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Results for “Endpoint Determination”

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PubMed2002

Effects of incubation temperature and estrogen exposure on aromatase activity in the brain and gonads of embryonic alligators.

During embryogenesis, incubation temperature and the hormonal environment influence gonadal differentiation of some reptiles, including all crocodilians. Current evidence suggests that aromatase, the enzyme that converts androgens to estrogens, has a role in sexual differentiation of species that exhibit temperature-dependent sex determination (TSD). During the temperature-sensitive period (TSP) of sex determination, we compared aromatase activity in the brain and gonads of putative male and female alligator embryos to determine if aromatase activity in the embryonic brain could provide the hormonal environment necessary for ovarian development in a TSD species. In addition, we assessed the pattern of aromatase activity in the brain and gonads of embryos treated with estradiol-17beta (E(2)) and incubated at male-producing temperatures to compare enzyme activity in E(2) sex-reversed females to control males and females. This has particular significance regarding wildlife species living in areas contaminated with suspected environmental estrogens. Gonadal aromatase activity remained low during the early stages of the TSP in both sexes and increased late in the TSP only in females. Aromatase activity in the brain increased prior to gonadal differentiation in both sexes. These results suggest that aromatase activity in the brain is not directly responsible for mediating differentiation of the gonad. E(2) exposure at male-producing temperatures resulted in sex-reversed females that had intermediate gonad function and masculinized brain activity. This study indicates the need to examine multiple end points and to determine the persistence of developmental alterations in contaminant-exposed wildlife populations.

Alligators and Crocodiles↗

PubMed2004

Enhanced detection of arrhythmia vulnerability using T wave alternans, left ventricular ejection fraction, and programmed ventricular stimulation: a prospective study in subjects with chronic ischemic heart disease.

INTRODUCTION: In previous studies, the prognostic value of T wave alternans (TWA) was similar to that of programmed ventricular stimulation (PVS). However, presently it is unclear if TWA and PVS identify the same patients or provide complementary risk stratification information. In addition, the effects of left ventricular ejection fraction (LVEF) on the prognostic value of TWA are unknown. The aim of this study was to determine if combined assessment of TWA, LVEF, and PVS improves arrhythmia risk stratification. METHODS AND RESULTS: This was a prospective study of 144 patients with coronary artery disease and LVEF < or =40% who were referred for PVS for standard clinical indications. The endpoint was the combined incidence of death, sustained ventricular arrhythmias, and appropriate implantable cardioverter defibrillator (ICD) therapy. TWA (hazard ratio 2.2, P = 0.03) and PVS (hazard ratio 1.9, P = 0.05) both were significant predictors of endpoint events, and TWA was the only independent predictor. LVEF markedly influenced the prognostic value of TWA, which was a potent predictor of events in subjects with LVEF between 30% and 40% (event rates: TWA+ 36%, TWA- 0%, P = 0.001) but did not predict events in subjects with LVEF <30% (hazard ratio 1.1, P > 0.5). PVS successfully identified additional low-risk patients within the cohort with negative or indeterminate TWA results (hazard ratio 4.7, P = 0.015) but did not provide incremental prognostic information for TWA+ patients (hazard ratio 0.9, P > 0.5). CONCLUSION: The combined use of TWA, LVEF, and PVS is a promising new approach to arrhythmia risk stratification that permits identification of high-risk and very-low-risk patients.

Aged↗

PubMed2000

The relationship between elution time and eluate volume using the Ultra-TechneKow DTE technetium-99m generator.

OBJECTIVE: The new Ultra-TechneKow Dry Ship Top Elute 99mTc generator (UTK-DTE generator; Mallinckrodt Medical, Inc., St. Louis, MO) was devised to facilitate fractionated elution with an ergonomically designed elution shield. Fractionation is accomplished traditionally by visually observing the eluted volume through 2 layers of leaded glass windows located in a lighted elution shield and generator auxiliary shield. The goal of our study was to use elution time to determine the endpoint for obtaining the required volume of 99mTc-eluate from a UTK-DTE generator. METHODS: After triplicate elution at several predetermined elution times, the initial weight of the evacuated collecting vial was subtracted from the total weight after elution to determine the elution volume. RESULTS: A quadratic relationship was established between the eluate volume (v, mL) and elution time (t, s) (v = 0.3594 + 0.1889 t - 0.0009 t2). This equation is suitable for use with the 10-mL elution vial. This formula may not be accurate for the first elution since the UTK-DTE generator is a dry-column generator when shipped. The following elution times were calculated for some commonly eluted volumes: 2 mL (9 s), 4 mL (22 s), 5 mL (28 s), 7 mL (45 s), and 10 mL (88 s). CONCLUSION: Our calculated elution time method can be used to predict the eluate volume from a UTK-DTE generator.

Algorithms↗

PubMed2000

Human neuroblastoma cell viability and growth are affected by altered culture conditions.

The effects of differing culture parameters are seldomly investigated, even though they influence the way immortalized cells grow and die. In this study, the changes in total cell number, confluency, membrane permeability, and DNA content were evaluated in SH-SY5Y and IMR-32 human neuroblastoma cells following culture at different seeding densities and media consistencies. These four endpoints were determined using a hemacytometer, phase-contrast microscope, trypan blue (0.4% v/v), and propidium iodide (50 microg/mL), respectively. Both cell lines (SH-SY5Y and IMR-32) responded in a similar manner to changing culture conditions, even though baseline values for all four endpoints were different. Higher seeding densities (19,200 and 38,400 cells/cm2) significantly increased the percent confluency and total cell number over time, but decreased the initial percentage of cells with fragmented (subG1) DNA in both cell lines when compared with lower seeding densities (4800 and 9600 cells/cm2, p < 0.05). Daily media changes significantly increased the percentage of cells in S and G2/M, but decreased the percentage of cells in G0/G1 phase of the cell cycle over time in both cell lines when compared with cultures without media changes (p < 0.05). Results suggest that environmental culture conditions greatly affect cellular mitosis and death. This information may be of particular relevance in the investigation of compounds that act on specific cell-cycle stages, such as antineoplastic agents.

Cell Communication↗

PubMed2003

Myocardial performance index as predictor of adverse outcomes following mitral valve surgery.

AIMS: We aim to determine whether the myocardial performance index, will be a good predictor of adverse outcomes following mitral valve surgery. METHOD: We prospectively measured pre-operative myocardial performance index in 22 consecutive patients, with moderate to severe mitral insufficiency, undergoing corrective mitral valve surgery. The primary endpoint was predefined as either peri-operative death or congestive heart failure. RESULTS: The primary endpoint occurred in nine patients. Five of the six patients with myocardial performance index >or=0.7 had primary endpoints. Chi-square testing demonstrated that the primary endpoint was significantly associated with advanced age (>or=70 years) and myocardial performance index >or=0.7 (P=0.003 and 0.01 respectively). There was a trend towards significant association of depressed left ventricle ejection fraction (left ventricle ejection fraction or=0.7. CONCLUSION: Our results suggest that myocardial performance index is a potentially useful predictor of increased risk of peri-operative death or congestive heart failure, in patients with moderate-severe mitral insufficiency undergoing corrective mitral valve surgery. In conjunction with left ventricle ejection fraction, it may be helpful in the pre-operative prognostication of these patients.

Adult↗

PubMed2006

Alternative clinical end points in rectal cancer--are we getting closer?

BACKGROUND: In rectal cancer a high risk of local recurrence has been reported for patients treated by surgery alone. It is also recognised that 20%-40% of rectal cancer patients continue to develop distant metastases and die, even when a very low risk of local recurrence has been achieved with the use of preoperative radiotherapy and total mesorectal excision (TME). Hence, the current design of randomised trials in rectal cancer continues to use the standard end points of local control and survival. This strategy is time-consuming. The recently published EORTC 22921 trial, which compared radiotherapy with chemoradiotherapy and tested the role of postoperative adjuvant chemotherapy, has taken 14 years from planning to results. The aim of this review was to use the evidence from both phase II and phase III trials to provide a comprehensive survey of alternative clinical trial end points in rectal cancer, where preoperative chemoradiation has now become the standard treatment. We describe their strengths and weaknesses. Some are clearly defined, easy to assess and can be obtained early, because surgical resection usually takes place within 6-8 weeks of the completion of treatment. Some pathological response end points reflect biological activity, although their effect on survival has yet to be validated in randomised controlled trials. We will propose measurement and analytical techniques for minimising bias and intra- and inter-observer variability of the non-validated end points in the hope of basing these judgements on as firm a ground as possible. METHODS: A literature search identified both randomised and non-randomised trials of preoperative radiation therapy (RT) and chemoradiation therapy (CRT) in rectal cancer from 1993 to 2005. The aim was to find those studies that documented potential alternative end points. RESULTS: Pathological parameters have been used as early end points to compare studies of preoperative radiotherapy or chemoradiation. In the light of the German CAO/ARO/AIO-94 study, which demonstrated an improved therapeutic ratio for preoperative treatment, enthusiasm for preoperative chemoradiation in the management of rectal cancer is increasing. Current evidence cannot indicate whether the degree of response to chemoradiation (e.g. complete pathological response; downsizing the primary tumour; sterilizing the regional nodes; tumour regression grades or residual cell density) or the achievement of a curative resection (CRM/R0 resection) is the best early clinical end point. Problems with these end points include lack of structured measurement and analysis techniques to control for intra- and inter-observer variation and lack of validation as surrogates for long-term clinical end points such as local control and survival. However, retrospective studies in rectal cancer have confirmed a strong association between the presence of microscopic tumour cells within 1 mm of the CRM and increased risks of both local recurrence and distant metastases. Further end points of current clinical relevance for which adequate methodologies for assessment are lacking include sphincter sparing end points, and assessment of long-term toxicities, ano-rectal function and their specific impact on quality of life. Recommendations are made as to the most appropriate information, which should be documented in future trials. CONCLUSIONS: Pathological complete response following preoperative chemoradiation does not reliably predict late outcome. There are other events not mediated through this end point and there are also unintended effects (often an excess of non-cancer related deaths). Disease-free survival currently remains the best (because it is relatively quick) primary end point in designing randomised phase III studies of preoperative chemoradiation in rectal cancer, although it is necessary to control for postoperative adjuvant chemotherapy. However, the CRM status can substantially account for effects on disease-free and overall survival after chemoradiation, radiation or surgery alone. Hopefully, randomised controlled trials, which utilise these alternative clinical end points, will in future determine the precise percentages of the effect of different chemoradiation schedules on disease-free and overall survival.

Biomarkers, Tumor↗

PubMed2001

Change: detection and modification.

Because human physiology is always changing, one of the challenges for those interested in biofeedback applications is how to establish techniques to determine if the biofeedback has altered the physiology. This paper explores some of the areas of concern and some solutions that have been reported.

Automation↗

PubMed2006

Some considerations in the design and interpretation of antimalarial drug trials in uncomplicated falciparum malaria.

BACKGROUND: Treatments for uncomplicated falciparum malaria should have high cure rates. The World Health Organization has recently set a target cure rate of 95% assessed at 28 days. The use of more effective drugs, with longer periods of patient follow-up, and parasite genotyping to distinguish recrudescence from reinfection raise issues related to the design and interpretation of antimalarial treatment trials in uncomplicated falciparum malaria which are discussed here. METHODS: The importance of adequate follow-up is presented and the advantages and disadvantages of non-inferiority trials are discussed. The different methods of interpreting trial results are described, and the difficulties created by loss to follow-up and missing or indeterminate genotyping results are reviewed. CONCLUSION: To characterize cure rates adequately assessment of antimalarial drug efficacy in uncomplicated malaria requires a minimum of 28 days and as much as 63 days follow-up after starting treatment. The longer the duration of follow-up in community-based assessments, the greater is the risk that this will be incomplete, and in endemic areas, the greater is the probability of reinfection. Recrudescence can be distinguished from reinfection using PCR genotyping but there are commonly missing or indeterminate results. There is no consensus on how these data should be analysed, and so a variety of approaches have been employed. It is argued that the correct approach to analysing antimalarial drug efficacy assessments is survival analysis, and patients with missing or indeterminate PCR results should either be censored from the analysis, or if there are sufficient data, results should be adjusted based on the identified ratio of new infections to recrudescences at the time of recurrent parasitaemia. Where the estimated cure rates with currently recommended treatments exceed 95%, individual comparisons with new regimens should generally be designed as non-inferiority trials with sample sizes sufficient to determine adequate precision of cure rate estimates (such that the lower 95% confidence interval bound exceeds 90%).

Animals↗

PubMed2000

Upper gastrointestinal tolerability of celecoxib, a COX-2 specific inhibitor, compared to naproxen and placebo.

OBJECTIVE: To determine the upper gastrointestinal (GI) tolerability of celecoxib, naproxen, and placebo in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: An analysis of 5, 12-week, randomized, double blind, parallel group, placebo controlled clinical trials was conducted. In these trials, patients were randomized to: naproxen 500 mg bid (n = 1,099), placebo (n = 1,136), celecoxib 50 mg bid (n = 690) (subtherapeutic dose), celecoxib 100 mg (n = 1,131) or 200 mg bid (n = 1,125) (therapeutic dose), or celecoxib 400 mg bid (n = 434) (supratherapeutic dosage). The incidence and time until moderate to severe abdominal pain, dyspepsia, nausea, and any of the aforementioned 3 upper GI symptoms (composite endpoint) were determined using time-to-event analysis. RESULTS: The cumulative incidences of moderate to severe abdominal pain, dyspepsia, or nausea (composite endpoint) were: naproxen 500 mg (12.0%; 95% CI 9.9%-14.0%), celecoxib 50 mg bid (7.1%; 95% CI 5.0%-9.2%), celecoxib 100 mg bid (7.8%; 95% CI 6.0%-9.5%), celecoxib 200 mg bid (8.1%; 95% CI 6.4%-9.9%), celecoxib 400 mg bid (6.0%; 95% CI 3.6%-8.4%), and placebo (8.5%; 95% CI 6.5%-10.8%). After controlling for independent predictors of the composite endpoint, relative risks (RR) for the various treatments relative to naproxen 500 mg bid were: celecoxib 50 mg (RR 0.54; 95% CI 0.37-0.77; p < 0.001), celecoxib 100 mg (RR 0.60; 95% CI 0.45-0.80; p < 0.001), celecoxib 200 mg bid (RR 0.63; 95% CI 0.47-0.83; p = 0.001), celecoxib 400 mg bid (RR 0.56; 95% CI 0.35-0.89; p = 0.015), and placebo (RR 0.63; 95% CI 0.47-0.85; p = 0.002). After controlling for independent predictors of the composite endpoint, celecoxib treatment group patients did not differ from placebo patients when reporting the composite endpoint, with p values ranging from 0.40 to 0.96. CONCLUSION: The upper GI tolerability of celecoxib is superior to naproxen. A dose-response relationship between celecoxib and upper GI symptoms was not apparent.

Abdominal Pain↗

PubMed2005

Do pain referral patterns determine patient outcome after total hip arthroplasty?

Quality of life outcome and patient satisfaction after total hip arthroplasty are complex phenomena and many confounding determinants have been identified. Degenerative disease of the hip joint may present with variable patterns of pain referral in the lower limb. However the effect of varied preoperative pain referral patterns on patient outcome and satisfaction after total hip arthroplasty has not previously been examined. From 2000 to 2003, 236 eligible patients scheduled to undergo primary total hip arthroplasty were prospectively enrolled. The principal pain referral pattern (as hip, thigh or knee) was identified in all patients. Health related quality of life (HRQOL) was examined using the Harris Hip score (HHS), the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) and the 36-Item Short-Form Health Survey (SF-36) pre-operatively, 1 year and 2 years postoperatively and with the HHS at 3 months postoperatively. All patients were followed up for a minimum of 2 years. The frequency of the pain referral distributions were; hip pain 41%, knee pain 32% and thigh pain 27%. Patients in all groups were comparable preoperatively with respect to age, HHS, and both mean and domain specific WOMAC and SF-36 scores. The mean duration of symptoms was significantly greater in patients with knee pain when compared to the remaining two pain patterns. All patients demonstrated improvements in HHS, SF-36 and WOMAC scores after surgery. At all times postoperatively there were significant differences in mean HHS and mean and domain specific WOMAC and SF-36 scores between patients with hip or thigh pain and those with knee pain (p < 0.001). While notable, differences between hip and thigh pain were not as consistent however. Based on these findings, it appears that pre-operative pain referral patterns of hip arthritis are among the determinant factors for patient outcome and satisfaction after total hip arthroplasty, as measured using validated HRQOL scoring systems.

Aged↗

PubMed2004

Prostate intraepithelial neoplasia in Noble rats, a potential intermediate endpoint for chemoprevention studies.

In most prostate chemoprevention studies conducted with animal models, the incidence and multiplicity of tumours have been used as endpoints for efficacy. However, the latency of tumours is usually over 1 year, making these studies costly and time consuming. The main purpose of this study was to assess the utility of prostate intraepithelial neoplasia (PIN), induced in Noble rats by continuous testosterone + oestradiol (T + E) administration, as a potential intermediate endpoint biomarker of efficacy in chemoprevention studies. Noble rats at the age of 12 weeks were treated for 36 weeks with T + E given subcutaneously via Silastic capsules. The incidence and multiplicity of PIN were assessed in various prostate glands by serial sections generated at three separate tissue levels. The efficacy of dehydroepiandrosterone (DHEA) and DHEA 8354 (1000 and 2000 mg/kg diet), difluoromethylornithine (DFMO) (1000 and 2000 mg/kg diet) and oltipraz (125 and 250 mg/kg diet) to inhibit PIN was assessed in two independent sets of experiments. T + E induced multiple PIN in the dorsolateral prostate (DLP) of 80-100% of the animals. DHEA and DHEA 8354 did not affect the incidence but decreased the multiplicity of PIN in the DLP, from 3.2 +/- 1.0 in control group to 1.5 +/- 1.0 in the low-dose and to 1.6 +/- 0.6 in the high-dose group for DHEA (P<0.05 and P<0.02, respectively), and to 1.9 +/- 0.8 in the high-dose (P<0.05) DHEA 8354. Both agents did not affect PIN in anterior prostate, seminal vesicles or ventral prostate. In a second experiment, DFMO and oltipraz were found not effective in inhibiting PIN. In this study, we provide new evidence that PIN in Noble rats, induced by continuous T + E treatment, is a useful intermediate endpoint for determining the efficacy of DHEA and other potential chemopreventive agents. The hormonal pathogenesis, high multiplicity, short latency, preferential location in the DLP, similarity in morphology and biology to PIN of human prostate, and the sensitivity to agents that suppress prostate carcinogenesis, makes PIN in Noble rats a promising intermediate endpoint for chemoprevention studies.

Animals↗

PubMed2006

Responsiveness and minimal important differences for patient reported outcomes.

Patient reported outcomes provide the patient's perspective on the effectiveness of treatment. The draft Food and Drug Administration guidance on patient reported outcomes for labeling and promotional claims raises a number of method and measurement issues that require further clarification, including methods of determining responsiveness and minimal important differences. For clinical trials, instruments need to be based on a clear conceptual framework, have evidence supporting content validity and acceptable psychometric qualities. The measures must also have evidence documenting responsiveness and interpretation guidelines (i.e., minimal important difference) to be most useful as effectiveness endpoints in clinical trials. The recommended approach is to estimate the minimal important difference based on several anchor-based methods, with relevant clinical or patient-based indicators, and to examine various distribution-based estimates (i.e., effect size, standardized response mean, standard error of measurement) as supportive information, and then to triangulate on a single value or small range of values for the MID. Confidence in a specific MID value evolves over time and is confirmed by additional research evidence, including clinical trial experience. The MID may vary by population and context, and no one MID will be valid for all study applications involving a PRO instrument. Responsiveness and MID must be demonstrated and documented for the particular study population, and these measurement characteristics are needed for PRO labeling and promotional claims.

Clinical Trials as Topic↗

PubMed2004

[Prognostic value of Charlson comorbidity index at 30 days and 1 year after acute myocardial infarction].

INTRODUCTION AND OBJECTIVES: The Charlson comorbidity index (CCI), an indicator of comorbidity, has been used as an adjusting variable in multivariate models. Because of its prognostic value per se for cardiovascular complications after acute myocardial infarction (AMI), we sought to determine the predictive value of the CCI for all-cause mortality and recurrent AMI 30 days and 1 year after the index event. PATIENTS AND METHOD: We analyzed 1035 consecutive patients admitted with the diagnosis of AMI (ST elevation=508 and non-ST elevation=527). The composite endpoint was determined after 30 days (13.9%) and 1 year (26.3%) of follow-up. The CCI was calculated on admission, and other variables with prognostic value were also recorded. CCI was stratified in 4 categories: 1: CCI=0 (control), 2: CCI=1, 3: CCI=2,4: CCI> or =3. Cox proportional risks analysis was used for the multivariate analysis, and the C-statistic was calculated to assess the discriminative power of the models. RESULTS: Hazard ratios (95% CI) estimated for each category of CCI were: 2=1.69 (1.10-2.59), 3=1.78 (1.08-2.92) and 4=1.57 (0.87-2.83) at 30 days; 2=1.62 (1.18-2.23), 3=2.00 (1.39-2.89) and 4=2.24 (1.50-3.36) at 1 year. Comparisons with the C-statistic between the nested multivariate models (with and without CCI) yielded values of 0.765 vs 0.750 after 30 days, and 0.751 vs 0.735 after 1 year. CONCLUSIONS: Our data indicate that CCI is an independent predictor of mortality or recurrent AMI 30 days and 1 year after the index AMI.

Aged↗

PubMed2004

Measuring responses to therapy in headache patients: new and traditional end-points.

Changes in numerical indices of the intensity, duration and frequency of attacks are traditionally used to assess the effectiveness of treatments for migraine and other primary headaches. However, recent clinical and therapeutic guidelines and guidelines for conducting clinical trials specify that the essential aim of symptomatic and prophylactic migraine treatments should be to reduce the global impact of the headaches on the patient's life. Some standardised instruments for assessing disability and health-related quality of life seem sensitive to treatment-induced changes in primary headache patients. However, further studies to determine the suitability of these instruments as outcome measures in clinical practice are necessary.

Disability Evaluation↗

PubMed2001

The mouse uterotrophic assay: a reevaluation of its validity in assessing the estrogenicity of bisphenol A.

The prevalence of synthetic chemicals in our environment that are capable of mimicking the female hormone estrogen is a growing concern. One such chemical, bisphenol A (BPA), has been shown to leach from a variety of resin-based and plastic products, including dental sealants and food and beverage containers, in concentrations that are sufficient to induce cell proliferation in vitro. The response to BPA in vivo has been varied; thus the aims of this study were to investigate a) whether BPA has an estrogenic effect in CD-1 mice, a strain that is useful for developmental studies; and b) whether the uterotrophic assay is a valid means of determining the estrogenicity of BPA by comparing it with other end points measured in the uterus. Immature female CD-1 mice were exposed to BPA in concentrations ranging from 0.1 to 100 mg/kg body weight for 3 days. Results showed that BPA induced a significant increase in the height of luminal epithelial cells within the uterus at concentrations of 5, 75, and 100 mg/kg and that BPA induced lactoferrin at concentrations of 75 and 100 mg/kg. A uterotrophic response (increase in uterine wet weight) was induced by 100 mg/kg BPA only. Further, the proportion of mice showing vaginal opening was greater after exposure to 0.1 and 100 mg/kg BPA, relative to the control animals and those receiving intermediate doses of BPA. These results demonstrate that BPA induces changes in the mouse uterus that differ depending on the exposure dose and the end point measured, and reveal that certain tissue effects show a nonmonotonic relationship with dose. These data also demonstrate that BPA induces estrogenic changes in the uterus of the CD-1 mouse, and highlight the need to reevaluate the validity of the mouse uterotrophic assay as an end point for determining the estrogenicity of suspected environmental estrogens.

Animals↗

PubMed1987

Occurrence and reproducibility of the "skip" phenomenon in bactericidal testing of Staphylococcus aureus.

A "skip" phenomenon, in which subcultures to determine bactericidal endpoints show discordant results, can make bactericidal testing of Staphylococcus aureus difficult to interpret. Either a single or several consecutive concentrations may be skipped, with insignificant growth from these concentrations, but heavy growth from higher antimicrobic concentrations. Replicate macrodilution minimum bactericidal concentration testing of cephalothin against S. aureus was investigated to determine the frequency and reproducibility of the skip phenomenon in this test. In preliminary testing, the skip phenomenon occurred at 24 hr in 11 of the 30 tests performed on ten S. aureus strains. Incubation of tubes for 48 hr before subculture markedly reduced the number of tests containing a skip tube (four of 30). The skip phenomenon was not reproducible either within concurrent replicate testing or on repeat testing of the same isolate on subsequent days. The ten strains were retested in replicative trials using the macrodilution test comparing Mueller-Hinton broth (MHB) and MHB supplemented with Tween 80. The number of skips occurring in the supplemented broth test was the same (two of 22) at 24 hr as nonsupplemented broth. For reproducible results, macrodilution minimum bactericidal testing requires performance of the test in duplicate, with repeat subculture at 48 hr if the skip phenomenon occurs in both trials at the 24-hr subculture. Killing curves performed on these isolates did not appear to demonstrate any relationship between the skip phenomenon and the paradoxical effect described by Eagle.

Cephalothin↗

PubMed1994

Novel concepts in modification of radiation sensitivity.

PURPOSE: To determine whether biological effects of radiation, such as apoptosis, that differ from classical clonogenic cell killing, can be modified with agents that would not be expected to modify classical clonogenic cell killing. This would expand the range of potential modifiers of radiation therapy. METHODS AND MATERIALS: EL4 murine lymphoma cell apoptosis was determined by electrophoretic analysis of deoxyribonucleic acid (DNA) fragmentation. DNA was extracted 24 h after irradiation or addition of inducing agents. Modifiers of radiation-induced apoptosis were added immediately after irradiation. The effects of radiation on wounded endothelial monolayers were studied by scraping a line across the monolayer 30 min after irradiation. Cell detachment was used as an endpoint to determine the protective effect of prolonged exposure to retinol prior to irradiation. RESULTS: EL4 cell apoptosis can be induced by tert-butyl hydroperoxide or the glutathione oxidant SR-4077. Radiation-induced EL4 cell apoptosis can be inhibited with 3-aminobenzamide, an agent that sensitizes cells to classical clonogenic cell killing. Radiation-induced endothelial cell detachment from confluent monolayers can be modified by pretreatment with retinol. CONCLUSION: These results raise the possibility that radiation could induce apoptosis by an oxidative stress mechanism that is different from that involved in classical clonogenic cell killing. These and other recent findings encourage the notion that differential modification of classical clonogenic cell killing and other important endpoints of radiation action may be possible.

Animals↗

PubMed2005

Cytokine profiling for prediction of symptomatic radiation-induced lung injury.

PURPOSE: To analyze plasma cytokine profiles before the initiation of radiation therapy to define a cytokine phenotype that correlates with risk of developing symptomatic radiation-induced lung injury (SRILI). METHODS AND MATERIALS: Symptomatic radiation-induced lung injury was evaluated in 55 patients (22 with SRILI and 33 without SRILI), according to modified National Cancer Institute common toxicity criteria. These plasma samples were analyzed by the multiplex suspension bead array system (Bio-Rad Laboratories; Hercules, CA), which included the following cytokines: interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17, granulocyte/macrophage colony-stimulating factor, interferon-gamma, monocyte chemotactic protein 1, macrophage inflammatory protein 1beta, tumor necrosis factor alpha, and granulocyte colony-stimulating factor. RESULTS: Significant differences in the median values of IL-8 were observed between patients with and without SRILI. Patients who did not develop SRILI had approximately fourfold elevated levels of IL-8 as compared with patients who did subsequently develop SRILI. Significant correlations were not found for any other cytokine in this study, including transforming growth factor beta1. CONCLUSIONS: Patients with lower levels of plasma IL-8 before radiation therapy might be at increased risk for developing SRILI. Further studies are necessary to determine whether IL-8 levels are predictive of SRILI in a prospective trial and whether this marker might be used to determine patient eligibility for dose escalation.

Aged↗