A case of transfusion transmitted malaria in Switzerland.
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Publications and source records attributed to A Maier.
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PURPOSE: To investigate sources of variation in radiosensitivity displayed by cancer patients and blood donors using the leukocyte apoptosis assay. METHODS AND MATERIALS: Probes were obtained from 105 healthy blood donors, 48 cancer patients displaying normal sensitivity to radiotherapy, 12 cancer patients displaying hypersensitivity to radiotherapy, 12 Ataxia telangiectasia blood donors, and 4 additional individuals with genetic diseases of potentially modified radiosensitivity; 2 neurofibromatosis (NF) donors, a Nijmegen breakage syndrome (NBS) donor, and an Immunodeficiency, Chromosome fragility, Facial anomaly syndrome (ICF) donor. Heparinized blood was diluted in medium, irradiated, and left to incubate for 48 h. CD4 and CD8 T-lymphocyte DNA was stained with propidium iodide and the cells were analyzed by flow cytometry. RESULTS: Radiation-induced apoptosis depended on age and cell type. Cohorts of hypersensitive cancer patients, NBS and AT donors displayed compromised apoptotic response. An asymmetric apoptotic response of T-lymphocytes was observed in an ICF donor and a cryptic hypersensitivity donor. Two NF donors displayed no abnormal sensitivity to radiotherapy but compromised apoptotic T-cell response to X-rays. CONCLUSION: Our studies reveal 4 physiologic sources of variation in radiation response-2 are genetic: cryptic hypersensitivity and hereditary disease, and 2 are epigenetic: cell type and donor age. They emphasize the important role of proteins involved in the recognition and repair of DNA double-strand breaks in determining the response of individuals to radiotherapy.
Transgenic mice were prepared by homologous recombination with a Col11a2 targeting gene in which an inverted neomycin-resistant gene was inserted between restriction sites in exons 27 and 28. The targeted allele was transcribed in shortened mRNAs, which could be detected by Northern blotting. However, translation of the full-length Col11a2 chain was unable to occur because of the presence of premature termination codons within the inverted neomycin-resistant gene. Analysis of pepsin-resistant collagen chains from rib cartilage of homozygous mice demonstrated the lack of synthesis of intact alpha2(XI) chains. However, pepsin-resistant collagen chains of either alpha1(XI) or alpha1(V) were still detected on sodium dodecyl sulfate polyacrylamide gel electrophoresis. Therefore, alpha2(XI) chains are not essential for the assembly of some molecular forms of triple-helical type V/XI collagen. The phenotype was milder than in the cho/cho mouse in which, as the result of mutation, translation of the full-length alpha1(XI) chain fails to occur and the mice die at birth (Li et al., 1995). Homozygous mice without expression of an alpha2(XI) chain had a smaller body size, receding snouts, and deafness. Nasal bones in the homozygous transgenic mice were specifically shorter and dimpled on their external surfaces. Chondrocytes in growth plates of all long bones were markedly disorganized and failed to align in columns. Analysis of growth plates from transgenic mice by in situ hybridization showed expression of alpha1(II) and alpha1(XI) but not of alpha1(I) or alpha1(V) which, in contrast, were expressed in the developing bone and in the bone collar. Expression of alpha1(X) specifically in the hypertrophic cartilage was observed in normal and transgenic mice. No obvious osteoarthritis was observed throughout the life of homozygous mice up to 1 year of age, although minor morphologic anomalies in the articular cartilages were discernible. The mild phenotype is consistent with similar mutations in the COL11A2 gene seen in patients with nonocular Stickler syndrome and some patients with otospondylomegaepiphyseal dysplasia (OSMED), as well as in patients with a nonsyndromic form of deafness called DFNA13.
BACKGROUND AND OBJECTIVE: Photodynamic tumor therapy (PDT) is based upon a photochemical reaction that is limited by the availability of molecular oxygen in the target tissue. The use of hyperbaric oxygenation (HBO) increases the amount of oxygen available for the process may thereby enhance the efficacy of PDT. We investigated the acute effects on tumor stenosis after combined PDT/HBO. PATIENTS AND METHODS: Thirty patients (22 males, 8 females, mean age: 68.8 years; range: 44-78 years) with inoperable non-small cell bronchogenic carcinoma and endobronchial stenosis were studied prospectively. Photosensitization was carried out using a hematoporphyrin-derivative 2 mg/kg BW 48 hours prior to PDT. The light dose was calculated as 300 J/cm fiber tip. The assessment of outcome 1 and 4 weeks after PDT/HBO was performed by endoscopy, chest X-ray, spirometry, laboratory parameters, subjective report of dyspnea, and Karnofsky performance status. RESULTS: At one and four weeks after the treatment, the patients felt a significant improvement of dyspnea and hemoptysis along with an objective subsiding of poststenotic pneumonia, though spirometric parameters revealed no significant difference. A significant reduction of tumor stenosis (P < 0.05) and an improvement of the Karnofsky performance status (P < 0.05) were documented 1 and 4 weeks after PDT/HBO. No therapy related complications were observed. CONCLUSIONS: Although the small number of patients does not allow to draw definitive conclusions to be drawn, the results suggests that combined PDT/HBO represents a new, safe, and technically feasible approach. It enables efficient and rapid reduction of the endoluminal tumor load and helps conditioning the patient for further treatment procedures.
BACKGROUND AND OBJECTIVE: Polyhematoporphyrin (Photosan) as sensitizers for photodynamic therapy (PDT) in advanced esophageal cancer carry the risk of prolonged photosensitivity of the skin. New sensitizers such as 5-aminolaevulinic acid (ALA) with low rates of skin phototoxicity appear to be promising alternatives. The aim of this study was to evaluate the efficacy of ALA compared to Photosan for PDT in advanced esophageal carcinoma regarding phototoxicity of the skin, reduction of dysphagia, tumor stenosis, and tumor length and Karnovsky performance status. STUDY DESIGN/MATERIALS AND METHODS: After diagnostic work-up, photosensitization was done in 22 patients with ALA (60 mg/kg body weight, oral, 6-8 hours prior to PDT) and in 27 patients with Photosan (2 mg/kg body weight, i.v., 48 hours before PDT). The light dose was calculated as 300 J/cm fibre tip. Light at 630 nm was applied using a pumped dye laser. In both groups, additional hyperbaric oxygenation was applied at a level of 2 absolute atmospheric pressure. RESULTS: Improvement regarding dysphagia, stenosis diameter, and tumor length could be obtained in both treatment arms with a significant difference in favour of the Photosan-group, P = 0.02; P = 0.0000; and P = 0.000014, respectively. The Karnovsky performance status also improved in both groups and showed no significant difference (P = 0.12). The median survival time for the ALA-group was 8.0 months, compared with 9.0 months for the Photosan group. No sunburn or other major treatment related complication occurred in both treatment arms. Thirty-day mortality was 0%. CONCLUSION: Despite the limitations of a non-randomized study, photosensitzation with Photosan seems to be more effective in PDT of advanced esophageal carcinoma compared to ALA.
BACKGROUND: Hematoporphyrin derivatives (HpD) as sensitizers for photodynamic therapy (PDT) in advanced esophageal cancer carry the risk of prolonged photosensitivity of the skin. New sensitizers such as 5-aminolaevulinic acid (ALA) with low rates of skin phototoxicity appear to be promising alternatives. The aim of this study was to evaluate the efficacy of ALA compared with HpD for PDT in advanced esophageal carcinoma regarding phototoxicity of the skin, reduction of dysphagia, tumor stenosis and length, and Karnovsky performance status. METHODS: After diagnostic workup, photosensitization was done in 22 patients with ALA (60 mg/kg body weight, oral, 6 to 8 hours before PDT) and in 27 patients with a hematoporphyrin derivative (2 mg/kg body weight, intravenously, 48 hours before PDT). The light dose was calculated as 300 J/cm fiber tip. Light at 630 nm was applied using a pumped dye laser. In both groups, additional hyperbaric oxygenation was applied at a level of 2 absolute atmospheric pressure. RESULTS: Improvement regarding dysphagia, stenosis diameter, and tumor length could be obtained in both treatment arms with a significant difference in favor of the HpD group (p = 0.02; p = 0.0000; and p = 0.000014, respectively). A questionnaire of patients in the HpD group confirmed that the ability of swallowing a meal was superior compared with the discomfort from limitation to sun exposure. No sunburn or other major treatment-related complication occurred in both treatment arms. CONCLUSIONS: Despite the limitations of a nonrandomized study, photosensitzation with HpD seems to be more effective in PDT of advanced esophageal carcinoma compared with ALA.
OBJECTIVES: Photodynamic tumor therapy (PDT) is based upon a photochemical reaction that is limited by the availability of molecular oxygen in the target tissue. The use of hyperbaric oxygenation (HBO) increases the amount of oxygen available for the process may thereby enhance the efficacy of PDT. We proved in a prospective, non-randomized clinical pilot study the acute effects on malignant bronchial stenosis and the technical feasibility of combined PDT/HBO. METHODS: Forty patients (29 males, 11 females, mean age: 64.3 years; range 39-82 years) with inoperable, advanced malignant bronchial tumor stenosis were studied prospectively. Photosensitization was carried out using a hematoporphyrin-derivative 2 mg/kg bw 48 h prior to PDT. The light dose was calculated as 300 J/cm fiber tip. The assessment of outcome 1 and 4 weeks after PDT/HBO was done by endoscopy, chest X-ray, spirometry, laboratory parameters, subjective report of dyspnea and Karnofsky performance status. RESULTS: At 1 and 4 weeks after the treatment the patients felt a significant improvement of dyspnea and hemoptysis alongside with an objective subsiding of poststenotic pneumonia, though spirometric parameters revealed no significant difference. A significant reduction of tumor stenosis (P<0.05) and an improvement of the Karnofsky performance status (P<0.05) were documented 1 and 4 weeks after PDT/HBO. No therapy related complications were observed. CONCLUSION: Although the small number of patients does not allow to draw definitive conclusions, the results suggest that combined PDT/HBO represents a new, safe and technically feasible approach. It enables efficient and rapid reduction of the endoluminal tumor load and helps conditioning the patient for further treatment procedures.
OBJECTIVE: Ruptures of the tracheobronchial tree present a life-threatening situation. Nevertheless, therapy is still controversial. Though conservative treatment by antibiotics and intubation with the cuff inflated distal to the tear is favored by some authors, surgical repair is unavoidable in many cases. METHODS: We present a series of 31 patients (mean age 43.6 years, range 8--72 years) with iatrogenous or post-traumatic tracheobronchial ruptures treated since 1975. Fifteen ruptures were longitudinal tears of the trachea, not extending lower than a distance of 3 cm from the bifurcation, 11 involved the bifurcation and/or the main bronchi. The total length of the longitudinal tears ranged from 2 to 12 cm, five were transverse near complete abruptions of the trachea or main bronchi. Involvement of the full thickness of the wall with free view into the pleural space or to the esophageal wall was present in 29 cases. Twenty-nine out of the 31 patients underwent surgical repair and two were treated conservatively. The length and depth of the lesion, the degree of subcutaneous emphysema, pneumothorax and/or pneumomediastinum as well as clinical signs suggesting incipient mediastinitis were considered when making the decision for surgery. RESULTS: Twenty-five out of the 29 patients experienced an uneventful recovery. Four patients died of sepsis unrelated to the tracheobronchial trauma. One of the two patients who underwent conservative therapy also recovered uneventfully. The other one died because of multi-organ failure due to underlying myocardial infarction. CONCLUSIONS: Conveniently localized short lacerations, especially if they do not involve the whole thickness of the tracheal wall, can be treated with antibiotics and intubation with the cuff inflated distal to the tear, avoiding high intra-bronchial pressures also after eventual extubation. In all other cases surgical repair is to be preferred.
OBJECTIVE: Any treatment of tracheo-esophageal fistulae in end-stage malignant stenosis of the esophagus must be weighed against associated morbidity and mortality. In a prospective study we investigated benefits and risks of the use of one type of coated, self-expandable stent. PATIENTS AND METHODS: We treated four male and two female patients, (mean age 68.3 years, range: 38-90 years), with malignant esophago-tracheal fistula non-resectable due to advanced tumour stage and/or functional reasons. All were in a poor general condition suffering from aspiration pneumonia and malnutrition. Four out of the six patients had had one or multiple extra- or endoluminal palliative treatments at a mean interval of 191 days (range: 7 days-15 ms) since the last intervention. The fistulae were sealed by using a covered, self-expandable stent (ULTRAFLEX esophageal stent system, Microinvasive, Boston Scientific Corporation, Boston, MA). RESULTS: Stenting did not cause any technical problems and all fistulae were successfully sealed in a one-step procedure. The median hospital stay was 4.6 days (range: 3-9 days). Except for one late stent induced recurrent fistula treated by re-stenting and tracheostomy, we did not observe any stent associated complications. Five patients died of tumour generalization. The median survival of the patients who died was 78 days (range: 35-129 days). One patient is alive and well at 120 days after stenting. CONCLUSION: In spite of the small number of patients the results suggest that this type of stent represents a safe and efficient approach for palliative endoscopic treatment of this high risk group. Local pretreatment does not preclude the successful use of the self-expandable coated stent.
Tetranectin is a C-type lectin that occurs in the mammalian musculoskeletal system. In the present report we describe the first studies on an avian tetranectin. A full-length chicken tetranectin cDNA was isolated. Comparison of the deduced amino acid sequence of chicken tetranectin with mouse and human tetranectin showed an identity of 67 and 68%, respectively. Northern blot analysis demonstrated broad expression of chicken tetranectin mRNA, which was first detected on embryonic day 4. Tetranectin protein was detected in chicken serum and egg yolk. Since muscle is one of few tissues in which tetranectin protein is retained, we examined the distribution of tetranectin in various muscle types in chicken. Myofibers strongly positive for tetranectin were observed in several muscles including m. tibialis ant. and m. sartorius (from embryonic day 10 to adult). Using antibodies to fast and slow myosin heavy chains (MHC) and double immunostaining techniques, we found that tetranectin was restricted to slow (type I) muscle fibers. Similarly only slow intrafusal fibers accumulated tetranectin. The pattern of immunostaining in chickens differs markedly from that seen in mouse muscles, indicating that tetranectin performs a role in muscle that is not associated with a hitherto recognized muscle type or function.
Kinetoplastid parasites compartmentalize the first seven enzymes of glycolysis in a peroxisome-like microbody, the glycosome. Genes encoding the most abundant protein of the glycosomal membrane, GIM5, have been cloned and the protein characterized. Two genes, GIM5A and GIM5B, encode 26 kDa proteins. Although many microbody membrane proteins are conserved in evolution, the only homologues of GIM5 in the available databases are from the closely related kinetoplastids Trypanosoma cruzi and Leishmania. The N- and C-termini are conserved between the two genes, and between species, and are oriented towards the cytosol. They are separated by a short loop that is located between two transmembrane domains and shows almost no sequence conservation. This suggests that the N- and C-terminal domains are more important for function. GIM5 forms dimers in vivo. Overexpression of GIM5B inhibits growth, whereas depletion of GIM5 to below 10% of wild-type levels is very rapidly lethal. This novel organellar membrane protein is therefore essential for bloodstream trypanosome survival.
PURPOSE: The aim of this study was to assess the value of endoanal ultrasound (EUS) in comparison to anal manometry and operative findings in patients suffering from faecal incontinence. Patient history, localisation of sphincter defects and therapeutic modalities were analysed. METHODS: Over a 3-years period, 92 patients with faecal incontinence were investigated by endoanal ultrasound. Results were compared with anal manometry in 81 cases. RESULTS: At EUS, 27 patients (29 %) showed no sphincter defect, 18 (20 %) had an isolated internal sphincter defect, 13 (14 %) an isolated defect of the external sphincter and 34 (37 %) presented with a combined internal/external sphincter defect. Manometry correlated in 30 % with endoanal ultrasound. Compared with surgery, endoanal ultrasound was correct in 100 % and manometry in only 54 %. An obstetric trauma was most frequently related to faecal incontinence. CONCLUSION: Endoanal ultrasound is a very sensitive method for localizing anal sphincter defects and is mandatory in the assessment of patients with faecal incontinence.
Mechanistic data, when available, have long been considered in risk assessment, such as in the development of the nitrate RfD based on effects in a sensitive group (infants). Recent advances in biology and risk assessment methods have led to a tremendous increase in the use of mechanistic data in risk assessment. Toxicokinetic data can improve extrapolation from animals to humans and characterization of human variability. This is done by the development of improved tissue dosimetry, by the use of uncertainty factors based on chemical-specific data, and in the development of physiologically based pharmacokinetic (PBPK) models. The development of the boron RfD illustrates the use of chemical-specific data in the improved choice of uncertainty factors. The draft cancer guidelines of the U.S. Environmental Protection Agency emphasize the use of mode of action data. The first choice under the guidelines is to use a chemical-specific, biologically based dose-response (BBDR) model. In the absence of a BBDR model, mode of action data are used to determine whether low-dose extrapolation is done using a linear or nonlinear (margin of exposure) approach. Considerations involved in evaluating a hypothesized mode of action are illustrated using 1,3-dichloropropene, and use of a BBDR model is illustrated using formaldehyde. Recent developments in molecular biology, including transgenic animals, microarrays, and the characterization of genetic polymorphisms, have significant potential for improving risk assessments, although further methods development is needed. Overall, use of mechanistic data has significant potential for reducing the uncertainty in assessments, while at the same time highlighting the areas of uncertainty.
We have used a high density microarray hybridization approach to characterize the transcriptional response of human hepatoma HepG2 cells to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We find that exposure to 10 nM TCDD for 8 hr alters by at least a factor of 2.1 the expression of 310 known genes and of an equivalent number of expressed sequence tags. Treatment with TCDD in the presence of 20 microg/mL of cycloheximide blocked the effect on 202 of these genes, allowing us to distinguish between primary effects of TCDD exposure, which take place whether cycloheximide is present or not, and secondary effects, which are blocked by inhibition of protein synthesis. Of the 310 known genes affected by TCDD, 30 are up-regulated and 78 are down-regulated regardless of cycloheximide treatment, and 84 are up-regulated and 118 are down-regulated only when protein synthesis is not inhibited. Functional clustering of genes regulated by TCDD reveals many potential physiological interactions that might shed light on the multiple biological effects of this compound. Our results, however, suggest that arriving at a sound understanding of the molecular mechanisms governing the biological outcome of TCDD exposure promises to be orders of magnitude more complicated than might have been previously imagined.
BACKGROUND AND OBJECTIVE: The photochemical reaction of photodynamic therapy (PDT) depends on the presence of molecular oxygen. Because of anoxic regions in tumor tissue and vascular shutdown during PDT, the efficiency is limited. Therefore, the use of hyperbaric oxygen, which increases the oxygen in tumor tissue, as well as the amount of singlet oxygen, may enhance the efficiency of PDT. STUDY DESIGN/MATERIALS AND METHODS: After diagnostic work-up, photosensitization was carried out with a hematoporphyrin-derivate 2 mg/kg body weight 48 hours before PDT. The light dose was calculated as 300 J/cm of fiber tip. Twenty-three patients were treated by PDT alone and 29 patients received PDT under hyperbaric oxygen at a level of two absolute atmospheric pressures. RESULTS: Improvement regarding dysphagia and stenosis-diameter could be obtained in both treatment arms with no significant difference (P = 0.43 and P = 0. 065, respectively). The tumor length also decreased in both groups and showed a significant difference in favour of the PDT/HBO group (P = 0.002). The mean overall survival was 11.3 months. The mean survival time for the PDT group was 8.7 months and for the PDT/HBO group 13.8 months (P = 0.021). CONCLUSION: According to this pilot study, combined PDT/HBO represents a new approach in the treatment of esophageal and cardia cancer, which appears to have enhanced the efficiency of PDT.
UNLABELLED: Background and Objective We wanted to determine the role of additional photodynamic therapy in a multimodal approach for the treatment of patients with advanced cancer of the gastro-esophageal junction. Study Design/Materials and Methods We reviewed 53 patients, after endoluminal palliation, with advanced cancer of the gastro-esophageal junction. Combined dilatation and retrograde tumor disobliteration with Nd-YAG laser before photodynamic therapy (PDT), brachyradiotherapy, or both, became necessary in 12 patients. Brachyradiotherapy was carried out in all patients. PDT before brachyradiotherapy was performed in 25 patients. The endoluminal treatment was completed by external beam irradiation in 30 patients (15 cases with PDT and 15 without PDT) with an at least fair performance status. RESULTS: Photodynamic therapy showed a significant difference regarding the mean opening of the tumor stenosis (mean, 6.4 mm; P = 0.0002), the mean decrease in tumor length (3.1 cm; P = 0.00001) and the increase in median survival (13. 8 months; P = 0.001). The combined multimodal approach by using PDT, brachyradiotherapy and external beam irradiation showed a median survival of 16.8 months. However, additional external beam irradiation showed no significant difference (P = 0.11). The rate of severe complications was 5.7%. The mortality rate was 1.9%. CONCLUSION: Photodynamic therapy has been shown to be an effective treatment for palliation of advanced cancer at the gastro-esophageal junction. The use of PDT combined with irradiation was associated with an acceptable survival rate, low rates of complications and reasonable quality of life.
BACKGROUND AND OBJECTIVE: Dose dependence of light cannot be discussed on the basis of dose alone. On a more fundamental scientific level, the propagation of light in tissue depends on optical parameters of treated tumor tissue. In a prospective, nonrandomized study, in vivo optical parameters of esophageal carcinoma were studied. STUDY DESIGN/MATERIALS AND METHODS: Nineteen intraoperative measurements of tumor optical parameters in six patients with esophageal carcinoma were performed. After diagnostic work-up and clinical staging, right-sided, posterolateral thoracotomy, and dissection of the esophagus were carried out. The tumor site was exposed and continuous endoluminal irradiation was started during determination of light penetration at the level of the adventitia of the esophagus. The tumors were located exactly between the endoluminal irradiation source and measurement probe in the thoracic cavity. Measurements were performed on tumors having different diameters to show the relationship between tumor diameter, extinction coefficient, and light penetration depth. RESULTS: The endoluminal incident intensity was 18.5 mW/cm(2). At a tumor diameter of 4, 6, 8, and 9 mm measured intensity of 5.12, 2.28, 0.88 and 0.65 mW/cm(2), an extinction coefficient of 0.321, 0.349, 0.381, and 0.373, as well as penetration depth of 3.21, 2.87, 2.62, and 2. 68 mm, respectively, could be measured. The correlation of tumor optical parameters, tumor diameter, penetration depth, and treatment time were expressed by the relative correction factor for different tumor diameters. CONCLUSION: The knowledge of tumor optical properties seems to be necessary to adapt dosimetry to the individual situation and manage optimal results of PDT in esophageal cancer.
PURPOSE: To report the anaesthetic management of a case of tracheal rupture, using different types of ventilation and additional hyperbaric oxygenation (HBO). CLINICAL FEATURES: An 8 cm postintubation tracheal tear was repaired in a 66-yr-old woman with acute myocardial reinfarction, mediastinal and subcutaneous emphysema, cardiac failure and unrecognized lymphoma. Intraoperative monitoring included dual oximetry: arterial (SaO2) and mixed venous saturations (SvO2). Maintenance of free surgical access and a series of life-threatening events like dislocation of the jet catheter required many ventilation modes. An episode of supraventricular tachycardia was interrupted by cardioversion. Differential lung ventilation with a combination of conventional and high-frequency jet ventilation (HFJV) modes preserved oxygenation (PO2 139.2 mm Hg, PCO2 42.4 mm Hg, FiO2 1.0) until acute tube obstruction and decrease of saturation values (SaO2 58%, SvO2 45%) required emergency HBO: immediate cardiac and respiratory stabilization was provided by double-lung HFJV and apneic oxygenation under hyperbaric conditions at 2.5 atmospheres absolute for 35 min (SaO2 100%). The patient recovered from surgery but died of non-Hodgkin lymphoma. CONCLUSION: The combination of different ventilation modes including HFJV and the additional use of HBO resulted in sufficient oxygenation during tracheal repair.