, ETV1, or ETV4 has been described in clinical prostate cancer. We investigated mechanisms of expression of four ETS genes, ERG, ETV1, ETV4, and FLI1, in 11 xenografts representing different stages of prostate cancer. All five androgen-dependent xenografts showed as major transcript overexpression of two splice variants of TMPRSS2:ERG, linking TMPRSS2 exon 1 or 2 sequences to ERG exon 4. In one of two androgen-sensitive xenografts, fusion transcripts of TMPRSS2 and ETV1 were detected. Array-based comparative genomic hybridization and interphase fluorescence in situ hybridization indicated both interstitial deletions and translocations as mechanisms of TMPRSS2:ERG gene fusion. Importantly, TMPRSS2 to ERG fusions were also observed in three of four androgen-independent, androgen receptor (AR)-negative xenografts and in two AR-negative clinical prostate cancer specimens; however, the fusion gene was not expressed. In almost all AR-negative tumor samples, overexpression of wild-type ETV4 or FLI1 was detected. Combined, our observations indicate a key role of fusion of TMPRSS2 and ETS genes in most androgen-regulated prostate cancers, which might be bypassed by androgen-independent expression of wild-type ETS factors in late-stage disease.
PREMIUMS PAID TO EXPERIENCE.
Authors: FREDERICK T. ROGERS
Journal: JAMA (1907)

destroyed, and that life itself may be sacrificed from the injection of paraffin into the tissues to correct slight de- formities, or to make the patient more comfortable, it seems to me worth while to call attention again to such clangers.Certainly all mishaps from the use of paraffin injections should be reported that the technic may be improved or the method abandoned if it proves unsatisfactory or too dangerous.
A piece of my mind. Long ago today
Authors: J. J. Gallo
Journal: JAMA (1989)

It was such a simple thing, merely a touch of the hand. Others had touched her also, but their touch had always seemed so mechanical, so cold, not even fully human. Theirs was a touch of necessity, but this one was different. This was a touch of love, of caring, of humanity. This was a touch that spoke without words, that said, "I know you are a person with a rich history, and not a faceless case or number." This touch allowed her, if only for a moment, to transcend time. The memories were a hodgepodge of feelings, sights, sounds, and smells, in random order, the way thoughts sometimes run from one to another, connected in peculiar ways. She really couldn't be sure which wisps and glimpses were accurate and which had become enriched with time, but she supposed that didn't matter now. He had a way of touching her
Dangers of Orally Administered Para-aminobenzoic Acid
Authors: Sophie Worobec, Alleine LaChine
Journal: JAMA (1984)

<h3>To the Editor.—</h3> It has been brought to our attention that the oral use of para-aminobenzoic acid (PABA) in daily doses up to 1,000 mg has been promoted to prevent phototoxic reactions. This concerns us for two reasons. First, although it has been shown that PABA is an effective sunscreen when used topically, there is no evidence that systemic PABA has any sunscreening properties.<sup>1</sup>Second, and more important for the consumer, there is considerable evidence that PABA taken orally can be toxic.<sup>2</sup> In the 1940s, PABA was administered orally in doses of 48 g/day to treat typhus fever. This was associated with lowering of the WBC count to below 4,000 cu mm in 30% of the patients. This count started to rise within three days after PABA therapy was discontinued.<sup>3,4</sup>Oral PABA was also used as an experimental treatment for discoid lupus erythematosus and systemic lupus erythematosus.
Maternal Mortality in Type 1 Diabetes
Authors: Pekka J. Leinonen, Vilho K. Hiilesmaa, Risto J. Kaaja, Kari A. Teramo
Journal: Diabetes Care (2001)

The ultimate complication of type 1 diabetes in combination with pregnancy is maternal death, which may result from complications of the pregnancy itself, diabetes and associated diseases, or causes related to neither pregnancy nor diabetes. From the clinical point of view, the greatest reward would be to identify possible preventable causes of maternal death beforehand, especially because these patients are under close surveillance during the entire pregnancy and postpartum period.

The reported incidence of maternal mortality of pregnant type 1 diabetic women has been ∼0.5% (1,2), which is 5–20 times higher than that of the general obstetric population. However, these estimates date back prior to 1980, and because of the developments in both the obstetric management and the treatment of diabetes during the past 20 years, we have estimated the risk of death and analyzed the causes of maternal mortality in a large single referral center for all pregnant type 1 diabetic women from Southern Finland.

Between 1975 and 1997, 972 type 1 diabetic women delivered, or intended to deliver, in the Department …
Comparison of the 'Open' vs 'Closed' Intensive Care Unit Formats
Authors: David Bihari
Journal: JAMA (1996)

To the Editor.  —Carson et al 1 claim to have demonstrated an improvement in outcome in critically ill medical patients managed in a closed ICU compared with those managed in an open unit. However, what is essentially a political position (and one that I also hold) is not supported by their results.  The samples of patients studied (124 in the open period, 121 in the closed period) were too small to compare standardized mortality ratios (SMRs) in any meaningful way (SMR, 0.90 and 0.78, respectively; no confidence intervals [CIs] given). Moreover, the investigators provide no evidence that the APACHE II system calibrated in their unit (ie, there was a linear relationship between observed and expected mortality across the entire range of risk) and also discriminated between survivors and patients who died (ie, gave an area of >80% under a receiver operating characteristic curve). Neither of these seems likely given the small numbers of
Polycythemia Vera: Stem-Cell and Probable Clonal Origin of the Disease
Authors: John W. Adamson, Philip J. Fialkow, Scott Murphy, Jaroslav F. Prchal, Laura Steinmann
Journal: New England Journal of Medicine (1976)

Two women with polycythemia vera and heterozygosity (GdB/GdA) at the X-chromosome-linked locus for glucose-6-phosphate dehydrogenase were studied to determine the nature of the cellular origin of their polycythemia. In contrast to unaffected tissue, such as skin fibroblasts, which consisted of both B and A types, the glucose-6-phosphate dehydrogenase of the patients' erythrocytes, granulocytes and platelets was only of Type A. These results provide direct evidence for the stem-cell nature of polycythemia vera and strongly imply a clonal origin for this disease. The fact that no descendants of the presumed normal stem cells were found in circulation suggests that bone-marrow proliferation in this disorder is influenced by local (intramarrow) regulatory factors.
Regional blood flow effects of dopexamine versus enalaprilat during propofol anaesthesia in rabbits with experimental chronic heart failure
Authors: D. W Blake, D. Way, L. Trigg, B. P McGrath
Journal: Cardiovascular Research (1994)

Objective: Chronic congestive heart failure (CHF) was induced in rabbits with doxorubicin in order to evaluate: (1) haemodynamic and regional blood flow responses to propofol anaesthesia; (2) modification of these cardio- vascular responses with background intravenous infusions of enalaprilat or dopexamine. Methods: Rabbits received either doxorubicin, 2 mg·kg−1 weekly intravenously for seven weeks (CHF, n = 6), or saline (controls, n = 6). Doppler flow probes were implanted on the ascending aorta, left renal artery, and lower abdominal aorta. In three separate studies propofol was infused for 40 min periods at 0.6 and then 1.2 mg·kg−1·min−1 after background infusions of either saline, enalaprilat (0.2 mg·kg−1 +0.003 mg·kg−1·min−1), or dopexamine (0.008 mg·kg−1·min−1). Results: In normal rabbits propofol (1.2 mg·kg−1·min−1) reduced mean arterial pressure from awake control by 33(SEM 3)%, cardiac output by 24(4)%, and hindlimb blood flow (HBF) by 10(2)%, but did not change renal blood flow. In rabbits with CHF, although resting mean blood pressure was lower, propofol did not alter blood pressure or hindlimb blood flow, but renal blood flow was reduced by 37(6)%. Conclusions: Both enalaprilat and dopexamine increased renal blood flow in the control and CHF groups. Enalaprilat caused marked hypotension during anaesthesia in the CHF group. Dopexamine increased mean arterial pressure, heart rate, and hindlimb blood flow during anaesthesia in controls, but not in CHF. Cardiovascular Research 1994;28:710-714
Ampicillin and mononucleosis.
Authors: T P Casey, J R Matthews
Journal: BMJ (1972)

herbal and other aperients and enemata, and I suspect they often spend long periods straining in an effort to overcome supposed constipation.Could the suggestion that the squatting posture protects leg veins be tested by observing the prevalence of venous dis- orders in communities which have adopted low-residue diets but retained the traditional squatting position (such as some affluent Asian communities)?-Iam, etc.,
Harry Potter casts a spell on accident prone children
Authors: Stephen Gwilym, Dominic P J Howard, Nev Davies, Keith Willett
Journal: BMJ (2005)

and human pathologies are similar.Trichotillomania may arise as a result of the misregulation of an innate self grooming behaviour that results in excessive repetition.It would be interesting to find out whether subsets of human patients with trichotillomania have defects in the Hoxb8 gene or in the paralogous family members Hoxc8 and Hoxd8.We thank Judith A James for supplying the mice shown in the photograph and Yaser Dorri for his help with the photography.
Unusual case of multiple spontaneous perforation of small bowel.
Authors: G. Gillespie
Journal: BMJ (1966)

These clinical and laboratory findings suggested a reduction in his blood-volume due to extravasation of plasma and made renal tubular necrosis unlikely.The transfusion of a further three bottles of plasma restored the pulse and blood-pressure to normal and reversed the peripheral vasoconstriction.Shortly afterwards there was a marked diuresis, with a corresponding fall in body weight and reduction in the circumference of his swollen limbs (see Fig. 2).His haemoglobin fell to 92% while his plasma protein concentra- don remained unchanged.Serial electrocardiograms showed transient ST and T-wave changes, but there was at no time evidence of jugular or pulmonary congestion.Four weeks after admission to hospital he was discharged, having apparently made a complete recovery.
IL-10 inhibits metalloproteinase and stimulates TIMP-1 production in human mononuclear phagocytes.
Authors: S Lacraz, L P Nicod, R Chicheportiche, H G Welgus, J M Dayer
Journal: Journal of Clinical Investigation (1995)

Human mononuclear phagocytes can modulate the turnover of extracellular matrix by producing metalloproteinases such as 92-kD gelatinase and interstitial collagenase as well as the tissue inhibitor of metalloproteinases (TIMP). We have previously reported that IL-4 and IFN gamma released by lymphocytes suppress metalloproteinase biosynthesis in macrophages without affecting TIMP production (Lacraz, S., L. Nicod, B. C. de Rochementeix, C. Baumberger, J. Dayer, and H. Welgus. 1992. J. Clin. Invest. 90:382-388.; Shapiro, S. D., E. J. Campbell, D. K. Kobayashi, and H. G. Welgus 1990. J. Clin. Invest. 86:1204-1210). Like IL-4, IL-10 is secreted by Th2 lymphocytes and is inhibitory to several macrophage functions. In the present study, IL-10 was tested and compared to IL-2, IL-4, IL-6, and IFN gamma for its capacity to modulate synthesis of 92-kD gelatinase, interstitial collagenase and TIMP in human macrophages and monocytes. We found that IL-10, just like IL-4, inhibited the production of 92-kD gelatinase and blocked LPS-, as well as killed Staphylococcus aureus-induced, interstitial collagenase production. The principal finding of this study, however, was that IL-10, in distinction to IL-4, produced a dose-dependent stimulation in the biosynthesis of TIMP-1. TIMP-2 production was not affected. IL-10 regulated the expression of 92-kD gelatinase and TIMP-1 at the pretranslational level. Furthermore, IL-10 regulation was cell type-specific, as it had no effect on the production of metalloproteinases or TIMP by human fibroblasts. In summary, IL-10 has a potent and unique effect upon tissue macrophages and blood monocytes by enhancing TIMP-1 production while decreasing metalloproteinase biosynthesis.
Brown confirms a 7.1% rise in NHS spending next year
Authors: Rebecca Coombes
Journal: BMJ (2004)

Health was confirmed as the government's biggest spending priority in Chancellor Gordon Brown's UK spending review this week.The NHS will receive an annual real terms rise of 7.1%paid for in part by the axing of more than 100 000 civil servants' jobs, including 727 from the Department of Health, and other efficiency savings.
<i>In Medicina, Veritas</i>
Authors: Francis D. Moore
Journal: New England Journal of Medicine (1982)

The post-revolutionary period in America was one of restoring order after strife and, in Boston, freedom after occupation. The wounds of what became a civil war as well as a revolution were deep and slow to heal. It was not to be expected that discipline could easily be introduced into the libertarian atmosphere of a successful anti-establishment revolt based on civil commotion and the idea of populist self-rule in a democracy. Botein has stated it clearly:Republican ideology notwithstanding, the social order that had emerged from the Revolutionary era was far less revolutionary than Patriot leaders had once forecast — . . .
EGFR signaling attenuates Groucho-dependent repression to antagonize Notch transcriptional output
Authors: Peleg Hasson, Nirit Egoz, Clint Winkler, Gloria Volohonsky, Songtao Jia, Tama Dinur, Talila Volk, Albert J Courey, Ze'ev Paroush
Journal: Nature Genetics (2004)
Messages From Afar
Authors: Robert C. Alexander
Journal: JAMA (1988)

To the Editor.—  The March 11 issue of JAMA contains an essay describing the treatment of a 62-year-old man with a paranoid psychosis. 1 The treatment was supportive in nature and played to the individual's strengths while encouraging him to keep his psychosis under wraps. Circumstances may have made other forms of treatment unlikely or impossible.  It is important, however, to consider the treatment described to avoid misunderstanding the nature of psychotic illness and what constitutes appropriate evaluation and therapy for this condition.  As described, the patient, an elevator operator, kept his delusions and hallucinations to himself for many years; he was hospitalized after he stated to a passenger on his elevator that  constantly get radio messages from Moscow—sent directly to me. They tell me to write down everything I see and hear.  Treatment of this patient apparently consisted of a three-day hospitalization, telling the patient not to share