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Biomedical subjects

D Hoffmann

Publications and source records attributed to D Hoffmann.

At least 55 records · Page 3Linked to original sources
PubMed1998

Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease.

BACKGROUND: In many patients with idiopathic Parkinson's disease, treatment with levodopa is complicated by fluctuations between an "off" period, when the medication is not working and the motor symptoms of parkinsonism are present, and an "on" period, when the medication is causing improved mobility, often accompanied by debilitating dyskinesias. In animal models of Parkinson's disease, there is overactivity in the subthalamic nucleus, and electrical stimulation of the subthalamic nucleus improves parkinsonism. We therefore sought to determine the efficacy and safety of electrical stimulation of the subthalamic nucleus in patients with Parkinson's disease. METHODS: We studied 24 patients with idiopathic Parkinson's disease in whom electrodes were implanted bilaterally in the subthalamic nucleus under stereotactic guidance with imaging and electrophysiologic testing of the location. Twenty were followed for at least 12 months. Clinical evaluations included the Unified Parkinson's Disease Rating Scale, a dyskinesia scale, and timed tests conducted before and after surgery, when patients were off and on medications. RESULTS: After one year of electrical stimulation of the subthalamic nucleus, the patients' scores for activities of daily living and motor examination scores (Unified Parkinson's Disease Rating Scale parts II and III, respectively) off medication improved by 60 percent (P<0.001). The subscores improved for limb akinesia, rigidity, tremor, and gait. In the testing done on medication, the scores on part III improved by 10 percent (P<0.005). The mean dose of dopaminergic drugs was reduced by half. The cognitive-performance scores remained unchanged, but one patient had paralysis and aphasia after an intracerebral hematoma during the implantation procedure. CONCLUSIONS: Electrical stimulation of the subthalamic nucleus is an effective treatment for advanced Parkinson's disease. The severity of symptoms off medication decreases, and the dose of levodopa can be reduced with consequent reduction in dyskinesias.

Activities of Daily Living↗
PubMed1998

Opposite motor effects of pallidal stimulation in Parkinson's disease.

We studied the effects--on parkinsonian signs, on levodopa-induced dyskinesias, and on levodopa response--of acute experimental high-frequency stimulation of the internal pallidum (GPi) during off-drug and on-drug phases. Thirteen quadripolar electrodes were evaluated in 8 patients with Parkinson's disease (PD). Stimulation of the most ventral contacts, lying at the ventral margin of or just below the GPi, led to pronounced improvement in rigidity and a complete arrest of levodopa-induced dyskinesias. The antiakinetic effect of levodopa was also blocked and the patients became severely akinetic. Stimulation of the most dorsal contacts, lying at the dorsal border of the GPi or inside the external pallidum, usually led to moderate improvement of off-drug akinesia and could also induce dyskinesias in some patients. When using an intermediate contact for chronic stimulation, a good compromise between these opposite effects was usually obtained, mimicking the effect of pallidotomy. We conclude that there are at least two different functional zones within the globus pallidus, at the basis of a different pathophysiology of the cardinal symptoms of PD. The opposite effects may explain the variable results of pallidal surgery reported in the literature and may also largely explain the paradox of PD surgery. A possible anatomical basis for these differential functional effects could be a functional somatotopy within the GPi, with the segregation of the pallidofugal fibers from the outer portion of the GPi, on one hand, forming the ventral ansa lenticularis and from the inner portion of the GPi, on the other hand, forming the dorsal lenticular fasciculus.

Apomorphine↗
PubMed1998

Inhibition of levodopa effects by internal pallidal stimulation.

We report three patients with bilateral GPi stimulation for stage 4 Parkinson's disease (PD) with severe levodopa-induced dyskinesias (LID). In all three it was possible to completely inhibit LID using high-stimulation parameters. Parallel to complete inhibition of LID, an inhibition of the anti-akinetic effect of levodopa was observed, whereas, at the same time, rigidity was markedly improved. GPi stimulation is adaptable over time, and stimulation parameters have to be programmed according to off- and on-period motor symptoms. The main interest of stimulation is the possibility of finding a compromise between LID alleviation in on-phase without loss of the beneficial motor effects and improvement in parkinsonism in off-phase. In some patients, residual dyskinesias have to be accepted so as not to aggravate on-period motor symptoms by a presumed overinhibition of basal ganglia outflow.

Antiparkinson Agents↗
PubMed1998

Treatment of tremor in Parkinson's disease by subthalamic nucleus stimulation.

The recent resurgent interest in functional surgery for the treatment of Parkinson's disease (PD) has focused on the effects on akinesia and levodopa-induced dyskinesia. Stimulation of the subthalamic nucleus (STN) improves akinesia and rigidity but its effects on tremor have not been studied. The objective of this study was to assess the efficacy of STN stimulation on tremor in patients with the complete parkinsonian triad with motor fluctuations. Of 27 consecutive patients with STN stimulation (26 bilateral), 15 exhibited tremor rated at least 2/4 according to item 20 (rest tremor) of the Unified Parkinson's Disease Rating Scale (UPDRS) in at least one limb. The mean preoperative tremor score was 11.3+/-5.6 in off-drug and 1.2+/-2.4 in on-drug conditions. The postoperative tremor scores at the last follow up (from 1-12 months) were 2.2+/-2.2 off-drug/on-stimulation and 0.2+/-0.4 on-drug/on-stimulation. Both rest and action tremors were improved in all patients. The UPDRS tremor score was reduced by 80%, rigidity score by 65%, and akinesia score by 51% on average. For the three symptoms, the stimulation effect was close to that induced before surgery by a suprathreshold dose of levodopa given in the morning. STN stimulation can be considered an interesting alternative to thalamic or internal pallidal surgery even in PD patients with severe high-amplitude tremor. In keeping with electrophysiological data in monkeys rendered parkinsonian by MPTP injections, our results emphasize the importance of the oscillation of a neuronal loop involving the STN in the pathophysiology of parkinsonian tremor.

Adult↗
PubMed1998

Long-term electrical inhibition of deep brain targets in movement disorders.

Stimulation of the thalamic nucleus ventralis intermedius (Vim) at high (130-Hz) frequency has been used over the last 8 years as a treatment in 134 patients with movement disorders (91 Parkinson's disease [PD], 23 essential tremor [ET], 21 various dyskinesias and dystonias, including four multiple sclerosis [MS]), implanted with long-term electrodes connected to a programmable stimulator. In PD patients, tremor was selectively suppressed for < or = 11 years. In ET patients, results were satisfactory, but in 35% of the cases deteriorated with time, when tremor had an action component. Other types of dyskinesias were much less influenced. Sixty-eight patients were bilaterally implanted, and 14 were implanted contralateral to a previous thalamotomy. Side effects were often minor, well tolerated, and immediately reversible. Three secondary scalp infections led to temporary removal of implanted material. There was no permanent morbidity. Long-term Vim stimulation, which is reversible, adaptable, and well tolerated, even by bilaterally operated-on (68 of 134) and by elderly patients, should replace thalamotomy in the regular surgical treatment of parkinsonian and essential tremors. More recently, we stimulated the subthalamic nucleus (STN) in 51 patients (44 bilateral) and the globus pallidus internus (GPi) in 12 patients (seven bilateral). STN stimulation has a spectacular effect on akinesia and rigidity and may improve the patients so as to maintain them all day at a level similar to their best "on" periods. A 30-50% reduction in drug dosage was possible in most of the patients. GPi stimulation has indications and effects similar to those of pallidectomy: abnormal involuntary movements are totally suppressed, whereas effects on akinesia and rigidity are not so important as they are with STN stimulation. For all three targets, morbidity is low and reversible, even when bilateral implantations are performed. The deep-brain stimulation method has now proved its safety as compared with ablative surgery and is able to provide a significant improvement to these severely disabled patients. Long-term follow up is establishing the security of the method, which should be considered in earlier stages of the disease actively to participate to rehabilitation.

Electric Stimulation↗
PubMed1998

[Robotics in neurosurgery: current status and future prospects].

Neurosurgery is in essence a field of application development for robots, based on multimodal image guidance. Specific motorized tools have already been developed and routinely applied in stereotaxy to position a probe holder or in conventional neurosurgery to hold a microscope oriented towards a given target. The potentialities of these approaches have triggered industrial developments which are now commercially available. These systems use databases, primarily coming from multimodal numerical images from X-ray radiology to magnetic resonance imaging. These spatially encoded data are transferred through digital networks to workstations where images can be processed and surgical procedures are pre-planned, then transferred to the robotic systems to which they are connected. We have been using a stereotaxic robot since 1989 and a microscope robot since 1995 in various surgical routine procedures. The future of these applications rely mainly on the technical progress in informatics, about image recognition to adapt the pre-planning to the actual surgical situation, to correct brain shifts (for instance), about image fusion, integrated knowledge such as brain atlases, as well as virtual reality. The future developments, covering surgical procedure, research and teaching, are sure to be far beyond our wildest expectations.

Forecasting↗
PubMed1998

Biosynthesis of the ansamycin antibiotic rifamycin: deductions from the molecular analysis of the rif biosynthetic gene cluster of Amycolatopsis mediterranei S699.

BACKGROUND: The ansamycin class of antibiotics are produced by various Actinomycetes. Their carbon framework arises from the polyketide pathway via a polyketide synthase (PKS) that uses an unusual starter unit. Rifamycin (rif), produced by Amycolatopsis mediterranei, is the archetype ansamycin and it is medically important. Although its basic precursors (3-amino-5-hydroxy benzoic acid AHBA, and acetic and propionic acids) had been established, and several biosynthetic intermediates had been identified, very little was known about the origin of AHBA nor had the PKS and the various genes and enzymes that modify the initial intermediate been characterized. RESULTS: A set of 34 genes clustered around the rifK gene encoding AHBA synthase were defined by sequencing all but 5 kilobases (kb) of a 95 kb contiguous region of DNA from A. mediterranei. The involvement of some of the genes in the biosynthesis of rifamycin B was examined. At least five genes were shown to be essential for the synthesis of AHBA, five genes were determined to encode the modular type I PKS that uses AHBA as the starter unit, and 20 or more genes appear to govern modification of the polyketide-derived framework, and rifamycin resistance and export. Putative regulatory genes were also identified. Disruption of the PKS genes at the end of rifA abolished rifamycin B production and resulted in the formation of P8/1-OG, a known shunt product of rifamycin biosynthesis, whereas disruption of the orf6 and orf9 genes, which may encode deoxysugar biosynthesis enzymes, had no apparent effect. CONCLUSIONS: Rifamycin production in A. mediterranei is governed by a single gene cluster consisting of structural, resistance and export, and regulatory genes. The genes characterized here could be modified to produce novel forms of the rifamycins that may be effective against rifamycin-resistant microorganisms.

Actinobacteria↗
PubMed1998

A structural role for glycosylation: lessons from the hp model.

BACKGROUND: Protein glycosylation, the covalent attachment of carbohydrates, is very common, but in many cases the biological function of glycosylation is not well understood. Recently, fluorescence energy transfer experiments have shown that glycosylation can strongly change the global conformational distributions of peptides. We intend to show the physical mechanism behind this structural effect using a theoretical model. RESULTS: The framework of the hp model of Dill and coworkers is used to describe peptides and their glycosylated counterparts. Conformations are completely enumerated and exact results are obtained for the effect of glycosylation. On glycosylation, the model peptides experience conformational changes similar to those seen in experiments. This effect is highly specific for the sequence of amino acids and also depends on the size of the glycan. Experimentally testable predictions are made for related peptides. CONCLUSIONS: Glycans can, by means of entropic contributions, modulate the free energy landscape of polypeptides and thereby specifically stabilize polypeptide conformations. With respect to glycoproteins, the results suggest that the loss of chain entropy during protein folding is partly balanced by an increase in carbohydrate entropy.

Amino Acid Sequence↗
PubMed1998

Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson's disease.

The aim of this study was to compare, retrospectively, the value of chronic bilateral stimulation of the internal globus pallidus (GPi) and the subthalamic nucleus (STN) in patients with young onset Parkinson's disease. We selected 13 consecutive patients with similar characteristics at the time of surgery: age at onset < 40 years, disabling motor fluctuations (Hoehn and Yahr stage 4 or 5 in off-drug phases) and levodopa-induced dyskinesias (LID). Eight patients were operated on in the STN and five in the GPi. The Unified Parkinson's Disease Rating Scale (UPDRS), timed motor tests and a LID scale were compared in on- and off-drug conditions before surgery and 6 months after surgery on stimulation using the chronic electrical parameters found to improve best the motor state of the individual patient, without adverse effects. In off-drug phases, the motor score of the UPDRS was improved by 71% with STN stimulation and by 39% with GPi stimulation on average. This difference was statistically significant (P < 0.05). Whereas rigidity and tremor showed good improvement in both groups, the decrease in the akinesia score was more pronounced in the STN group. In the STN group, the improvement of all motor symptoms was very close, or equal, to the best levodopa response. Thus the levodopa test was predictive of outcome. The improvement in off-drug period motor handicap allowed a decrease in the levodopa-equivalent dose only in the STN group (-56%). The voltage, frequency and pulse width used for chronic stimulation were lower in the STN group. In the on-drug phases there was a marked improvement in LID in the GPi group, as measured by the dyskinesias score during an acute levodopa test, whereas there was only a small decrease in the STN group (P < 0.05). However, in the long term, the reduction of levodopa dosage in the STN group led to an indirect reduction of LID similar to that in the GPi group during activities of everyday life. In conclusion, the overall results favour the neurosurgical treatment of Parkinson's disease by stimulating the STN rather than the GPi.

Adult↗
PubMed1997

Risk of squamous cell carcinoma and adenocarcinoma of the lung in relation to lifetime filter cigarette smoking.

BACKGROUND: Over the past few decades, the incidence of adenocarcinoma (AC) of the lung increased much more rapidly than that of squamous cell carcinoma (SCC) in men and women. During this time period, filter cigarettes with substantially reduced "tar" and nicotine yields in the smoke came to dominate the market. METHODS: The risk of SCC and AC in lifelong smokers of filter cigarettes relative to lifelong nonfilter cigarette smokers was assessed in a case-control study performed between 1977 and 1995 with 2292 lung carcinoma patients and 1343 hospital controls who were current smokers. RESULTS: Odds ratios (OR) for SCC in male and female subjects who had smoked filter cigarettes exclusively during their lives were slightly reduced relative to lifetime nonfilter cigarette smokers in men (OR = 0.8; 95% confidence interval [CI], 0.5-1.2), and significantly reduced in women (OR = 0.4; 95% CI, 0.2-0.8). No reduction in risk was observed for AC of the lung in men or women. CONCLUSIONS: Evidence that the increasing predominance of AC over SCC may be due in part to the reduced risk of SCC (but not AC) associated with lifelong filter cigarette smoking is strongest in women; for men, further studies that include larger numbers of lifetime filter smokers are needed to confirm this finding. A lack of protection against AC from low yield filter cigarettes may result from smokers' "compensating" with deeper and more frequent inhalation, thereby increasing delivery of carcinogens to the peripheral lung. The smoke of modern cigarettes also contains higher concentrations of nitrosamines that primarily produce AC.

Adenocarcinoma↗
PubMed1997

Identification of tobacco-specific carcinogen in the cervical mucus of smokers and nonsmokers.

BACKGROUND: In 1996, an estimated 15,700 new cases of cancer of the uterine cervix and 4,900 deaths from this disease were expected to occur in the United States. In a recent international study, human papillomavirus DNA was found in more than 90% of cervical tumor specimens examined, irrespective of the nationality of the patients from whom the samples were obtained. Although infection with human papillomavirus is the major known risk factor for the development of cervical cancer, it alone is not sufficient. Other etiologic factors that have been associated with this disease include deficiencies in micronutrients, lower socioeconomic status, oral contraceptive use, and cigarette smoking. Several compounds from cigarette smoke (nicotine and its major metabolite, cotinine) have been identified in cervical mucus, and the occurrence of smoking-related DNA damage in the cervical epithelium has been documented. PURPOSE: This investigation was conducted to determine for the first time whether carcinogenic tobacco-specific N-nitrosamines are present in the cervical mucus of cigarette smokers and of nonsmokers (most likely as a result of environmental exposure). METHODS: Cervical mucus specimens from 15 smokers and 10 nonsmokers were subjected to supercritical fluid extraction with the use of carbon dioxide that contained 10% methanol, and the resultant extracts were analyzed for tobacco-specific nitrosamines by use of a very sensitive method that involved gas chromatography and mass spectroscopy analyses. RESULTS: In a total of 16 samples obtained from 15 women who were current smokers (two samples from the same woman), we detected the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) at concentrations that ranged from 11.9 to 115.0 ng/g of mucus. Only one of a total of 10 cervical mucus specimens obtained from 10 women who claimed to be nonsmokers did not contain detectable NNK, and NNK concentrations ranged from 4.1 to 30.8 ng/g of mucus in the specimens from the remaining nine women. The concentrations of NNK in specimens from cigarette smokers were significantly higher than those from nonsmokers (mean +/- standard deviation: 46.9 +/- 32.5 ng/g of mucus versus 13.0 +/- 9.3 ng/g of mucus; two-tailed Student's t test, P = .004). CONCLUSION: The cervical mucus of cigarette smokers contains measurable amounts of the potent carcinogen NNK. This compound represents the first tobacco-specific carcinogen identified in this physiologic fluid of women who smoke cigarettes. The presence of NNK in the cervical mucus of nonsmokers is likely due to environmental exposure or to the fact that some of the subjects in this study may not have revealed that they occasionally smoked cigarettes. IMPLICATIONS: The presence of NNK in human cervical mucus further strengthens the association between cervical cancer and tobacco smoking.

Adult↗
PubMed1997

A study of tobacco carcinogenesis, LIII: carcinogenicity of N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mink (Mustela vison).

In an earlier study, young male and female mink (Mustela vison) were found to be highly susceptible to the carcinogenic effect of N'-nitrosonornicotine (NNN). In this follow-up study we tested (i) the importance of the age of the animals with regard to the carcinogenic effect of NNN, (ii) the carcinogenic activity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and (iii) the combined carcinogenic effect of NNN plus NNK. (I) In the previous study, the latency of nasal tumor induction by NNN (11.9 mM) averaged 84 +/- 40 weeks upon twice weekly applications, starting at the age of 3 weeks and continuing for 38 weeks. In this bioassay, giving NNN in 28 weeks but starting at the age of 3 months, it took, on the average, 97 +/- 29 weeks to induce malignant nasal tumors, primarily esthesioneuroepithelioma with invasion of the brain. (ii) NNK (6.3 mM), given by s.c. injection, induced nasal carcinoma with invasion of the forebrain after 77 +/- 39 weeks. (iii) NNN (11.9 mM) plus NNK (6.3 mM) led to the same type of carcinoma but at an accelerated pace, namely after 71 +/- 57 weeks. This study supports the earlier observation that tobacco-specific N-nitrosamines induce malignant tumors of the nasal cavity with invasion of the brain, dependent to some degree on the age of the mink at first application. NNK appears to be a stronger carcinogen than NNN in mink which follows the observations made with mice, rats and hamsters. It is suggested that combined administration of NNN with NNK induces a stronger carcinogenic effect than NNN or NNK given alone.

Age Factors↗
PubMed1997

The changing cigarette, 1950-1995.

Nicotine is recognized to be the major inducer of tobacco dependence. The smoking of cigarettes as an advantageous delivery system for nicotine, accelerates and aggravates cardiovascular disease, and is causally associated with increased risks for chronic obstructive lung disease, cancer of the lung and of the upper aerodigestive system, and cancer of the pancreas, renal pelvis, and urinary bladder. It is also associated with cancer of the liver, cancer of the uterine cervix, cancer of the nasal cavity, and myeloid leukemia. In 1950, the first large-scale epidemiological studies documented that cigarette smoking induces lung cancer and described a dose-response relationship between number of cigarettes smoked and the risk for developing lung cancer. In the following decades these observations were not only confirmed by several hundreds of prospective and case-control studies but the plausibility of this causal association was also supported by bioassays and by the identification of carcinogens in cigarette smoke. Whole smoke induces lung tumors in mice and tumors in the upper respiratory tract of hamsters. The particulate matter of the smoke elicits benign and malignant tumors on the skin of mice and rabbits, sarcoma in the connective tissue of rats, and carcinoma in the lungs of rats upon intratracheal instillation. More than 50 carcinogens have been identified, including the following classes of compounds: polynuclear aromatic hydrocarbons (PAH), aromatic amines, and N-nitrosamines. Among the latter, the tobacco-specific N-nitrosamines (TSNA) have been shown to be of special significance. Since 1950, the makeup of cigarettes and the composition of cigarette smoke have gradually changed. In the United States, the sales-weighted average "tar" and nicotine yields have declined from a high of 38 mg "tar" and 2.7 mg nicotine in 1954 to 12 mg and 0.95 mg in 1992, respectively. In the United Kingdom, the decline was from about 32 mg "tar" and 2.2 mg nicotine to less than 12 mg "tar" and 1.0 mg nicotine per cigarette. During the same time, other smoke constituents changed correspondingly. These reductions of smoke yields were primarily achieved by the introduction of filter tips, with and without perforation, selection of tobacco types and varieties, utilization of highly porous cigarette paper, and incorporation into the tobacco blend of reconstituted tobacco, opened and cut ribs, and "expanded tobacco." In most countries where tobacco blends with air-cured (burley) tobacco are used, the nitrate content of the cigarette tobacco increased. In the United States nitrate levels in cigarette tobacco rose from 0.3-0.5% to 0.6-1.35%, thereby enhancing the combustion of the tobacco. More complete combustion decreases the carcinogenic PAH, yet the increased generation of nitrogen oxides enhances the formation of the carcinogenic N-nitrosamines, especially the TSNA in the smoke. However, all analytical measures of the smoke components have been established on the basis of standardized machine smoking conditions, such as those introduced by the Federal Trade Commission, that call for 1 puff to be taken once a minute over a 2-s period with a volume of 35 ml. These smoking parameters may have simulated the way in which people used to smoke the high-yield cigarettes; however, they no longer reflect the parameters applicable to contemporary smokers, and especially not those applicable to the smoking of low- and ultra-low-yield filter cigarettes. Recent smoking assays have demonstrated that most smokers of cigarettes with low nicotine yield take between 2 and 4 puffs per minute with volumes up to 55 ml to satisfy their demands for nicotine. The overview also discusses further needs for reducing the toxicity and carcinogenicity of cigarette smoke. From a public health perspective, nicotine in the smoke needs to be lowered to a level at which there is no induction of dependence on tobacco.

Benzopyrenes↗
PubMed1997

Trends in survival from colonic cancer: the impact of subspecialization.

BACKGROUND: Data from population-based registries have demonstrated a recent increase in case survival for colonic cancer which has been attributed to earlier diagnosis. The present study was performed to identify time trends in case survival for patients with colonic cancer in a single institution, and to identify factors associated with any such improvement. METHODS: Data regarding 1264 patients with colonic cancer who were diagnosed between January 1981 and December 1995 were obtained from the Royal Adelaide Hospital Cancer Registry. Prognostic factors examined were age, sex, Australian clinicopathologic stage (ACPS), differentiation and year of diagnosis. Survival analyses were performed using the Kaplan-Meier method, and differences between patient subgroups were tested using univariate and multivariate Cox analyses. Patterns of adjuvant therapy were stable throughout the study period. RESULTS: The study group comprised 1264 patients. Key independent predictors of case survival after controlling for covariables were found to be earlier-stage disease (P < 0.001), moderately or well differentiated tumours (P < 0.001), and more recently diagnosed tumours (P = 0.011). Specifically, the 5-year survival rates (+/- SE) increased from 40.3% (+/- 3.2) for 1981-83 to 48.3% (+/- 3.3) for 1984-86 and 51.6% (+/- 2.1) for 1987-95. This increase in case survival was temporally associated with the establishment of a specialty colorectal surgical unit within the Royal Adelaide Hospital. CONCLUSIONS: This study of patients with colonic cancer from a single institution confirms previously observed, population registry-based, increases in case survival over recent years. Such improvement was independent of trends in tumour stage and differentiation and the use of adjuvant therapies. This provides evidence that survival outcomes for colonic cancer are influenced by surgical expertise.

Australia↗
PubMed1997

Chemical composition and carcinogenicity of smokeless tobacco.

In the United States, smokeless tobacco (ST) is marketed as chewing tobacco and as oral snuff. During the past 15 years, consumption of chewing tobacco has declined by 30.6%, whereas snuff use has significantly increased, namely, by 51.8%. This increase is primarily due to the growing popularity of oral snuff use among teenage and young adolescent males. Chewing of tobacco is associated with an increased risk for oral cancer. Snuff dipping is causally and specifically associated with cancer of the cheek, gum, and pharynx. In laboratory animals, snuff induces cancer of the mouth. Several carcinogens have been identified in ST, the tobacco-specific N-nitrosamine (TSNA), N'-nitrosonornicotine (NNN), and 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) being the most important. NNN and NNK are formed from nicotine during curing, aging, and especially during fermentation of tobacco. Oral swabbing of a low concentration of a mixture of NNN plus NNK in water induces oral tumors in rats. The concentration of the strongly carcinogenic TSNA is higher in snuff than in other ST products. According to our analytical studies, the three leading snuff brands in the US (92% of the market) contain far higher concentrations of nicotine, unprotonated nicotine, and TSNA than the less popular brands. Thus, the leading US snuff brands are the strongest inducers of nicotine dependence and also have the highest carcinogenic potential.

Animals↗