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PubMed1978

[Specific variability in the number of cells with X-chromatin in short-term buccal epithelium cultures from women following exposure to hormones at different phases in their individual diurnal biorhythm].

Changes in the number of cells with X- and K-chromatin were studied in the buccal epithelium of 4 women in vivo for 29 h, every 2--4 h, and similarly in cultures (3 h) with and without any hormone: ACTH, insulin, thyroxin. The biorhythm of the cells with X-chromatin (established by Kanyuka in 1973) both in vivo and ie vitro within the range of from 44 to 340 0/00 per 24 h was confirmed; individual variability of the mean heterochromatin index value (X-HClm) was revealed in vitro with and without any hormones. Cell incubation with hormones at the time of minimal X-HCl in vivo led to increase in the number of cells with X-chromatin within 3 h from 50 to 240 0/00, whereas incubation at the time of maximal X-HCl in vivo--to reduction from 190 to 70 0/00. It is suggested that the specific response to the hormones is preceded by the nonspecific tissue response, determined by its condition at the time of action (by the individual X-HCl biorhythm phase) and realized in the systemic reconstruction of the number of cells at various mitotic cycle phases. Stereotypic reaction was expressed in the changes in character of the nuclear chromatin sondensation; these processes were reversible.

Adrenocorticotropic Hormone↗
PubMed1985

Heterogeneous distribution of glycoconjugates in human kidney tubules.

Paraffin sections of normal human kidney were stained with a battery of ten lectin-horseradish peroxidase conjugates. Staining of proximal tubules revealed a relatively uniform distribution of glycoconjugates having bi- and/or triantennary N-linked sugar chains as well as terminal beta-galactose and alpha-fucose in all cells. In contrast, terminal alpha- and beta-galactose and alpha-fucose were localized in only some cells of the thin limbs, whereas N-linked sugar chains and terminal alpha-N-acetylgalactosamine occurred in all cells. In the ascending thick limbs, terminal alpha-N-acetylgalactosamine was found in some cells and N-linked sugar chains and terminal beta-galactose were present in all cells. The distal convoluted tubules contained N-linked oligosaccharides and terminal beta-galactose in all cells. Terminal alpha-N-acetylgalactosamine was found in some but not all profiles of distal convoluted tubules in a few kidneys. In the initial (connecting) segment of cortical collecting ducts, cells varied in their content of glycogen and glycoconjugates with terminal alpha- and beta-galactose, alpha-fucose and alpha-N-acetylgalactosamine, but cells in this segment evidenced uniform localization of N-linked sugar chains. A similar distribution of sugars occurred in the medullary ray segment of cortical collecting ducts, except for terminal beta-galactose which was present in all cells. In the medullary collecting ducts, there was also considerable cell-to-cell variation in the content and distribution of glycogen and glycoconjugates having N-linked sugar chains, terminal alpha-galactose, alpha-fucose, alpha-N-acetylgalactosamine, and the disaccharide galactose-(beta 1----3)-N-acetylgalactosamine. The content and distribution of glycoconjugates in the nephron varied only slightly between kidneys from different individuals, but individual variability was extensive in the collecting ducts. The reasons for these individual differences have not been determined, however. Cellular heterogeneity of glycosubstances within the different regions of the human kidney correlates with similar findings in other mammals and implies diverse functional roles for the various types of complex carbohydrates in the kidney.

Adolescent↗
PubMed1998

Genetic and dietary influences on urinary oxalate excretion.

Several genes contribute to the development of calcium oxalate nephrolithiasis as it is a polygenic disease. To explore the influence of genetic factors on oxalate excretion we have examined the distribution of oxalate excretions in 101 normal individuals who consumed self-selected diets. The distribution was apparently trimodal, consistent with the existence of three classes of oxalate excretors reflecting two allelic genes determining high and low oxalate excretion occurring with frequencies of 0.32 and 0.68 respectively. The pattern of inheritance in eight families was compatible with the expression of a pair of codominant alleles. A comparison of the distribution of excretory classes among the 101 normal individuals with that of 101 calcium oxalate stone formers suggests that high oxalate excretion may be associated with a 4-fold increased risk of stone disease and intermediate excretion with a 1.6-fold increase. Control of dietary factors influencing oxalate excretion apparently improved the discrimination between excretory classes in 17 individuals but the intra-individual variability in oxalate excretion was not reduced in four of nine individuals in whom this parameter was evaluated. More stringent dietary control than that applied in this study may be required before more extensive genotyping of individuals is attempted.

Adult↗
PubMed2005

Historical and other patterns of monomethyl and inorganic mercury in the Florida panther (Puma concolor coryi).

Since the late 1980s, elevated levels of mercury have been reported in the tissues of the Florida panther (Puma concolor coryi) from the Florida Everglades. The extent, degree, and length of time of mercury contamination in the Florida panther are unknown. The objective of this study was to determine the historical and other patterns of monomethyl and inorganic mercury in the Florida panther by analysis of mercury in panther hair from museum collections. In addition, this study evaluated the effects of preservation of skins on mercury concentrations in hair and the representativeness of museum collections for evaluating historical trends of contamination in the Florida panther. Hair from 42 Florida panther specimens collected from 1896 to 1995 was analyzed for both monomethyl and inorganic mercury. Monomethyl mercury (MMHg) and inorganic mercury (IHg) were found in all specimens. Monomethyl mercury in hair from untanned skins was significantly higher than MMHg in hair from tanned skins. For untanned specimens, the mean MMHg concentration in hair was 1.62 +/- 1.87 mug/g (range 0.11 to 6.68 mug/g, n = 16). Monomethyl mercury accounted for 88% of the total mercury in untanned Florida panther hair. No sexual or geographical differences were found. Although MMHg is generally stable in hair, the tanning process appears to reduce the amount of MMHg in hair. In addition, exogenous IHg contamination of the panther hair was found in museum specimens, especially in older specimens. The implication of these and other factors in interpreting results of museum studies is discussed. The presence of MMHg in panther hair since the 1890s indicates long-term and widespread exposure of the Florida panther to mercury. Levels of MMHg are significantly greater in the 1990s than the 1890s. When combined with field studies of mercury in the Florida panther, considerable individual variability is observed, reflecting short-term changes in exposure of individual panthers to mercury. Although museum specimens showed a significant increase in MMHg over the last 100 years, they did not show the magnitude of increase that field populations of Florida panthers did. A number of Florida panthers appeared to be at risk from mercury over their lifetimes, especially individuals from the early 1990s.

Animals↗
PubMed2001

Treatment options and future prospects for the management of eyelid malignancies: an evidence-based update.

PURPOSE: To provide evidence-based clinical recommendations for treatment options and future prospects for the management of common malignant eyelid tumors, including global ratings for the strength of published evidence supporting them. CLINICAL RELEVANCE: Approximately 5% to 10% of all skin cancers occur in the eyelid. Incidence studies indicate that basal cell carcinoma is the most frequent malignant eyelid tumor, followed by squamous cell carcinoma, sebaceous gland carcinoma, and malignant melanoma. Many therapeutic methods have been suggested to combat the morbidity and mortality associated with these lesions. LITERATURE REVIEWED: A MEDLINE and PubMed literature search (1966-1999) was conducted for English language abstracts and appropriate (selected) full-text references retrieved regarding treatment of malignant eyelid tumors. These sources then were used to prepare recommendations for patient care. Each recommendation was rated according to: (1) its importance in the care process and (2) the strength of evidence supporting the given recommendation. RESULTS: All recommendations were rated as level A (very important to patient-care outcome). For basal cell carcinoma, squamous cell carcinoma, and sebaceous gland carcinoma, the published evidence supporting two recommendations (Mohs' micrographic surgery or excision with frozen-section control) were graded as I (providing strong evidence in support of a recommendation). For sebaceous gland carcinoma, the recommendations also included conjunctival map biopsies. The published evidence supporting all other recommendations for these three eyelid tumors were graded II (substantial evidence in support of a recommendation), primarily because of the small numbers of patients in each clinical study. For malignant melanoma, the recommendation for therapy (i.e., excision with variable margins depending on tumor thickness) was based on published papers individually variably rated as I, II, and III, reflecting ongoing debate as to the best method of therapy. CONCLUSIONS: Published reports regarding the treatment of malignant eyelid tumors include a myriad of treatment options. The strongest evidence favors complete surgical removal using histologic controls for verifying tumor-free margins of excision.

Adenocarcinoma, Sebaceous↗
PubMed1998

The vestibulo-ocular reflex and angular displacement perception in darkness in humans: adaptation to a virtual environment.

The vestibulo-ocular reflex (VOR) and angular displacement perception were measured in 25 healthy humans in darkness before and after exposure to incoherent visual-vestibular stimulation (VVS): 45 min of repeated passive 180 degrees whole-body rotations around the vertical axis concurrent with only 90 degrees rotation in a visual virtual square room. Large inter-individual variability was observed for both VOR gain and turning estimates. The individual VOR gains were not correlated with perceived angles of rotation either before or after VVS. After VVS, the angular displacement perception decreased by 24+/-16% while the VOR gain did not change significantly. The results suggest that adaptive plasticity in turning perception and adaptive plasticity in VOR might be independent of one another.

Adaptation, Physiological↗
PubMed1999

The platelet level indicates the erythropoietic capacity for preoperative autologous blood donation.

UNLABELLED: The erythropoietic capacity for preoperative autologous blood donation (ECPABD) shows marked inter individual variability. This study was performed to evaluate factors useful to predict individual ECPABD from data available before the first donation. The subjects consisted of 74 adult patients who received autologous blood donation, with a mean of 61 +/- 12.8 yr (SD). We classified the patients into four groups using our criteria for evaluating the ECPABD and investigated the relationships among age, disease, pre-platelet count, and the rate of platelet increase. RESULTS: (1) Advanced age and the status of disease were not distinctly correlated with low ECPABD. (2) Patients with a high pre-platelet levels had a low ECPABD regardless of the haemoglobin. (3) Patients in which the platelet count increased in accordance with the level of collection exhibited low pre-platelet counts and high ECPABD. CONCLUSION: In patients with high pre-platelet levels, we reduced the amount collected, considered early use of recombinant human erythropoietin and reevaluated the application of autologous blood donation.

Adult↗
PubMed1998

Determination of free extracellular levels of methotrexate by microdialysis in muscle and solid tumor of the rabbit.

PURPOSE: To determine of the pharmacokinetic profile of methotrexate (MTX) in blood and extracellular fluid (ECF) of VX2 tumor and muscle in rabbits. METHODS: Microdialysis probes were inserted into VX2 tumor and in muscle tissue. Following intravenous administration of MTX (30 mg/kg), serial collection of arterial blood samples and dialysates of muscle and tumor ECF for 4 h was carried out. Quantitation of MTX and determination of free plasma concentrations was performed by fluorescence polarization immunoassay and ultrafiltration, respectively. Correlations were established between the unbound plasma and ECF MTX concentrations. RESULTS: Total and free plasma concentrations exhibited a parallel three exponential decay in both healthy and tumorigenic animals. Total clearance (8.9 vs 6.5 ml-1.min-1.kg-1) and volume of distribution (4.0 vs 2.9 l.kg-1), however, tended to decrease in the tumor-bearing group. The ECF/plasma AUC ratio equaled 14.2 +/- 8.8% in muscle and 23.9 +/- 15.9% in tumor. The concentration-time profile of muscle ECF MTX was parallel and highly correlated (r = 0.97) to that determined in plasma. In contrast, free MTX plasma levels were not correlated with tumor ECF concentrations (r = 0.564). CONCLUSIONS: In addition to the well-known pharmacological variability in the concentration-effect relationship, the important inter-individual variability in tumor exposure to MTX may partly explain that studies in patients with solid tumors have often failed to demonstrate firm correlations between MTX blood pharmacokinetics and the chemotherapeutic response.

Animals↗
PubMed2005

The SPINK1 N34S mutation is not associated with Type 2 diabetes mellitus in a population of the USA.

AIMS: Mutations in the serine protease inhibitor (SPINK1) gene have been associated with all forms of chronic pancreatitis. Recently, an association of SPINK1 mutations with early-onset Type 2 diabetes mellitus has been reported in patients from Bangladesh. Therefore, we determined the frequency of SPINK1 N34S mutations in patients with Type 2 diabetes mellitus from the USA. METHODS: The study population of Hispanic and non-Hispanic white people consisted of 387 patients with Type 2 diabetes and familial clustering of the disease, 232 family members without diabetes, 259 patients with Type 2 diabetes without a family history, and 302 ethnically matched healthy controls as part of the San Luis Valley Diabetes Study. We performed linkage- and association-analysis in 82 multiplex families with Type 2 diabetes mellitus. RESULTS: No significant linkage or allele sharing was detected between Type 2 diabetes mellitus and the SPINK1 locus. The frequency of the N34S mutation was determined by fluorescence polarization and was similar between patients (n = 14/387 patients with familial clustering; n = 2/259 patients without family history) and controls (n = 5/232 family members without diabetes; n = 10/302 individuals). Variables such as ethnicity, age of diabetes onset and percentage of individuals with impaired glucose tolerance did not differ significantly between carriers and homozygous normal individuals. CONCLUSION: The SPINK1 N34S mutation appears not to predispose Hispanic or non-Hispanic white people from the USA to the development of Type 2 diabetes mellitus.

Chronic Disease↗
PubMed1993

Beta-amyloid protein precursor and tau mRNA levels versus beta-amyloid plaque and neurofibrillary tangles in the aged human brain.

To learn whether or not the levels of beta-amyloid protein precursor (APP) and tau mRNAs are related to the formation of beta-amyloid and neurofibrillary tangles, we quantified these mRNA levels in three cortical regions of 38 aged human brains, which were examined immunocytochemically for beta-amyloid and tangles. Marked individual variabilities were noted in APP and tau mRNA levels among elderly individuals. The mean APP mRNA level was slightly reduced in the beta-amyloid plaque (+2) group, but not in the plaque (+) group, compared to the plaque (-) group. Some brains in the plaque (-) group showed increased APP expression, the extent of which was not seen in the plaque (+) or (+2) group. The differences in the mean tau mRNA levels were not statistically significant among the tangle (-), (+), and (+2) groups. These results show that beta-protein and tau deposition do not accompany increased expression of the APP and tau genes, respectively, and thus suggest that factors other than gene expression may be at work in the progression of beta-amyloid and/or tangle formation in the aged human brain.

Aged↗
PubMed1994

[Ethnic factors in evaluation of drug efficacy and safety].

Ethnic difference is considered to be a major barrier in world-wide drug development. There seem to be many ethnic factors, genetic, environmental and cultural differences. There exists genetic polymorphism in drug metabolism especially for N-acetylation, debrisoquine hydroxylation and S-mephenytoin hydroxylation. The frequency of slow acetylator, poor metabolizer of debrisoquine and S-mephenytoin are 10%, less than 1% and 20% in Japanese and 50%, 10% and 5% in Caucasians respectively. Clinical responses and adverse effect of drugs are associated with these phenotypes. A retrospective study was conducted to determine whether inter-ethnic pharmacokinetic difference is larger than intra-ethnic variability. Individual pharmacokinetic parameters for most drugs were found to be extremely variable, but similarities of pharmacokinetic parameters were observed for Cmax and AUC between Japanese and other races. The results suggest that intra-ethnic variability is larger than inter-ethnic difference. The knowledge of genetic polymorphisms must find its way into clinical practice in order to achieve rational drug therapy that is more effective and safer for the benefit of the patient.

Drug Evaluation↗
PubMed2001

Bogalusa Heart Study: a long-term community study of a rural biracial (black/white) population.

The Bogalusa Heart Study, a long-term population study with a continued relationship with a community, addresses the problem of capacity building in minority health research. The study was originally funded as a Specialized Center of Research-Arteriosclerosis (SCOR-A) by the National Heart Lung and Blood Institute (NHLBI). These centers were to conduct research on atherosclerosis, coronary artery disease (CAD), hypertension, diabetes mellitus, and complications of cardiovascular-renal disease as the major causes of deaths in the United States. From earlier research on atherosclerosis, we became interested in the underlying characteristics in early life that would eventually lead to clinical morbidity and mortality from heart disease. An observation at autopsy showed the degree of atherosclerotic involvement in human aortas, from young to older individuals (Figure 1). For example, at age 40 years, marked individual variability occurred in the severity and involvement with atherosclerotic disease. Some individuals showed very little disease, while almost 70% of the surface was diseased in others. Further studies on arterial wall matrix showed aortas from young individuals varied with the extent of disease and its chemical composition. This background stimulated an interest in studying children for early clinical evidence of major adult heart diseases. The Bogalusa Heart Study was begun in 1972 as an epidemiology study of cardiovascular risk factors in children and adolescents; it eventually evolved into observations of young adults. Bogalusa, LA, is a biracial (black/white) rural community 70 miles north of New Orleans, comparable to many other communities in southeastern United States.

Adolescent↗
PubMed2001

Bogalusa Heart Study: a long-term community study of a rural biracial (Black/White) population.

The Bogalusa Heart Study, a long-term population study with a continued relationship with a community, addresses the problem of capacity building in minority health research. The study was originally funded as a Specialized Center of Research-Arteriosclerosis (SCOR-A) by the National Heart Lung and Blood Institute (NHLBI). These centers were to conduct research on atherosclerosis, coronary artery disease (CAD), hypertension, diabetes mellitus, and complications of cardiovascular-renal disease as the major causes of deaths in the United States. From earlier research on atherosclerosis, we became interested in the underlying characteristics in early life that would eventually lead to clinical morbidity and mortality from heart disease. An observation at autopsy showed the degree of atherosclerotic involvement in human aortas, from young to older individuals (Figure 1). For example, at age 40 years, marked individual variability occurred in the severity and involvement with atherosclerotic disease. Some individuals showed very little disease, while almost 70% of the surface was diseased in others. Further studies on arterial wall matrix showed aortas from young individuals varied with the extent of disease and its chemical composition. This background stimulated an interest in studying children for early clinical evidence of major adult heart diseases. The Bogalusa Heart Study was begun in 1972 as an epidemiology study of cardiovascular risk factors in children and adolescents; it eventually evolved into observations of young adults. Bogalusa, LA, is a biracial (black/white) rural community 70 miles north of New Orleans, comparable to many other communities in southeastern United States.

Adolescent↗
PubMedDate not supplied

Genetic influences in individual susceptibility to noise: a review.

Individual animals and humans show differing susceptibility to noise damage even under very carefully controlled exposure conditions. This difference in susceptibility may be related to unknown genetic components. Common experimental animals (rats, guinea pigs, chinchillas, cats) are outbred-their genomes contain an admixture of many genes. Many mouse strains have been inbred over many generations reducing individual variability, making them ideal candidates for studying the genetic modulation of individual susceptibility. Erway et al. (1993) demonstrated a recessive gene associated with early presbycusis in the C57BL/6J inbred mouse. A series of studies have shown that mice homozygous for Ahl allele are more sensitive to the damaging effects of noise. Recent work has shown that mice homozygous for Ahl are not only more sensitive to noise, but also are probably damaged in a different manner by noise than mice containing the wild-type gene (Davis et al., 2001). Recent work in Noben-Trauth's lab (Di Palma et al., 2001) has shown that the wild-type Ahl gene codes for a hair cell specific cadherin. Cadherins are calcium dependent proteins that hold cells together at adherins junctions to form tissues and organs. The cadherin of interest named otocadherin or CDH23, is localized to the stereocillia of the outer hair cells. Our working hypothesis, suggests that otocadherin may form the lateral links between stereocilia described by Pickles et al (1989). Reduction of, or missing otocadherin weakens the cell and may allow stereocilia to be more easily physically damaged by loud sounds and by aging.

Aging↗
PubMedDate not supplied

[Metabolism of beta-adrenergic substances. Therapeutic implications].

The metabolism of the main beta-adrenoceptor stimulants which are not catechol derivatives involves conjugation with glucuronic or sulphuric acids in several animal species and conjugation with sulphuric acid in man. These drugs are not metabolized by MAO like isoproterenol or by COMT like the catechol derivatives: isoproterenol, trimetoquinol, hexoprenaline and rimiterol. Sulphate conjugation, in man, increases with the number of hydroxy groups. For salbutamol, pirbuterol, terbutaline and fenoterol, about 30%, 30%, 15% and 10% are respectively present in plasma as the unchanged active compound. Clenbuterol, a new specific beta 2-adrenoceptor stimulant, is a 4-amino-3,5 dichloro-benzene derivative and cannot be conjugated. It is cleared from the body mainly by the renal route (43% of the administered dose) and has eight minor metabolites, identical in several animal species and in man. Tulobuterol with no hydroxy substitute does not undergo conjugation, but is metabolized to 4-hydroxy tulobuterol. This metabolite is shown to be eight times more potent than tulobuterol. Metabolism depends greatly upon the route of administration: intravenous, subcutaneous, oral, by aerosol or instillation into the bronchial tree. Conjugation or COMT inactivation can take place in the gut wall (terbutaline), in lungs (isoproterenol, terbutaline, rimiterol) or by hepatic first-pass. These processes decrease the amount of drug reaching the blood and the receptor sites. Metabolism in the lung is important for ibuterol (terbutaline diisobutyrate), which is more lipophilic than terbutaline and spreads throughout tissues where it is hydrolyzed to active terbutaline. Biotransformations are determined by environmental or genetic factors and by the associated therapy and can change dramatically from one patient to another (interindividual variability) or for the same patient by multiple dosing (intra-individual variability). These differences in the rates of the metabolism can explain, partly, the differences observed in the response to beta-adrenoceptor stimulants by responder or non-responder patients. Decision about a therapeutic dosage regiment involves the choice of the drug, of the route of administration and of the dose. This choice is made on the basis of the dose/response relationship. In the kinetic approach, pharmacokinetic data obtained after a single dose facilitate the development of an appropriate dosage regimen.

Adrenergic beta-Agonists↗
PubMed1994

Abuse history and chronic pain in women: II. A multivariate analysis of abuse and psychological morbidity.

OBJECTIVE: To assess the potential role of childhood and adulthood physical and sexual abuse and complaints of chronic pain in accounting for psychiatric symptomatology in adult women. METHODS: We assessed sexual abuse, physical abuse, depression, anxiety, and somatization in 64 women with chronic pelvic pain, 42 women with chronic headache, and 46 women without chronic pain complaints. Using multiple regression analyses, we tested a model comprising sociodemographic, chronic pain, childhood sexual abuse and physical abuse, and adulthood sexual abuse and physical abuse variables in the prediction of depression, anxiety and somatization. RESULTS: This model significantly predicted all three outcomes. However, childhood sexual abuse was not significant in the prediction of any of the outcome variables, whereas childhood physical abuse was significant in the prediction of all three. Further, the adulthood abuse variable set contributed significantly to the prediction of somatization, and the individual variable of adulthood sexual abuse was predictive of anxiety. CONCLUSIONS: The relation observed between childhood sexual abuse and the outcomes of depression, anxiety, and somatization in women may be a function of its association with other forms of abuse, particularly childhood physical abuse. Further investigation is clearly needed of the nature of the relations between the various categories of abuse and psychological morbidity.

Adolescent↗
PubMedDate not supplied

Walking and bicycling: an evaluation of environmental audit instruments.

PURPOSE: This paper reviews existing environmental audit instruments used to capture the walkability and bikability of environments. The review inventories and evaluates individual measures of environmental factors used in these instruments. It synthesizes the current state of knowledge in quantifying the built environment. The paper provides health promotion professionals an understanding of the essential aspects of environments influencing walking and bicycling for both recreational and transportation purposes. It serves as a basis to develop valid and efficient tools to create activity-friendly communities. DATA SOURCES: Keyword searches identified journal articles from the computer-based Academic Citation Databases, including the National Transportation Library, the Web of Science Citation Database, and MEDLINE. Governmental publications and conference proceedings were also searched. STUDY INCLUSION AND EXCLUSION CRITERIA: All instruments to audit physical environments have been included in this review, considering both recreation- and transportation related walking and bicycling. Excluded are general methods devised to estimate walking and cycling trips, those used in empirical studies on land use and transportation, and research on walking inside buildings. DATA EXTRACTION METHODS: Data have been extracted from each instrument using a template of key items developed for this review. The data were examined for quality assurance among three experienced researchers. DATA SYNTHESIS: A behavioral model of the built environment guides the synthesis according to three components: the origin and destination of the walk or bike trip, the characteristics of the road traveled, and the characteristics of the areas surrounding the trip's origin and destination. These components, combined with the characteristics of the instruments themselves, lead to a classification of the instruments into the four categories of inventory, route quality assessment, area quality assessment, and approaches to estimating latent demand for walking and bicycling. Furthermore, individual variables used in each instrument to measure the environment are grouped into four classes: spatiophysical, spatiobehavioral, spatiopsychosocial, and policy-based. MAJOR CONCLUSIONS: Individually, existing instruments rely on selective classes of variables and therefore assess only parts of built environments that affect walking and bicycling. Most of the instruments and individual measures have not been rigorously tested because of a lack of available data on walking and bicycling and because of limited research budgets. Future instrument development will depend on the acquisition of empirical data on walking and bicycling, on inclusion of all three components of the behavioral model, and on consideration of all classes of variables identified.

Bicycling↗
PubMed1999

Biotransformation of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in freshly isolated human lung cells.

Metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was characterized in human lung cells isolated from peripheral lung specimens obtained from 12 subjects during clinically indicated lobectomy. NNK biotransformation was assessed in preparations of isolated unseparated cells (cell digest), as well as in preparations enriched in alveolar type II cells, and alveolar macrophages. Metabolite formation was expressed as a percentage of the total recovered radioactivity from [5-(3)H]NNK and its metabolites per 10(6) cells per 24 h. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was the major metabolite formed in all lung cell preparations examined, and its formation ranged from 0.50 to 13%/10(6) cells/24 h. Formation of alpha-carbon hydroxylation end-point metabolites (bioactivation) and pyridine N-oxidation metabolites (detoxification), ranged from non-detectable to 0.60% and from non-detectable to 1.5%/10(6) cells/24 h, respectively, reflecting a large degree of intercellular and inter-individual variability in NNK metabolism. Formation of the alpha-hydroxylation end-point metabolite 4-hydroxy-1-(3-pyridyl)-1-butanol (diol) was consistently higher in alveolar type II cells than in cell digest or alveolar macrophages (0.0146 +/- 0.0152, 0.0027 +/- 0.0037 and 0.0047 +/- 0.0063%/10(6) cells/24 h, respectively; n = 12; P < 0.05). SKF-525A was used to examine cytochrome P450 contributions to the biotransformation of NNK. SKF-525A inhibited keto reduction of NNK to NNAL by 85, 86 and 74% in cell digest, type II cells, and macrophages, respectively (means of 11 subjects, P < 0.05). Type II cell incubates treated with SKF-525A formed significantly lower amounts of total alpha-hydroxylation metabolites compared with type II cells without SKF-525A (0.0776 +/- 0.0841 versus 0.1694 +/- 0. 2148%/10(6) cells/24 h, respectively; n = 11; P < 0.05). The results of this first study examining NNK biotransformation in freshly isolated human lung cells indicate that NNK metabolism is subject to a large degree of inter-individual and intercellular variability, and suggest a role for P450s in human lung cell NNK metabolism. Both alveolar type II cells and alveolar macrophages may be potential target cells for NNK toxicity based on their alpha-carbon hydroxylation capabilities. In addition, carbonyl reduction of NNK to NNAL is SKF-525A sensitive in human lung cells.

Aged↗