Tankyrase inhibition aggravates kidney injury in the absence of CD2AP.

Inappropriate activation of the Wnt/ß-catenin pathway has been indicated in podocyte dysfunction and injury, and shown to contribute to the development and progression of nephropathy. Tankyrases, multifunctional poly(ADP-ribose) polymerase (PARP) superfamily members with features of both signaling and cytoskeletal proteins, antagonize Wnt/ß-catenin signaling. We found that tankyrases interact with CD2-associated protein (CD2AP), a protein essential for kidney ultrafiltration as CD2AP-knockout (CD2AP-/-) mice die of kidney failure at the age of 6-7 weeks. We further observed that tankyrase-mediated total poly-(ADP-ribosyl)ation (PARylation), a post-translational modification implicated in kidney injury, was increased in mouse kidneys and cultured podocytes in the absence of CD2AP. The data revealed increased activity of ß-catenin, and upregulation of lymphoid enhancer factor 1 (LEF1) (mediator of Wnt/ß-catenin pathway) and fibronectin (downstream target of Wnt/ß-catenin) in CD2AP-/- podocytes. Total PARylation and active ß-catenin were reduced in CD2AP-/- podocytes by tankyrase inhibitor XAV939 treatment. However, instead of ameliorating podocyte injury, XAV939 further upregulated LEF1, failed to downregulate fibronectin and induced plasminogen activator inhibitor-1 (PAI-1) that associates with podocyte injury. In zebrafish, administration of XAV939 to CD2AP-depleted larvae aggravated kidney injury and increased mortality. Collectively, the data reveal sustained activation of the Wnt/ß-catenin pathway in CD2AP-/- podocytes, contributing to podocyte injury. However, we observed that inhibition of the PARylation activity of tankyrases in the absence of CD2AP was deleterious to kidney function. This indicates that balance of the PARylation activity of tankyrases, maintained by CD2AP, is essential for normal kidney function. Furthermore, the data reveal that careful contemplation is required when targeting Wnt/ß-catenin pathway to treat proteinuric kidney diseases associated with impaired CD2AP.

Podocyte apoptosis is prevented by blocking the Toll-like receptor pathway.

High serum lipopolysaccharide (LPS) activity in normoalbuminuric patients with type 1 diabetes (T1D) predicts the progression of diabetic nephropathy (DN), but the mechanisms behind this remain unclear. We observed that treatment of cultured human podocytes with sera from normoalbuminuric T1D patients with high LPS activity downregulated 3-phosphoinositide-dependent kinase-1 (PDK1), an activator of the Akt cell survival pathway, and induced apoptosis. Knockdown of PDK1 in cultured human podocytes inhibited antiapoptotic Akt pathway, stimulated proapoptotic p38 MAPK pathway, and increased apoptosis demonstrating an antiapoptotic role for PDK1 in podocytes. Interestingly, PDK1 was downregulated in the glomeruli of diabetic rats and patients with type 2 diabetes before the onset of proteinuria, further suggesting that reduced expression of PDK1 associates with podocyte injury and development of DN. Treatment of podocytes in vitro and mice in vivo with LPS reduced PDK1 expression and induced apoptosis, which were prevented by inhibiting the Toll-like receptor (TLR) signaling pathway with the immunomodulatory agent GIT27. Our data show that LPS downregulates the cell survival factor PDK1 and induces podocyte apoptosis, and that blocking the TLR pathway with GIT27 may provide a non-nephrotoxic means to prevent the progression of DN.

Frequent use of sugar products by schoolchildren in 20 European countries, Israel and Canada in 1993/1994.

The aim of this study was to describe the daily use of certain between-meal sugar products (soft drinks and sweets) of schoolchildren in 20 European countries, Israel and Canada as a part of the Cross-National Survey on Health Behaviour in School-Aged Children--a WHO Collaborative Study. The data were collected using standardised anonymous questionnaires in school classrooms during the 1993/1994 school year. In each country nationally or regionally representative samples of about 1,300 schoolchildren (450 in Greenland) were targeted. Use of sugar products was analysed according to sex, age, country, self-reported school performance and self-reported family economy. One third to one half of the children (30-48 per cent) drank coke or other soft drinks more than once a day in Israel, Northern Ireland, Scotland, the Slovak Republic and Flemish-speaking Belgium. Use of soft drinks was very uncommon in Finland, Sweden, Norway, Denmark, Latvia and Estonia. The strongest association (odds ratios) was between the use of soft drinks and good family economy; in Russia (20.3), in Lithuania (11.3), in Latvia (10.0), in Poland (8.5) and in Estonia (8.0). In Israel, Scotland, Northern Ireland, Russia and French-speaking Belgium 41-29 per cent of the children ate sweets more than once a day. Boys drank soft drinks and ate sweets slightly more often than girls did. In conclusion, large differences were found between the different countries in the frequency of use of soft drinks and sweets. This should be considered when developing the content of oral health promotion programmes.

Metal ion-dependent hydrolysis of RNA phosphodiester bonds within hairpin loops. A comparative kinetic study on chimeric ribo/2'-O-methylribo oligonucleotides.

Several chimeric ribo/2'- O -methylribo oligonucleotides were synthesized and their hydrolytic cleavage studied in the presence of Mg2+, Zn2+, Pb2+and the 1,4,9-triaza-cyclododecane chelate of Zn2+(Zn2+[12]aneN3) to evaluate the importance of RNA secondary structure as a factor determining the reactivity of phosphodiester bonds. In all the cases studied, a phosphodiester bond within a 4-7 nt loop was hydrolytically more stable than a similar bond within a linear single strand, but markedly less stable than that in a double helix. With Zn2+and Zn2+[12]aneN3, the hydrolytic stability of a phosphodiester bond within a hairpin loop gradually decreased on increasing the distance from the stem. A similar but less systematic trend was observed with Pb2+. Zn2+- and Pb2+-promoted cleavage was observed to be considerably more sensitive to the secondary structure of the chain than that induced by Zn2+[12]aneN3. This difference in behaviour may be attributed to bidentate binding of uncomplexed aquo ions to two different phosphodiester bonds. Mg2+was observed to be catalytically virtually inactive compared with the other cleaving agents studied.

Oral hygiene habits of 11-year-old schoolchildren in 22 European countries and Canada in 1993/1994.

This study is part of the Cross-National Survey on Health Behaviour in School-aged Children--a WHO Collaborative Study, which started in 1982. The aim of the study was to describe the oral hygiene habits (toothbrushing and flossing) of 11-year-old schoolchildren in 22 European countries (Austria, Belgium, the Czech Republic, Denmark, Estonia, FInland, France, Germany, Greenland, Hungary, Israel, Latvia, Lithuania, Northern Ireland, Norway, Poland, Russia, Scotland, the Slovak Republic, Spain, Sweden, and Wales) and Canada. The data were collected from standardized anonymous questionnaires in school classrooms during the 1993-1994 school year. At least 1300 school children, representing the whole country, participated in the study in each country. Oral hygiene habits were analyzed according to gender, age, country, school performance, and family economy. The children brushed most favorably in Sweden, Denmark, German, Austria, and Norway (83-73% brushed twice a day). More-than-once-a-day toothbrushing was especially uncommon (from 26 to 33%) among boys in Finland, Lithuania, Russia, Estonia, and Latvia. Toothbrushing frequency differed significantly according to school performance in Canada, the Czech Republic, Scotland, Poland, Northern Ireland, and Wales and between different socio-economic groups in Northern Ireland, Wales, the Czech Republic, Scotland, Poland, and Russia. Use of dental floss was rare. In general, flossing was less frequent among boys than among girls. Daily flossing was most common among Canadian adolescents (25%). In conclusion, there are considerable differences in toothbrushing frequency among children in European countries.

Trends in toothbrushing frequency among Finnish adolescents between 1977 and 1995.

OBJECTIVE: To analyse trends in development of the toothbrushing frequency of Finnish adolescents and the socio-economic factors associated with these trends between 1977 and 1995. DESIGN: The data were collected as part of a nation-wide research programme, the Adolescent Health and Lifestyle Survey, which started in 1977. Since then a 12-page questionnaire has been sent every other year. Dental health behaviour was studied from the outset. SUBJECTS: The sample represented 12-, 14-, 16- and 18-year-old children and adolescents in Finland. The sample size varied between 3,205-10,626, making a total of 66,687 participants. OUTCOME MEASURES: The recommended toothbrushing frequency, twice-a-day, was studied. The socio-economic factors included age, gender, self-assessed school performance, level of education, socio-economic status of the householder, and socio-economic category of the residential area. RESULTS: Among boys, daily toothbrushing increased from 1977 to 1995, but among girls it remained stable. Among boys, the prevalence of twice-a-day toothbrushing frequency varied from 13 per cent to 25 per cent between the ages of 12 and 18 years, and among girls from 32 per cent to 60 per cent, respectively. Among 12- to 14-year-old boys, the socio-economic differences almost disappeared. There were no changes among 12- to 14-year-old girls but there was an unexpected declining trend in toothbrushing among 16- to 18-year-old girls. Apparently further improvement in the toothbrushing frequency of girls had stopped. CONCLUSIONS: Although there was a clear trend towards improvement of toothbrushing frequency among boys, their toothbrushing frequency still lagged far behind that of girls.

How does the use of different sugar products predict caries in 18-year-old Finns?

The aim of this study was to determine whether self-reported (but diagnosed previously by a dentist) caries incidence of eighteen-year-olds could be predicted based on their use of sweets, cakes sugar-sweetened coffee or tea between the ages of twelve and eighteen. The data were collected as part of the nationwide research program, the Adolescent Health and Lifestyle Survey. All Finns born in 1968 and having their birthdays on 20-25th July formed the same (N = 1106). The 1981 survey (adolescents at the age of twelve) was the baseline, and follow-up questionnaires were sent in 1983, 1985 and 1987. The chi-square test and logistic regression model were used in the analyses. Different sugar products were slightly more significant predictors with the chi-square test than by logistic regression model. Among boys, the most common predictor, daily use of sugar-sweetened coffee, was an important predictor, although the risk was quite low. For girls, no predictors were found.

Dental services utilization between 1977 and 1995 by Finnish adolescents of different socioeconomic levels.

Equal distribution of health care services has long been a major goal of health policy in the Nordic countries. According to these guidelines, every child is expected to have an examination and treatment at least every second year. The aim of this study was to analyze the trends and, in particular, the socioeconomic differences in dental visits between 1977 and 1995. The data were collected as part of a nationwide research program, the Adolescent Health and Lifestyle Survey, which began in 1977. Every second year a self-administered questionnaire was mailed to a representative sample of 14-, 16- and 18-year-old Finns. The sample sizes in the surveys varied from 2422 to 9556, making a total of 56,605 subjects in the whole study. The response rates in different years varied from 77% to 88%. The percentage of adolescents visiting a dentist increased between 1977 and 1981 and thereafter remained stable. Dental visits seemed to correlate with the occupational and educational status of the parents up to 1983, but not after that. The Finnish primary oral health care policy seems to have gained a major objective by eliminating social inequality in dental service utilization among adolescents.

Toothbrushing frequency between the ages of 12 and 18 years-- longitudinal prospective studies of Finnish adolescents.

The purpose of this study was to analyse the establishment of the toothbrushing frequency as a healthy habit by Finnish adolescents between 12 and 18 years of age. The data were collected as part of the nation-wide research programme, the Adolescent Health and Lifestyle Survey. All Finns born in 1968 with birthdays on 20-25 July formed the sample (N=1106). Questionnaires were mailed to the whole sample in February 1981 (12 years of age), -83 (14 years), -85 (16 years) and -87 (18 years). The rate of return for all four questionnaires was 62 percent (six-year follow-up) and for two questionnaires (two-year follow-up studies) 79 percent (12 and 14 years), 72 percent (14 and 16 years) and 68 percent (16 and 18 years). Those adolescents who brushed their teeth more than once a day at age 12, were more stable in their behaviour during the following six years than those who brushed their teeth less often. Over two thirds of the respondents, both boys and girls, indicated one or more changes in their toothbrushing frequency in the four questionnaires during the six-year follow-up. The rate of improvement in toothbrushing frequency was higher among girls than boys, and the rate of deterioration in toothbrushing frequency was higher among boys than girls. One sixth of the adolescents still showed a deterioration in their brushing frequency between the ages of 16 and 18. It may be concluded that although toothbrushing frequency will be gradually adopted as a health habit when the adolescents mature between 12 and 18 years, only half the girls and one fifth of the boys adopt the recommended frequency. Health education should still improve performance in those groups which have not established the recommended toothbrushing frequency.

Prolonged-release hard gelatin capsules of furosemide for the treatment of dogs.

The object of this study was to examine whether prolonged-release hard gelatin capsule formulations could be developed for dogs. Different viscosity grades of hydroxypropyl methylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC) were used to control drug release. Furosemide was chosen because of its wide use in the management of heart failure in dogs. In vitro, selecting different viscosity grades allowed good control of drug release, whereas in vivo the difference between formulations was clearly smaller. Although all formulations gave prolonged release, both inter- and intra-individual variation in the plasma concentration-time curves was high. It is difficult to develop prolonged-release formulations for drugs such as furosemide with highly variable pharmacokinetic properties. However, hard gelatin capsules containing hydrophilic polymers could still be a suitable choice for some drugs.

Lanthanide chelates as a tool in nucleic Acid chemistry.

The potentiality of lanthanide chelates as photoluminescent markers and cleaving agents of nucleic acids is discussed, the main emphasis being on the chelates derived from aromatic nitrogen bases.

Opinions of dental students in Dar es Salaam (Tanzania) and in Kuopio (Finland) concerning studies and expectations for future career.

The aim of this study was to compare the social background, career choice and future plans of dental students in a developing country, Tanzania, and in an industrialized country, Finland. In Dar es Salaam 100 per cent (n = 25) and in Kuopio 95 per cent (n = 120) of all dental students participated in this study during the academic year 1990-91 by returning an anonymous questionnaire. The similarities that Tanzanian and Finnish dental students shared were related to their feelings and opinions about dental studies and stress. In both places, dental studies seemed to be perceived quite stressful. However, most of the students from both countries planned to pursue further studies after graduation. As future career options, teaching and research were preferred among the Tanzanian students (38 per cent), while the majority of Finnish students (56 per cent) planned to work in community service. The observed difference in the preferred career options was most probably due to differing practical opportunities for a graduating dentist in the two countries.