tbuckley/cabot-search huggingface dataset:
Hepatic Venous Blood and the Development of Pulmonary Arteriovenous Malformations in Congenital Heart Disease
Authors: Deepak Srivastava, Tamar Preminger, James E. Lock, Valerie Mandell, John F. Keane, John E. Mayer, Harry Kozakewich, Philip J. Spevak
Journal: Circulation (1995)

Background Pulmonary arteriovenous malformations (PAVMs) are a known complication after some types of cavopulmonary anastomoses (CVPAs). Their cause is unknown, but they may be related to the absence of pulsatile flow or the presence or absence of circulating factors. These PAVMs are diffuse and are presumed to be progressive and irreversible. Methods and Results All patients with congenital heart disease (CHD) seen at Children’s Hospital, Boston, Mass, between 1970 and 1993 were reviewed. We report on the 10 patients with CHD who were found to have developed PAVMs, as diagnosed by cardiac catheterization. Diagnoses included heterotaxy syndrome/polysplenia, with interrupted inferior vena cava and hepatic veins draining to the right atrium (n=6); heterotaxy/asplenia (n=1); corrected transposition with pulmonary stenosis (n=1); and biliary atresia and associated CHD (n=2). PAVMs were diagnosed 0.1 to 7.0 years (median, 3.5 years) after creation of a CVPA that resulted in exclusion of hepatic venous flow from one or both lungs in 8 of the 10 patients; the remaining 2 patients had normal drainage of hepatic veins to the lungs but had biliary atresia. In all, the common anatomic feature was the exclusion of normal hepatic venous return from the affected pulmonary arterial circulation. All patients with interrupted inferior vena cava, azygous continuation to the superior vena cava, and hepatic veins draining to the right atrium (polysplenia syndrome) were reviewed to determine the incidence of PAVMs in those with CVPA (ie, hepatic venous flow excluded from the pulmonary arteries) and without CVPA. Six of 28 (21%) of those with versus 1 of 56 (1.8%) of those without CVPA developed PAVMs ( P =.004). The 1 patient without CVPA who had PAVMs also had biliary atresia. Among patients with CVPA, the probability of developing PAVMs was 15% and 28% at 3 and 5 years, respectively, after CVPA. The histological and angiographic appearances of PAVMs after CVPA are similar to those seen in PAVMs associated with hepatic cirrhosis. Conclusions We postulate that PAVMs after CVPA are related to the diversion of normal hepatic venous flow from the pulmonary circulation. In this sense, these PAVMs may be analogous to those associated with liver disease, which have been found to resolve after liver transplantation. Redirection of hepatic flow to the pulmonary bed in some patients with CHD and PAVMs may lead to reversibility of the PAVMs.
Trends in Regulation and Development of New Drugs
Authors: John C. Ballin
Journal: JAMA (1981)

The year 1980 was characterized by much rhetoric but little action with respect to either legislative or regulatory reform of the prevailing system of drug development. However, it was also a year that witnessed some notable advances in therapeutics, particularly those made possible by the new technology of genetic engineering. This review will examine some of the continuing problems of drug development in this country and briefly discuss noteworthy new drugs and technologies that have advanced the art of therapeutics during 1980. <h3>Pharmaceutical Productivity</h3> The trend toward reduced pharmaceutical productivity in the United States, often called "drug lag," continues unabated. The most recent data published by Wardell<sup>1</sup>indicate that the number of new chemical entities developed by American drug firms and undergoing initial studies in man continues to decrease. At the same time, the number of such potential drugs being tested initially in patients in foreign countries continues to
Chronic Kidney Disease Predicts Cardiovascular Disease
Authors: Thomas H. Hostetter
Journal: New England Journal of Medicine (2004)

The prevalence of end-stage renal disease continues to rise in the United States. Even more disturbingly, the current number of patients with early chronic kidney disease — the pool from which future end-stage renal disease patients will emerge — exceeds the present number with end-stage renal disease by a factor of 30 to 60.1,2 However, early chronic kidney disease will not progress to end-stage renal disease in all patients. Indeed, many will probably die of other conditions first. Over the past few years, investigators have shown that many people in this vast pool of patients with chronic kidney disease . . .
Book Review Thyroid Cancer: A Comprehensive Guide to Clinical Management Second edition. Edited by Leonard Wartofsky and Douglas Van Nostrand. 708 pp., illustrated. Totowa, N.J., Humana Press, 2006. $195. 1-58829-462-5 Management of Thyroid Cancer and Related Nodular Disease By I. Ross McDougall, with Gerald J. Berry. 397 pp., illustrated. London, Springer-Verlag, 2006. $189. 1-85233-965-9
Authors: Jayne Franklyn
Journal: New England Journal of Medicine (2006)
It sticks in our throats too
Authors: S. Ainsworth, W. Jones
Journal: BMJ (2009)

The UK Medicines and Healthcare Products Regulatory Agency (MHRA) claims to “enhance and safeguard the health of the public by ensuring that medicines and medical devices work, and are acceptably safe.”1 Why is it then that instead of changing advice in the summary of product characteristics for the most effective treatment for oral thrush2 to minimise the potential for harm they instead make it an “off licence” product for the very group most in need of it?3

Miconazole oral gel was launched in 1978 and has been used to treat countless infants with symptoms of oral thrush. After more than 30 years of unchanged use the manufacturer, Janssen-Cilag, with the support of the MHRA, chose to change its licensed use in May 2008 such that it is no longer recommended in infants aged under 4 months.3 You might assume that this action was taken in the light of serious adverse events, possibly even a fatality. But no, the reason for the change is the potential …
TARGETING GLIOMA INITIATING CELLS IN GBM: ABTC-0904, A RANDOMIZED PHASE 0/II STUDY TARGETING THE SONIC HEDGEHOG-SIGNALING PATHWAY
Authors: A. E. Sloan, C. J. Nock, J. Supko, X. Ye, N. Takebe, J. Rich, M. Prados, S. Grossman
Journal: Neuro-Oncology (2014)

BACKGROUND: New therapeutic approaches are urgently needed for recurrent GBM (rGBM). Recent studies suggest that GBM oncogenesis and recurrence are regulated by glioma initiating cells (GIC), a minority population of quiescent cells driven by embryonic signaling pathways and resistant to radiation and chemotherapy. Our hypothesis was that interrupting the sonic hedgehog signaling pathway (SHh), an integral mediator of GIC proliferation, would slow tumor progression and improve six month progression free survival (PFS6) in correlation with decreased GSC proliferation and self-renewal. METHODS: A two armed, randomized phase 0/II study of Vismodegib, an inhibitor of SMO was performed in 40 patients undergoing resection for rGBM. Arm I was randomized to receive Vismodegib for 7 days pre-operatively; Arm II was not treated with drug pre-operatively. All patients were treated with Vismodegib alone post-operatively until progression or death. Our primary objective was to estimate six month progression-free survival (PFS6), with secondary endpoints of median overall survival (mOS), response and toxicity. Secondary objectives included determination of: intra-tumoral PK and PD; inhibition of SHh signaling by RT-PCR and immunohistochemistry; and inhibition of GIC proliferation and self-renewal by neurospheres proliferation and limited dilution assays. RESULTS: PK/PD data and tumor specimens obtained from 39/40 patients demonstrated plasma and tissue levels for patients in Arm I (treated pre-operatively) were within therapeutic range. SHh signaling intermediates (Gli-1, Gli-2, PTCH-1b) as determined by RT-PCR and IHC were significantly lower in Arm I vs. Arm II (p < 0.0002). Finally, proliferating CD133 + neurospheres in serum free-media were derived from 17 of the 39 cultures assessed. Array CGH was consistent with GIC (rather than NSC) as the cells of origin, and the proportion of tumor-derived CD133+ neurospheres undergoing proliferation and self-renewal was decreased in Arms I vs. II (p <0.0053 & p < 0.003 respectively). Median PFS and OS was 1.8m and 8.3m respectively; toxicity was minimal. CONCLUSIONS: Vismodegib was well tolerated but poorly efficacious as a single agent in rGBM. However, phase PK and PD studies demonstrated that this agent achieved therapeutic intra-tumoral concentration in rGMB and had biological activity on proliferation and self-renewal of GBM derived CD133+ neurospheres. The phase O/II trial design facilitates a more thorough understanding of an agent's biological effects than the standard phase II trial, and has the potential to enable a more rational approach to this complex and deadly disease. Thus this data suggests that novel combinations pairing SHh pathway inhibition with other agents should be pursued despite lack of single agent efficacy. SECONDARY CATEGORY: Clinical Neuro-Oncology.
Lipids of alveolar macrophages, polymorphonuclear leukocytes, and their phagocytic vesicles
Authors: Robert J. Mason, Thomas P. Stossel, Martha Vaughan
Journal: Journal of Clinical Investigation (1972)

Phagocytic vesicles were isolated from rabbit alveolar macrophages and guinea pig polymorphonuclear leukocytes that had ingested emulsified paraffin oil. Phospholipids and their fatty acids were determined in whole cells and in the phagocytic vesicle and pellet fractions separated from them. The cholesterol-to-phospholipid ratios in the vesicle fractions were distinctly higher than those of the respective whole cells or pellet fractions. The vesicle fractions also had higher phospholipid-to-protein ratios than did the whole cells. The phospholipids of the phagocytic vesicle fraction from macrophages contained relatively more sphingomyelin, lyso-(bis)phosphatidic acid, and phosphatidylserine and less lecithin, phosphatidylethanolamine, and phosphatidylinositol than did the whole cells or pellet fractions. The phospholipids of phagocytic vesicles from polymorphonuclear leukocytes contained significantly more phosphatidylinositol than did the pellet fractions. Lyso(bis)phosphatidic acid, which constituted 15% of the phospholipid in rabbit alveolar macrophages and 25% of that in their phagocytic vesicles, contained almost 60% oleic acid and 20% linoleic acid. This lipid was not detected in rabbit peritoneal macrophages or in rat alveolar macrophages.The polyunsaturated fatty acids of leukocyte phospholipids were chiefly linoleic, whereas in macrophages arachidonic accounted for almost 20% of the total fatty acids. The macrophages produced malondialdehyde when ingesting polystyrene beads or emulsified paraffin oil, from which it was inferred that peroxidation of endogenous lipid can occur during phagocytosis. Polymorphonuclear leukocytes in which less than 3% of phospholipid fatty acids were arachidonic did not produce malondialdehyde during phagocytosis of these inert particles, but did when ingesting an emulsion containing linolenate, thus providing evidence for peroxidation of ingested lipid. Isolated phagocytic vesicles from alveolar macrophages contained lipid peroxides and generated malondialdehyde when incubated with ADP, FeCl(3), and NADH.
Detection of Expiratory Flow Limitation by Manual Compression of the Abdominal Wall
Authors: VINCENT NINANE, DMITRI LEDUC, SOPHIA ABDEL KAFI, MARWAN NASSER, MYRIAM HOUA, ROGER SERGYSELS
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

We have assessed a new method, manual compression of the abdominal wall (MCA) during expiration, in the detection of expiratory flow limitation. Twelve stable patients with chronic obstructive pulmonary disease (COPD) and five normal subjects were studied during spontaneous breathing in the supine and seated posture. MCA was performed during expiration with one hand at the umbilical level and we measured flow, volume, pleural (Ppl) and gastric (Pga) pressures and abdominal anteroposterior (AP) diameter at the umbilical level with magnetometers. No increase in expiratory flow during MCA relative to the preceding breath despite associated increases in pressures was considered as indicating expiratory flow limitation. In seven additional patients with increased upper airway collapsibility (obstructive sleep apnea syndrome [OSAS]), MCA was compared with negative expiratory pressure (NEP). In normal seated subjects, MCA was associated with a decrease in abdominal AP dimension (mean ± SD: − 27 ± 6%), an increase in Pga (14.7 ± 7.4 cm H2O) and Ppl (6.2 ± 2.2 cm H2O), and an increase in expiratory flow. MCA caused similar changes in abdominal AP dimension and pressures in seated patients with COPD but six of them (50%), including four patients with FEV1 less than 1 L, had no increase in expiratory flow. In the supine posture, MCA always increased expiratory flow in normal subjects but four additional patients with COPD showed evidence of flow limitation. MCA invariably increased expiratory flow in patients with OSAS whereas the NEP method suggested flow limitation in some cases. We conclude that MCA is a very simple method that allows detection of flow limitation in different positions.
Intra-aortic Balloon Pump Assist for Cardiogenic Shock After Cardiopulmonary Bypass
Authors: MORTIMER J. BUCKLEY, JOSEPH M. CRAVER, HERMAN K. GOLD, ELDRED D. MUNDTH, WILLARD M. DAGGETT, W. GERALD AUSTEN
Journal: Circulation (1973)

Intra-aortic balloon pump assist (IABP) was applied to 26 patients who could not be with-drawn from total cardiopulmonary bypass (CB) subsequent to elective surgery for multiple cardiac procedures. Eighty-eight per cent were able to separate from CB with IABP and were assisted for 36 to 168 hours. Seventeen were withdrawn from the balloon. Eleven (42%) are hospital survivors. Ten (38%) are alive at the time of this report. IABP was most effective when applied early to patients who had recognizable acute ischemic injury to the myocardium at the time of operation and/or presence of hypertrophied left ventricular myocardium with small chamber volume. Support in these conditions gave 50% survival. Poorest results were in patients with either extensive acute infarction or severe chronic irreversible myocardial damage.
Cimetidine Impairs Elimination of Chlordiazepoxide (Librium) in Man
Authors: PAUL V. DESMOND
Journal: Annals of Internal Medicine (1980)

We have studied chlordiazepoxide (Librium) disposition and elimination in eight normal subjects before and after 1 week of Cimetidine therapy, 300 mg orally four times a day. Cimetidine strikingly impaired the clearance of chlordiazepoxide from plasma, and this was, at least in part, due to decreased demethylation of the drug to N-desmethylchlordiazepoxide. Since the volume of distribution of chlordiazepoxide was not altered by cimetidine, the elimination half-life of chlordiazepoxide was also significantly prolonged by cimetidine therapy.
A memorable ward round
Authors: D. Seaton
Journal: BMJ (2009)

Some 25 years ago, I was a young consultant physician about to start an early morning ward round with my usual team of registrar, senior house officer, and preregistration house physician. All started according to plan except that the SHO was absent. I knew her to be diligent, so I assumed she had probably been distracted by some other pressing call of duty. By …
Renal Carbuncle
Authors: Fletcher H. Colby, Myles P. Baker, Walter T. St. Goar
Journal: New England Journal of Medicine (1957)

INFECTIONS of the renal parenchyma extensive enough to cause a conglomerate mass of infected kidney tissue are called renal carbuncles. A renal carbuncle, essentially, is an exaggeration of a cortical infection and, like that condition, is usually caused by a hematogenous spread of organisms, particularly staphylococci, from some other focus in the body.In the past, respiratory infections have, at times, been followed by renal infections severe enough to require nephrectomy. More often, however, severe inflammation of the renal parenchyma is preceded by a staphylococcal infection of the skin, such as a furuncle, paronychia or carbuncle. Such preceding infections are . . .
Episodes of high coarse particle concentrations are not associated with increased mortality.
Authors: J Schwartz, G Norris, T Larson, L Sheppard, C Claiborne, J Koenig
Journal: Environmental Health Perspectives (1999)

Fine particle concentration (i.e., particles <2.5 microm in aerodynamic diameter; PM2.5), but not coarse particle concentration, was associated with increased mortality in six U.S. cities. Others criticized this result, arguing that it could result from differences in measurement error between the two size ranges. Fine particles are primarily from combustion of fossil fuel, whereras coarse particles (i.e., particles between 2.5 and 10 microm in aerodynamic diameter) are all crustal material, i.e., dust. One way to determine if coarse particles are a risk for mortality is to identify episodes of high concentrations of coarse, but not fine, particles. Spokane, Washington, is located in an arid area and is subject to occasional dust storms after crops have been harvested. Between 1989 and 1995, we identified 17 dust storms in Spokane. The 24-hr mean PM10 concentration during those storms was 263 microg/m3. Using control dates that were the same day of the year in other years (but with no dust storm on that day) and that had a mean PM10 concentration of 42 microg/m3, we compared the rate of nonaccidental deaths on the episode versus nonepisode days. There was little evidence of any risk [relative risk (RR) = 1.00; 95% confidence interval (CI), 0.81-1.22] on the episode days. Defining episode deaths as those occurring on the same or following day as the dust storm produced similar results (RR = 1.01; CI, 0.87-1.17). Sensitivity analyses, which tested more extensive seasonal control, produced smaller estimates. We conclude that coarse particles from windblown dust are not associated with mortality risk.
Metals and kidney autoimmunity.
Authors: P E Bigazzi
Journal: Environmental Health Perspectives (1999)

The causes of autoimmune responses leading to human kidney pathology remain unknown. However, environmental agents such as microorganisms and/or xenobiotics are good candidates for that role. Metals, either present in the environment or administered for therapeutic reasons, are prototypical xenobiotics that cause decreases or enhancements of immune responses. In particular, exposure to gold and mercury may result in autoimmune responses to various self-antigens as well as autoimmune disease of the kidney and other tissues. Gold compounds, currently used in the treatment of patients with progressive polyarticular rheumatoid arthritis, can cause a nephrotic syndrome. Similarly, an immune-mediated membranous nephropathy frequently occurred when drugs containing mercury were commonly used. Recent epidemiologic studies have shown that occupational exposure to mercury does not usually result in autoimmunity. However, mercury induces antinuclear antibodies, sclerodermalike disease, lichen planus, or membranous nephropathy in some individuals. Laboratory investigations have confirmed that the administration of gold or mercury to experimental animals leads to autoimmune disease quite similar to that observed in human subjects exposed to these metals. In addition, studies of inbred mice and rats have revealed that a few strains are susceptible to the autoimmune effects of gold and mercury, whereas the majority of inbred strains are resistant. These findings have emphasized the importance of genetic (immunogenetic and pharmacogenetic) factors in the induction of metal-associated autoimmunity. (italic)In vitro(/italic) and (italic)in vivo(/italic) research of autoimmune disease caused by mercury and gold has already yielded valuable information and answered a number of important questions. At the same time it has raised new issues about possible immunostimulatory or immunosuppressive mechanisms of xenobiotic activity. Thus it is evident that investigations of metal-induced renal autoimmunity have the potential to produce new knowledge with relevance to autoimmune disease caused by xenobiotics in general as well as to idiopathic autoimmunity.
Identification of canary grass (<i>Phalaris aquatica</i>) pollen allergens by immunoblotting: IgE and IgG antibody‐binding studies
Authors: C. Suphioglu, M. B. Singh, R. J. Simpson, L. D. Ward, R. B. Knox
Journal: Allergy (1993)

The pollen of canary grass, which was introduced as a pasture grass from Europe, is a major allergen in the external environment of southern Australia. Seventeen allergenic fractions of canary grass pollen, ranging in mol. mass from 14 to 100 kDa. have been identified by immunoblotting, using IgE antibodies from sera of 24/30 grass‐pollen‐allergic subjects. The highest frequency of IgE binding (77%) was to a major 34‐kDa fraction (tentatively designated Pha a I). This protein bas been partially purified and identified as a group I allergen by immunodepletion experiments, with partially purified Lol p I (from rye‐grass pollen), atopic serum, and Lol p I‐specific MAb. In addition, microsequencing of the N ‐terminus of Pha a I showed an amino acid sequence identical to Lol p I. In a separate study. IgE binding to Western blots of Pha a I, Lol p I. and Cyn d I was investigated in 24 sera and found to occur in 19/24. 18/24, and 9/24. respectively. IgE binding to ail three major allergens, and to both Pha a I and Lol p I, occurred in 8/24 sera. Our findings suggest that while tbe N ‐terminal sequence of Pha a I is identical to Lol p I, there may be specific allergenic epitopes exclusive to this allergen that are important for allergenicity in southern Australia.
I am a survivor
Authors: R. Wiener
Journal: BMJ (1995)

I am a survivor of childhood sexual abuse. I prefer the term survivor to that of victim, which implies a passivity—once a victim, always a victim. Survivor means that however terrible the experience it is possible to come to terms with it and grow through it.

I am not alone. About 10% of the population will have experienced some form of childhood sexual abuse, ranging from inappropriate cuddling or being flashed at to oral, vaginal, or anal penetration by one or more older people. As in most cases my abusers were male, though as a male I was less likely to be abused than a female would have been. In addition there will be many other adults who, as children, were physically or emotionally abused, and adults, primarily women, who are victims of rape and for whom many of the points in this account will be equally valid.

This means that at any general practitioner's surgery, hospital clinic, training session, dental waiting room, or any place where there are patients, there are likely to be some survivors. The percentage will be higher if it is a service dealing with mental health problems. You might say, “So what.” The fact is that the medical experience can prove particularly …