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PubMed2006

Titration curves: a useful instrument for assessing the buffer systems of acidic mining waters.

BACKGROUND, AIMS AND SCOPE: The acidification of mine waters is generally caused by metal sulfide oxidation, related to mining activities. These waters are characterized by low pH and high acidity due to strong buffering systems. The standard acidity parameter, the Base Neutralization Capacity (BNC), is determined by endpoint titration, and reflects a cumulative parameter of both hydrogen ions and all buffering systems, but does not give information on the individual buffer systems. We demonstrate that a detailed interpretation of titration curves can provide information about the strength of the buffering systems. The buffering systems are of importance for environmental studies and treatment of acidic mining waters. METHODS: Titrations were carried out by means of an automatic titrator using acidic mining waters from Germany and Canada. The curves were interpreted, compared with each other, to endpoint titration results and to elemental concentrations contained therein. RESULTS AND DISCUSSION: The titration curves were highly reproducible, and contained information about the strength of the buffer systems present. Interpretations are given, and the classification and comparison of acidic mining waters, by the nature and strength of their buffering systems derived from titration curves are discussed. The BNC-values calculated from the curves were more precise than the ones determined by the standard endpoint titration method. Due to the complex buffer mechanisms in acidic mining waters, the calculation of major metal concentrations from the shape of the titration curve resulted in estimates, which should not be confused with precise elemental analysis results. CONCLUSION: Titration curves provide an inexpensive, valuable and versatile tool, by which to obtain sophisticated information of the acidity in acidic water. The information about the strength of the present buffer systems can help to understand and document the complex nature of acidic mining water buffer systems. Finally, the interpretation of titration curves could help to improve treatment measurements and the ecological understanding of these acidic waters.

Acids↗

PubMed2026

Time to subsequent therapy (TTST) as an endpoint in clinical studies: development of standardized documentation of subsequent therapy through systematic literature review, expert interviews, and Delphi survey.

BACKGROUND: The endpoint Time to Subsequent Therapy (TTST) is an intermediate endpoint used in research and regulatory assessments. TTST denotes initiation of subsequent therapy and is a clearly definable, clinically relevant event for healthcare professionals. However, it has not been systematically established to which extent TTST is subjectively meaningful to patients. The objective of this study was to define TTST as a patient-relevant intermediate endpoint. METHODS: The study examined five oncological indications (breast cancer, prostate cancer, melanoma, multiple myeloma, and non-small cell lung cancer) using a systematic literature review, analysis of case report forms used in international randomized controlled trials, review of German Federal Joint Committee (G-BA) documents, semi-structured interviews and a two-stage Delphi survey with healthcare professionals, patients, and relatives. RESULTS: A total of 35 individuals participated in qualitative interviews. Most of them rated TTST as particularly significant. The Delphi Survey included 264 interviewees in round one, and 117 in round two. Patient-relevance of TTST was confirmed by 81% of respondents (95% confidence interval 76%, 85%). Nine treatment scenarios that justify TTST were identified. To capture patient-relevance, prospective collection of reasons for and consequences of therapy change are required. A checklist with standardized response formats plus free-text fields was developed: a comprehensive master checklist for flexible, complete documentation and a short version focused on therapy change-specific items. CONCLUSIONS: TTST is an intermediate endpoint whose systematic documentation of characteristics demonstrating patient-relevance can be standardized in research and clinical practice using the developed checklists.

Humans↗

PubMed2005

The screening of chemicals for juvenoid-related endocrine activity using the water flea Daphnia magna.

U.S. Environmental Protection Agency is charged with developing a screening and testing paradigm for detecting endocrine toxicity of chemicals that are subject to regulation under the Food Quality Protection and the Safe Drinking Water Acts. In this study, we developed and evaluated a screening assay that could be employed to detect juvenoid-related endocrine-modulating activity in an invertebrate species. Juvenoid activity, anti-juvenoid activity, and juvenoid potentiator activity of chemicals was assessed using the water flea Daphnia magna. Male sex determination is under the regulatory control of juvenoid hormone, presumably methyl farnesoate, and this endpoint was used to detect juvenoid modulating activity of chemicals. Eighteen chemicals were evaluated for juvenoid agonist activity. Positive responses were detected with the juvenoid hormones methyl farnesoate and juvenile hormone III along with the insect growth regulating insecticides pyriproxyfen, fenoxycarb, and methoprene. Weak juvenoid activity also was detected with the cyclodiene insecticide dieldrin. Assays performed repetitively with compounds that gave either strong positive, weak positive, or negative response were 100% consistent indicating that the assay is not prone to false positive or negative responses. Five candidate chemicals were evaluated for anti-juvenoid activity and none registered positive. Four chemicals (all trans-retinoic acid, methoprene, kinoprene, bisphenol A) also were evaluated for their ability to potentiate the activity of methyl farnesoate. All registered positive. Results demonstrate that an in vivo assay with a crustacean species customarily employed in toxicity testing can be used to effectively screen chemicals for juvenoid-modulating activity.

Animals↗

PubMed1993

A modified screening procedure to detect pyruvate kinase deficiency.

Beutler's screening procedure was used to detect pyruvate kinase deficiency in the local population. In this test, hemolysate and the reagent mixture are incubated and then placed at a spot on filter paper to be examined for fluorescence. Complete nonfluorescence marks the reaction endpoint, and fluorescence beyond 30 minutes indicates pyruvate kinase deficiency. It was difficult to determine this endpoint due to uneven sedimentation of unhemolyzed red cells on the spot. In this modified technique, the leukocyte-depleted red cell suspension was frozen and thawed for complete red cell lysis before being used for the test. Using both techniques, 493 health individuals and 126 anemic patients were screened for pyruvate kinase deficiency. By the conventional technique, 3.7% remained fluorescent after 30 minutes, whereas by the modified technique, none were fluorescent after 30 minutes. Quantitative assay indicated that all samples had pyruvate kinase activity levels greater than the lower limit of the reference range. We also demonstrated that blood samples from individuals with thalassemia trait were primarily responsible for the aberrant results from the conventional screening procedure.

Fluorescence↗

PubMed2004

Osseous surgery for crown lengthening: a 6-month clinical study.

BACKGROUND: Despite the fact that surgical crown lengthening is a commonly performed treatment, little is known about the specific surgical endpoints of the procedure or the stability of the newly attained crown height over time. Recent clinical reports have ranged across a spectrum from significant tissue rebound to remarkable stability using similar surgical techniques. The purpose of this study was to assess the stability of surgical crown lengthening procedures performed by various surgeons using specific guidelines to determine surgical endpoints. Specifically, we sought to determine the following: 1) What is the immediate increase in clinical crown height following surgery? 2) How stable is the established crown length over a 6-month period? 3) How much supporting bone is removed to establish the new crown length? 4) How does the position of the flap margin relative to the alveolar bone at surgical closure relate to the stability of crown height? METHODS: Twenty-five patients requiring crown lengthening of 43 teeth were included in this study. Clinical indices recorded at eight sites on each molar and six sites on each premolar included plaque, bleeding on probing, probing depth, and relative attachment level from a customized probing stent. Surgical measurements at the same sites included the distance from stent to alveolar bone both before and after osseous surgery and the distance from flap margin to alveolar bone after suturing. Clinical measurements were repeated at 1, 3, and 6 months after surgery. Sites were divided into three groups. All sites on teeth targeted for crown lengthening were labeled treated sites (TT). Interproximal sites on neighboring teeth were labeled adjacent (AA) if they shared a proximal surface with a treated tooth and nonadjacent (AN) if they were on the opposite side, away from the treated tooth. RESULTS: Throughout the entire 6-month healing period, descriptive statistics revealed no significant time or group differences in plaque and bleeding scores. At treated sites, the mean gain of crown height at surgery was 2.27 +/- 1.1 mm. This was reduced to 1.91 +/- 1.08 mm at 1 month, 1.69 +/- 1.02 mm at 3 months, and 1.57 +/- 1.01 mm at 6 months. At adjacent sites, the gain of crown length was 2.18 +/- 0.98 mm, 1.61 +/- 0.98 mm, 1.43 +/- 0.96 mm, and 1.30 +/- 0.96 mm at surgery, 1, 3, and 6 months, respectively. At non-adjacent sites the crown height increased 1.06 +/- 1.07 mm, 1.00 +/- 0.93 mm, 0.84 +/- 1.00 mm, and 0.76 +/- 0.85 mm, respectively. These mean measurements were significantly different for each treatment group at each time interval and appeared not to have stabilized between 3 and 6 months. The mean osseous reduction at treated, adjacent, and non-adjacent sites was 1.13 +/- 0.90 mm, 0. 78 +/- 0.75 mm, and 0.065 +/- 0.69 mm, respectively. Frequency distribution of osseous reduction demonstrated that 23.6% of treated sites had 0 mm, 44.3% had 1 mm, 25.4% had 2 mm, 6.2% had 3 mm, and less than I % had > or = 4 mm of bone removed to establish crown height More bone removal was noted at premolar than at molar sites; however, this was not statistically significant. When tissue rebound following surgery was plotted against post-surgical flap position, it was noted that the closer the flap margin was sutured to the alveolar crest, the greater the tissue rebound during the post-surgical period. This rebound ranged from 1.33 +/- 1.02 mm when the flap was sutured < or = 1 mm from the alveolar crest, to -0.16 +/- 1.15 mm when the flap was sutured > or = 4 mm from the alveolar crest. CONCLUSIONS: These data suggest that there is a significant tissue rebound following crown-lengthening surgery that has not fully stabilized by 6 months. The amount of tissue rebound seems related to the position of the flap relative to the alveolar crest at suturing. These findings support the premise that clinicians should establish proper crown height during surgery without overreliance on flap placement at the osseous crest.

Alveolar Process↗

PubMed2006

[Advancement of treatment for prostate cancer].

The number of prostate cancer patients is rapidly increasing in Japan, as aging people are more common and the lifestyle is more westernized. Another reason is that prostate specific antigen (PSA) is prevalent and PSA test can detect organ-confined prostate cancer in the early stage. In the past, endocrine therapy was the main treatment modality since many prostate cancer patients were diagnosed in the advanced stage. However, endocrine therapy is not suitable for young patients with organ-confined prostate cancer. Surgery and radiation therapy are becoming standard therapy for these patients. Although retropubic radical prostatectomy is widely performed,urinary incontinence and sexual dysfunction are still problems. Other approaches such as laparoscopic prostatectomy, portless endoscopic prostatectomy and perineal prostatectomy are also performed. Radiation therapy is commonly used for organ-confined prostate cancer in Europe and the U.S.A. The advancement in computer technology has made it possible to accumulate enough radiation dose to target without damaging the surrounding organs (3 D conformal, intensity-modulated radiotherapy). Heavy ion particle radiotherapy is also attempted in some institutes. Moreover, brachytherapy can be another choice in radiation therapy. In Japan, only high-dose brachytherapy with (192)Ir has been performed. In July 2003, permanent seed brachytherapy with (121)I was legally approved in Japan, and more organ-confined prostate cancer patients are expected to undergo this treatment. There are several treatment modalities for organ-confined prostate cancer patients these days. Therefore, not only tumor grade and stage, but also patients'lifestyle and thought should be considered in determining treatment.

Brachytherapy↗

PubMedDate not supplied

A comparison of two methods for determining nasal irritant sensitivity.

Nasal irritation and irritant-induced reflexes (rhinorrhea and congestion) are prominent symptoms associated with indoor and ambient air pollution, and marked heterogeneity in individual sensitivity has been suggested. Nevertheless, there is currently no generally accepted functional index of nasal irritant sensitivity available for clinical use. To address this issue, we compared two objective measures of nasal irritant sensitivity: a CO2 detection task, and CO2-induced transient disruption of respiratory pattern (pulsed CO2 acting as an odorless irritant). Using a respiratory flow thermocouple to produce a continuous recording of respiratory pattern, we challenged 20 normal adult volunteers (13 males and 7 females, average age 39.4 years) with brief (approximately 3 second) pulses of the odorless irritant carbon dioxide. Increasing levels of CO2 (10-70%, vol/vol), paired with filtered air in random order, were presented unilaterally by nasal cannula of fixed geometry, synchronized with the inspiratory phase of the respiratory cycle. All subjects yielded CO2 detection thresholds, whereas within the constraints of the testing method (subjective irritation rating < or = "very strong"), only 13 of 20 subjects (65%) exhibited transient disruption of their breathing pattern. Further, although decreased respiratory volume (indirectly measured) appeared to be a common feature, several distinct patterns of respiratory alteration were observed, rendering objective scoring more difficult. Finally, some subjects showed CO2-induced respiratory disruption intermittently from trial to trial, implying that rapid adaptation occurs. Determination of the CO2 detection threshold therefore appears to be the more objective and consistently applicable endpoint for determining individual nasal irritant sensitivity.

Adult↗

PubMed1991

Biological dosimetry with cytogenetic endpoints.

The induction of chromosome aberrations in the lymphocytes of people who have been exposed to ionizing radiation has provided a much-used quantifiable biological dosimeter with which it is possible to obtain a reliable estimate of the dose of radiation to which the people have been exposed. The induction of aberrations by truly radiomimetic (non-S-dependent) chemicals should also be capable of leading to an estimate of the amount of the chemical that has reached the nuclei of the target cells, and thus give a measure of the damage inflicted. In this case, however, it is not yet possible to relate aberration yield to the initial exposure in a quantifiable manner. Other cytogenetic endpoints, such as micronuclei and sister chromatid exchanges (SCEs), can also be used to estimate whether or not exposures have occurred. Since micronuclei are the result of broken or lagging chromosomes, they too can be used to estimate the dose of ionizing radiation to which a person has been exposed. The use of aberrations or micronuclei for estimating the dose of S-dependent chemicals, however, still remains problematical. SCEs, which are not readily induced by ionizing radiations, have proved to be the most sensitive mammalian endpoint for determining exposure to such S-dependent chemicals. Nevertheless, the utility of SCEs, or any cytogenetic endpoint for that matter, for estimating the dose of any S-dependent chemical has not been shown because of dosimetric problems and because DNA repair can remove many of the adducts before the cells enter S, both of which preclude the use of these endpoints as biological dosimeters for such agents.

Chromosome Aberrations↗

PubMed2007

Bacterial host resistance models in the evaluation of immunotoxicity.

To assess potential immunomodulatory effects of a drug, pollutant, or natural product, an analysis of an exposed host's ability to resist challenge with a viable bacteria is one of the best gauges. Many factors govern whether a host exposed to a test agent and then infected becomes ill or dies at rates greater than infected control counterparts. Beyond the status of the host's immunocompetence, a bacterium's route of entry into the host and its inherent virulence are important variables determining how (and rate at which) an infection resolves. A pre-determination of endpoint(s) to be defined is critical during planning of resistance assays. If a study is to determine overall changes in immunocompetence due to exposure (regardless of regimen or dosage of test agent), then assessing shifts in morbidity/mortality at a defined lethal dose [LD(x)] value for the chosen route of infection would suffice. However, if a study is to define extent of immunomodulation in a particular body organ/cavity--or specific alterations in particular aspects of the humoral or cell-mediated immune responses--then careful selection of the pathogen, dose of the inoculum, means of infection of target site, and extent of the post-infection period to be examined, need to be made prior to host exposure to the test toxicant. This review will provide the Reader with background information about bacterial infections and how endpoint selection could be approached when designing resistance assays. An overview of protocols involved in the assays (e.g., bacterial preparation, host infection, post-infection endpoint analyses) and information about three bacteria that are among the most commonly employed in resistance assays is provided as well.

Animals↗

PubMed2003

Emerging standards in statistical practice: implications for clinical trials in rehabilitation medicine.

This article discusses selected issues in statistical practice that occur during the conduct of clinical trials in medical rehabilitation: (1) supplementing null hypothesis statistical testing and P values, (2) determining sample size and statistical power, (3) handling missing data, and (4) dealing with multiplicity (i.e., multiple endpoints, multiple statistical comparisons, and repeated measurements). Suggested strategies to address these issues are offered in light of the International Conference on Harmonisation guideline "Statistical Principles for Clinical Trials."

Clinical Trials as Topic↗

PubMed2003

Variation, replication, and power analysis of Myriophyllum spp. microcosm toxicity data.

Myriophyllum spp. have been proposed as a new standard laboratory aquatic macrophyte test species for the registration of pesticides. The main objectives of this investigation were to determine the power of Myriophyllum sibiricum and Myriophyllum spicatum toxicity data derived from an outdoor microcosm bioassay, to evaluate the variation of 10 different aquatic plant endpoints and to calculate the minimum detectable difference for these endpoints, to determine the replication required to detect ecologically significant changes from control for these endpoints, and to make recommendations for future field studies with Myriophyllum spp. Control data from four different studies that characterized haloacetic acid toxicity with Myriophyllum spp. for durations of three to six weeks during the summer of 1999 with five treatment levels (n = 3), including control, were examined. Endpoint coefficient of variation ranged, on average, from 6 to 28%. Node number and plant length endpoints were consistently the most statistically powerful for both plant species. It was possible to detect approximately 30% change from control in both endpoints with high statistical power (beta = 0.2, alpha = 0.05, n = 3). The range of minimum detectable differences was 40 to 60% for the other endpoints. Replication to detect a > or = 25% change from control would require an n of 2 to 21, depending on the endpoint. Myriophyllum sibiricum had slightly lower coefficients of variation and thus required fewer replicates than M. spicatum to be statistically significantly different from control values. Variation within microcosm studies was not significantly different from that of controlled laboratory studies, implying that most of the variation observed in the field is inherent in the plants. Based on statistical sensitivity, ecological relevance, and toxicological sensitivity, we recommend using plant length and root endpoints as indicators of toxicity under field conditions.

Acetic Acid↗

PubMed2006

Efficacy of solifenacin in patients with severe symptoms of overactive bladder: a pooled analysis.

BACKGROUND: The efficacy of antimuscarinic drug therapy in patients who have more severe symptoms of overactive bladder (OAB) at baseline has not been evaluated thoroughly. OBJECTIVE: This analysis determined the effects of solifenacin in patients with severe OAB symptoms at baseline. METHODS: All randomized, placebo-controlled phase III studies of solifenacin were pooled to determine the effects in patients with severe OAB symptoms at baseline. In these studies, patients were randomized to treatment with placebo or solifenacin 5 or 10 mg once daily. Baseline severity was defined according to the number of incontinence episodes/24 h, number of urgency episodes/24 h, and micturition frequency/24 h. The proportion of patients with restoration of continence, resolution of urgency, and normalization of micturition frequency at endpoint was determined. Mean change from baseline to endpoint in the number of episodes/24 h for incontinence, urgency, and micturition, and in the volume voided/micturition were assessed. Comparisons of change from baseline to endpoint were done with analysis of covariance (ANCOVA), and comparisons of percentage change from baseline to endpoint were based on van Elteren's test. RESULTS: Results from four multinational phase III studies of solifenacin with 2848 patients were pooled. The proportion of patients with restoration of continence, resolution of urgency, and normalization of micturition frequency at endpoint was significantly greater with solifenacin than with placebo among patients with severe OAB at baseline. Solifenacin 5 and 10 mg were significantly (p < 0.05) more effective than placebo for reductions in the number of episodes of incontinence, urgency, and micturition, and for the increase in volume voided/micturition among most subgroups of patients who were highly symptomatic at baseline (incontinence, urgency, or micturitions). CONCLUSION: Solifenacin was significantly more effective than placebo for patients with severe symptoms of OAB. The significant and consistent response was observed for all endpoints with solifenacin 10 mg and for most endpoints with solifenacin 5 mg using different definitions of baseline disease severity, and supports the overall effectiveness of solifenacin in highly symptomatic patients.

Adult↗

PubMed2002

Sensitivity of the rooted macrophyte Myriophyllum aquaticum (Vell.) verdcourt to seventeen pesticides determined on the basis of EC(50).

Explore the source record for details and available documents.

Carotenoids↗

PubMed2002

Neurological evaluation of toxic axonopathies in rats: acrylamide and 2,5-hexanedione.

This research was conducted to determine which neurological test or combination of tests can provide sufficient functional information to compliment biochemical or morphological endpoints in mechanistic studies of toxic axonopathies. Using several neurological indices, we evaluated the effects of two prototypical neurotoxicants that cause distal axonopathy: acrylamide monomer (ACR) and 2,5-hexanedione (HD). For each toxicant, rats were exposed to two daily dosing rates (ACR, 50 mg/kg per day i.p. or 21 mg/kg per day, p.o.; HD, 175 or 400 mg/kg per day, p.o.) and neurological endpoints were determined two to three times per week. Specific tests included observations of spontaneous locomotion in an open field, and measurements of hindlimb landingfoot splay, forelimb and hindlimb grip strength and the hindlimb extensor thrust response. For all neurological parameters, the magnitude of defect induced by either neurotoxicant was not related to daily dose-rate, e.g. both the lower and higher ACR dose-rates produced the same degree of neurological dysfunction. Instead, dose-rate determined onset and progression of neurotoxicity, e.g. the higher ACR dose-rate produced moderate neurotoxicity after approximately 8 days of intoxication, whereas the lower dose-rate caused moderate neurotoxicity after 26 days. Regardless of dose-rate, ACR-exposed rats exhibited gait abnormalities (ataxia, splayed hindlimbs), in conjunction with increased landing hindfoot spread and decreased hindlimb grip strength and extensor thrust HD intoxicated rats exhibited hindlimb muscle weakness as indicated by a gait abnormality (dropped hocks) and decreases in grip strength and the extensor thrust response. However, hindlimb landingfoot spread was not affected by HD exposure. For both neurotoxicants, gait changes preceded or coincided with alterations in other neurologic indices. These results suggest that observations of spontaneous behavior in an open field represent a practical approach to assessing temporal development and extent of neurological dysfunction induced by axonopathic toxicants such as ACR and HD.

Acrylamide↗

PubMed2000

In vitro efficacy of a novel chemoradiopotentiator--taxoltere metro.

PURPOSE: To evaluate the in vitro cytotoxic and radiopotentiating effects of a novel paclitaxel analog (taxoltere metro) on Chinese hamster ovary (CHO) cells and human colon cancer cells. METHODS AND MATERIALS: Three cell lines (CHO cells, HCT116 human colon carcinoma cells [paclitaxel-sensitive], and VM46 cells [paclitaxel-resistant subline of HCT116]) were employed in this study. Cell survival was determined using the standard colony-forming assay. The ID50 value (drug concentrations required to reduce colony formation to 50% of the control value) was determined as a cytotoxic index from each cell survival curve. The sensitizer enhancement ratio (SER) as a radiopotentiating endpoint was determined as the ratio of the D0 values (with or without drugs) under hypoxic or air conditions. RESULTS: Taxoltere metro was 5-15 times more effective in killing CHO cells than paclitaxel under both hypoxic and euoxic treatment conditions. Cytocidal effects of taxoltere metro on HCT116 cells and VM46 cells were 28 and 70 times higher than those of paclitaxel (p<0.001), respectively. Taxoltere metro also produced significant radiopotentiating effects on euoxic CHO and HCT116 cells, but not on hypoxic cells. The SER value of taxoltere metro for CHO cells was about 2.3 at a dose of 100 nM. With HCT116 cells, taxoltere metro yielded an SER of 1.2 at the low dose of 10 nM. In contrast, the parent compound paclitaxel yielded little or no radiosensitization with either CHO or HCT116 cells. CONCLUSION: The results demonstrate that taxoltere metro is significantly more potent than paclitaxel in chemoradiopotentiating CHO cells and HCT116 human colon carcinoma cells. The data strongly suggest that taxoltere metro could be a promising chemoradiopotentiating agent for treatment of cancer.

Animals↗

PubMed1996

[Colorimetric broth microdilution for antifungal susceptibility testing].

A colorimetric broth microdilution modification of the National Committee for Clinical Laboratory Standards (NCCLS) for antifungal susceptibility testing was developed and evaluated. The test method modification includes; air-dried microdilution trays, in which serial two-fold dilutions of three antifungal agents, amphotericin B (AMPH), flucytosine (5-FC) and fluconazole (FCZ) were first prepared and evaporated, then reconstituted by adding 100 microliters of yeast inocula, and an oxidation-reduction color indicator (sodium resazurin, Sigma) added to RPMI 1640 medium buffered to pH7.0 with 0.165M morpholinepropanesulfonic acid. The trays were incubated in air at 35 degrees C and were inspected after 24 and 48hr of incubation. The MICs were defined as the lowest concentration of the respective agents; no color change (blue) for AMPH, and slight color change (blue to purple) for 5-FC and FCZ. The MICs of AMPH, 5-FC and FCZ were determined for four reference strains and 100 clinical isolates, in comparison with the NCCLS macrodilution method. The four reference strains were tested seven times each by macrodilution method (MACRO) and 14 times each against all three antifungal agents by microdilution method (MICRO). Overall, 100% of MICs determined by MACRO, 96% of those determined at 24hr incubation by MICRO, and 93% of those determined at 48hr incubation by MICRO fell within the 3-log2 dilutions, although 20 to 33% were out of the acceptable MIC ranges of the NCCLS M27-P proposal. Excellent reproducibility in determining growth endpoint by color change was also demonstrated, giving 99 to 100% agreements in duplicated dilutions. When the MICs determined for 100 clinical isolates against three antifungal agents were compared, those determined at 24hr incubation by MICRO gave 61.7% of agreement within the 3-log2 dilutions of the NCCLS MACRO, and those determined at 48hr incubation by MICRO were 86.2%. The MICRO read at 24hr trended to the lower MICs, except for 5-FC. While the MICs of MICRO read at 48hr were mostly comparable (78 to 97% agreement) to those of MACRO, especially against 5-FC (97%) and AMPH (85%), but the discrepant MICs of Candida tropicalis against FCZ were noted. With these results, it can be concluded that the resazurin colorimetric broth microdilution method is easy to perform and highly precise, and may provide MICs comparable to those determined by the reference NCCLS macrodilution method.

Amphotericin B↗

PubMed2004

Efficacy and other milestones for human papillomavirus vaccine introduction.

Last year, the World Health Organization (WHO) convened a gathering of experts, including scientists, national regulatory authorities, industry representatives, epidemiologists and government officials from both developed and developing countries to discuss appropriate endpoint measurements for HPV vaccine efficacy and effectiveness trials. The consultation also considered the regulatory requirements and public health issues that vaccine candidates should address before deployment, particularly in developing countries. This report summarizes the discussions and the conclusions reached over the course of the consultation. The general consensus of the consultation was that it would be desirable to have a globally-agreed, measurable efficacy endpoint for considering deployment of HPV vaccines in public health settings. After hearing from experts about virological and clinical endpoints to be considered, requirements of regulatory authorities of various countries and endpoints used to measure efficacy and effectiveness for another known cancer vaccine (hepatitis B), the experts agreed that ethical and time considerations make it necessary to use a surrogate endpoint, and not invasive cervical cancer, to define efficacy of HPV vaccines. While regulatory authorities of each country ultimately will determine the endpoints required for licensure, the consultation recommended that the endpoint for efficacy in population-based studies be, based on current knowledge, histologically-classified cervical intraepithelial neoplasias (CIN) of moderate or high-grade, as well as cancer. Since persistent infection with the same high-risk type is considered a predictor for moderate or high-grade cervical dysplasias and cancer, they might represent a useful endpoint in future vaccine efficacy studies. Indeed, if vaccines prove to be effective against transient or persistent HPV infections, it is likely that they will protect women against cervical cancer. The consultation recognized that in the context of many developing countries, efficacy alone might not provide enough information for countries to decide whether or not to adopt HPV vaccines as a public health prevention tool against cervical cancer. The consultation unanimously agreed that additional clinical bridging studies as well as studies to clarify local epidemiology should be conducted in certain developing countries to determine the potential impact of vaccination. Such countries should also undertake targeted interventions to ensure acceptability and programmatic feasibility of the vaccination. Recognizing that upon vaccine introduction it will be some years before a reduction in cervical cancer is detectable at the population level, the consultation stressed the importance of maintaining existing cervical screening programmes while such long-term studies are conducted. The following paper explains the background and rationale behind these conclusions and elaborates on specific considerations for vaccine study and introduction in developing countries.

Biomarkers↗

PubMed1999

A low individualized GH dose in young patients with childhood onset GH deficiency normalized serum IGF-I without significant deterioration in glucose tolerance.

OBJECTIVE: Many GH deficient (GHD) patients have impaired glucose tolerance and GH substitution in these patients has caused deleterious effects on glucose tolerance with hyperinsulinaemia. This further impairment of glucose tolerance might be due to an unphysiologically high dose of GH. Whether such a deterioration can be avoided by an optimal GH replacement dose is not known. In most previous studies, the GH dose was calculated according to body weight or body surface area and not adjusted according to the serum IGF-I response. DESIGN: The study was of open design and investigations were performed before the start of GH substitution and after nine months of treatment. The GH dose was adjusted according to the response in serum IGF-I, and in patients with sub-normal serum IGF-I levels (all but two) we aimed for a serum IGF-I level in the middle of the normal range. The median GH dose at the end of the study was 0.14 IU/kg/week. PATIENTS: Ten patients, eight males and two females, with childhood onset GHD were examined. Their median age was 27 years (range 21-28). MEASUREMENTS: Overnight and 24-h fasting levels of glucose, insulin and IGFBP-1 were measured. Directly after the 24-h fast an oral glucose tolerance test (OGTT), with measurements of glucose, insulin and IGFBP-1 was performed. An intravenous glucose tolerance test (IVGTT) was performed after overnight fasting. Body composition was measured with bio-impedance analysis (BIA) and quality of life was assessed using a self-rating questionnaire, Qol-AGHDA. RESULTS: After GH treatment, there were no significant changes in glucose tolerance, measured by overnight and 24-h fasting levels of glucose, insulin and IGFBP-1, an oral glucose tolerance test (after 24-h fasting) and an intravenous glucose tolerance test (after overnight fasting). Percentage fat mass and BMI correlated negatively with both the 24 h fasting IGFBP-1 levels and the IGFBP-1 responses after the OGTT. All patients decreased their percentage of fat mass measured by BIA [median -2.9%; range -1.0-(-6.6); P = 0.005]. The administered GH dose correlated negatively with the relative change in whole body resistance (r = -0.66; P = 0.04). All, but one of the patients improved their quality of life score after GH therapy. CONCLUSIONS: In a group of young patients with childhood onset GH deficiency, 9 months of treatment with a low GH dose (median 0.14 IU/kg/week) caused no significant deterioration of glucose tolerance. The strong negative associations between BMI or percentage fat mass and IGFBP-1 suggest that serum IGFBP-1 is more closely related than insulin to body composition in GH deficient patients. It is important to consider which critical endpoints should determine the GH dose. We would suggest that, apart for normalizing the serum IGF-I level, another main endpoint should be normalization of, or at least avoidance of any deterioration in glucose tolerance.

Adult↗