Inkeri Ruokonen

Boron neutron capture therapy of brain tumors: clinical trials at the Finnish facility using boronophenylalanine

SummaryTwo clinical trials are currently running at the Finnish dedicated boron neutron capture therapy (BNCT) facility. Between May 1999 and December 2001, 18 patients with supratentorial glioblastoma were treated with boronophenylalanine (BPA)-based BNCT within a context of a prospective clinical trial (protocol P-01). All patients underwent prior surgery, but none had received conventional radiotherapy or cancer chemotherapy before BNCT. BPA-fructose was given as 2-h infusion at BPA-dosages ranging from 290 to 400 mg/kg prior to neutron beam irradiation, which was given as a single fraction from two fields. The average planning target volume dose ranged from 30 to 61 Gy (W), and the average normal brain dose from 3 to 6 Gy (W). The treatment was generally well tolerated, and none of the patients have died during the first months following BNCT. The estimated 1-year overall survival is 61%. In another trial (protocol P-03), three patients with recurring or progressing glioblastoma following surgery and conventional cranial radiotherapy to 50–60 Gy, were treated with BPA-based BNCT using the BPA dosage of 290 mg/kg. The average planning target dose in these patients was 25–29 Gy (W), and the average whole brain dose 2–3 Gy (W). All three patients tolerated brain reirradiation with BNCT, and none died during the first three months following BNCT. We conclude that BPA-based BNCT has been relatively well tolerated both in previously irradiated and unirradiated glioblastoma patients. Efficacy comparisons with conventional photo radiation are difficult due to patient selection and confounding factors such as other treatments given, but the results support continuation of clinical research on BPA-based BNCT.

Effect of high-dose statin treatment on plasma concentrations of endogenous nitric oxide synthase inhibitors.

Asymmetric dimethylarginine (ADMA) and monomethylarginine (LMMA) are endogenous inhibitors of nitric oxide synthase. A high level of ADMA in plasma has shown to be a significant risk factor for acute coronary syndromes and elevated plasma ADMA levels are prevalent in patients with hypercholesterolemia. It was therefore hypothesized that lowering plasma cholesterol levels with statin treatment would also lower ADMA concentrations. This double-blind study addressed the effect of high-dose statin treatment on plasma levels of ADMA and LMMA. Forty-eight subjects with mild hypercholesterolemia were randomly assigned to receive simvastatin 80 mg/d, atorvastatin 40 mg/d, or placebo for 8 weeks. Both statins decreased low-density lipoprotein cholesterol effectively (simvastatin 54% and atorvastatin 49%). However, concentrations of arginine derivatives remained unchanged during statin treatment and did not correlate with cholesterol levels. This study indicates that statin treatment has no clear influence on plasma ADMA or LMMA concentrations.

Asymmetrical dimethylarginine (ADMA) and risk of acute coronary events: Does statin treatment influence plasma ADMA levels?

The purpose of this study was to evaluate the hypothesis that high serum levels of ADMA, an indicator of endothelial dysfunction, are associated with an elevated risk of acute coronary events in middle-aged men. To test the hypothesis that lipid lowering medication with statins lowers circulating ADMA levels, we also investigated the effect of simvastatin and atorvastatin treatment on plasma ADMA concentration. In a prospective nested case-control study in 150 middle-aged non-smoking men from Eastern Finland, those who were in the highest quartile for serum ADMA (>0.62 micromol/l) had a 3.9-fold (95% CI: 1.25-12.3, P=0.02) increase in risk of acute coronary events compared with other quartiles. In an 8-week randomised double-blind placebo-controlled trial, plasma ADMA concentrations remained unchanged in simvastatin 80 mg/day (n=16), atorvastatin 40 mg/day (n=16) and placebo (n=16) groups over the study period. Our findings indicate that high serum levels of ADMA, a potential marker for endothelial dysfunction, may increase the risk of acute coronary syndromes. However, aggressive treatment with either simvastatin or atorvastatin did not reduce plasma ADMA levels.

A STUDY WITH A FOLLOW-UP OF THE EFFECTS OF MUSIC EDUCATION ON HOLISTIC DEVELOPMENT OF EMPATHY '

Half of the 32 children, aged 6 yr. old, took part in the 12-hr. holistic empathy education program with music exercises over three months. Others were controls. Children were tested at a pretest, 3 months later at the posttest after the training, and follow-up test, 9 months after posttest. The Feshbach and Roe Empathy Slide Test, the Weir and Duveen Prosociability Rating Scale, and the Kalliopuska Prosociability Rating Scale for Teachers were used. Empathy and prosociability increased significantly from pretest to posttest after empathy education. As hypothesized, comparison of pretest and follow-up test results showed a significant increase in empathy for the test group and a nonsignificant increase among controls.

Clinical implementation of 4-dihydroxyborylphenylalanine synthesised by an asymmetric pathway.

Boron neutron capture therapy (BNCT) is an experimental therapeutic modality combining a boron pharmaceutical with neutron irradiation. 4-Dihydroxyborylphenylalanine (L-BPA) synthesised via the asymmetric pathway by Malan and Morin [Synlett. 167-168 (1996)] was developed to be the boron containing pharmaceutical in the first series of Finnish BNCT clinical trials. The final product was >98.5% chemically pure L-BPA with L-phenylalanine and L-tyrosine as the residual impurities. The solubility of L-BPA was enhanced by complex formation with fructose (BPA-F). The pH and osmolarity of the BPA-F preparation is in the physiological range. Careful attention was given to the pharmaceutical quality of the BPA-F preparations. Prior to starting clinical trials the acute toxicity of L-BPA was studied in male albino Sprague-Dawley rats. In accordance with earlier studies no adverse effects were observed. After completion of the development work L-BPA solution was administered to brain tumour patients in conjunction with clinical studies for development and testing of BPA-based BNCT. No clinically significant adverse events attributable to the L-BPA i.v. infusions were observed. We conclude that our synthesis development, complementary preclinical and clinical observations justify the safe use of L-BPA up to clinical phase III studies with L-BPA produced by the asymmetric pathway, originally presented by Malan and Morin in 1996.

Dietary intake and indicators of magnesium and zinc status in male athletes

Abstract Indices of magnesium and zinc status were measured in 114 male endurance athletes and 117 healthy controls. Dietary energy, magnesium and zinc intakes, calculated from 122-item food use questionnaires for 1 month, were higher in athletes (p 0.05). Levels of serum zinc (95% CIs for the mean in athletes: 13.3–14.0 μmol/L, controls: 13.4–14.1 μmol/L) and erythrocyte magnesium (athletes: 6.72–7.00 μmol/g Hb, controls: 6.88–7.12 μmol/g Hb) did not differ significantly between the groups. The athletes had higher (p

Effects of Music Education on Development of Holistic Empathy

To survey the empathy of 6-yr.-old children and the role of music education in developing empathy from two day-care centers 15 children took part for 3 mo. in music activities once a week; the remaining 15 were controls. Children were tested before and after a period of musical activities. The childrens empathy was measured with the Feshbach and Roe Empathy Test and the Ikonen-Nylund Test on Sociability. The teachers completed Weir and Duveens Prosociability Scale and the Kalliopuska Prosociability Scale. In the trained group empathy increased significantly relative to that of the control group. The holistic view of empathy stresses that an optimal empathy campaign should develop affective, cognitive, and kinaesthetic aspects of empathy.

Children's creativity in day care

In this research, childrens creativity in pretend play and the conditions for creativity during high involvement are studied from four points of view: as a zone for proximal development, as a skill, as a personal orientation and as a culturally shared environment creation. The theoretical model is influenced by Vygotskys ideas of creativity as cultural mediation. The research methods are systematic observation and skill evaluation. The participants are 280 Finnish four- to five-year-old children in day care. The results highlight the importance of play both by sheer volume and also by childrens involvement in it. Childrens internalised skills result in personal choices and a personal network of peer contacts. The different choices result in different creative culture production environments. Creative children attract each other and they meet in creative social processes. However, less creative children get excluded from the creative core. Thus, children who need creative scaffolding the most get it the least. The possibilities of involving children in creative processes are discussed.

Inborn Errors in Metabolism and 4-Boronophenylalanine–Fructose-Based Boron Neutron Capture Therapy

Abstract Laakso, J., Ruokonen, I., Lapatto, R. and Kallio, M. Inborn Errors in Metabolism and 4-Boronophenylalanine–Fructose-Based Boron Neutron Capture Therapy. Radiat. Res. 160, 606–609 (2003) Infusions of boronophenylalanine–fructose complex (BPA-F), at doses up to 900 mg/kg of BPA and 860 mg/kg of fructose, have been used to deliver boron to cancer tissue for boron neutron capture therapy (BNCT). In patients with phenylketonuria (PKU), phenylalanine accumulates, which is harmful in the long run. PKU has been an exclusion criterion for BPA-F-mediated BNCT. Fructose is harmful to individuals with hereditary fructose intolerance (HFI) in amounts currently used in BNCT. The harmful effects are mediated through induction of hypoglycemia and acidosis, which may lead to irreversible organ damage or even death. Consequently, HFI should be added as an exclusion criterion for BNCT if fructose-containing solutions are used in boron carriers. Non-HFI subjects may also develop symptoms, such as gastrointestinal pain, if the fructose infusion rate is high. We therefore recommend monitoring of glucose levels and correcting possible hypoglycemia promptly. Except for some populations with extremely low PKU prevalence, HFI and PKU prevalences are similar, approximately 1 or 2 per 20,000.

Music behind scores: case study of learning improvisation with Playback Orchestra method

For music students in the early stages of learning, the music may seem to be hidden behind the scores. To support home practising, Juntunen has created the Playback Orchestra method with which the students can practise with the support of the notation program playback of the full orchestra. The results of testing the method with first-grade string instrument students showed that the group who used the playback method learned faster than the group who did not. The clear and expressive body movements that are developed effectively by the playback method also provide support for leading a group by playing. The aim of this recent pilot study was to discover if improvisation benefits from an audio learning component. The research is a qualitative case study combined with quasi-experimental tests and quantitative analyses. The improvisation task was to describe a storm in a long musical tale, Mickey Mouse in a Storm, which had several episodes in different atmospheres. The results showed that the playback group was clearly better in terms of ‘joy of playing’, ‘concentrating’, ‘finding ones own improvising ideas’ and ‘understanding the overall picture’. The most crucial finding was that ‘intensive continuity’ improved faster in the playback group.