Biomedical subjects

M Koskinen

Publications and source records attributed to M Koskinen.

At least 37 records · Page 2Linked to original sources

PubMed2001

Central auditory processing of durational changes in complex speech patterns by newborns: an event-related brain potential study.

In this study, newborns' ability to discriminate durational changes in the fricative /s/ within a nonsense word was investigated. The results showed that infrequent increments and decrements of a speech sound duration elicit a mismatch negativity kind of response in sleeping human newborns. In the auditory event-related potential to these deviant stimuli two negative waves of this response were revealed. The first negative wave peaked at about 150 msec and the second at about 350 msec after the change onset. At least one negative deflection, which was interpreted as evidence for stimulus change-detection, was observed in every infant.

Adult↗

PubMed2000

Specific DNA adducts induced by some mono-substituted epoxides in vitro and in vivo.

Alkyl epoxides are important intermediates in the chemical industry. They are also formed in vivo during the detoxification of alkenes. Alkyl epoxides have shown genotoxicity in many toxicology assays which has been associated with their covalent binding to DNA. Here aspects of the formation and properties of DNA adducts, induced by some industrially important alkenes and mono-substituted epoxides are discussed. These include propylene oxide, epichlorohydrin, allyl glycidyl ether and the epoxy metabolites of styrene and butadiene. The major DNA adducts formed by epoxides are 7-substituted guanines, 1- and 3-substituted adenines and 3-substituted cytosines. In addition, styrene oxide and butadiene monoepoxide are able to modify exocyclic sites in the DNA bases, the sites being in the case of styrene oxide N(2)- and O(6)-positions of guanine, N(6)-adenine as well as N(4)-and O(2)-cytosine. In vivo the main adduct is the 7-substituted guanines. The 1-substituted adenines have also shown marked levels, and these adducts should also be targets in biomonitoring of human exposures. Due to its low mutagenicity, 7-substituted guanines are considered as a surrogate marker for other mutagenic lesions, e.g. those of 1-adenine or 3-uracil adducts.

Animals↗

PubMed2000

Styrene oxide-induced 2'-deoxycytidine adducts: implications for the mutagenicity of styrene oxide.

The reaction between 2'-deoxycytidine and styrene 7,8-oxide (SO) resulted in alkylation at the 3-position and at the O(2)-position through the alpha- and beta-carbons of the epoxide but at the N(4)-position only through the alpha-carbon. The 3-alkylated adducts were found to deaminate to the corresponding 2'-deoxyuridine adducts (37 degrees C, pH 7.4) with half-lives of 6 min and 2.4 h for the alpha- and beta-isomers, respectively. The N(4)-alkylated products were stable at neutral pH. The O(2)-alkylated products were unstable being prone to depyrimidation and to isomerisation between alpha- and beta-isomers. In SO-treated double-stranded DNA, enzymatic hydrolysis allowed the identification of the beta3-deoxyuridine and alphaN(4)-deoxycytidine adducts (1.9 and 0.5% of total alkylation, respectively), in addition to the previously identified DNA-adducts. The 3-substituted uracil may have implications for the mutagenicity of SO.

Animals↗

PubMed2000

Adenine N3 is a main alkylation site of styrene oxide in double-stranded DNA.

Styrene 7,8-oxide (SO), a major metabolite of styrene, is classified as a probable human carcinogen. In the present work, salmon testis DNA was reacted with SO and the alkylation products were analysed after sequential depurination in neutral or acidic conditions followed by HPLC separation and UV-detection. A novel finding was that the N-3 position of adenine was the next most reactive alkylation site in double-stranded DNA, comprising 4% of the total alkylation, as compared to alkylation at the N-7 position of guanine, 93% of the total alkylation. Both alpha- and beta-products of SO were formed at these two sites. Other modified sites were N2-guanine (1.5%, alpha-isomer), 1-adenine (0.4%, both isomers) and N6-adenine (0.7%, both isomers) as well as 1-hypoxanthine (0.1%, alpha-isomer), formed by deamination of the corresponding 1-adenine adduct. The results indicated that in double-stranded DNA N-7 of guanine and N-3 of adenine account for 97% of alkylation by SO. However, these abundant adducts are not stable, the half-life of depurination in DNA for 3-substituted adenines being approximately 10 and approximately 20 h, for alpha- and beta-isomers, respectively, and 51 h for both isomers of 7-substituted guanines.

Adenine↗

PubMed2000

Dna adducts, mutations, and cancer 2000.

The main achievements in the DNA adduct field in the 1990s have been technical innovations of methods for specific adducts reaching sensitivities required for low levels encountered in humans. Over 20 specific adducts or closely related groups of adducts have been determined in humans. The sources of the DNA-binding agents are endogenous and exogenous or both. In some of these studies adduct levels have been correlated to metabolic or DNA repair genotypes. An example of DNA adduct studies in human target tissue is taken on UV photoproducts in skin in situ. Adduct-induced mutations, specific mutation spectra, and their relationship to cancer are discussed. The quantitative adduct techniques will enable comparisons of endogenous and exogenous adduct levels and will give important clues to the etiology of human cancer. Furthermore, adducts will provide an intermediary tool for genotyping studies, both for metabolic enzyme and for DNA repair system genotypes. As the common polymorphisms are likely to cause at most moderate increases in the risk of cancer, the intermediary adduct endpoint is a necessary proof of causal relationships. The present and future biomonitoring studies will cover many endpoints to link the mechanistic steps from DNA adducts to cancer via mutations and modulating host susceptibility factors.

Animals↗

PubMed2000

Dysfunction of the auditory cortex persists in infants with certain cleft types.

Language and learning disabilities occur in almost half of individuals with oral clefts. The characteristics of these cognitive dysfunctions vary according to the cleft type, and the mechanisms underlying the relation between cleft type, cognitive dysfunction, and cleft-caused middle-ear disease are unknown. This study investigates preattentive auditory discrimination, which plays a significant role in language acquisition and usage, in infants with different cleft types. A mismatch negativity (MMN) component of brain evoked potentials, which indexes preconscious sound discrimination, and brain responses to rare sine-wave tones were recorded in 12 healthy infants and 32 infants with oral clefts at the ages of 0 and 6 months. Infants with clefts were subdivided into two categories: those with cleft lip and palate (CLP) (n=11 at birth, n=6 at the age of 6 months) and those with cleft palate only (CPO) (n=17 at birth, n=8 at the age of 6 months). At both ages, brain responses to rare sounds tended to be smaller in both cleft subgroups than in healthy peers. However, in the latency range of 300 to 500 ms, the MMN was significantly smaller in infants with CPO. In infants with CLP, the MMN was comparable to that of healthy infants. Differences in auditory discrimination between infants with CLP and CPO, as reflected by MMN, were detectable at birth and persisted into later infancy. This pattern parallels known behavioural differences between children with these cleft types. Brain responses to rare sounds, in contrast, had no differentiative power with respect to the cleft type.

Auditory Cortex↗

PubMed2000

Comparison of bioimpedance and radioisotope methods in the estimation of extracellular water volume before and after coronary artery bypass grafting operation.

To estimate extracellular water volume (ECW) changes in connection with coronary artery bypass grafting operation, simultaneous ECW estimations by 51Cr-EDTA dilution and whole-body bioimpedance techniques were performed in 15 patients. The assessments of ECW were compared with patients' weighing results. Whole-body bioimpedance-derived ECW correlated significantly with 51Cr-EDTA dilution-based ECW in the pre-operative period (r=0.74; P<0.005); the bias was 0.2 +/- 1.1 l (+/-SD). In the post-operative period, the agreement between these methods was poor, the bias being 0.5 +/- 2.5 l, and no significant correlation between the methods was found (r=0.38; P>0.05). Whole-body bioimpedance-derived ECW changes correlated significantly with weight changes of the patient induced by the operation (r=0.52; P<0.05). 51Cr-EDTA dilution-based ECW changes correlated neither with weight changes (r=0.33; P>0.05) nor with bioimpedance-derived ECW changes (r=0.03; P>0.05). Alterations in radioisotope tracer distribution and loss of it due to blood leakage in the post-operative period were presumed to explain the discrepancy between dilution technique and weighing results. The results suggest that bioimpedance is a useful non-invasive method for assessment of extracellular volume changes induced by coronary artery bypass grafting operations. 51Cr-EDTA dilution-based ECW determination is not suitable in related conditions.

Aged↗

PubMed2000

Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats.

FC1271a is a novel triphenylethylene compound with a tissue-selective profile of estrogen agonistic and weak antagonistic effects. It specifically binds to the estrogen receptor alpha and beta with affinity closely similar to that of toremifene and tamoxifen. To study the in vivo effects of the compound, 4-month-old rats were sham operated (sham) or ovariectomized (OVX) and treated daily for 4 weeks with various doses of FC1271a or vehicle (orally). FC1271a was able to oppose OVX-induced bone loss by maintaining the trabecular bone volume of the distal femur. Accordingly, the OVX-induced loss of bone strength was prevented at doses of 1 and 10 mg/kg. FC1271a also prevented the OVX-induced increase in serum cholesterol in a dose-dependent manner. No significant changes in uterine wet weight or morphology were observed in the OVX-rats treated with 0.1 or 1 mg/kg FC1271a, but at a dose of 10 mg/kg it had a slightly estrogenic effect. In immature rats the effect of FC1271a on uterine wet weight was less stimulatory than that of toremifene or tamoxifen, but more stimulatory than that of raloxifene or droloxifene. The appearance of the dimethylbenzanthracene (DMBA)-induced mammary tumors was inhibited by treatment of DMBA-treated rats with FC1271a in a dose-dependent manner. In human MCF-7 breast cancer cell tumors raised in nude mice in the presence of estrogen, the growth and expression of pS2 marker gene could not be maintained after estrogen withdrawal by treatment with FC1271a. No formation of DNA adducts was observed in the liver of the FC1271a-treated rats. In conclusion, the bone-sparing, antitumor, and cholesterol-lowering effects of FC1271a combined with a low uterotropic activity and lack of liver toxicity indicate that FC1271a could be an important alternative in planning antiosteoporosis therapy for estrogen deficiency.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1999

Separate deamination mechanisms for isomeric styrene oxide induced N1-adenine adducts.

[formula: see text] Styrene 7,8-oxide (SO) induced N1-2'-deoxyadenosine 5'-phosphate (AMP) adducts deaminate to corresponding inosine derivatives. For the beta-isomer of N1-SO-AMP, the chiral alpha-carbon was found to be involved in the hydrolytic deamination, suggesting formation of an oxazolinium ring as an intermediate and that a water molecule attacks the benzylic carbon. The mechanism differs from the one suggested for the alpha-isomer of N1-SO-AMP, for which deamination occurs by direct attack of water at the 6-position of purine ring.

Adenine↗

PubMed1999

Antireflux surgery enhances gastric emptying.

OBJECTIVE: To evaluate the influence of antireflux surgery on gastric emptying. DESIGN: Nonrandomized controlled trial 3 months before and after surgical intervention. SETTING: Secondary and tertiary referral center. PATIENTS AND CONTROL SUBJECTS: Twenty consecutive patients (7 women, 13 men), mean age 49.2 years, with symptomatic, objectively confirmed gastroesophageal reflux disease and 10 healthy control subjects (3 women, 7 men), mean age 37.3 years. INTERVENTION: Laparoscopic or open Nissen fundoplication (in 1 case Toupet 180 degrees posterior hemifundoplication). MAIN OUTCOME MEASURES: Gastric emptying scintigraphy, using solid food, in control subjects and patients 3 months before and 3 months after the operation; time to halving of the maximal activity and the activity remaining at 60, 100, and 120 minutes. RESULTS: Preoperative symptoms included pyrosis in 19 of 20 patients and regurgitation in 18. Three months postoperatively, 19 patients were symptom-free. The mean time to halving of the maximal activity decreased from 113 to 78 minutes (P = .001). Delayed gastric emptying was found postoperatively in 3 patients, compared with preoperative values, using activity at 60, 100, 120 minutes and the mean time to halving of the maximal activity as the variables. Compared with control subjects, gastric emptying was slower in patients preoperatively and faster postoperatively, but the difference was not statistically significant. CONCLUSION: Gastric emptying is enhanced after antireflux surgery, along with cessation of symptoms and healing of esophagitis.

Adult↗

PubMed1999

Effect of Bis(guanylhydrazones) on Growth and Polyamine Uptake in Plant Cells.

In the present work the effect of several bis(guanylhydrazones) on the growth of Helianthus tuberosus tuber explants was studied. Different aliphatic congeners of glyoxal bis(guanylhydrazone) were tested. Most of the compounds displayed an inhibitory effect on growth, and a correlation between the structure of the molecule and the inhibitory activity was observed. Experiments carried out with glyoxal bis(guanylhydrazone) and its congeners methyl-, ethylmethyl-, and methylpropylglyoxal bis(guanylhydrazones) show that as the total number of side chain carbon atoms in the molecule increases, the inhibitory potency also increases. A depletion of spermidine levels was also found in the explants treated with ethylmethylglyoxal bis(guanylhydrazone), which turned out to be one of the most potent growth inhibitors. The addition of spermidine caused a significant reversion of the antiproliferative action of glyoxal bis(guanylhydrazone). The effect of these compounds on spermidine uptake in protoplasts isolated from carrot phloem parenchyma was also investigated. Only a slight competition was found when antagonists were present at concentrations 20 times higher than the polyamine, thus suggesting that bis(guanylhydrazones) do not share, at least at low concentrations, the polyamine transport system in plant cells.Key Words. Bis(guanylhydrazones)-Carrot protoplasts-Growth-Helianthus tuberosus-Polyamines-Uptakehttp://link.springer-ny.com/link/service/journals/00344/bibs/18n1p39.html

Journal Article↗

PubMed1999

Immobilization of a biologically active coating on a hydrophobic L-lactide-epsilon-caprolactone copolymer.

The electron beam radiation induced grafting method was used to attach a reactive polyacrylamide (PAA) layer (20 wt %) on the surface of a biodegradable poly-L-lactide-co-epsilon-caprolactone (PLLA-co-CL). The biocompatibility of graft-polymer obtained was studied by cytotoxicity test and no signs of toxicity were observed. Heparin and sol-gel-produced silica-gel coatings were successfully attached on the top of the polymeric material produced. The amount of heparin immobilized directly on the surface can be controlled by reaction conditions: reaction time, temperature and pH of the incubation solution. By using acidic conditions, up to 98 microg cm(-2) of heparin was immobilized on the surface. The sol-gel-produced silica-gel layer formed by dipping technique was 30 microm thick and the cracking of the layer was minimal after bending several times to 90 degrees.

Journal Article↗

PubMed1999

32P-postlabelling of propylene oxide 1- and N(6)-substituted adenine and 3-substituted cytosine/uracil: formation and persistence in vitro and in vivo.

Propylene oxide, a widely used monofunctional alkylating agent, has been shown to be genotoxic in in vitro test systems and induces tumors in the nasal tissues of experimental animals. Propylene oxide, like related alkylating agents, forms several different adducts with DNA bases, but predominantly at the 7-position of guanine. We have previously described the in vitro and in vivo formation and stability of this major adduct. The aim of the present study was to perform a similar investigation of other adducts of propylene oxide. 1-(2-Hydroxypropyl)adenine (1-HP-adenine) and 3-(2-hydroxypropyl)cytosine (3-HP-cytosine), as well as their rearrangement products to N(6)-(2-hydroxypropyl)adenine (N(6)-HP-adenine) and 3-(2-hydroxypropyl)uracil (3-HP-uracil), respectively, were analysed by a very sensitive (32)P-postlabelling method involving nuclease P1 enhancement and radioisotope detector-coupled HPLC separation. All four adducts could be detected in DNA treated in vitro with propylene oxide. The sum of the levels of 1- and N(6)-HP-adenine amounted to 3.5% and the sum of 3-HP-cytosine and 3-HP-uracil to 1.7%, respectively, of 7-(2-hydroxypropyl)guanine (7-HP-guanine). In male Fischer 344 rats exposed to 500 p.p.m. propylene oxide by inhalation for 20 days, 1-HP-adenine was detected in all analysed tissues, including nasal epithelium, lung and lymphocytes, whereas N(6)-HP-adenine was only found in the tissues of the nasal cavities. The highest level of 1-HP-adenine (2.0 mol/10(6) mol of normal nucleotides, i.e. 2% of 7-HP-guanine) was found in the respiratory nasal epithelium, which also represents the major target for tumour induction in the rat following inhalation of propylene oxide. The levels of this adduct in the lung and in the lymphocytes were considerably lower, amounting to 15 and 9%, respectively, of that of the respiratory nasal epithelium. In rats killed 3 days after cessation of exposure, practically no decrease in 1-HP-adenine was observed, indicating no or very slow repair. 3-HP-uracil could only be detected in the respiratory nasal epithelia of propylene-exposed rats and its concentration was as low as 0.02 mol/10(6) mol of normal nucleotides (0.02% of 7-HP-guanine). Since 3-HP-uracil was chemically much more stable than the latter, the obtained animal data suggest repair of the cytosine and/or uracil adducts. Incubation of propylene oxide-reacted DNA with a protein extract from mammalian cells indicated that an enzymatic repair mechanism exists for removal of 3-HP-cytosine, but not for 3-HP-uracil or 1- and N(6)-HP-adenine. Another finding was that uracil glycosylase is probably not involved. The level of 1-HP-adenine in the propylene oxide-exposed rats was approximately 50 times lower than that of 7-HP-guanine. Nevertheless, this adduct is conveniently analysed and has high chemical stability and recovery, which results in high sensitivity (detection limit 0.3 mol/10(9) mol of normal nucleotides using 10 microgram DNA). 1-HP-adenine might, therefore, be considered as an alternative to 7-HP-guanine for monitoring exposure to propylene oxide.

Adenine↗

PubMed1999

The long-term effect of early mineral, vitamin D, and breast milk intake on bone mineral status in 9- to 11-year-old children born prematurely.

BACKGROUND: Although the short-term benefits of mineral supplementation in preterm infants has been established, the long-term benefits are less clear. The purpose of the study was to evaluate effects of early-life mineral, vitamin D, and breast milk intake on bone mineral status in children 9 to 11 years of age who were born prematurely. METHODS: Seventy preterm infants born 1985 through 1987 were randomized into four groups: to receive a vitamin D dose of 500 or 1000 IU/day and calcium- and phosphorus-supplemented or unsupplemented breast milk. At 3 months of age, radial bone mineral content was determined by single-photon absorptiometry and vitamin D metabolites were assessed. At 9 to 11 years of age, the bone mineral status of the radius and lumbar spine was assessed using dual energy x-ray absorptiometry. RESULTS: At the age of 3 months, the preterm infants with diets supplemented with minerals had 36% higher bone mineral content than the preterm infants whose diet was not supplemented with minerals. At the age of 9 to 11 years, in contrast, bone mineral status was comparable among the groups, irrespective of different mineral supplementation during the neonatal period. Interestingly, the lumbar bone mineral apparent density was positively related to lactation in mineral-supplemented children. There was neither short-term nor long-term benefit to bone mineral status of a vitamin D dose of 1000 IU/day compared with 500 IU/day. CONCLUSIONS: The short-term benefit to bone mineral density in preterm infants of mineral supplementation of the early diet is obvious, but, in the long term, the effects seem to disappear. The results also imply that a relatively long period of breast-feeding may be needed to optimize long-term bone mineral acquisition in the lumbar spine.

Absorptiometry, Photon↗

PubMed1998

32P-postlabelling of N6-adenine adducts of epoxybutanediol in vivo after 1,3-butadiene exposure.

Epoxybutanediol is one of the epoxide metabolites of butadiene (BD). A pair of diastereomeric N-1-adenine adducts were formed by reacting epoxybutanediol with deoxyadenosine 5'-monophosphate (5'-dAMP). These two N-1-adenine adducts rearranged in a base-catalysed reaction to an N6-trihydroxybutyl-adenine adduct, which was characterized by UV and mass spectroscopy. Using the 32P-postlabelling/HPLC assay the same adducts were detected in diepoxybutane (DEB)-treated DNA in vitro and in liver DNA samples from rats exposed to BD by inhalation. Adenine adducts of epoxybutanediol are probably suitable for monitoring BD exposure.

Animals↗

PubMed1998

DNA binding of tamoxifen and its analogues: identification of the tamoxifen-DNA adducts in rat liver.

DNA binding of tamoxifen and some structurally-related drugs (toremifene, clomiphene, triparanol and raloxifene) in rat liver was studied using the 32P-postlabelling method. As only tamoxifen was shown to form high levels of DNA adducts, the identity of these adducts was studied. Recently, we have identified by mass spectroscopy the two main tamoxifen adducts in rat liver DNA as the N-desmethyltamoxifen and tamoxifen adducts of N2-deoxyguanosine in which the linkage is through alpha-carbon in the tamoxifen structure. Minor adducts were identical to different diastereomers of alpha-(N2-deoxyguanosinyl)tamoxifen and of alpha-(N6-deoxyadenosinyl)tamoxifen. Altogether these adducts accounted for at least 95% of adducts formed in vivo, implicating that the alpha-hydroxylation of the ethyl group is the major activation pathway for DNA adducts.

Animals↗

PubMed1998

Risk factors and prognosis for psychiatric morbidity in children and adolescents.

Because of the new epidemiological studies during the past two decades our knowledge concerning child and adolescent psychiatric disorders has grown up. There exists data concerning the distribution of different disorders in the community. The development in the methodology of child psychiatric investigation has made it possible to study also the risk factors and prognostic features of child psychiatric disorders. In this paper risk and prognostic factors of various child psychiatric disorders are reviewed. All the findings from studies made in different countries are not suitable as such in Finland. No large scale epidemiological studies concerning the risk and prognostic factors of various child psychiatric disorders are available in Finland. The cohort-66 study offers a possibility to elucidate also these factors.

Adolescent↗

PubMed1997

Analysis of tamoxifen-induced DNA adducts by 32P-postlabelling assay using different chromatographic techniques.

DNA isolated from livers of rats receiving tamoxifen was analysed by the 32P-postlabelling method. The postlabelled DNA hydrolysis mixture was analysed both by reversed-phase HPLC with 32P on-line detection and by TLC on polyethyleneimine plates followed by autoradiography. Using the HPLC method, five well separated adduct peaks could be detected, while by the TLC method, two groups of adduct spots were observed. The detection limit of the TLC assay was lower (0.5 adducts/10(10) nucleotides) than that of the HPLC assay (3 adducts/10(10) nucleotides). Thus, the TLC assay is more sensitive but also more laborious. The advantages of the HPLC assay were, in addition to better resolution, the ease of quantification and operation.

Animals↗