Surgical strategies for patients with supplementary motor area epilepsy. The Grenoble experience.
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Adolescent↗
Biomedical subjects
D Hoffmann
Publications and source records attributed to D Hoffmann.
p53 mutations in head and neck squamous cell carcinomas from Sudanese snuff (toombak) users.
Toombak is a type of snuff used extensively in the Northern Sudan by a virtually non-smoking/nondrinking population. This Sudanese snuff contains inordinately high levels of the tobacco-specific nitrosamines (TSNAs) Nl-nitrosonornicotine (NNN) and (4-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These are considered to be major contributors to the induction of cancers of the aerodigestive tract in tobacco chewers, snuff dippers, and smokers. To determine if toombak use may be associated with the induction of mutations in the p53 tumor suppressor gene, we screened four head and neck squamous cell carcinomas (SCCs) obtained from three toombak-using patients and one non-toombak-using patient using polymerase chain reaction/single-stranded conformational polymorphism analysis and DNA sequencing. p53 mutations were found in tumors resected from two of three toombak-using patients, one at codon 282 (CGGarg-->TGGtrp) and the other in intron 6 (AT-->GC). No p53 mutations were observed in the tumor from the non-toombak-using patient. The observed mutations were similar in spectrum to those induced by nitrosamines in mouse lung tumors. No K-ras (codons 12 and 13) or H-ras (codon 12) mutations were found in any of the tumors. These results suggest that toombak components such as TSNAs may induce p53 mutations in head and neck SCCs and are likely contributors to the tobacco-induced carcinogenic load in humans.
Animals↗
[Relationship between anatomic lesions of the temporal lobe and temporal lobe epilepsy].
A structural lesion of the brain is a frequent finding in intractable partial epileptic patients. We analyse anatomo-electro-clinical characteristics of 58 patients in which MR showed a lesion inside the temporal lobe. They are 29 males and 29 females with a mean age at surgery of 23.5 +/- 10.7 years (2.6-45.9). The mean epilepsy duration is of 13.4 +/- 8 years (1.3-35.5), with a mean seizure frequency of 28.7 +/- 43.6 per month, with a great inter-individual variability (from 3 per month to 15 a day). The minimum follow-up is 3.5 years. A video-EEG monitoring was performed in 21 cases, while a stereo-EEG investigation was judged mandatory in 26. On the basis of anatomo-electro-clinical correlations and of the results of presurgical investigations, the epileptogenic area was proved to be temporal in 49 cases, temporal but controlateral to the lesion in 1, and at least bilobar in 8 patients.
Adolescent↗
[Characteristics of the global population].
We analyse clinical characteristics, presurgical investigations, surgical procedures and outcome of 137 patients operated-on for a drug-resistant partial epilepsy, in Grenoble from January 1990 to December 1993. Moreover we present data of 63 patients suffering from a "pure" temporal lobe epilepsy selected using the following criteria: 1. surgery limited to temporal lobe structures 2. totally cured after surgery (Engel's class la).
Adolescent↗
[Amblyopia from anisometropia without strabismus].
Fifty non-strabismic children with primary anisometropia were reviewed retrospectively. At entry, patients ranged in age from 1 to 10 years with an average of 4.5 years. The follow-up ranged from 0.5 to 9 years with an average of 3.5 years. Criteria for inclusion were a difference in refractive error between the two eyes of at least 1.00 D of spherical value and/or 0.75 D of cylindrical value. In all cases, anisometropia was totally corrected by prescribing glasses. Anisometropic amblyopia was considered to be present when isoacuity at far was not reached despite the glasses, part-time occlusion therapy of the good eye was prescribed. Amblyopia was present in 86% of the patients and was found with all types of anisometropia. It was more severe in anisohyperopia and/or anisoastigmatism. After adequate treatment, amblyopia was clinically cured or less severe in 78% of the patients.
Amblyopia↗
Five leading U.S. commercial brands of moist snuff in 1994: assessment of carcinogenic N-nitrosamines.
BACKGROUND: Moist snuff is the only tobacco product in the United States with increasing sales (an increase of 38.4% between 1981 and 1993) and with increased consumption, primarily by male adolescents aged 12-18 years old and young adults aged 19 years old or older. It is known from previous studies that levels of nicotine and the proportion of unprotonated (free) nicotine, as well as the pH, which affects nicotine delivery, vary considerably among the leading snuff brands. Whether concentrations of major carcinogens, such as the nicotine-derived tobacco-specific N-nitrosamines (TSNAs), like N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), also vary among these brands has not been determined previously. PURPOSE: Our purpose was threefold: 1) to determine the concentrations of major carcinogenic nicotine-derived N-nitrosamines in each of the five most popular moist snuff brands; 2) to analyze the quantitative differences in the various snuff components (e.g., NNN) between two major brand categories: a category comprising the brands known to have high levels of unprotonated nicotine (Copenhagen, Skoal fine cut, and Kodiak) versus a category comprising the brands known to have low levels (Hawken and Skoal Bandits); and 3) to compare the differences in the concentrations of nicotine (previously determined), NNN, NNK, and total TSNAs between these two major brand categories. METHODS: Three boxes of each of the five leading U.S. moist snuff brands were bought in July 1994 from retailers in six areas and transferred immediately to the analytical laboratory. After extraction, N-nitrosamino acids and TSNAs were determined on a gas chromatograph interfaced with a thermal energy analyzer (GC-TEA) and integrator. Each 5-g sample of ground, freeze-dried tobacco was extracted twice, and each extract was analyzed twice by GC-TEA. All P values reported are two sided. RESULTS: Copenhagen, Skoal fine cut, and Kodiak as a group had statistically significant higher levels of nicotine (P = .0017), NNN (P < .0001), NNK (P = .0119), and total TSNAs (P < .0001) than the Hawken and Skoal Bandits group. Concentrations (means +/- SD) of nicotine, NNN, NNK, and total TSNAs comparing the two major brand categories are as follows: nicotine--11.6 +/- 1.01 mg/g versus 6.96 +/- 3.62 mg/g (P = .0017), NNN--7.74 +/- 1.70 micrograms/g versus 4.17 +/- 1.35 micrograms/g (P < .0001), NNK--1.23 +/- 0.68 micrograms/g versus 0.61 +/- 0.41 micrograms/g (P = .0119), and total TSNAs--14.3 +/- 3.82 micrograms/g versus 6.3 +/- 2.56 micrograms/g (P < .0001). CONCLUSIONS: The three leading U.S. snuff brands (Copenhagen, Skoal fine cut, and Kodiak; making up 92% of the U.S. market) showed not only high levels of pH, nicotine, and unprotonated (free) nicotine, but also high concentrations of the strongly carcinogenic TSNAs in comparison with the fourth and fifth best selling moist snuff brands, Hawken and Skoal Bandits (3% of the U.S. market).
Carcinogens↗
Thermovoltage across a vacuum barrier investigated by scanning tunneling microscopy: Imaging of standing electron waves.
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Journal Article↗
The epidemiology of renal cell carcinoma. A second look.
BACKGROUND: From 1973 to 1991, the incidence of kidney cancer in the United States increased by 35.4%. METHODS: A multicenter, hospital-based case-control study was conducted from 1977 to 1993 through an interview of 788 patients with renal cell carcinoma and 779 control subjects. RESULTS: Compared with those who never smoked, the odds ratio (OR) for renal cell carcinoma among current cigarette smokers was 1.4 (95% confidence interval [CI] 1.02-2.0) for men and 1.1 (95% CI 0.7-1.6) for women. Among men, there was a rising trend in the odds ratios with increasing pack-years of smoking (P < 0.01) but not with the number of cigarettes smoked per day. The OR among those currently smoking nonfilter cigarettes exclusively was 2.4 (95% CI 1.2-4.9) for men and 2.0 (95% CI 0.4-11.1) for women. No increased risk was observed among current smokers of filter cigarettes. Among men, the OR associated with chewing tobacco was 3.2 (95% CI 1.1-8.7). Total alcohol consumption was unrelated to the risk of renal cell carcinoma. A joint effect was observed among subjects with a high body mass index who reported a history of hypertension (OR = 1.9, 95% CI 1.01-3.5) for men and 3.2 (95% CI 1.3-7.7) for women. CONCLUSION: High body weight and hypertension were related jointly to renal cell carcinoma. Smoking nonfilter cigarettes and long term cigarette smoking (> or = 30 years) was a predictor for renal cell carcinoma risk in men. No significant association was found between smoking and renal cell carcinoma in women.
Aged↗
Pharmacological characterization of a new 4-amidinophenyl-alanine thrombin-inhibitor (CRC 220).
The new thrombin inhibitor CRC 220 was characterized in vivo for its antithrombotic effects. CRC 220 led to a dose-dependent prolongation of clotting parameters as determined in rats, rabbits, dogs, sheeps, pigs and monkeys. We evaluated the efficacy of CRC 220 to prevent thrombus formation in arteries and in the microcirculation in different animal models. In a rabbit model of tissue factor-induced coagulation activation, infusion of 0.5 mg/kg x h CRC 220 (3 hours) led to a significant prevention of fibrinogen decrease. In a rat model of lethal LPS-induced DIC CRC 220 significantly prevented the mortality rate after a 4h-infusion of 0.75 mg/kg x h. Thrombin-induced platelet aggregation in rat lungs could be prevented by the i.v. bolus injection of CRC 220. A dose of 0.3 mg/kg leads to a reduction of more than 80% of platelet deposition in the lung, significant inhibition was still observed 90 minutes after CRC 220 administration; at this time the inhibitor had already been cleared from plasma. Arterial thrombosis was induced in rabbits by squeezing and stenosis of the A. carotis. The i.v. bolus administration of CRC 220 dose-dependently prevented thrombus formation, an ED50 of 0.03 mg/kg was calculated. This dose was associated with only a minor prolongation of aPTT.
Animals↗
Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation.
In monkeys rendered parkinsonian, lesions and electrical stimulation of the subthalamic nucleus reduce all major motor disturbances. The effect of electrical stimulation of the subthalamic nucleus was assessed in three patients with disabling akinetic-rigid Parkinson's disease and severe motor fluctuations. Quadripolar electrodes connected to a pulse generator were implanted in the subthalamic nuclei on both sides. Patients were evaluated with the unified Parkinson's disease rating scale and timed motor tests. 3 months after surgery, activities of daily living scores had improved by 58-88% and motor scores by 42-84%. This improvement was maintained for up to 8 months in the first patient operated upon. One patient was confused for 2 weeks after surgery, and another developed neuropsychological impairment related to a thalamic infarction which improved over 3 months. In one patient, stimulation could induce ballism that was stopped by reduction of stimulation. This is the first demonstration in human beings of the part played by the subthalamic nuclei in the pathophysiology of Parkinson's disease.
Electric Stimulation Therapy↗
Bilateral subthalamic nucleus stimulation for severe Parkinson's disease.
Subthalamic nucleus (STN) lesions or high-frequency stimulations could improve parkinsonian symptoms in monkeys treated by MPTP. We have applied the procedure of chronic stimulation to the STN in severely disabled parkinsonian patients. This article presents the case of the first patient operated on bilaterally. Bilateral STN stimulation has greatly improved akinesia and rigidity. The benefit was maintained < or = 15 months after surgery. Unilateral stimulation induced motor effects mainly in contralateral limbs. Further studies are needed to evaluate the value of this procedure in the treatment of Parkinson's disease.
Antiparkinson Agents↗
1H MRS of human brain abscesses in vivo and in vitro.
Five patients, each with a brain abscess, were examined by means of 1H MR spectroscopic imaging in vivo. The aspirated pus was analyzed in vitro by means of 1D and 2D COSY 1H MRS. In addition to resonance lines from compounds (lactate, alanine and lipids) often found in the spectra from intracranial tumors, resonance lines were detected from a number of markers of infectious involvement (acetate, succinate, and various amino acids). These results suggest that 1H MRS in vivo might contribute in establishing noninvasively a differential diagnosis between brain abscess and tumor.
Acetates↗
Tobacco consumption and lung cancer.
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Anticarcinogenic Agents↗
Role of the hypothalamic hamartoma in the genesis of gelastic fits (a video-stereo-EEG study).
Patients having a hypothalamic hamartoma frequently present epileptic attacks of laughter, and they later experience multiple additional seizure types, which invariably lead to a severe drug-resistant epilepsy. If this association is now well-known, relationships between the hypothalamic mass and the different types of seizures remain still mysterious. We report the case of a 16-year-old girl suffering from this peculiar epileptic picture, in whom a stereo-EEG study was performed, allowing us to record both the hamartoma, the neighboring hypothalamic structures, and other bilateral cortical areas. It showed that gelastic fits were strictly linked to ictal discharges which began and remained well localized in the hamartoma. Conversely, atonic seizures, which might result from a secondary epileptogenesis, admitted a widely extended bilateral frontal cortical origin, sparing the lesion, and slightly involving the posterior hypothalamus. Stereotactic radiosurgery of the hamartoma proved to be ineffective on both types of seizures, probably because of the too low dose of X-rays delivered (18 grays), as suggested by the absence of hypothalamic mass changes on MRI. Such data, never reported to our knowledge, seem able to contribute to a better understanding of this very peculiar epileptic syndrome, and perhaps to a better adapted therapeutic management.
Adolescent↗
Transepithelial transport properties of peptidomimetic thrombin inhibitors in monolayers of a human intestinal cell line (Caco-2) and their correlation to in vivo data.
Peptidomimetic thrombin inhibitors (TI), derived from L-Asp-D-Phe were examined in confluent monolayers of a human colon carcinoma cell line (Caco-2) to elucidate their transepithelial transport properties. Effect availabilities, based on activated partial thromboplastin time (aPTT) measurements in rats, after peroral administration of five TI correlated reasonably well with permeability coefficients obtained from in vitro transport studies in Caco-2 monolayers, whereas physicochemical properties, such as molecular mass, solubilities, pKa and octanol-buffer partition coefficients failed to yield meaningful relationships. Substitution of the beta-carboxylic group of L-Asp leads to analogues which are mainly transported by passive diffusion, while an unsubstituted carboxylic group favours carrier-mediated active transport. The effects of concentration, temperature, competitive inhibitors and direction dependence on in vitro transport were investigated. The results obtained are compatible with a saturable carrier-mediated transport, operating parallel to a passive paracellular route. The Michaelis-Menten parameters for the active transport component (Km = 1.67 mM, Vmax = 26.5 pmol min-1 mg protein-1) indicate an involvement of the intestinal di/tripeptide transport system for one of the TI. The Caco-2 transport model may be helpful for the design of perorally active peptidomimetics.
Biological Availability↗
Assessment of chlorinated pesticide residues in cigarette tobacco based on supercritical fluid extraction and GC-ECD.
It has been established that the organochlorinated compounds (OCC) DDT and DDE are xenoestrogens which influence both normal and neoplastic estrogen-responsive tissues. Therefore, it has been hypothesized that OCC contribute to the risk for breast cancer. Although the food chain has been recognized as a major source of human exposure to these compounds, tobacco and tobacco smoke were also considered as sources of exposure to OCC. This study was aimed at quantifying OCC in tobacco and cigarette smoke and at documenting changes in the concentrations of these pesticides in tobacco products since 1970 when OCC were banned for use on tobacco. To determine the levels of OCC residues on tobacco, we developed a new method based on superficial fluid extraction, followed by clean-up on an alumina column, and analysis by gas chromatography with electron capture detection. The detection limit for an individual OCC is 1 ng/g tobacco, the relative SD is < 10% for each analyte and the new method compares well with the standardized method that involves conventional organic solvent extraction. The major OCC determined in the tobaccos and in cigarette smoke of US commercial brands that were manufactured in the proceeding three decades were p.p'-isomers of DDD (1540-20 220 ng/g tobacco), DDT (720-13 390 ng) and DDE (58-730 ng). Since 1970, the concentrations of individual OCC in tobacco have gradually decreased by > 98%. The transfer rate from tobacco into mainstream smoke amounts to 22% for DDD, 19% for DDT and 27% for DDE. Today, the concentrations of the OCC in US tobacco are below the maximum permissible limits set by the Environmental Protection Agency. While until 1970 the OCC in tobacco and tobacco smoke contributed significantly to the bioaccumulation of the pesticides in smokers, at this time tobacco and cigarette smoke are a minor source of human exposure.
Chromatography, Gas↗
Self-regulation of smoking intensity. Smoke yields of the low-nicotine, low-'tar' cigarettes.
It has been assumed for some time that the 'tar' and nicotine data for individual cigarette brands, as reported by the Federal Trade Commission (FTC), do not adequately reflect the levels of exposure to toxic and carcinogenic agents in the smoke. The trend of decreasing 'tar' and nicotine yields of the sales-weighted average US cigarettes was not followed by a proportionate decline of lung cancer incidence and mortality rates. Utilizing a 'tobacco smoke inhalation testing system', we determined smoking profiles for four men and four women who smoked low-nicotine cigarettes ( < or = 0.8 mg/cigarette according to FTC), and for two men and two women who smoked cigarettes with medium-nicotine (0.9-1.2 mg) yields. The recorded smoking profiles were programmed into a smoking machine to establish mainstream smoke yields for 'tar', nicotine, benzo[a]pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. The analytical data obtained for each smoker's cigarette were compared with corresponding measurements in the smoke from the same cigarette brand that was generated by machine-smoking under the standardized FTC conditions (1 puff of 2 s duration and 35 ml volume drawn once/min). Significant increases in terms of total volume of smoke inhaled and exposures to 'tar', nicotine, and lung carcinogens were measured (2- to 4-fold) and, because of smokers' compensation for low nicotine delivery, much greater overall exposure resulted from smoking low-nicotine cigarettes. Although these measurements were obtained for a limited number of smokers, they strongly indicate that both low- and medium-nicotine cigarettes are being smoked much more intensely than would be implied from the FTC-data. Therefore, there is an urgent need to accurately quantify the exposure of consumers of the various types of cigarettes to toxic and carcinogenic agents.
Adult↗
Synthesis and characterisation of novel thrombin inhibitors based on 4-amidinophenylalanine.
Thrombin inhibitors have been thought to play a pivotal role in myocardial infarct and stroke incidences and their aftermath. Quite some time ago potent synthetic thrombin inhibitors became known based on peptide derivatives D-Phe-Pro-Arg and benzamidine. One of them, fairly well characterised was beta-naphthylsulphonylglycyl-D,L-4-amidino-phenylalanylpiperidi de (NAPAP). NAPAP was prone to being administered intravenously due to its short plasma half life. Drawbacks to this compound such as effects on histamine release and blood pressure may have obstructed its clinical use. Long half life and oral bioavailability would be desirable for prophylactic treatment of thrombotic disorders. We have used NAPAP as a template for new synthetic compounds to improve some characteristics of its profile. For screening purposes we have investigated fairly simple surrogate parameters, aspects that were considered to contribute to pharmacological effects. Potency was correlated to thrombin inhibition, side effects were addressed by specificity toward thrombin as well as reduction in basicity, and plasma half life was considered to be modulated by plasma stability of the compound. Oral bioavailability would be affected by instability during the passage through the gut wall. Chemical introduction of a carboxylic group and exchange of the naphthyl group for 4-methoxy-2,3,6-trimethylphenyl led to a compound that when compared to NAPAP, exhibited a 4-fold increase in thrombin inhibitory activity and a 3-fold increase in trypsin specificity. Plasma stability decreased to 22 h, however, sufficient enough not to play a major role in plasma half life. Gut homogenate stability of the compound has not changed. The potency increase did not translate into a reduction in IC50-values for the coagulation assay aPTT and TT, in contrast to the IC50-values for thrombin-induced platelet aggregation.
Antithrombins↗