Biomedical subjects
D Hoffmann
Publications and source records attributed to D Hoffmann.
Video-stereo-electroencephalographic investigation of orbitofrontal cortex. Ictal electroclinical patterns.
Explore the source record for details and available documents.
[Value of image guided neurosurgery in neuro-oncology].
Brain tumor surgery, stereotactic or by resection, is based on the precise knowledge of the spatial position of the target and of their relationships with the normal brain structures. Modern computed neuroimaging allows image guidance of neurosurgical procedures, using robots driven by the coordinates of the target and of the entry point. We have developped a stereotactic robot as well as a robotized microscope which are guided from digitized images. They are used in routine daily practice and will become part of the standard neurosurgical equipment.
Smoking and lung cancer: scientific challenges and opportunities.
Explore the source record for details and available documents.
Observation of vortex dynamics in two-dimensional Josephson-junction arrays.
Explore the source record for details and available documents.
Tumor-selective prodrug activation by fusion protein-mediated catalysis.
A two component system, consisting of a fusion protein and an appropriate prodrug, suited to perform selective tumor therapy in vivo is presented. The fusion protein, due to its humanized carcinoembryonic antigen-specific variable region, specifically binds to carcinoembryonic antigen-expressing tumors and has an enzymatic activity comparable to that of human beta-glucuronidase. The prodrug is a nontoxic glucuronide-spacer derivative of doxorubicin decomposing to doxorubicin by enzymatic deglucuronidation. In vivo studies in nude mice bearing human carcinoembryonic antigen-expressing tumor xenografts revealed that 7 days after injection of 20 mg/kg fusion protein a high specificity ratio (> 100:1) was obtained between tumor and plasma or tumor and normal tissues. Injection of 250 mg/kg of prodrug at day 7 resulted in tumor therapeutic effects superior to those of conventional chemotherapy without any detectable toxicity. These superior therapeutic effects which were observed using established human tumor xenografts can be explained by the approximately 4-12-fold higher doxorubicin concentrations found in tumors of mice treated with fusion protein and prodrug than in those treated with the maximal tolerable dose of drug alone. The nondetectable toxicity in the animals treated with fusion protein and prodrug is probably caused by up to 5-fold lower drug concentrations in normal tissues compared to the animals treated with doxorubicin. Thus, a more tumor-selective therapy, resulting in stronger therapeutic effects and reduced toxicity seems to be possible by the appropriate use of the humanized nontoxic fusion protein and the nontoxic prodrug.
Characterization and transcriptional profiles of a Drosophila gene encoding an insect defensin. A study in insect immunity.
Insect defensins are a family of 4-kDa, cationic, inducible antibacterial peptides which bear six cysteine residues engaged in three intramolecular disulfide bridges. They owe their name to certain sequence similarities with defensins from mammalian neutrophiles and macrophages. We report the characterization of a novel defensin isoform from Drosophila and the cloning of the gene encoding a preprodefensin. The gene, which is intronless and present in a single copy/haploid genome, maps at position 46CD on the right arm of the second chromosome. The analysis of the upstream region of the gene reveals the presence of multiple putative cis-regulatory sequences similar to mammalian regulatory motifs of acute-phase-response genes. Transcriptional profiles indicate that the Drosophila defensin gene is induced by bacterial challenge with acute-phase kinetics. It is also expressed in the absence of immune challenge during metamorphosis. These and other data on the Drosophila defensin gene lead us to suggest that insect and mammalian defensins have evolved independently.
Toombak: a major risk factor for cancer of the oral cavity in Sudan.
BACKGROUND: Snuff dipping as practiced in North America and Western Europe is causally associated with cancer of the oral cavity and pharynx. In the Sudan, natives use local Nicotiana rustica, a tobacco species with high levels of nicotine and nornicotine, to prepare their own snuff which they call toombak. The finely ground tobacco leaves are mixed with sodium bicarbonate, water is added, and a paste is made. The resulting "saffa" is placed in the oral vestibule where it remains up to several hours. In general, a saffa is replaced 10-30 times per day. METHODS: A cross-sectional survey was initiated for establishing the extent of toombak dipping in the Northern Sudan. Using earlier published methods, toombak and the saliva of toombak dippers were analyzed for the major carcinogens, the nicotine- and nornicotine-derived tobacco-specific N-nitrosamines. RESULTS: Survey data on the use of toombak in the Nile Province in the Northern Sudan encompass 2,000 households with 5,500 adults. About 40% of the males dip toombak, including 9% who are also cigarette smokers. The toombak habit is especially prevalent (> 45%) among males ages 40 years or older. Among women, toombak use is popular only in the older age groups, where up to 10% engage in the habit, whereas cigarette smoking is uncommon (< 1.5%). So far, only one descriptive study has dealt with toombak dipping and oral cancer. Among 62 patients with oral cancer 50 were toombak users; the majority of these had tumors at the site of contact with the tobacco, or in adjacent areas. Chemical analytical studies revealed that toombak contains at least 100-fold higher concentrations of the tobacco-specific N-nitrosamines (TSNA) than US and Swedish commercial snuff brands. The TSNA are by far the most powerful and most abundant carcinogens in snuff. Their concentrations in the saliva of toombak dippers are about the same as those in a solution that had been assayed in rats by twice daily swabbing of the oral cavity and had induced tumors of the cheek and palate. CONCLUSION: The need for in-depth epidemiological studies and further laboratory research to prove that toombak chewing causes cancer is discussed. The data at hand point to the urgent need for educational programs and preventive measures against the use of toombak.
Fusion protein mediated prodrug activation (FMPA) in vivo.
A two component system, consisting of a fusion protein and an appropriate prodrug, suited to perform selective tumor therapy in vivo, is presented. The fusion protein, owing to its humanized carcinoembryonic antigen (CEA)-specific variable region, specifically binds to CEA-expressing tumors and has an enzymatic activity comparable to human beta-glucuronidase. The prodrug is a nontoxic glucuronide-spacer-derivative of doxorubicin decomposing to doxorubicin by enzymatic deglucuronidation. In vivo studies in nude mice bearing human CEA-expressing tumor xenografts revealed that 7 d after injection of 20 mg/kg fusion protein, a high specificity ratio (> 100:1) was obtained between tumor and plasma. Injection of 250 mg/kg of prodrug at d 7 resulted in tumor therapeutic effects superior to conventional chemotherapy without any detectable toxicity. These superior therapeutic effects that were observed using established human tumor xenografts can be explained by the approx 10-fold higher drug concentrations found in tumors of mice treated with fusion protein and prodrug than in those treated with the maximal tolerable dose of drug alone.
Stereo-EEG of interictal and ictal electrical activity of a histologically proved heterotopic gray matter associated with partial epilepsy.
Magnetic resonance imaging allows the identification of heterotopic gray matter (HGM) in medically intractable partial epilepsies. The relationships between HGM and the epileptogenic zone remain, however, unclear. In a case of a temporo-parietal epilepsy studied by stereo-EEG, interictal and ictal electrical activity of a temporal HGM were recorded, showing: (1) an intralesional electrical activity, (2) the possible presence of asynchronous spikes, and (3) an early but never initial, or isolated, involvement during ictal discharges. This suggests that the presurgical and surgical management of HGM must be guided, as for other lesions, by the coherence existing between ictal clinical and electrical features, and anatomical data.
Low ignition propensity cigarettes: smoke analysis for carcinogens and testing for mutagenic activity of the smoke particulate matter.
In 1990, more than 20% of the almost 5200 deaths from fires in the United States occurred in fires from cigarettes. This fact led to the investigation of cigarettes with low ignition propensity. 32 experimental cigarettes differing in tobacco, cigarette circumference and in cigarette paper were tested for ignition propensity. This communication reports the results of comparative analyses of smoke from two low-propensity experimental cigarettes, A and B, which differed only in the porosity and treatment of the paper, and of the smoke from a reference cigarette C and from two leading US commercial cigarettes D and E. Model cigarette A delivered higher smoke yields of total particulate matter (TPM), nicotine, CO and benzo[a]pyrene than the other four cigarettes, but had lower smoke yields of the carcinogenic, volatile, and tobacco-specific N-nitrosamines than cigarettes C, D and E. The TPM of cigarette A was less active as a frameshift mutagen in tests with Salmonella strain TA98 than was the TPM of cigarettes C, D and E. TPM of cigarette A was also less active as a frameshift mutagen in tester strain TA1538 than was the TPM of reference cigarette C. However, when the mutagenic potencies of the particulate matters were compared on a cigarette-to-cigarette basis, there were no significant differences between the TPM of the individual cigarettes. Replacing the conventional cigarette filter with a perforated filter may significantly reduce the smoke yield of cigarette A. If this can be achieved without changing the ignition propensity, detailed chemical-analytical analyses and in vitro and in vivo assays for toxicity, ciliatoxicity, mutagenic activity and carcinogenicity need to be obtained for the smoke of such a prototype cigarette.
Tobacco-specific N-nitrosamines and Areca-derived N-nitrosamines: chemistry, biochemistry, carcinogenicity, and relevance to humans.
Nicotine and the minor tobacco alkaloids give rise to tobacco-specific N-nitrosamines (TSNA) during tobacco processing and during smoking. Chemical-analytical studies led to the identification of seven TSNA in smokeless tobacco (< or = 25 micrograms/g) and in mainstream smoke of cigarettes (1.3 micrograms TSNA/cigarette). Indoor air polluted by tobacco smoke may contain up to 24 pg/L of TSNA. In mice, rats, and hamsters, three TSNA, N'-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), are powerful carcinogens; two TSNA are moderately active as carcinogens; and two TSNA appear not to be carcinogenic. The TSNA are procarcinogens, agents that require metabolic activation. The active forms of the carcinogenic TSNA react with cellular components, including DNA, and with hemoglobin (Hb). The Hb adducts in chewers and smokers serve as biomarkers for the uptake and metabolic activation of carcinogenic TSNA and the urinary excretion of NNAL as free alcohol and as glucuronide for the uptake of TSNA. The review presents evidence that strongly supports the concept that TSNA contribute to the increased risk for cancer of the upper digestive tract in tobacco chewers and for the increased risk of lung cancer, especially pulmonary adenocarcinoma, in smokers. The high incidence of cancer of the upper digestive tract especially among men on the Indian subcontinent has been causally associated with chewing of betel quid mixed with tobacco. In addition to the TSNA, the betel quid chewers are exposed to four N-nitrosamines that are formed during chewing from the Areca alkaloids, two of these N-nitrosamines are carcinogens. The article also reviews approaches toward the reduction of the carcinogenic potency of smokeless tobacco, betel quid-tobacco mixtures, and cigarette smoke. Although the safest way to reduce the risk for tobacco-related cancers is to refrain from chewing and smoking, modifications of smokeless tobacco and of cigarettes are indicated to lead to less toxic products. Another more recent approach for reducing the carcinogenic effect of tobacco products is the application of chemopreventive agents, primarily of micronutrients. Future aspects in tobacco carcinogenesis, especially as it relates to TSNA, are expected in the field of molecular biochemistry and in biomarker studies, with the goal of identifying those tobacco and betel quid chewers and tobacco smokers who are at especially high risk for cancer.
Assessment of chlorinated pesticides and polychlorinated biphenyls in adipose breast tissue using a supercritical fluid extraction method.
A precise and highly reproducible analytical method was developed for the assessment of organochlorinated pesticide and polychlorinated biphenyl residues in adipose tissue (> or = 50 mg). The method can be utilized for epidemiological studies on the significance of these environmental pollutants in the etiology of breast cancer. Supercritical fluid extraction (SFE) with CO2 and modified CO2 (addition of 5% dichloromethane) is employed to remove incurred pesticide residues from adipose tissues that have been surgically removed from breast cancer patients and controls. An alumina sorbent, placed in the extracting vessel together with a specimen, removes the bulk of co-extracted lipids; a subsequent purification of the SFE extracts by column chromatography on alumina removes the remaining traces of lipids that would interfere with the gas chromatographic analysis with electron capture detection. The method was tested by analyzing a Certified Reference Material 430 pork fat with known amounts of pesticide residues that are commonly found in fat or in foods with a high fat content. The recoveries of analytes ranged from 73.4% for endrin to 115% for alpha-, beta- and gamma-hexachlorocyclohexane, hexachlorobenzene and dieldrin, with standard deviations of 4-12% for individual analytes. The analysis of adipose tissue for organochlorinated compounds on the basis of this new method suggested that the pesticide levels were higher in breast cancer patients than in controls. However, the small number of samples analyzed in this study (n = 5, both groups) precludes definitive conclusions. The most abundant compounds in both cases and controls were p, p-DDE (379 +/- 286 and 160 +/- 149 p.p.b.) and PCB (223 +/- 145 and 124 +/- 65.7 p.p.b.), followed by the termiticide chlordane residues oxychlordane and transnonachlor.
Laser-induced ultracold Rb(5S1/2)+Rb(5P1/2) collisions.
Explore the source record for details and available documents.
Stereo-electroencephalography methodology: advantages and limits.
Since January 1990, 70 patients with medically intractable partial epilepsy underwent a stereo-EEG investigation in our center. We first described technical requirements, and gave an overview of the variety of the explored cerebral regions and implantation patterns realized, pointing out the low rate of morbidity (1.4%). The three-dimensional epileptogenic zone thus defined led to a tailored individualized surgical excision in 60 patients, while 9 are waiting for surgery and the remaining 1 has been excluded (1.4%). Conceptual and technical aspects of the stereo-EEG methodology were discussed in order to underline its peculiarities in the field of "depth recordings", and more generally among the broader group of "invasive" procedures.
Acute and long-term effects of subthalamic nucleus stimulation in Parkinson's disease.
In animal models of Parkinson's disease (PD), it is postulated that the excessive output from the subthalamic nucleus (STN) plays a critical role. Selective lesions or high frequency electrical stimulation of the STN can alleviate parkinsonian symptoms in MPTP-treated monkeys. We decided to carry out STN stimulation in patients suffering from severe akinetic forms of PD. After approval of the institutional ethical committee, we operated on a parkinsonian patient aged 51, suffering for 8 years from a strongly disabling akinetorigid form of PD, complicated by an on-off effect (Hoehn and Yahr stage 5 in the worst-off motor phase). Stereotactic surgery was done on one side under local anesthesia. The theoretical target was chosen according to stereotactic atlases, based on ventriculographic landmarks such as anterior and posterior commissures (AC and PC). The final position of the chronic electrodes was optimized using electrophysiological recording and stimulation along with clinical assessment and surface EMG of agonist and antagonist muscles of the examined limbs. A spontaneous increase in neuronal activity was recorded in an area located 2-4 mm under the level of the intercommissural plane, 10 mm from the midline, at mid-distance between AC and PC. Within the same place, a 130-Hz stimulation induced acute and reversible akinesia alleviation mainly on the contralateral limbs, comparable to that obtained with dopaminergic drugs. No dyskinesia, such as hemiballism, was induced by introduction of electrodes or by stimulation. Then a long-term quadripolar DBS Medtronic electrode was inserted in this area. Studies of the effects of chronic stimulation were extensively performed to determine the best spatiotemporal and electrical stimulation variables.(ABSTRACT TRUNCATED AT 250 WORDS)
[Therapeutic strategy in supratentorial glioma in adults].
Explore the source record for details and available documents.
[Young adults are doing research: a project from the nursing school of the Rudolfinerhaus in Vienna].
Explore the source record for details and available documents.