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Spice extracts as dose-modifying factors in radiation inactivation of bacteria.

Three spices, chili, black pepper, and turmeric, were tested for the effect of their aqueous extracts on the sensitivity of three bacteria, Escherichia coli, Bacillus megaterium, and Bacillus pumilusspores, to gamma-radiation. It was found that the extracts of the three spices offered protection to these organisms against inactivation by gamma-radiation. These spice extracts were also tested for their protection of naked plasmid DNA. Radiation-induced degradation of plasmid pUC18 DNA was reduced in the presence of the spice extracts. The maximum protection was offered by the chili extract followed by that of black pepper and turmeric. The two known antioxidants, curcumin and piperine from turmeric and black pepper, respectively, were shown to protect the plasmid DNA from the degradation by gamma-radiation. Experiments with the plasmid pUC18 DNA indicated that the spice extracts probably protected microorganisms by protecting their DNA. These studies indicated the importance of spices among ingredients in food as dose-modifying factors during radiation processing.

Alkaloids↗

Gonadotropins are essential modifier factors for gonadal tumor development in inhibin-deficient mice.

We previously demonstrated that mice deficient in inhibin develop gonadal sex cord-stromal tumors with nearly 100% penetrance. These ovarian and testicular tumors develop as early as 4 weeks of age and eventually cause cachexia-like symptoms and death in the inhibin-deficient mice. Gonadectomized inhibin-deficient mice initially do not develop this wasting syndrome, but eventually will develop adrenal cortical tumors with similar penetrance. These studies have demonstrated that inhibin is a secreted type of tumor suppressor in the gonads and adrenal glands. Gonadotropins are implicated to influence gonadal tumor development in humans as well as experimental animals, and in inhibin-deficient mice, serum FSH levels are elevated. To determine whether gonadotropins influence the development and/or progression of the tumors in the inhibin-deficient mice, we took advantage of a naturally occurring mutant mouse, hypogonadal (hpg); hpg/hpg mice lack a functional GnRH gene and, therefore, have suppressed FSH and LH levels. Heterozygous hpg/+mice were crossed to heterozygous inhibin mutant mice to generate compound homozygous mutant mice that lack both inhibin and GnRH. These compound homozygous mutant mice do not develop a wasting syndrome, do not exhibit gonadal or adrenal tumors, and can survive for more than 1 yr. These results demonstrate that gonadotropins are essential modifier factors for tumor development in inhibin-deficient mice.

Animals↗

Relationship among metabolizing genes, smoking and alcohol used as modifier factors on prostate cancer risk: exploring some gene-gene and gene-environment interactions.

BACKGROUND: Prostate cancer (PCa) is one of the most common male cancers, but the burden of this disease shows remarkable worldwide variation. The role of susceptibility low penetrance genes and environmental factors in the etiology of (PCa) is unclear, but may involve, in some cases, multiple alleles at multiple loci and environmental factors. STUDY OBJECTIVES: To assess whether CYP1A1, GSTM1, GSTT1 susceptibility genotypes, smoking status and alcohol consumption factors contribute to PCa risk, gene-gene and gene-environment interactions were analyzed. DESIGN AND PARTICIPANTS: We explored interactions on a multiplicative scale conducting a population-based case-control and a case-only study on 103 incident PCa patients and 132 unrelated controls. MAIN RESULTS: The interaction odds ratios (IOR) for PCa risk were increased in men who had both susceptibility genotypes GST (M1; T1) null and CYP1A1-M1* in a case-control and case-only design (IOR(cc): 1.11; 95% CI: 0.12-10.02; IOR(cc): 6.23; 95%, CI: 0.51-75.89; IOR(co): 2.80; 95% CI: 0.44-17.45 and IORco: 2.65; 95%, CI: 0.30-25.40). No clear evidence for interaction on a multiplicative scale between smoking status, alcohol consumption and genetic polymorphisms in PCa risk was observed. CONCLUSIONS: Our findings suggest that the interaction between genetic polymorphisms in GST (T1; M1) and CYP1A1-M1* would play a significant role as a modifying factor on PCa risk in Chilean people. However, these preliminary exploratory results should be confirmed in a larger study.

Alcohol Drinking↗

Evidence for nucleotide excision repair as a modifying factor of O6-methylguanine-DNA methyltransferase-mediated innate chloroethylnitrosourea resistance in human tumor cell lines.

We examined the O6-methylguanine-DNA methyltransferase (MGMT) protein as well as MGMT activity levels and the excision repair cross-complementing rodent repair deficiency gene, ERCC2 (XPD), protein levels in 14 human tumor cell lines not selected for chloroethylnitrosourea (CENU) resistance. These results were compared with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) cytotoxicity and UV light sensitivity. MGMT protein correlated significantly with MGMT activity (r = 0.9497, p = 0.0001). There was no significant linear correlation between BCNU cytotoxicity and MGMT content as determined by both Western analysis (r = 0.139, p = 0. 6348) and activity assay (r = 0.131, p = 0.6515). However, MGMT-rich cell lines were found to be more resistant than MGMT-poor cell lines to BCNU (t = 2.2375, p = 0.0225) but not to UV (t = 1.1734, p = 0.1317). Furthermore, the most BCNU-sensitive cell lines were all MGMT-poor. UV sensitivity was significantly correlated to BCNU cytotoxicity (r = 0.858, p = 0.0001). Significant correlations were found between ERCC2 protein levels and BCNU cytotoxicity (r = 0.786, p = 0.0009) or UV sensitivity (r = 0.874, p = 0.0001). Our results confirm that MGMT plays an important role in CENU resistance, but not in UV resistance. The correlation of UV sensitivity with BCNU cytotoxicity suggests that nucleotide excision repair is an important modifying factor of MGMT-mediated innate CENU resistance in human tumor cell lines, especially in highly resistant cell lines. ERCC2 may be implicated in this process.

Antineoplastic Agents, Alkylating↗

Modifying factors in urinary bladder carcinogenesis.

N-Butyl-N-(4-hydroxybutyl)nitrosamine (BBN) is a potent carcinogen in the urinary bladder of animals. The BBN model of bladder cancer is an excellent model of human urinary bladder cancer and has already led to a greater knowledge of its pathogenesis. In our studies, histogenesis and morphological characteristics of BBN urinary bladder cancer were analyzed in different animal species such as rats, mice, hamsters and guinea pigs and also in different rat strains. Papillary or nodular hyperplasia (PN hyperplasia) is found to be a preneoplastic lesion of the rat urinary bladder. Therefore, the promoting and inhibitory effects of various chemicals in two-stage urinary bladder carcinogenesis were judged by measuring PN hyperplasia in rats. Dose-dependent and organ-specific effects of the urinary bladder promoter, saccharin, in the induction of PN hyperplasia were shown in rats after initiation by BBN. The promoting effect of saccharin was seen more clearly in the urinary bladder of rats after potent initiation. A strain difference in susceptibility of the urinary bladder to the promoter was also shown. These results suggest that the above various factors may also have modifying activities on urinary bladder carcinogenesis in man.

Animals↗

The modifiable factors contributing to leading causes of death in South Carolina.

In 1996, there were 34,035 deaths in South Carolina. Almost 70 percent of these deaths were due to chronic diseases. There are known ways to prevent chronic diseases from developing or at least delay their developmental process, thereby lengthening years of life. The purpose of this paper is to report modifiable risk factors for mortality related to leading causes of death. The top ten causes of death in South Carolina were obtained from the South Carolina Department of Health and Environmental Control. Estimates of the number of deaths due to certain modifiable risk factors were made using results of a study published by McGinnis and Foege. The percentage of deaths due to each cause was adapted to South Carolina death certificate data from the national estimates. Results indicate that small modifications in individual lifestyles could prevent or delay nearly 50 percent of deaths in South Carolina annually. Tobacco use, diet and physical activity, and misuse of alcohol contribute to the largest number of deaths. Other modifiable behaviors contributing to the 50 percent mortality are microbial agents, toxic agents, firearms, sexual behavior, motor vehicle accidents, and illicit use of drugs. The implication in these findings is that these risk factors for mortality are mainly modifiable. There are many causes of death that may be delayed due to these modifiable risk factors. By looking at preventable causes of death, rather than focusing on traditional causes of death, it becomes clear that prevention strategies are critically important.

Cause of Death↗

Non-specific bronchial hyperreactivity: correlation to asthma and modifying factors.

Bronchial hyperreactivity can be induced and modified by allergic and non-allergic factors affecting the airways. Bronchospasm can also be induced by small amounts of many of these agents and by other factors as well. Allergic and non-allergic subjects can be affected. Bronchial obstruction in asthma due to allergic reactions is to a large extent dependent on the degree of nonspecific bronchial reactivity. This can be influenced by different modes of treatment.

Airway Resistance↗

Continuous i.c.v. infusion of brain-derived neurotrophic factor modifies hypothalamic-pituitary-adrenal axis activity, locomotor activity and body temperature rhythms in adult male rats.

Brain-derived neurotrophic factor is a neurotrophin belonging to the nerve growth factor family, which is involved in the differentiation and survival of many types of neurons. It also participates in neuroprotection and neuronal plasticity in adult rats. Our previous studies showed that a single brain-derived neurotrophic factor injection modifies hypothalamic-pituitary-adrenal axis activity in adult male rats. To investigate the effect of chronic brain-derived neurotrophic factor administration on some physiological parameters, adult rats were implanted with osmotic micro-pumps to deliver brain-derived neurotrophic factor continuously for 14 days in the lateral ventricle (12 microg/day/rat). mRNA levels were evaluated by in situ hybridization analysis, peptide contents and plasma hormone concentrations by radioimmunoassay. Animals were also equipped with telemetric transmitters to study locomotor activity and temperature rhythms modifications, since hypothalamic-pituitary-adrenal axis is known to modulate these two parameters. Decreased body weight was used as a control of brain-derived neurotrophic factor access to hypothalamic areas as already documented. In the hypothalamus the continuous brain-derived neurotrophic factor treatment increases: (i) the mRNA steady state levels of corticotropin releasing hormone and arginin-vasopressin in the paraventricular nucleus, the supraoptic nucleus, and the suprachiasmatic nucleus; (ii) the surface of corticotropin releasing hormone and arginin-vasopressin mRNA signals in these nuclei as detected by in situ hybridization, and (iii) the corticotropin releasing hormone and arginin-vasopressin contents. The plasma concentrations of adrenocorticotropic hormone and corticosterone were decreased and increased, respectively. Finally, this treatment increased daily locomotor activity and temperature, and provoked some circadian perturbations. These results obtained after chronic brain-derived neurotrophic factor administration extend data on the brain-derived neurotrophic factor involvement in the hypothalamic-pituitary-adrenal axis regulation and illustrate its effects on the locomotor and temperature rhythms. They also allow demonstrating that the regulation of the hypothalamic-pituitary-adrenal axis by brain-derived neurotrophic factor differs according to the brain-derived neurotrophic factor administration mode, i.e. acute injection or chronic administration.

Adrenocorticotropic Hormone↗

Modifying factors on repair phenomena.

Every step of radiation damage repair can be modified by several factors like temporal and local energy distribution (LET), physiological conditions, biochemical and chemical composition of the target environment. Most interesting in the case of space radiation is the possible influence of high LET and of microgravity which could change the repair i.e. fusion capacity as well as the phenomenon of self assembly.

Animals↗

Tobacco and myocardial infarction in middle-aged women: a study of factors modifying the risk.

BACKGROUND: Although myocardial infarction (MI) is strongly related to smoking, few have studied why some smokers are more vulnerable than others. This study explored how the risk of MI in current and former smokers is modified by other cardiovascular risk factors. METHODS: Incidence of MI (fatal and nonfatal) amongst 10619 women, 48.3 +/- 8.2 years old, were studied in relation to smoking, hypertension, hypercholesterolaemia, diabetes, marital status and occupational level over a mean follow-up of 14 years. RESULTS: Of the 3738 smokers, one-third had at least one major biological risk factor besides smoking; 228 women had MI during follow-up. Smoking and hypertension showed a synergistic effect on incidence of MI. The adjusted relative risks (RR) were 12.2 (95% CI: 7.5-19.8) for smokers with hypertension, 5.3 (CI:3.3-8.1) for smokers with normal blood pressure and 2.4 (CI:1.4-4.3) for never-smokers with hypertension (reference: normotensive never-smokers). The corresponding RRs for diabetic smokers and diabetic never-smokers were 19.0 (CI: 10.2-35.4) and 8.8 (CI: 4.4-17.4), respectively (reference: nondiabetic never-smokers). In terms of attributable risks, hypertension, hypercholesterolaemia and diabetes accounted for 12.9, 11.5 and 7.2%, respectively, of MI in female smokers. Low socio-economic level and being unmarried accounted for 19.6 and 1.6%, respectively. CONCLUSIONS: Although smoking is a major risk factor for MI, the risk varies widely between women with similar tobacco consumption. The results illustrate the need of a global risk factor assessment in female smokers and suggest that female smokers should be targets both for intensified risk factor management and programmes to stop smoking.

Adult↗

Covalent attachment of the SUMO-1 protein to the negative regulatory domain of the c-Myb transcription factor modifies its stability and transactivation capacity.

The transcription factor c-Myb is subject to several types of post-translational modifications, including phosphorylation, acetylation, and ubiquitination. These modifications regulate the transcription and transforming activity as well as the proteolytic stability of c-Myb. Here we report the covalent modification of c-Myb with the small ubiquitin-related protein SUMO-1. Mutational analysis identified two major sumolation sites (Lys(499) and Lys(523)) in the negative regulatory domain. Interestingly, the single mutation K523R completely abolished modification of c-Myb with SUMO-1, suggesting that sumolation of Lys(523) is required for modification of other lysines in c-Myb. In accordance with this observation, we found that the SUMO-1-conjugating enzyme Ubc9 interacted only with a region surrounding Lys(523) (also called the PEST/EVES motif). Experiments aimed at determining the proteolytic stability of sumolated and unmodified forms of c-Myb revealed that at least two covalently attached SUMO-1 molecules dramatically increased the stability of c-Myb. However, mutations of the SUMO-1 modification sites did not alter its stability, suggesting that a mechanism(s) other than competition of ubiquitin and SUMO-1 for the same lysine is involved in the stabilization of sumolated c-Myb protein. Finally, the K523R mutant of c-Myb, entirely deficient in sumolation, was shown to have an increased transactivation capacity on a Myb-responsive promoter, suggesting that SUMO-1 negatively regulates the transactivation function of c-Myb. Thus, modification of c-Myb with SUMO-1 represents a novel mechanism through which the negative regulatory domain can exert its suppressing activity on c-Myb transactivation capacity.

Amino Acid Sequence↗

Position-effect variegation--an assay for nonhistone chromosomal proteins and chromatin assembly and modifying factors.

The past decade has brought us much information about gene regulation in eukaryotes and the importance of chromatin in gene expression. Clearly, we need to advance our understanding of chromatin assembly and modification. Hopefully, many Su(var) and E(var) loci will be cloned and their analysis will demonstrate that they are involved in this process. It will be interesting to see what classes of products they encode. Clearly, antibodies must be made against these proteins to determine: (1) the chromosomal distribution of those that encode chromatin structural proteins, (2) the tissue and temporal distribution of these proteins during development, and (3) the time of action during specific portions of the cell cycle for those genes encoding factors that regulate chromatin assembly or modifying proteins. In addition, it would be intriguing to identify and isolate those sequences or segments of DNA that serve as nucleation sites for the assembly of euchromatin and heterochromatin. The necessary materials for identifying these sequences are in place with the large number of variegating strains and revertants of those rearrangements and Su(var) and E(var) mutations that exist. From our current understanding of PEV, it appears that PEV provides a useful model for the study of determinative events that occur during development. This includes both the establishment of different lineages and the somatic memory or imprinting of the initial determinative decision. Clearly, PEV is more than a simple assay system for the identification of NHCPs, and ultimately the understanding of the mechanisms underlying PEV should lend insights into how such determinative events occur and are propagated.

Aneuploidy↗

Factors modifying exposure to environmental tobacco smoke in children (Athens, Greece).

The aim of the study was to investigate individual, family, and environmental factors which may modify exposure of children to environmental tobacco smoke (ETS). A total of 2,108 children of both genders, aged up to 14 years old, were enrolled in the study. Parents of the children provided information concerning several factors that may affect exposure to ETS. Cotinine-to-creatinine ratios in spot urine samples were measured for each child. These values were logtransformed and regressed on a series of exposure variables. Among children, 73 percent were exposed to ETS generated by at least one smoker in the household. Exposure to ETS was affected by the following factors: cigarettes smoked by parents while the child was at home (increase by 37 percent per 10 cigarettes daily, 95 percent confidence interval [CI] = 32-43 percent); precautions taken by parents (no cf yes, increase by 38 percent, CI = 24-54 percent); child's age (decrease by nine percent per year, CI = -11-8 percent); gender (male lower than female by 13 percent, CI = -21-3 percent); day of the week (Monday cf Tuesday-through-Sunday, increase by 28 percent, CI = 14-44 percent); floor surface area (decrease by nine percent per 20 m2, CI = -14-5 percent); heating (central cf non-central decrease by 14 percent, CI = -25-2 percent); maternal education (decrease by nine percent per five years, CI = -18-0 percent); paternal education (decrease by seven percent per five years, CI = -15-2 percent). It is concluded that several household-related factors affect exposure to ETS and that this exposure can be reduced by about one-third by simple precautions taken by smoking parents.

Adolescent↗

Carbohydrate-induced hypertriglyceridemia: modifying factors and implications for cardiovascular risk.

High-carbohydrate/low-fat, isocaloric diets have repeatedly been shown to increase plasma triglyceride concentrations. The present review addresses recent developments relevant to several important unresolved issues. These include the type of dietary carbohydrate that is most likely to induce hypertriglyceridemia, predictors of individual susceptibility, modifiable physiologic factors that may mitigate the plasma triglyceride response, underlying metabolic mechanisms that are responsible for increased plasma triglycerides, and implications of altered serum lipid profiles for atherogenic risk. Although some progress has been made in this field, the central public health issue - the net effect on cardiovascular risk - remains unresolved.

Arteriosclerosis↗

Genetic and environmental factors modify bovine spongiform encephalopathy incubation period in mice.

The incubation period (IP) and the neuropathology of transmissible spongiform encephalopathies (TSEs) have been extensively used to distinguish prion isolates (or strains) inoculated into panels of inbred mouse strains. Such studies have shown that the bovine spongiform encephalopathy (BSE) agent is indistinguishable from the agent causing variant Creutzfeldt-Jakob disease (vCJD), but differs from isolates of sporadic CJD, reinforcing the idea that the vCJD epidemic in Britain results from consumption of contaminated beef products. We present a mouse model for genetic and environmental factors that modify the incubation period of BSE cross-species transmission. We have used two mouse strains that carry the same prion protein (PrP) allele, but display a 100-day difference in their mean IP following intracerebral inoculation with primary BSE isolate. We report genetic effects on IP that map to four chromosomal regions, and in addition we find significant factors of host environment, namely the age of the host's mother, the age of the host at infection, and an X-cytoplasm interaction in the host.

Age Factors↗

Relation of aortic stiffness to factors modifying the risk of atherosclerosis in healthy people.

To identify factors predicting aortic stiffness, we studied the modulus of elasticity of the thoracic aorta in relation to sex, obesity, blood pressure, physical activity, smoking, ethanol consumption, salt intake, and serum lipid and insulin levels in 55 healthy people born in 1954. A transverse cine magnetic resonance image of the thoracic aorta was made, and the modulus of elasticity was determined as brachial artery cuff pulse pressure/aortic strain, where strain was determined as the ratio of pulsatile aortic luminal area change to the diastolic luminal area. The average of measurements made in the ascending and descending aorta was used as the elastic modulus of the thoracic aorta. Habitual physical activity, smoking, and alcohol use were quantified by 2-month prospective daily recording and salt intake by 7-day food records. The aortic elastic modulus ranged from 100 to 2091 10(3) dyne/cm2 (median, 390 10(3) dyne/cm2). In multiple regression analyses, log10 aortic elastic modulus was related directly to mean blood pressure (standardized coefficient [beta] = .37, P = .002), serum high-density lipoprotein cholesterol (beta = .36, P = .012), square root of daily energy expenditure in physical activity (beta = .33, P = .005), and log10 serum insulin (beta = .27, P = .047) and inversely to serum low-density lipoprotein cholesterol (beta = -.26, P = .035). A relation to salt intake was also observed, but the regression slope was dependent on mean blood pressure (P = .005 for interaction). These data suggest that many modifiable constitutional and lifestyle characteristics may contribute to the stiffness of the thoracic aorta.

Adult↗

Pathogenesis and modifying factors of dental erosion.

Dental erosion is caused by acidic solutions which come into contact with the teeth. Because the critical pH of dental enamel is approximately 5.5, any solution with a lower pH value may cause erosion, particularly if the attack is of long duration, and repeated over time. Saliva and salivary pellicle counteract the acid attacks but if the challenge is severe, a total destruction of tooth tissue follows. Ultrastructural studies have shown that erosive lesions are seen in prismatic enamel as characteristic demineralization patterns where either the prism cores or interprismatic areas dissolve, leading to a honeycomb structure. In aprismatic enamel the pattern of dissolution is more irregular and areas with various degrees of mineral loss are seen side by side. In dentin the first area to be affected is the peritubular dentin. With progressing lesions, the dentinal tubules become enlarged but finally disruption is seen also in the intertubular areas. If the erosion process is rapid, increased sensitivity of the teeth is the presenting symptom. However, in cases with slower progression, the patient may remain without symptoms even though the whole dentition may become severely damaged. Regarding the role of causative agents, present data does not allow the ranking of different acids with regard to their potential of causing erosion. Neither is there consensus as to how effective fluorides are in preventing the progression of erosive lesions, or how the chemical and structural factors of tooth tissue in general might modify this pathological process.

Acids↗

A single dose of granulocyte colony-stimulating factor modifies radiation-induced death in B6D2F1 mice.

Granulocyte colony stimulating factor (G-CSF) stimulates the proliferation of progenitor cells committed to myeloid differentiation. In animal models, G-CSF is able to stimulate granulocyte recovery and promote survival after lethal or sublethal irradiation when administered as daily injections, suggesting an influence on the residual hematopoietic primitive precursors surviving irradiation. In this study, we clearly demonstrate that a single dose of G-CSF (1 mg/kg) administered to B6D2F1 mice 2 hours after a lethal dose 95/30 irradiation achieves a 78% survival at day +30 after irradiation. Survival of G-CSF treated mice compares favourably with that of syngenic bone marrow transplantation recipients (78% vs 90%, ns).

Animals↗