Adaptive mutation using statistics mechanism for genetic algorithms

Copyright @ 2004 Springer-Verla

Preclinical animal research on therapy dosimetry with dual isotopes

Preclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of sublethal damage, and repopulation during or after the therapy. Models for radiation response of preclinical tumour models after peptide receptor radionuclide therapy based on the linear quadratic model are presented. The accuracy of the radiation dose is very important for observation of dose-effects. Uncertainties in the radiation dose estimation arise from incomplete assay of the kinetics, low accuracy in volume measurements and absorbed dose S-values for stylized models instead of the actual animal geometry. Normal dose uncertainties in the order of 20% might easily make the difference between seeing a dose-effect or missing it altogether. This is true for the theoretical case of a homogeneous tumour type behaving in vivo in the same way as its cells do in vitro. Heterogeneity of tumours induces variations in clonogenic cell density, radiation sensitivity, repopulation capacity and repair kinetics. The influence of these aspects are analysed within the linear quadratic model for tumour response to radionuclide therapy. Preclinical tumour models tend to be less heterogenic than the clinical conditions they should represent. The results of various preclinical radionuclide therapy experiments for peptide receptor radionuclide therapy are compared to the outcome of theoretical models and the influence of increased heterogeneity is analysed when the results of preclinical research is transferred to the clinic. When the radiation dose and radiobiology of the tumour response is known well enough it may be possible to leave the current phenomenological approach in preclinical radionuclide therapy and start basing these experiments on radiation dose. Then the use of a gamma ray-emitting radionuclides for a chemically comparable beta-particle-emitting paired isotope for therapy evaluation would be feasible

Acute Kidney Injury due to Sodium Bromate Intoxication: A Report of Two Cases

Sodium bromate is a strong oxidant used as a neutralizing solution in hair permanents, as well as an auxiliary agent in printing and dyeing. Accidental or deliberate ingestion of bromate solution has rarely been reported in Korea. The clinical manifestations of bromate intoxication are vomiting, diarrhea, central nervous system symptoms, oliguric or non-oliguric acute kidney injury, hemolytic anemia, and deafness; most of these manifestations are reversible, with the exception of renal failure and deafness. Here, we report on two patients who demonstrated distinct clinical progressions. In the first case, a 16-year-old woman was successfully treated with hemodialysis and recovered renal function without hearing loss. However, in the second case, delayed hemodialysis resulted in persistent renal failure and hearing loss in a 77-year-old woman. This suggests that emergency therapeutic measures, including hemodialysis, should be taken as soon as possible, as the rapid removal of bromate may be essential to preventing severe intoxication and its sequelae

Expansion of Human Airway Basal Stem Cells and Their Differentiation as 3D Tracheospheres

Although basal cells function as human airway epithelial stem cells, analysis of these cells is limited by in vitro culture techniques that permit only minimal cell growth and differentiation. Here, we report a protocol that dramatically increases the long-term expansion of primary human airway basal cells while maintaining their genomic stability using 3T3-J2 fibroblast coculture and ROCK inhibition. We also describe techniques for the differentiation and imaging of these expanded airway stem cells as three-dimensional tracheospheres containing basal, ciliated, and mucosecretory cells. These procedures allow investigation of the airway epithelium under more physiologically relevant conditions than those found in undifferentiated monolayer cultures. Together these methods represent a novel platform for improved airway stem cell growth and differentiation that is compatible with high-throughput, high-content translational lung research as well as human airway tissue engineering and clinical cellular therapy

Family history is neglected in the work-up of patients with colorectal cancer: a quality assessment using cancer registry data

In the diagnostic work-up of hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome), high-risk patients can be identified using information from the family history on cancer (‘Amsterdam criteria’ and ‘Bethesda guidelines’). To investigate to what extent the medical specialists apply these criteria to patients with colorectal carcinoma and a suspicion of HNPCC, we collected information on diagnostic work-up of 224 patients of seven hospitals in the region of the Comprehensive Cancer Centre West in Leiden, The Netherlands. These patients were diagnosed with colorectal cancer between 1999 and 2001 and satisfied at least one of the Bethesda guidelines. A complete family history was recorded for 38 of the 244 patients (16%). Patients with a complete family history were more likely to be referred to the Clinical Genetic Centre than those with an incomplete or absent family history (53% vs. 13% and 4%, respectively; P < 0.0001), and more likely to be analyzed for microsatellite instability (MSI), which is a characteristic of HNPCC (34% vs. 6% and 1%, respectively; P < 0.0001). We conclude that the family history is neglected in the majority of patients with colorectal cancer and MSI-analysis is only performed in a small proportion of the patients that meet the guidelines for this analysis

GP-initiated preconception counselling in a randomised controlled trial does not induce anxiety

BACKGROUND: Preconception counselling (PCC) can reduce adverse pregnancy outcome by addressing risk factors prior to pregnancy. This study explores whether anxiety is induced in women either by the offer of PCC or by participation with GP-initiated PCC. METHODS: Randomised trial of usual care versus GP-initiated PCC for women aged 18–40, in 54 GP practices in the Netherlands. Women completed the six-item Spielberger State Trait Anxiety Inventory (STAI) before PCC (STAI-1) and after (STAI-2). After pregnancy women completed a STAI focusing on the first trimester of pregnancy (STAI-3). RESULTS: The mean STAI-1-score (n = 466) was 36.4 (95% CI 35.4 – 37.3). Following PCC there was an average decrease of 3.6 points in anxiety-levels (95% CI, 2.4 – 4.8). Mean scores of the STAI-3 were 38.5 (95% CI 37.7 – 39.3) in the control group (n = 1090) and 38.7 (95% CI 37.9 – 39.5) in the intervention group (n = 1186). CONCLUSION: PCC from one's own GP reduced anxiety after participation, without leading to an increase in anxiety among the intervention group during pregnancy. We therefore conclude that GPs can offer PCC to the general population without fear of causing anxiety. Trial Registration: ISRCTN5394291

Mortality in Dutch hospitals: Trends in time, place and cause of death after admission for myocardial infarction and stroke. An observational study

<p>Abstract</p> <p>Background</p> <p>Patterns in time, place and cause of death can have an important impact on calculated hospital mortality rates. Objective is to quantify these patterns following myocardial infarction and stroke admissions in Dutch hospitals during the period 1996–2003, and to compare trends in the commonly used 30-day in-hospital mortality rates with other types of mortality rates which use more extensive follow-up in time and place of death.</p> <p>Methods</p> <p>Discharge data for all Dutch admissions for index conditions (1996–2003) were linked to the death certification registry. Then, mortality rates within the first 30, 90 and 365 days following admissions were analyzed for deaths occurring within and outside hospitals.</p> <p>Results</p> <p>Most deaths within a year after admission occurred within 30 days (60–70%). No significant trends in this distribution of deaths over time were observed. Significant trends in the distribution over place of death were observed for both conditions. For myocardial infarction, the proportion of deaths after transfer to another hospital has doubled from 1996–2003. For stroke a significant rise of the proportion of deaths outside hospital was found. For MI the proportion of deaths attributed to a circulatory disease has significantly fallen ovtime. Seven types of hospital mortality indicators, different in scope and observation period, all show a drop of hospital mortality for both MI and stroke over the period 1996–2003. For stroke the observed absolute reduction in death rate increases for the first year after admission, for MI the observed drop in 365-day overall mortality almost equals the observed drop in 30-day in hospital mortality over 1996–2003.</p> <p>Conclusion</p> <p>Changes in the timing, place and causes of death following admissions for myocardial infarction and stroke have important implications for the definitions of in-hospital and post-admission mortality rates as measures of hospital performance. Although necessary for understanding mortality patterns over time, including within mortality rates deaths which occur outside hospitals and after longer periods following index admissions remain debatable and may not reflect actual hospital performance but probably mirrors transfer, efficiency, and other health care policies.</p

Clinical impact of HLA class I expression in rectal cancer

Contains fulltext : 69499.pdf (publisher's version ) (Open Access)PURPOSE: To determine the clinical impact of human leukocyte antigen (HLA) class I expression in irradiated and non-irradiated rectal carcinomas. EXPERIMENTAL DESIGN: Tumor samples in tissue micro array format were collected from 1,135 patients. HLA class I expression was assessed after immunohistochemical staining with two antibodies (HCA2 and HC10). RESULTS: Tumors were split into two groups: (1) tumors with >50% of tumor cells expressing HLA class I (high) and (2) tumors with < or =50% of tumor cells expressing HLA class I (low). No difference in distribution or prognosis of HLA class I expression was found between irradiated and non-irradiated patients. Patients with low expression of HLA class I (15% of all patients) showed an independent significantly worse prognosis with regard to overall survival and disease-free survival. HLA class I expression had no effect on cancer-specific survival or recurrence-free survival. CONCLUSIONS: Down-regulation of HLA class I in rectal cancer is associated with poor prognosis. In contrast to our results, previous reports on HLA class I expression in colorectal cancer described a large population of patients with HLA class I negative tumors, having a good prognosis. This difference might be explained by the fact that a large proportion of HLA negative colon tumors are microsatellite instable (MSI). MSI tumors are associated with a better prognosis than microsatellite stable (MSS). As rectal tumors are mainly MSS, our results suggest that it is both, oncogenic pathway and HLA class I expression, that dictates patient's prognosis in colorectal cancer. Therefore, to prevent confounding in future prognostic analysis on the impact of HLA expression in colorectal tumors, separate analysis of MSI and MSS tumors should be performed

Thin-section Computed Tomography findings before and after azithromycin treatment of neutrophilic reversible lung allograft dysfunction

Recently a novel subgroup of bronchiolitis obliterans syndrome (BOS) has been described in patients after lung transplantation with high neutrophil counts in broncho-alveolar lavage and recovery of lung functional decline with azithromycin treatment. We aimed to describe the thin-section computed tomography (CT) findings of these neutrophilic reversible allograft dysfunction (NRAD) patients before and after azithromycin.status: publishe