Announcement of the Fulker Award for a Paper Published in <Emphasis Type="Italic">Behavior Genetics</Emphasis>, Volume 34, 2004

Announcement

Announcement of the Fulker Award for a Paper Published in Behavior Genetics, Volume 34, 2004     

Predicted effects of toxicant mixtures are confirmed by changes in fish species assemblages in Ohio, USA, rivers

The purposes of this study were to investigate whether exposure to toxicant mixtures is associated with fish assemblage characteristics in the field and to describe the relationships between predicted chronic and acute mixture risks and observed impacts. Fish abundance and abiotic monitoring data from Ohio, USA, surface waters were compiled and analyzed. Variability of biotic and abiotic parameters was large. Exposure assessment, risk assessment with species-sensitivity distributions, and mixture toxicity rules were used to calculate a relative risk predictor: The multisubstance potentially affected fraction of species (msPAF). Predicted acute and chronic risks ranged from low values to more than 10 and 50% of species potentially affected, respectively. Pearson correlations between predicted risk and observed assemblage characteristics were nonsignificant for total abundance, number of species, Shannon-Weaver index, and evenness. Moderately significant correlations were found between predicted risk and abundance for 23% of individual species. Both abundance increases and decreases were observed. Generalized linear model (GLM) regressions revealed significant nonlinear associations between predicted risk and the abundance for 50% (metals and ammonia) and 55% (household product ingredients) of the species. Local ecological impact was expressed as the fraction of species expected but not observed, both with and without attribution of impact to mixture exposure. The association between predicted impacted fraction and the fraction of species expected but not observed was not significant. Predicted acute and chronic impacted fractions were associated significantly with the observed fraction of species likely lost by the action of toxicant mixtures under field conditions, with wide confidence bounds. These findings confirm the view that higher mixture impacts are expected in the field at higher msPAF.     

A Note on the Statistical Power in Extended Twin Designs

The power to detect sources of genetic and environmental variance varies with sample size, study design, effect size and the statistical significance level chosen. We explored whether the power of the classical twin study may be increased by adding non-twin siblings to the classical twin design. Sample sizes to detect genetic and shared environmental variation were compared for kinships with only twins, kinships consisting of twins and one additional sibling, and kinships with twins and two additional siblings. The effect of adding siblings to the classical twin design was considered for univariate and bivariate analyses. For the univariate case, adding one non-twin sibling resulted in a decrease in sample size needed to detect additive genetic influences in the presence of environmental influences. However, adding two additional siblings did not decrease the number of subjects as compared to the classical twin design. The sample size required to detect common environmental factors was also greatly decreased by adding one non-twin sibling. Adding two non-twin siblings resulted in a small additional decrease. In models including additive genetic, dominant genetic, and unique environmental effects, adding one sibling to a twin family decreased the required sample size to detect dominant genetic influences. Adding two siblings to a twin family resulted in only a slight additional decrease in sample size. In the bivariate case a similar pattern of results was found, in addition to the observation that the overall required sample size, as expected, was lower than in the univariate case. The decrease in sample size from bivariate testing was more pronounced in a design with one or two additional siblings, as compared to a design with twins only. It is concluded that a well considered choice of family design, i.e. including families with twins and one or two additional siblings increases the statistical power to detect sources of variance due to additive and non-additive genetic influences, and common environment.     

Alpha-interferon with very-low-dose donor lymphocyte infusion for hematologic or cytogenetic relapse of chronic myeloid leukemia induces rapid and durable complete remissions and is associated with acceptable graft-versus-host disease.

Donor lymphocyte infusion (DLI) results in complete cytogenetic remission (CCR) of relapsed chronic-phase chronic myeloid leukemia (CML-CP) after allogeneic stem cell transplantation (SCT) in up to 80% of patients. The main complication of DLI is graft-versus-host disease (GVHD). Decreasing the dose of DLI is associated with less GVHD but also with a longer interval between treatment and CCR. We postulated that combining alpha-interferon (alpha-IFN) with DLI would enable us to decrease the dose of DLI, thereby limiting GVHD, and at the same time to decrease the interval between DLI and CCR for patients with either a hematologic or cytogenetic relapse. For molecular relapses, we hypothesized that because of a lower tumor load, very low doses of DLI without alpha-IFN could be an effective treatment. Two groups of CML-CP patients treated with DLI at a very low dose of 0.5 to 1.0 x 10(7) mononuclear cells per kilogram, containing 2 to 6 x 10(6) CD3+ T cells per kilogram, were analyzed: 13 patients with a cytogenetic or a hematologic relapse after allogeneic SCT (group A) were treated with additional alpha-IFN therapy at a dose of 3 x 10(6) U 5 d/wk, and 8 patients with a molecular relapse were treated without alpha-IFN (group B). Twelve patients from group A reached a CCR. The median interval between DLI and CCR was 7 weeks (range, 5-18 weeks) for group A. All patients with a CCR reached complete donor chimerism at a median of 10 weeks after DLI (range, 6-121 weeks). Eleven patients reached molecular remission at a median of 15 weeks after DLI (range, 8-34 weeks). In group B, all patients reached a molecular remission at a median of 14 weeks (range, 12-29 weeks). Five patients from group A developed acute GVHD grade II to IV and extensive chronic GVHD. In group B, 1 patient developed acute GVHD grade II to IV and subsequently developed extensive chronic GVHD. With a median follow-up of 62 months, 10 patients in group A are alive and in continuous CCR. One patient had a molecular relapse, for which she successfully received additional DLI; another patient reached molecular remission only after 5 doses of DLI. Two patients from group A died of a gram-negative sepsis, and 1 died of an acute myocardial infection. In group B, all patients are alive and in molecular remission with a median follow-up of 20 months. One patient's disease progressed but was successfully treated with DLI plus alpha-IFN. In conclusion, very-low-dose DLI in combination with alpha-IFN as treatment for cytogenetic or hematologic relapses of CML-CP after allogeneic SCT reduced the interval to obtain a CCR with acceptable GVHD when compared with the literature. Patients with a CCR also reached complete donor chimerism and complete molecular remissions. For patients with a molecular relapse, very-low-dose DLI alone is sufficient to induce molecular remissions in most patients and is associated with limited GVHD.     

Clinical Practice Guidelines for Diagnosis and Treatment of Chronic Lymphocytic Leukemia (CLL) in The Netherlands

Introduction

In recent years, considerable progress has been made in the treatment of patients with chronic lymphocytic leukemia (CLL), and new potent drugs have become available. Therefore, the CLL working party revised the Dutch guidelines. Not only efficacy but also quality of life and socio-economic impact were taken into account in the formulation of treatment recommendations.

Taste and smell perception and quality of life during and after systemic therapy for breast cancer

Purpose

The purpose of the study was to assess self-reported taste and smell perception after chemotherapy in breast cancer patients compared with women without cancer, and to assess whether taste and smell perception is associated with quality of life after the end of chemotherapy.

Methods

We included 135 newly diagnosed breast cancer patients who completed chemotherapy and 114 women without cancer. Questionnaires on taste, smell, and quality of life were completed shortly after and 6 months after chemotherapy (patients) or at two moments with 6 months’ time window in between (comparisons).

Results

Self-reported taste and smell perception were significantly lower in patients shortly after chemotherapy compared to the comparison group. Most patients recovered 6 months after chemotherapy, although patients who were still receiving trastuzumab then reported a lower taste and smell perception compared to patients who were not. A lower self-reported taste and smell were statistically significantly associated with a worse quality of life, social, emotional, and role functioning shortly after chemotherapy. Six months after chemotherapy, taste and smell were statistically significantly associated with quality of life, social and role functioning, but only in patients receiving trastuzumab.

Conclusions

Most taste and smell alterations recovered within 6 months after the end of chemotherapy for breast cancer, but not for patients receiving trastuzumab. These results highlight the importance of monitoring taste and smell alterations during and after treatment with chemotherapy and trastuzumab, as they may impact quality of life.

     

'Oversaturation' of transferrin after intravenous ferric gluconate (FerrlecitR) in haemodialysis patients

BACKGROUND: Chronic haemodialysis causes blood loss and iron-deficiency.This can be corrected with intravenous preparations, e.g. sodiumferric-gluconate (FeGl). In two patients complaints of hypotensionand malaise during FeGl infusion coincided with high levelsof serum iron and a calculated transferrin iron saturation above100%. Iron toxicity could be the cause of these complaints.Free iron is known to aggravate the toxicity of free radicalsand other reactive oxygen products that are constantly formedin the body. We compared four rates of FeGl infusion with regardto iron parameters. METHODS: 20 dialysis patients received a total of 36 infusions of FeGl.A rapid infusion of 125 mg (Protocol A (n=10)) or 62.5 mg (ProtocolB (n=7)) of FeGl was given during the last 30 min of dialysis.A slow infusion of 125 mg (Protocol C (n=9)) or 62.5 mg (ProtocolD (n=10)) was given during 4 or 4.5 h of dialysis. Blood wastaken at regular intervals before, during, and after dialysisfor determination of serum iron, transferrin, ferritin, haematocrit,total protein, albumin, and lactate dehydrogenase (LDH). Transferrinsaturation was calculated from transferrin and serum iron. RESULTS: With rapid infusion A (125mg) the highest levels of serum iron(median 120 (range 40–159) micromol/l) and transferrinsaturation (207 (84–331)%) were seen at the end of theinfusion. These were significantly higher than the peak levelswith B, C, and D (P0.03). With rapid infusion B (62.5 mg), peaklevels were intermediately high (serum iron 61 (50–96)µmol/l; transferrin saturation 118 (91–174)%). Withslow infusion C (125 mg) similar peak levels were seen (serumiron 83 (43–106) µmol/l; transferrin saturation141 (88–172)%). With slow infusion D (62.5 mg), the lowestpeak levels were seen (serum iron 38 (31–55) µmol/l;transferrin saturation 78 (43–92)%). These levels weresignificantly lower than those with A, B and C (p0.002). Onlywith D all patients showed a transferrin saturation lower than100%. Ferritin was increased before the next dialysis in allpatients. LDH was not significantly elevated during any infusion. CONCLUSIONS: The commonly used rapid infusion rate (A) of FeGl causes ‘oversaturation’of transferrin. This is compatible with iron toxicity due tofree iron which may explain our patients' complaints. Free ironcannot be measured directly. LDH as a crude measure of celldamage was not elevated. Better measurements to prove free irontoxicity, like lipid peroxides, are not yet readily available.Infusion during a longer period at a lower dose (D) is effectiveand eliminates ‘oversaturation’ of transferrin andprobably the danger of iron toxicity.     

ADHD: sibling interaction or dominance: an evaluation of statistical power

Sibling interaction effects are suggested by a difference in phenotypic variance between mono-zygotic (MZ) twins and dizygotic (DZ) twins, and a pattern of twin correlations that is inconsistent with additive genetic influences. Notably, negative sibling interaction will result in MZ correlations which are more than twice as high as DZ correlations, a pattern also seen in the presence of genetic dominance. Negative sibling interaction effects have been reported in most genetic studies on Attention Deficit Hyperactivity Disorder (ADHD) and related phenotypes, while the presence of genetic dominance is not always considered in these studies. In the present paper the statistical power to detect both negative sibling interaction effects and genetic dominance is explored. Power calculations are presented for univariate models including sources of variation due to additive genetic influences, unique environmental influences, dominant genetic influences and a negative sibling interaction (i.e., contrast effect) between phenotypes of twins. Parameter values for heritability and contrast effects are chosen in accordance with published behavior genetic studies on ADHD and associated phenotypes. Results show that when both genetic dominance and contrast effects are truly present and using a classical twin design, genetic dominance is more likely to go undetected than the contrast effect. Failure to detect the presence of genetic dominance consequently gives rise to slightly biased estimates of additive genetic effects, unique environmental effects, and the contrast effect. Contrast effects are more easily detected in the absence of genetic dominance. If the significance of the contrast effect is evaluated while also including genetic dominance, small contrast effects are likely to go undetected, resulting in a relatively large bias in estimates of the other parameters. Alternative genetic designs, such as adding pairs of unrelated siblings reared together to a classical twin design, or adding non-twin siblings to twin pairs, greatly enhances the statistical power to detect contrast effects as well as the power to distinguish between genetic dominance and contrast effects.     

EphA2 Targeted Doxorubicin-Nanoliposomes for Osteosarcoma Treatment

Pharmaceutical Research - To employ Doxorubicin-loaded liposomes, modified with YSA-peptide to target EphA2, to reduce adverse effects against primary bone cells and maximize toxicity against...     

Involvement of astrocyte metabolic coupling in Tourette syndrome pathogenesis

Tourette syndrome is a heritable neurodevelopmental disorder whose pathophysiology remains unknown. Recent genome-wide association studies suggest that it is a polygenic disorder influenced by many genes of small effect. We tested whether these genes cluster in cellular function by applying gene-set analysis using expert curated sets of brain-expressed genes in the current largest available Tourette syndrome genome-wide association data set, involving 1285 cases and 4964 controls. The gene sets included specific synaptic, astrocytic, oligodendrocyte and microglial functions. We report association of Tourette syndrome with a set of genes involved in astrocyte function, specifically in astrocyte carbohydrate metabolism. This association is driven primarily by a subset of 33 genes involved in glycolysis and glutamate metabolism through which astrocytes support synaptic function. Our results indicate for the first time that the process of astrocyte-neuron metabolic coupling may be an important contributor to Tourette syndrome pathogenesis.