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11.
According to FDA regulations, a combination drug is not efficacious unless each component contributes to the claimed effects. For a univariate endpoint, this implies that the combination at specific doses must be superior to each of its components at the same doses. More demanding is the property of synergy, in which the effect of the combination must be superior to the effect expected based on those of its components. If it is equal to those effects, it is additive, and if it is inferior, it is antagonistic. We give regions in the combination dose plane where these concepts are well defined. If the effect of the combination is greater than the greatest effect achievable by any of its components it is therapeutically synergistic. A combination can be antagonistic, yet its components can still contribute to the claimed effects. If it is additive, synergistic or therapeutically synergistic, its components must contribute to the claimed effects. We relate these concepts and provide designs and sequential procedures for determining whether a combination is therapeutically synergistic, synergistic, additive, antagonistic and contributing or antagonistic and non-contributing. 相似文献
12.
EM Renz 《Canadian Metallurgical Quarterly》1997,50(7):225-227
The Dieulafoy lesion, also referred to as exulceratio simplex, caliber-persistent artery anomaly, or cirsoid aneurysm, is a relatively rare, yet possibly fatal cause of gastrointestinal bleeding. Recent journal articles suggest that this pathological entity is not as uncommon as once thought. Advances in endoscopic technique and esophagogastroduodenoscopy (EGD) have greatly assisted in earlier diagnosis and added options to the treatment regimen for this lesion. The relationship of this anomaly to possible exsanguination makes it essential that both medical and surgical endoscopists be knowledgeable of the anatomy, diagnosis, and management of this pathology. Several therapeutic approaches to Dieulafoy's lesion are available and are described. 相似文献
13.
FG Abath EM Xavier JD Silva MA Morais Júnior SM Montenegro 《Canadian Metallurgical Quarterly》1997,92(5):637-641
Sm15 and Sm13 are recognized by antibodies from mice protectively vaccinated with tegumental membranes, suggesting a potential role in protective immunity. In order to raise antibodies for immunochemical investigations, the genes for these antigens were expressed in pGEX and pMal vectors so that comparisons could be made among different expression systems and different genes. The fusion proteins corresponding to several parts of the gene for the precursor of Sm15 failed in producing antibodies recognizing the parasite counterpart. On the other hand, antibodies raised against Sm13 MBP-fusion proteins recognized the 13 kDa tegumental protein. Thus the peculiarities of the gene of interest are important and the choice of the expression system must sometimes be decided on an empirical basis. 相似文献
14.
J Hellman EM Zanzot PM Loiselle SF Amato KM Black Y Ge JT Kurnick HS Warren 《Canadian Metallurgical Quarterly》1997,176(5):1260-1268
The binding of IgG in antiserum to Escherichia coli J5 to the surface of Enterobacteriaceae and to cell wall fragments released from serum-exposed bacteria was studied in a search for potentially protective epitopes other than lipopolysaccharide (LPS). IgG titers to multiple heterologous gram-negative smooth bacteria increased following incubation of the bacteria in serum and decreased following absorption with serum-exposed heterologous bacteria. IgG eluted from absorbing bacteria bound to at least three conserved bacterial outer membrane proteins (OMPs), but not LPS, as assessed by immunoblotting. The same OMPs were present in LPS-containing macromolecular cell wall fragments released by incubation of heterologous gram-negative bacteria in human serum. Part of the protection offered by J5 antiserum could be from binding of IgG to conserved OMPs at the bacterial surface or to OMPs in cell-wall fragments released from dying bacteria. 相似文献
15.
Spores of Bacillus subtilis NCTC 8236 were treated with glutaraldehyde, Lugol's iodine, polyvinylpyrrolidone-iodine (PVP-I), sodium hypochlorite or sodium dichloroisocyanurate (NaDCC). After exposure survivors were enumerated on nutrient agar containing potential revival agents (subtilisin, lysozyme, calcium dipicolinate, calcium lactate). Of these, only calcium lactate had any significant enhancing effect and then only with iodine-treated spores. Calcium lactate (9 mmol l-1) in nutrient broth enhanced the rate and extent of germination of iodine-treated spores but not of spores previously subjected to glutaraldehyde, hypochlorite or NaDCC. 相似文献
16.
BACKGROUND: Monocytic tissue factor (TF), initiating the extrinsic blood coagulation pathway, is often upregulated under septic or inflammatory conditions. The complex activating mechanism remains largely unclear and no effective strategy has been firmly established. In this study, we used a model monocytic cell line (human leukemic THP-1 promonocytes) to address (1) the nature of TF activation in response to bacterial endotoxin and (2) the application of anti-inflammatory cytokines in relieving monocytic hypercoagulation. RESULTS: TF in THP-1 cells was substantially activated by exposure to bacterial endotoxin (LPS; 5 micrograms/ml) for 6 h. Human recombinant IL-4 (500 ng/ml) and IL-10 (500 ng/ml) inhibited TF activation induced by LPS. To determine if these cytokines depressed LPS recognition resulting in such inhibition, we employed an anti-CD14 mAb (UCHM-1; Sigma Chemical) to address the role of CD14 in LPS transmembrane signaling. LPS-induced TF activation was depressed by 35% upon inclusion of the anti-CD14 mAb (1:10 dilution). This antibody alone mimicked TF activation which accounted for 35% of the LPS-induced TF activation, suggesting the activating role of CD14 ligation. In addition, the anti-CD14 mAb elicited the production of nitric oxide (NO) which was found to be independent of TF activation. NO production could serve as an independent index for monitoring LPS recognition. IL-4 depressed the anti-CD14 mAb-induced TF activation as well as NO elicitation, indicating the blockade of CD14 ligation. In contrast, IL-10 showed differential inhibitory activities. TF activation induced by either LPS or anti-CD14 mAb was inhibited by IL-10 which did not show any inhibition on NO elicitation under these conditions. In a separate approach, neither IL-4 nor IL-10 inhibited phorbol ester-induced NO elicitation. More direct evidence came from an epifluorescent demonstration showing that IL-4 blocked binding of FITC-conjugated LPS and anti-CD14 mAb to THP-1 cells. CONCLUSIONS: Taken together, the results suggest that LPS action in relation to TF activation consists of CD14-independent and -dependent signaling including CD14 ligation. We also showed that anti-inflammatory cytokines (IL-4 and -10) significantly depressed TF activation. IL-4 antagonized CD14-dependent LPS recognition leading to the depression in TF activation. 相似文献
17.
P. A. Hausladen D. C. Weisser N. R. Lobanov L. K. Fifield H. J. Wallace 《Nuclear instruments & methods in physics research. Section B, Beam interactions with materials and atoms》2002,190(1-4):402-404
We report on improvements in the overall intensity of a sputter ion source that evolved originally from an NEC MCSNICS. Beam output increases benefit both AMS measurements and nuclear physics experiments using low natural abundance beams. In particular, minor changes in source geometry suggested by a combination of electrostatic calculations and simple design principles have yielded increases in extracted negative ion intensity of nearly a factor of 4. 相似文献
18.
19.
EM Van der Aa IJ Meuwsen AC Boersen AC Wouterse JH Copius Peereboom-Stegeman FG Russel 《Canadian Metallurgical Quarterly》1994,15(3):279-289
The mechanism of uptake of p-aminohippurate (PAH) by syncytial microvillous membrane vesicles of human term placenta was investigated. Initial PAH uptake and efflux were increased in the presence of a pH-gradient and a Cl(-)-gradient, respectively. Forced negative and positive membrane potentials did not influence the uptake, which indicated that the transport is not electrogenic. The pH-dependent increase is probably the result of a higher rate of diffusion due to a lower degree of dissociation of PAH. Because several organic anions failed to transstimulate PAH uptake and FCCP did not decrease the uptake in the presence of an inwardly directed H(+)-gradient, ruling out a PAH/OH- antiport, an anion exchange system does not appear to be present in these membranes. Since electrogenicity and anion exchange seem not to be involved in the Cl(-)-dependent increase, an allosteric effect of Cl- on the transporter might be possible. Various organic anions were able to inhibit pH-stimulated PAH uptake significantly. Kinetic analysis of the probenecid sensitive part of uptake provided further evidence for mediated transport of PAH (Km = 7.4 +/- 2.6 mM and Vmax = 2.0 +/- 0.4 nmol/mg/15 s). Non-inhibitable diffusion accounted for the main part of total transport. Concentration dependent inhibition of PAH transport by probenecid showed a Ki of 2.5 +/- 0.9 mM. It is concluded that human placental syncytial microvillous membrane vesicles possess a low affinity transport mechanism for PAH with low specificity. The importance of this system, for placental excretion of anionic drugs, will depend on the intrasyncytial concentration of these drugs, caused by the transport across the basal membrane. 相似文献
20.
BACKGROUND: Hearing loss is generally regarded as a rare side effect of erythromycin therapy. However, our own clinical experiences in erythromycin-treated patients led us to suspect that this complication may be more common among renal allograft recipients. The purpose of this study was to evaluate the incidence, predisposing factors, clinical characteristics, and outcomes of erythromycin-induced hearing loss among renal allograft recipients. METHODS: We reviewed medical records of renal transplant patients treated for pneumonia with intravenous erythromycin lactobionate. Patients were evaluated for the occurrence of clinically significant hearing loss (including onset, duration, and reversibility), other signs and symptoms of ototoxicity (vertigo and tinnitus), daily erythromycin dose and duration of treatment, concurrent ototoxic drug therapy, renal and hepatic function, and history of previous otic disease. RESULTS: Eleven (32%) of 34 courses of intravenous erythromycin therapy resulted in hearing loss. The incidence of hearing loss was 53% (eight of 15 courses) in patients treated with 4 g of erythromycin daily compared with 16% (three of 19 courses) among those receiving 2 g/d (P = .05). In addition, courses of erythromycin were longer in those suffering auditory toxicity (9.6 +/- 4.7 days) than in nontoxic patients (5.7 +/- 3.6 days) (P < .05). Hepatic and renal function did not differ between toxic and nontoxic patients. All episodes of erythromycin-induced hearing loss were reversible. CONCLUSIONS: We conclude that clinically significant hearing loss occurs in more than 30% of renal allograft recipients treated for pneumonia with intravenous erythromycin lactobionate. Patients who require prolonged courses of erythromycin and those treated with 4 g/d are at particular risk for the development of auditory toxicity. With prompt recognition and modification of therapy, erythromycin-induced hearing loss appears to be completely reversible. 相似文献