tbuckley/cabot-search huggingface dataset:
On the Plugging of Minute Vessels in the Grey Matter of the Brain, as a Cause of the Delirium and Stupor in Severe Febrile Diseases; and on Other Symptoms of the 'Typhoid State'
Authors: H. C. Bastian
Journal: BMJ (1869)

Mass balance and metabolism studies using radiolabeled substances are well recognized as an important part of the drug development process. In this study, we directly assessed the use of fluorine nuclear magnetic resonance (<sup>19</sup>F NMR) to achieve quantitative mass balance, metabolism, and distribution information for fluorinated compounds, without the need for radiolabeled synthesis or study. As a test case, the disposition of pefloxacin, a fluoroquinolone antibiotic, was evaluated in rats using quantitative <sup>19</sup>F NMR in parallel with a radiolabeled study. Urine, bile, and feces samples were collected over specific periods after oral administration of either 25 mg/kg [<sup>14</sup>C]pefloxacin or 25 mg/kg pefloxacin and were subsequently profiled by radioactivity or <sup>19</sup>F NMR, respectively. The percentage of dose excreted in each matrix was comparable between the two methods, with the total dose recovered by radioactivity and <sup>19</sup>F NMR determined to be 86.8% and 81.8%, respectively. In addition, plasma samples were collected to determine the exposure of pefloxacin and its circulating metabolites. The plasma exposure of pefloxacin determined by <sup>19</sup>F NMR was within 5% to that calculated by a validated liquid chromatography-tandem mass spectrometry bioanalytical method. By both methods, pefloxacin was identified as the major circulating entity, with pefloxacin glucuronide as the major circulating metabolite. Quantitative analysis of metabolites in excreta was generally comparable between the two methods. In selected tissues, both methods indicated that the parent drug accounted for most of the drug-related material. In summary, we have demonstrated that <sup>19</sup>F NMR can be used as an alternative method to conventional radiolabeled studies for compounds containing fluorine without the need for radiolabeled synthesis/study.
Abnormal regional metabolism and mechanical function in patients with ischemic heart diseases: improvement after successful regional revascularization by aortocoronary bypass.
Authors: K Chatterjee, J M Matloff, H J Swan, W Ganz, V S Kaushik, P Magnusson, M M Henis, J S Forrester
Journal: Circulation (1975)

Left ventricular anterior wall metabolism was investigated concurrently with global myocardail metabolism by simultaneous preoperation sampling of anterior interventricular venous (AIV) and coronary sinus (CS) as well as arterial bloods in seven patients with severe obstructive lesions of the major coronary arteries, including left anterior descending. Postoperative study was performed two weeks to six months following successful aortocoronary artery bypass surgery. All grafts including the aorto-left anterior descending artery grafts were patent. Preoperatively in three of the seven patients, anterior wall lactate extraction (R%L) was negative at rest. The average R%L at rest (7 +/- 14%) was abnormal and was negative (-49 +/- 26%) at a maximum supraventricular pacing rate (MPR) of 137 +/- 4.6 beats/min. Postoperatively, not only was resting R%L (39 +/- 4;4%) normal but also it remained normal during atrial pacing (32 +/- 8.5%) even though the postoperative MPR (164 +/- 4.4 beats/min) was much higher than the preoperative MPR; Postoperatively AIV pO2 both at rest (21 +/- 1.1 mm Hg) and at MPR (22 +/- 1.3 mm Hg) and directly determined O2 saturations (resting: 34 +/- 3.0%; MPR:35 +/- 2.1%) tended to be higher than the preoperative values (AIV pO2, resting: 18 +/- 1.7; MPR: 19 +/- 1.7 mm Hg; AIV O2 saturation resting: 30 +/- 2.7; MPR: 33 +/- 3.3%), although only differences in pO2 were statistically significant. In five of the seven patients in whom the pre and postoperative left ventricular angiograms could be compared, systolic wall motion of the left ventricular anterior wall improved markedly postoperatively. Average global myocardial lactate extraction (G%L) preoperatively was normal (19 +/- 4.8%) at rest but was negative (-22 +/- 12%) at MPR. Postoperatively however, G%L both at rest (44 +/- 5.5%) and at MPR (34 +/- 7.9%) were normal. Coronary sinus pO2 and O2 saturation were also higher postoperatively compared to the preoperative values. Over-all left ventricular performance indicated by increase in ejection fraction also improved postoperatively. This improvement was not caused by increased coronary blood flow. Postoperative coronary sinus blood flow both at rest (114 +/- 19 ml/min) and at MPR (199 +/- 27 ml/min) however were less than the preoperative values (resting 136 +/- 24, MPR 261 +/- 40 ml/min), There was also no increase in global O2 delivery and O2 consumption despite higher heart rate and rate-pressure product achieved during postoperative pacing stress and the patients did not develop angina. These findings suggest that improved regional and global metabolism and mechanical functions observed postoperatively in these patients may be due to redistribution of blood flow to the ischemic and nonischemic myocardium following successful aortocoronary artery bypass surgery.
Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor- viral RNA interactions
Authors: A.-S. Beignon
Journal: Journal of Clinical Investigation (2005)

HIV-1 directly activates human plasmacytoid DCs (pDCs) by upregulating the expression of costimulatory and MHC molecules and maturation markers, increasing T cell stimulatory activity, and inducing the production of type I interferons and TNF-α. A consequence of this activation is the bystander maturation of myeloid DCs and overall enhancement of antigen-presenting function. However, little is known about the mechanism(s) of pDC activation by HIV-1. Here we demonstrate by in vitro studies that IFN-α production by pDC in response to HIV-1 requires at least 2 interactions between the cell and virus. Initially, envelope-CD4 interactions mediate endocytosis of HIV-1, as demonstrated through the use of inhibitors of binding, fusion, endocytosis, and endosomal acidification. Subsequently, endosomally delivered viral nucleic acids, particularly RNA, stimulate pDCs through TLRs, as activation is reproduced with purified genomic RNA but not viral RNA packaging–deficient HIV-1 and blocked with different inhibitory TLR ligands. Finally, by using genetic complementation, we show that TLR7 is the likely primary target. Viral RNA rather than DNA in early retrotranscripts appears to be the active factor in HIV-1 that induces IFN-α secretion by pDCs. Since the decline in pDCs in chronic HIV-1 infection is associated with high viral loads and opportunistic infections, exploiting this natural adjuvant activity of HIV-1 RNA might be useful in the development of vaccines for the prevention of AIDS.
Estrogen Sulfation Genes, Hormone Replacement Therapy, and Endometrial Cancer Risk
Authors: Timothy R. Rebbeck, Andrea B. Troxel, Yiting Wang, Amy H. Walker, Saarene Panossian, Stephen Gallagher, Ekaterina G. Shatalova, Rebecca Blanchard, Greta Bunin, Angela DeMichele, Stephen C. Rubin, Mona Baumgarten, Michelle Berlin, Rita Schinnar, Jesse A. Berlin, Brian L. Strom
Journal: JNCI Journal of the National Cancer Institute (2006)

Unopposed estrogen replacement therapy is associated with increased risk of endometrial cancer. To investigate the mechanism of this association, we evaluated whether risk of endometrial cancer was associated with the genotypes involved in steroid hormone metabolism and the duration of exogenous hormone use.A population-based case-control study in nine counties of the Philadelphia metropolitan area was undertaken with 502 case patients with endometrial cancer and 1326 age- and race-matched control subjects. Data regarding exogenous hormone use were obtained by interview, and genotypes of the genes COMT, CYP1A1, CYP1A2, CYP1B1, CYP3A4, PGR, SULT1A1, SULT1E1, and UGT1A1 were obtained by polymerase chain reaction techniques. Conditional logistic regression was used to examine the relationship among genotype, hormone use, and endometrial cancer risk.Associations were observed between the risk of endometrial cancer and genotypes of the following steroid hormone metabolism genes: CYP1A1*2C (adjusted odds ratio [OR] = 1.68, 95% confidence interval [CI] = 1.08 to 2.61); SULT1A1*3 (adjusted OR = 0.51, 95% CI = 0.29 to 0.92); and the G --> A variant in the promoter of SULT1E1 at position -64 (adjusted OR = 1.45, 95% CI = 1.06 to 1.99). We observed a statistically significant interaction between estrogen replacement therapy use and SULT1A1*2 genotype: the SULT1A1*2 allele and long-term use of estrogen replacement therapy were associated with statistically significantly higher risk of endometrial cancer (adjusted OR = 3.85, 95% CI = 1.48 to 10.00) than that of the SULT1A1*2 allele and no estrogen replacement therapy use.Among women with long-term use of estrogen replacement therapy or combined hormone replacement therapy, the risk of endometrial cancer may be associated with functionally relevant genotypes that regulate steroid hormone sulfation.
Concerns about report suggesting glucosamine and chondroitin protect against cartilage loss
Authors: David T Felson
Journal: Annals of the Rheumatic Diseases (2015)

Concerns about report suggesting glucosamine and chondroitin protect against cartilage lossWe wish to raise several concerns about the validity and conclusions of the recent report from Martel-Pelletier and coauthors 1 regarding potential effects of glucosamine and chondroitin (G +C) on cartilage loss over time.The report used data from the Osteoarthritis Initiative (OAI), a large observational study from which the authors attempted to draw inferences about the effects of these treatments.First, it is not clear why the authors chose to divide subjects into those on analgesics/nonsteroidal anti-inflammatory drugs (NSAIDs) versus those not on analgesics/NSAIDs before examining the effects of G+C.We are unaware of any data and none is cited that would suggest that G+C would have different effects on cartilage in those taking versus those not taking analgesics/ NSAIDs.We note that the use of analgesics/NSAIDs in most persons in OAI was intermittent, not continuous.If analgesic/ NSAID users had lower cartilage volumes than non-users, they could have adjusted for analgesic/NSAID use in analyses.If the authors believed that the effects of G+C would be different by analgesic/NSAID use, they should have tested for a difference using an interaction term.If the effects were not different, they should have analysed all subjects on G+C versus all those not on G+C adjusting for differences between the groups.Based on the extensive data presented in their paper, we strongly suspect that such an analysis would have yielded no significant findings-no association of G+C with protection against cartilage loss.Also, in examining the effects of a treatment on outcomes in an observational study, one generally attempts to either match those on treatment with those not on treatment so that both treated and non-treated groups are similar in terms of their risk of outcomes (in this case cartilage loss) or adjust for differences between groups using multivariable analyses.Table 2 in their study shows considerable evidence that the G+C group was different from the non-G+C group in ways that might well have affected their rate of cartilage loss, yet the authors present a univariate analysis of the effect of G+C on cartilage loss in their tables.In the text, they acknowledge that a multivariable analysis showed no significant effect of G+C on cartilage loss.The authors should have presented adjusted analyses and made primary conclusions based on these.
The Functions of the Macrophage in Malignant Disease
Authors: P Alexander
Journal: Annual Review of Medicine (1976)

In the past many different names were given to cells which we now realize are all macrophages. This came about because of the different appearances macrophages manifest when carrying out their diverse functions in different locations. Evidence that the immediate precursor of the macrophage is a blood monocyte, derived from radiosensitive cells in the bone marrow, is now overwhelming. When appropriately stimulated, macrophages are capable of active multiplication and mitotic figures are commonly seen in mononuclear phagocytes in granulomas, at sites of inflammation, and in the reticuloendothelial (RE) system and the peritoneal cavity following systemic or local treatment with a number of bacterial products (I). Consequently the number of macrophages in the body can be increased both by division as differentiated macrophages and by stimulating the output of monocytes from the bone marrow. Macrophages together with polymorphonuclear leukocytes constitute the first line of defense of the body against most infections, and specific  requiring Band T-Iymphocytes in general comes into play as a back-up mechanism and for long-term protection. The term  immunity was originally coined to describe protection provided by macrophages, and its extension to specific immune processes, in which lymphocytes are the effector cells, is of relatively recent origin. The idea that macrophages are involved in the rejection of allogeneic cells injected into the peritoneal cavity was advanced more than 20 years ago (2), and their role in the homograft reaction has been investigated extensively (3-6). Macrophages contribute at several stages to the genesis of specific  leading to antibody production and cell-mediated  directed against specific antigens (see below). In addition they act with nonspecific opsonins and recognition factors by exerting an antibacterial action which is not specific in the strict immuno­ logical sense but has a high degree of selectivity. The recognition by the RE system
Open all hours: night visits in general practice
Authors: T O'Dowd, H Sinclair
Journal: BMJ (1994)

<h3>Objectives</h3> A <i>Neisseria gonorrhoeae</i> antimicrobial susceptibility quality control comparison programme was re-established in Latin America and the Caribbean to ensure antimicrobial susceptibility data produced from the region are comparable nationally and internationally. <h3>Methods</h3> Three panels, consisting of <i>N. gonorrhoeae</i> isolates comprising reference strains and other characterised isolates were sent to 11 participating laboratories between 2013 and 2015. Antimicrobial susceptibilities for these isolates were determined using agar dilution, Etest or disc diffusion methods. Modal minimum inhibitory concentrations (MICs) for each panel isolate/antibiotic combination were calculated. The guidelines of the Clinical and Laboratory Standards Institute were used for interpretations of antimicrobial susceptibility. The agreement of MICs with the modal MICs was determined for each of the participating laboratories as well as for each of the antibiotics tested. <h3>Results</h3> Five of 11 laboratories that participated in at least one panel had an overall average agreement between participants’ MIC results and modal MICs of &gt;90%. For other laboratories, agreements ranged from 60.0% to 82.4%. The proportion of agreement between interpretations for all the antibiotics, except penicillin and tetracycline, was &gt;90%. The percentages of agreement between MIC results and their modes for erythromycin, spectinomycin, cefixime and azithromycin were &gt;90%. Tetracycline, ceftriaxone and ciprofloxacin agreement ranged from 84.5% to 89.1%, while penicillin had 78.8% agreement between MICs and modal MICs. <h3>Conclusions</h3> The participating laboratories had acceptable results, similar to other international quality assurance programmes. It is important to ensure continuation of the International Gonococcal Antimicrobial Susceptibility Quality Control Comparison Programme to ensure that participants can identify and correct any problems in antimicrobial susceptibility testing for <i>N. gonorrhoeae</i> as they arise and continue to generate reproducible and reliable data.
Re-educating natural killer cells
Authors: Joseph C. Sun
Journal: The Journal of Experimental Medicine (2010)

The development and function of natural killer (NK) cells is dictated by signals received through activating and inhibitory receptors expressed on the cell surface. During their maturation in the bone marrow, NK cells undergo an education process that ensures they are tolerant to healthy peripheral tissues. Several recent studies advance our understanding of self-tolerance mechanisms at work in NK cells. These studies demonstrate that the developmental programming in NK cells is not fixed, and that perturbations to the peripheral environment (via transplantation or viral infection, for example) greatly influence the ability of mature NK cells to mount an effector response. This newfound ability of mature NK cells to be "re-educated" may be clinically applicable in the immunotherapeutic use of NK cells against infection and cancer.
A T cell-dependent experimental liver injury in mice inducible by concanavalin A.
Authors: G Tiegs, J Hentschel, A Wendel
Journal: Journal of Clinical Investigation (1992)

Male NMRI or BALB/c mice developed severe liver injury as assessed by transaminase release within 8 h when an intravenous dose greater than 1.5 mg/kg concanavalin A (Con A) was given. Histopathologically, only the liver was affected. Electron micrographs revealed leukocyte sticking to endothelial cells and bleb formation of hepatocytes. The hepatotoxicity of the lectin correlated neither with its agglutination activity nor with its sugar specificity. Administration of 0.5 mg/kg dexamethasone or 50 mg/kg cyclosporine A or 50 mg/kg FK 506 (Fujimycin) resulted in protection of the animals whereas indomethacin pretreatment failed to protect. Con A hepatitis was accompanied by the release of IL-2 into the serum of the animals. Mice with severe combined immunodeficiency syndrome lacking B as well as T lymphocytes were resistant against Con A. Athymic nude mice with immature T lymphocytes were also resistant. Pretreatment of mice with an antibody against T lymphocytes fully protected against Con A as did monoclonal anti-mouse CD4. Monoclonal anti-mouse CD8 failed to protect. Pretreatment of mice with silica particles, i.e., deletion of macrophages, prevented the induction of hepatitis. These findings provide evidence that Con A-induced liver injury depends on the activation of T lymphocytes by macrophages in the presence of Con A. The model might allow the study of the pathophysiology of immunologically mediated hepatic disorders such as autoimmune chronic active hepatitis.
Effect of a rapid access flexible sigmoidoscopy clinic on the yield of early stage rectal cancer
Authors: R C A Macadam
Journal: Gut (2003)

We read with interest the debate on population based endoscopic screening for colorectal cancer ( Gut 2003; 52 :323–6). While we agree that the case for population screening is compelling, we believe that Macafee and Scholefield’s statement that “earlier diagnosis is unlikely to occur through increased awareness or patient education alone” is unnecessarily pessimistic.

We have recently had the opportunity to audit the impact of a dedicated rapid access flexible sigmoidoscopy clinic established in the endoscopy department of Dewsbury and District Hospital …
Physiotherapy for prevention of lower back injuries in wrestling
Authors: E Dimitrova, S Stanev
Journal: British Journal of Sports Medicine (2011)

Introduction About 10% of all sport injuries in wrestling occur in lower back area.1 The purpose of this report is to summarise the incidence of lower back injuries in wrestling and the mechanisms involved, and to represent our experience in physiotherapy (PT) for prevention of these injuries. Methods From a sample of 95 wrestlers (males), 11 lower back injuries were found (11.6%). Problems such as muscle and joint injuries and dysfunctions occur quite frequently. Treatment of dysfunctions begins with PT program, that emphasises analytical stretching2 and strengthening of the back and abdominal musculature. We allow a return to sport when the athlete has regained at least 70% of his viability and pain-free full range of motion. Results Lower back injureis can be due to numerous factors: extensions, combined with twisting in take-downs (5 out of 11 wrestlers −45.5 %), extensions against resistance as in lifting an opponent off the mat (6 out of 11 wrestlers −54.5 %). Reduction in low back injuries was found as a result of a physiotherapy program. 8 out of 11 wrestlers who were treated from low back injuries returned to high-level competitions. In three cases the condition was not treated on time and it became chronic. As a result of our study, many changes have been made to the strength and conditioning training. Conclusion In cases of low back injuries an early diagnosis is essential, so that treatment can be commenced as soon as possible. Preventive physiotherapy program is essential and should be included in every training program as an integral part of the warm-up and recovery.
Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia
Authors: Bing Zhang, Wenyuan Xiao, Hong Qiu, Fuming Zhang, Heather A. Moniz, Alexander Jaworski, Eduard Condac, Gerardo Gutierrez-Sanchez, Christian Heiss, Robin D. Clugston, Parastoo Azadi, John J. Greer, Carl Bergmann, Kelley W. Moremen, Dean Li, Robert J. Linhardt, Jeffrey D. Esko, Lianchun Wang
Journal: Journal of Clinical Investigation (2013)

Congenital diaphragmatic hernia (CDH) is a common birth malformation with a heterogeneous etiology. In this study, we report that ablation of the heparan sulfate biosynthetic enzyme NDST1 in murine endothelium (Ndst1ECKO mice) disrupted vascular development in the diaphragm, which led to hypoxia as well as subsequent diaphragm hypoplasia and CDH. Intriguingly, the phenotypes displayed in Ndst1ECKO mice resembled the developmental defects observed in slit homolog 3 (Slit3) knockout mice. Furthermore, introduction of a heterozygous mutation in roundabout homolog 4 (Robo4), the gene encoding the cognate receptor of SLIT3, aggravated the defect in vascular development in the diaphragm and CDH. NDST1 deficiency diminished SLIT3, but not ROBO4, binding to endothelial heparan sulfate and attenuated EC migration and in vivo neovascularization normally elicited by SLIT3-ROBO4 signaling. Together, these data suggest that heparan sulfate presentation of SLIT3 to ROBO4 facilitates initiation of this signaling cascade. Thus, our results demonstrate that loss of NDST1 causes defective diaphragm vascular development and CDH and that heparan sulfate facilitates angiogenic SLIT3-ROBO4 signaling during vascular development.