A Bayesian network model for biomarker-based dose response.

A Bayesian network model was developed to integrate diverse types of data to conduct an exposure-dose-response assessment for benzene-induced acute myeloid leukemia (AML). The network approach was used to evaluate and compare individual biomarkers and quantitatively link the biomarkers along the exposure-disease continuum. The network was used to perform the biomarker-based dose-response analysis, and various other approaches to the dose-response analysis were conducted for comparison. The network-derived benchmark concentration was approximately an order of magnitude lower than that from the usual exposure concentration versus response approach, which suggests that the presence of more information in the low-dose region (where changes in biomarkers are detectable but effects on AML mortality are not) helps inform the description of the AML response at lower exposures. This work provides a quantitative approach for linking changes in biomarkers of effect both to exposure information and to changes in disease response. Such linkage can provide a scientifically valid point of departure that incorporates precursor dose-response information without being dependent on the difficult issue of a definition of adversity for precursors.

Recent advances in research on radiofrequency fields and health: 2004-2007.

The widespread use of wireless telecommunications devices, particularly mobile phones and wireless networks, has resulted in increased human exposure to radiofrequency (RF) fields. Although national and international agencies have established safety guidelines for exposure to RF fields, concerns remain about the potential for adverse health outcomes to occur in relation to RF field exposure. The extensive literature on RF fields and health was reviewed by a number of authorities, including the Royal Society of Canada (1999). This report is the third in a series of updates to the original report of the Royal Society of Canada, covering the period 2004-2007. In particular, the present study examined new data on (1) dosimetry and exposure assessment, (2) biological effects of RF fields such as enzyme induction, and (3) toxicological effects, including genotoxicity and carcinogenicity. Epidemiological studies of the potential health effects of RF exposure, particularly from mobile phones, were determined, along with human and animal studies of neurological and behavioural effects. Within the last 4 yrs investigators concluded that there is no clear evidence of adverse health effects associated with RF fields, although continued research is recommended to address specific areas of concern, including exposure to RF fields among children using mobile phones. The results of the ongoing 13-country World Health Organization INTERPHONE study of mobile phones may provide important new information on the potential cancer risks associated with mobile phone use.

Rapid diagnosis of pulmonary TB by BAL enzyme-linked immunospot assay in an immunocompromised host.

Immunocompromised patients with acid-fast bacilli (AFB) smear-negative active pulmonary tuberculosis (pTB) often present with nonspecific clinical symptoms and findings. T-cell interferon-gamma release assays (TIGRA) performed on whole blood (using ELISA) or peripheral blood mononuclear cells (using enzyme-linked immunospot assay (ELISPOT)) are more sensitive for the diagnosis of Mycobacterium tuberculosis (MTB) infection than the tuberculin skin test (TST), but cannot distinguish active from latent MTB infection. The present authors report a 38-yr-old female presenting with a 3-week history of malaise, dyspnoea, fevers and coughing, who had received immunosuppressive therapies over 8 months for mixed connective tissue disease. Chest radiograph and thoracic computed tomography showed ground glass opacities in both lower lobes. The TST-induration was 0 mm and AFBs or MTB nucleic acid was not detected on sputum and bronchial secretions. However, TIGRAs performed on peripheral blood cells were reactive. A high frequency of MTB-specific T-cells compatible with the immunodiagnosis of active pTB was detected among bronchoalveolar lavage cells using ELISPOT. Antituberculous therapy was initiated 18 days before MTB was discovered on sputum cultures. Detection of Mycobacterium tuberculosis-specific T-cells in the bronchoalveolar lavage using enzyme-linked immunospot assay is a promising tool for the diagnosis of active pulmonary tuberculosis in immunocompromised patients with negative acid-fast bacilli smears.

Recent advances in research on radiofrequency fields and health: 2001-2003.

The widespread use of wireless telecommunications devices, particularly mobile phones, has resulted in increased human exposure to radiofrequency (RF) fields. Although national and international agencies have established safety guidelines for exposure to RF fields, concerns remain about the potential for adverse health outcomes to occur in relation to RF field exposure. The extensive literature on RF fields and health has been reviewed by a number of authorities, including the Royal Society of Canada (1999), the European Commission's Scientific Committee on Toxicity, Ecotoxicity, and the Environment (CSTEE, 2001), the British Medical Association (2001), the Swedish Radiation Protection Authority (Boice & McLaughlin, 2002), and the Health Council of The Netherlands (2002). This report provides an update on recent research results on the potential health risks of RF fields since the publication of the Royal Society of Canada report in 1999 (See Krewski et al., 2001a) and our previous 2001 update (Krewski et al., 2001b), covering the period 2001-2003. The present report examines new data on dosimetry and exposure assessment, biological effects such as enzyme induction, and toxicological effects, including genotoxicity, carcinogenicity, and testicular and reproductive outcomes. Epidemiological studies of mobile phone users and occupationally exposed populations are examined, along with human and animal studies of neurological and behavioral effects. All of the authoritative reviews completed within the last 2 yr have concluded that there is no clear evidence of adverse health effects associated with RF fields. However, following a recent review of nine epidemiological studies of mobile phones and cancer, Kundi et al. (2004) concluded that the possibility of an enhanced cancer risk cannot be excluded. These same reviews support the need for further research to clarify the possible associations between RF fields and adverse health outcomes that have appeared in some reports. The results of the ongoing World Health Organization (WHO) study of mobile phones will provide important new information in this regard.

Changes in gene and protein expression in magnetic field-treated human glioma cells.

Because few cancer studies have examined protein profiles and genetic regulation from a single carcinogen exposure, the objective of this study was to determine genetic change via microarray and to evaluate whether that change was a precursor to cellular protein changes. In separate but experimentally identical studies, human glioma SF767 cells were exposed for 3 h to 60-Hz magnetic fields (sham or 1.2 muT). Microarray results suggested that magnetic field treatment resulted in the up-regulation of 5 genes, whereas 25 genes were down-regulated. The mean abundance of 10 identified proteins was altered following 1.2 muT exposure relative to sham (3 increase, 7 decrease). These studies suggest a limited but complicated response in the glioma cells to the magnetic field treatment.

Unstable sitting in the workplace--are there physical activity benefits?

The increasingly popular practice of using a stability ball (exercise/fitness ball) as a sitting surface runs counter to conventional human factors/ergonomics guidelines for seated workspace design. Employees sitting on stability balls in an office environment present safety risks that might be justifiable if the practice has a definitive benefit to the promotion of health. However, the published studies and best evidence to date call into question even the theoretical basis for this practice and do not suggest significant health benefits. First, biomechanical studies do not confirm the intended trunk muscle activation. Second, energy expenditure studies show a small (if any) increase in metabolic demand that is unlikely to be effective in combating sedentary work risk factors. Until studies demonstrate more conclusive benefits, the practice of stability ball sitting should be viewed skeptically as a general workplace recommendation in the interest of health or wellness.

Construction of a lacZ-kanamycin-resistance cassette, useful for site-directed mutagenesis and as a promoter probe.

A lacZ gene without a promoter, but containing its ribosome-binding site, was cloned next to the kanamycin-resistance (KmR) gene of plasmid pUC4K, yielding a lacZ-KmR cassette. From the resulting plasmid, pKOK5, the lacZ-KmR cassette was recloned by means of BamHI into plasmid pKOK4, a mobilizable derivative of pBR322 which mediates ampicillin, chloramphenicol and tetracycline resistance. The lacZ-KmR cassette can be excised from pKOK5 or pKOK6 by digestion with BamHI, SalI or PstI. It can be used for insertion mutagenesis by ligation of the cassette to target DNA that has been linearized by one of these enzymes. Insertions can be selected by the KmR phenotype and mapped by digestion, e.g., with PstI and SalI. The orientation of the inserted cassette can be determined by digestion, e.g., with EcoRI or HindIII. Within the lacZ-KmR cassette, the transcription of the lacZ and the KmR genes are directed towards each other, and the two genes are separated by the bidirectionally active terminator from phage fd. In Escherichia coli, no transcription emanating from the cassette was detected. Transcription within DNA mutagenized by the cassette can be monitored by the promoterless lacZ gene. The lacZ-KmR cassette is currently used by us for the site-directed mutagenesis of hydrogen uptake gene-specific DNA from Rhizobium leguminosarum B10.

Construction of a mobilizable cloning vector for site-directed mutagenesis of gram-negative bacteria: application to Rhizobium leguminosarum.

A mobilizable cloning vector was constructed from defined fragments to serve as a suicide plasmid for site-directed mutagenesis. The new vector, pKOK4, closely resembles plasmid pBR325. However, the inverted duplication existing in the latter was not introduced. The useful cloning sites of pBR325 (EcoRI, HindIII, EcoRV, BamHI, SalI, PstI and PvuI) were retained and are located in one of the three resistance markers, ApR, CmR or TcR, respectively. Also, in pKOK4 the CmR gene retains its own promoter. The mob site of plasmid RP4 was introduced as a 760-bp fragment at a defined location. The mobilization frequency of pKOK4 within Escherichia coli strains is approx. 4 x 10(-2) per recipient cell. The size of pKOK4, deduced from the construction, is 6368 bp. We used pKOK4 for site-directed mutagenesis of hup-specific DNA from Rhizobium leguminosarum B10. Integration of the vector could be distinguished reliably from marker exchange by screening for the antibiotic resistance(s) of the plasmid. This reduced the number of clones to be retested by colony and Southern hybridization to approx. 1% of the original number. Of these, almost 70% contained the desired marker exchange.

Correlation between the effects of neuroleptics on prolactin release, mammary stimulation and the vaginal cycle in rats.

The correlation between hyperprolactinaemia induced by the administration of neuroleptic drugs, disturbances of the vaginal cycle and mammary gland stimulation in rats was investigated as a test model simulating the clinical syndrome of hyperprolactinaemia and amenorrhoea with anovulation. In acute experiments in which clozapine, sulpiride and chlorpromazine were administered orally to rats of both sexes, there were rapid increases in the level of prolactin in the serum with peak values between 15 and 60 min. The responses of female rats to various doses of sulpiride were consistently higher than those of male rats. Hyperprolactinaemia induced by sulpiride in dioestrous rats failed to desensitize the ovaries to the ovulatory effect of exogenous luteinizing hormone releasing hormone. Studies of these substances and of metoclopramide, haloperidol and thioridazine were then carried out in females rats by daily oral administration over a period of 13 days. The increases in the level of prolactin in the serum were paralleled by disruption of the vaginal cycle up to and including constant dioestrus and by mammary gland stimulation which, like the preceding phenomena, showed dose-dependence. The potencies of these six neuroleptics, as estimated from their effects on the mammary gland, appeared to be haloperidol greater than sulpiride greater than or equal to metoclopramide = thioridazine greater than chlorpromazine greater than clozapine.

50-Hertz magnetic field and calcium transients in Jurkat cells: results of a research and public information dissemination (RAPID) program study.

An effect on intracellular calcium continues to be proposed as a biochemical pathway for the mediation of biologic effects of electrical-power-frequency magnetic fields (MF). However, reproducible results among laboratories are difficult to attain and the characteristics of magnetic field effects on intracellular free calcium ([Ca(2+)](i)) are not well understood. We attempted to repeat the studies of Lindström et al. [Intracellular Calcium Oscillations in a T-Cell Line by a Weak 50 Hz Magnetic Field. J Cell Physiol 156:395-398 (1993)] by investigating the effect of a 1.5-G 50-Hz MF on [Ca(2+)](i) in the Jurkat lymphocyte T-cell line. Changes in [Ca(2+)](i) were determined using microscopic imaging of fura-2 loaded Jurkat cells on poly-l-lysine-coated glass coverslips. The MF was generated by a single coil constructed with bifilar wire and located in the same plane as the cells. Cells were randomly exposed for 8 min to MF, sham field (SF), or no field (NF) conditions. The exposure condition remained coded until data analysis was complete. Each exposure period was preceded by an 8-min data collection to establish a baseline for [Ca(2+)](i). After each exposure condition, cells were exposed to anti-CD3 antibody that induced a rapid increase in [Ca(2+)](i) in responsive cells; this provided a positive control. [Ca(2+)](i) was analyzed for individual cells as spatially-averaged background-corrected 340/380 nm ratios, and a [Ca(2+)](i) transient was considered significant for positive deviations from baseline of 3 [multiple] an estimate of noise in the baseline. Typically, 25-50 cells/field were viewed and approximately 50% had no [Ca(2+)](i) transients in the baseline period and also responded to positive control. Only cells responding to positive control and lacking changes in [Ca(2+)](i) during the baseline period were considered qualified for assessment during the exposure period. The incidences of [Ca(2+)](i) transients during the exposure period for two experiments (40 [multiple] objective) were 16.5, 14.6, and 14.2% for MF, SF, and NF, respectively, and were not statistically significantly different. Previous studies by Lindström et al. [Intracellular Calcium Oscillations in a T-Cell Line after Exposure to Extremely-Low-Frequency Magnetic Fields with Variable Frequencies and Flux Densities. Bioelectromagnetics 16:41-47 (1995)] showed a high response rate (92%) for exposure to 1. 5-G 50-Hz MF when individual cells were preselected for investigation. We found no such effect when examining many cells simultaneously in a random and blind fashion. These results do not preclude an effect of MF on [Ca(2+)](i), but suggest that responsive cells, if they exist, were not identified using the approaches that we used in this study.

Hyperthermia in radiofrequency-exposed rhesus monkeys: a comparison of frequency and orientation effects.

To compare the effects of exposure to a near-resonant frequency of microwaves at two orientations with a higher frequency exposure, five rhesus monkeys were exposed for 4 hr to 225 MHz, electric field oriented parallel to the long axis of the body (225 MHz-E), and to 225 MHz, magnetic field orientation (225 MHz-H), or to 1290 MHz, electric field orientation. On a separate occasion, the monkeys were exposed at night to 225 MHz-E. Exposures were conducted with the animal chair restrained in an anechoic chamber with rectal temperature continuously monitored. Blood samples were taken hourly during the 225-MHz-E exposures for cortisol analysis. The power densities used were 0, 1.2, 2.5, 5.0, 7.5, 10.0, and 15.0 mW/cm2 for 225 MHz-E (day), 0 and 5 mW/cm2 (225 MHz-E night and 225 MHz-H), and 0, 20, 28, and 38 mW/cm2 (1290 MHz). The monkeys were unable to tolerate exposure at power densities equal to or greater than 7.5 mW/cm2 (5.1 W/kg) at 225 MHz-E for longer than 90 min. The criterion for tolerance was that the rectal temperature would not exceed 41.5 degrees C. Average rectal temperature increases for day exposure to 225 MHz-E were 0.4 and 1.7 degrees C for 4-hr exposures to 2.5 and 5.0 mW/cm2 (1.7 and 3.4 W/kg). No changes in circulating cortisol levels occurred during any exposures to 5 mW/cm2 or less. Night exposures to 5 mW/cm2 (3.4 W/kg) at 225 MHz-E raised mean rectal temperature 2.1 degrees C. Exposure to 5 mW/cm2 (1.2 W/kg) at 225 MHz-H for 4 hr resulted in a 0.2 degree rise in mean rectal temperature. For 4 hr of 1290-MHz exposure to 20, 28, or 38 mW/cm2 (2.9, 4.0, and 5.4 W/kg), the mean body temperature increases were 0.4, 0.7, and 1.3 degrees C, respectively. The degree of hyperthermia caused by radiofrequency (rf) exposure was shown to be frequency and orientation dependent for equivalent power densities of exposure.

Evaluation of in vitro effects of 50 and 60 Hz magnetic fields in regional EMF exposure facilities.

A weak association between magnetic-field exposure and increased incidences of cancer has been reported. While alterations in cellular processes after in vitro magnetic-field exposures have also been reported to provide plausibility for this association, other laboratories have been unable to repeat the findings. As part of an accelerated electric- and magnetic-field (EMF) research program, the National Institute of Environmental Health Sciences with the Department of Energy identified the replication of the published positive effects as a priority. Regional EMF exposure facilities were established to investigate major in vitro effects from the literature. These included effects on gene expression, intracellular calcium, colony growth in soft agar, and ornithine decarboxylase activity. The laboratories that first reported these effects provided experimental protocols, cell lines, and other relevant experiment details. Regional facility studies included sham/sham exposures (no applied field in either chamber) and were done in a blinded fashion to minimize investigator bias. In nearly all experiments, no effects of magnetic-field exposure were found. The effort provided insight into dealing with the difficulty of replication of subtle effects in complex biological systems. Experimental techniques provided some clues for the differences in experimental results between the regional facility and the original investigator. Studies of subtle effects require extraordinary efforts to confirm that the effect can be attributed to the applied exposure.

Dihydrotestosterone causes reversible infertility in male rats.

Dihydrotestosterone released continuously from a subcutaneously implanted Silastic elastomer was more potent than testosterone in reducing circulating gonadotropin and androgen concentrations and in inducing testicular atrophy and infertility despite normal ejaculatory function as judged by the presence of vaginal plugs in cage mates. All effects were reversible. Thus quantities of dihydrotestosterone which reduce circulating gonadotropin concentrations suffice to maintain the weights of accessory sex organs but not spermatogenesis. That the latter is possible with higher doses even in the complete absence of luteinizing hormone and follicle-stimulating hormone (state after hypophysectomy) has been shown by others.

[Improved radiological diagnosis in the stomach by means of an improved contrast material (author's transl)]. / Erweiterte diagnostische Möglichkeiten der röntgenologischen Magenuntersuchung mit verbessertem Kontrastmittel.

Our experience with a cheap contrast medium, which we prepare ourselves, is described, stretching over a period of 18 months. It is based on the bubbly barium first described by Op den Orth and is made by means of carbon dioxide in a soda water syphon. It is better for detailed contrast examination of the stomach than the commercially available contrast media. It is thought that this is due to optimal viscosity for wetting of the mucosa, optimal size of the barium sulphate particles, which are larger than one micron, and greater distension of the stomach due to greater quantities of CO2. The use of bubbly barium for routine examination of the stomach, using double contrast and hypotonia with graded compression, almost always results in demonstration of the areae gastricae in large parts of the stomach. We regard this as a sign of a good examination, since we are then able to demonstrate small lesions such as complete or incomplete erosions, ulcer scars or flat ulcers.

[Scintigraphy for doubtful vertebral fractures (author's transl)]. / Die Szintigraphie bei röntgenologisch unklaren Wirbelkörperverletzungen.

Fractures, particularly those of vertebral bodies, cannot always be demonstrated radiologically. The use of scintigraphy for this purpose is known but, in our opinion, this is not used sufficiently. Diagnosis of fractures by scintigraphy is almost 100% reliable. In the presence of degenerative changes in the spine, this is frequently the only method for differentiating between old and new fractures. By using the almost universally available substance 99mTc one has a cheap method with virtually no radiation dose. The earliest accumulation of 99mTc-MDP after fracture of a vertebral body was seen four hours after the trauma; absence of uptake three days after trauma excludes a fracture.

[Pneumonitis with fatal pulmonary fibrosis (Hamman-Rich syndrome) due to parathion-(E-605-) poisoning]. / Pneumonitis mit letaler Lungenfibrose (Hamman-Rich-Syndrom) bei Parathion-(E-605-) Vergiftung.

A patient with chronic Parathione (E 605) poisoning was observed over a period of 55 days. During that time he developed progressive changes, which were identical to those of progressive idiopathic pulmonary fibrosis. The rapid development of an alveolitis, followed by a lethal pulmonary fibrosis, differed in no way, macroscopically nor microscopically, from the lung changes in paraquat poisoning (paraquat lung). The radiological course has been correlated with the clinical and post mortem findings.

[Areae gastricae and varioliform erosions--the criteria concerning the quality of radiological examinations of the stomach (author's transl)]. / Areae gastricae und varioliforme Erosionen--Qualitätskriterien der röntgenologischen Magenuntersuchung.

Two hundred otherwise unselected patients had barium meal examinations for upper abdominal pain; in 93% of these the areae gastricae could be visualised on more than one third of the gastric surface. In 17%, i.e. 34 patients, varioliform erosions were found; these confirmed by gastroscopy in 11.5%, i.e. 23 patients. Varioliform erosions are a frequent cause of obscure upper abdominal pain or gastro-intestinal haemorrhage. Their diagnosis is therefore of great importance. Regular demonstration of the areae gastricae is associated with an increased ability to show these erosions and must therefore be regarded as a measure of the excellence of a radiological examination of the stomach.

[Varioloform (complete) erosions in the stomach and duodenum]. / Die varioliformen (kompletten) Erosionen in Magen und Duodenum.

One thousand five hundred and eighty-three patients who were x-rayed for dyspepsia showed varioliform erosions in 15.3%. Men had an incidence of 9.8%, almost twice as common as in women (5.5%). Mucosal polyps, usually of the hyperplastic type, occurred in 2.4%. 15% of patients with gastric ulcers and 16% of patients with duodenal ulcers had varioliform erosions. On the other hand, amongst patients with erosions, 11% had gastric ulcers and 8.3% duodenal ulcers. The definitions of erosion which have been given in the literature are partly contradictory, and are discussed. Varioliform erosions, also known as complete erosions, may be acute or chronic. They are the third most common cause of bleeding from the upper gastrointestinal tract. With modern radiological methods of examining the stomach, they are no longer a rare finding.

[Massive osteolysis (Gorham-Stout's syndrome) with local neurofibromatosis (author's transl)]. / Die massive Osteolyse (Gorham-Stout-Syndrom) mit lokaler Neurofibromatose. Uberlegungen zu einem seltenen Krankheitsbild mit kasuistischem Beitrag.

The rare condition of massive osteolysis is illustrated by a 75-year-old man with involvement of the right arm which began at the age of 16. Serial radiographs over a period of 33 years are compared. In addition to the typical haemangiomatous vascular proliferation and connective tissue growth in the affected bone, there were also changes in the peripheral nerves, such as neurinomas and neurofibromas, which have not been previously described. Arteriography is usually not able to demonstrate the angiomatous tissue, but this was convincingly seen by means of sequential scintigraphy (99mTc-MDP). This finding, with absence of uptake on a subsequent bone scan, may be regarded as the typical isotope finding in massive osteolysis.

Pediatric videonasoendoscopy for speech and voice evaluation.

Many otolaryngologists and speech clinicians have found videofiberoptic evaluations to be invaluable for assessment of velopharyngeal and laryngeal function in adults. However, many professionals question the feasibility of routine use of these procedures in the pediatric population. This article describes a method for successful completion of videonasoendoscopic speech and voice evaluations of children as young as 3 years of age. The importance of the ENT/speech team is emphasized in both the collection and interpretation of data. In addition, contributions of videonasoendoscopic observations to diagnosis, medical treatment, and therapy for speech and voice disorders are discussed.