Effects of cognitive-motor intervention for pediatric posterior fossa tumor survivors: results of a pilot study.

The purpose of this prospective pilot study was to evaluate the feasibility and effects of cognitive-motor intervention on the cognitive and motor abilities of pediatric survivors of posterior fossa tumors. The study involved patients aged 7 to 18 years with cognitive deficits who had completed primary treatment for posterior fossa tumors. 25 participants (Mage=11.3 ± 2.93, 64% male; 17 medulloblastoma, 1 ependymoma, 1 desmoplastic medulloblastoma, 6 piloid astrocytoma; 22 in remission (Mmonths =45), 3 in stabilization (Mmonths=49)) were recruited from the Research Institute for Brain Development and Peak Performance. The intervention consisted of two phases with a 3-month break for home training, and a total duration of 6 months. Each phase lasted 7 weeks and included two assessment procedures (pre- and post-intervention) and 10 training sessions over a period of 5 weeks (two 3-hour sessions per week). At baseline and pre- and post-intervention, all participants underwent a battery of cognitive and motor tests. Each training session included gross motor training (GMT), graphomotor training (GT), and cognitive-motor training (CMT). Statistical analysis was performed using the Friedman test for repeated measures and post-hoc Durbin-Conover test. The results indicated significant improvements in visuospatial working memory, visual attention, eye-hand coordination, semantic verbal fluency, auditory-motor synchronization, reaction time, and a decrease in the rate of ataxia. These improvements remained stable even in the absence of direct intervention. The findings demonstrate positive effects and feasibility of the intervention and suggest the need for further research in this area including randomized controlled feasibility studies with a larger sample.

Videoocular assessment of eye movement activity in an ataxia-telangiectasia: a case study.

PURPOSE: Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by progressive neurological deficits, including prominent oculomotor dysfunction. We report 5 cases of eye movement assessment in children 9-15 years old with A-T. METHODS: Three different oculomotor tasks (gaze holding, visually guided saccades and visual search) were used, and video-oculography was performed. Additionally, the scale for the assessment and rating of ataxia (SARA) score was used to assess severity of the cerebellar ataxia. RESULTS: Unstable gaze holding, nystagmus and saccadic intrusions were found. In addition to psychophysiological assessment results, we provide quantitative analysis of oculomotor activity, revealing a specific abnormal oculomotor pattern, consisting of (i) marked saccade hypermetria, (ii) unstable gaze holding, and (iii) gaze-evoked nystagmus. CONCLUSION: Our study opens the prospect to evaluate efficacy and safety of alternative methods for supporting the patient and improving his/her life quality.

Comparison of Neurocognitive Functioning and Fine Motor Skills in Pediatric Cancer Survivors and Healthy Children.

Background: The late treatment outcomes of pediatric brain tumors and of hematopoietic and lymphoid tissue tumors are an important focus of both rehabilitation and research. Neurocognitive and motor disorders induce further learning problems impeding social-emotional adaptation throughout a whole lifespan. Core deficits in short-term and working memory, visuospatial constructional ability, verbal fluency, and fine motor skills underlie distorted intellectual and academic achievement. This study aimed to assess the individual differences in cognitive ability and fine motor skills of pediatric tumor survivors and the age-matched healthy controls. Methods: A total of 504 tumor survivors after treatment and 646 age-matched healthy controls underwent neurocognitive and fine motor assessments. Findings: The group of tumor survivors scored significantly worse in both neurocognitive and fine motor skill in compared with the healthy control group. The pediatric brain tumor survivors (PBT group) performed worse in cognitive (p < 0.001 for verbal fluency and p < 0.001 for visuospatial constructional ability) and motor tests (p < 0.001) compared to the healthy controls. Hematopoietic and Lymphoid Tissues tumors survivors (THL group) performed worse in verbal fluency (p < 0.01) and visuospatial constructional test (p < 0.001) compared to the control group. Furthermore, the PBT group had worse results in visuospatial constructional ability (p < 0.05) and fine motor (p < 0.001) ability than the THL group. Significant differences between females and males were found in fine motor test performance in the PBT group (p < 0.05), as well as in verbal fluency (p < 0.01) and visuospatial constructional ability (p < 0.01) in the control group. Neurocognitive and fine motor skill characteristics in the THL group did not correlate with age.

Vibrational and impedance analysis of the ß-stannic acid samples plasticized by perchloric acid.

The ß-stannic acid powders(I) containing various amounts of perchloric acid with an initial concentration of 56.2 wt% HClO4 were studied by IR and Raman spectroscopy combined with XRD analysis and impedance spectroscopy. The addition of aqueous perchloric acid to I at room temperature leads to the adsorption compound formation. The degree of ionization of HClO4 is 100%. Based on these studies, a structural model has been proposed, according to which the hydrated H+ and ClO4 ¯ ions fill the pores/capillaries of I. The structure of I does not change during the adsorption process of ions. The finely dispersed powder of I turns into a viscous transparent gel with an optimal ratio of reagents, which indicates its plasticization. The electrochemical properties of the plasticized samples were investigated by impedance method. It was found that plasticization can increase the proton conductivity by more than two orders of magnitude. The plasticized samples have sensory properties. The plot of conductivity σ ¯ 25 versus weight fractions of perchloric acid solution W pa reveals a linear dependence at RH = 32% and t = 25 °C in a wide range of W pa values. The maximum value of σ ¯ 25 = 0.43 S cm-1 is achieved at W pa = 0.61. The straight line has a break at the very beginning due to the perchloric acid flow threshold.

Structure, Thermal Properties and Proton Conductivity of the Sulfonated Polyphenylquinoxalines.

This paper briefly reviews the results of scientific research on the proton conductivity of sulfonated polyphenylquinoxalines. Synthesis, structure (IR spectroscopy, SEM, quantum-chemical modeling, molecular weight distribution), moisture capacity, thermal properties, and proton conductivity of sulfonated polyphenylquinoxalines (sulfur content 2.6, 4.2, 5.5, and 7%) were studied. The relative stable configurations of sulfonated polyphenylquinoxalines with different positions of benzene rings and sulfogroups with the help of quantum chemical modeling were modeled. Sulfonation of the starting polyphenylquinoxalines was confirmed by IR spectroscopy and elemental analysis. The SEM method was used to study the surface of sulfonated polyphenylquinoxalines, and sulfonation regions were found. It was shown that sulfonated polyphenylquinoxalines contain water and are stable up to 250 °C; on further heating, the decomposition of the sulfogroups occurs. The conductivity of the obtained polymer electrolytes was studied by impedance spectroscopy, and long-term tests were carried out. It is shown that the proton conductivity at an ambient humidity of 98 rel. % reaches values 10-6-10-3 S/cm depending on the degree of sulfonation. It was shown that even after long-term storage in air (7 years), samples of sulfonated polyphenylquinoxalines with a high sulfur content of 7% at 98% air humidity have a conductivity of 8 × 10-4 S/cm.

The feasibility and efficacy of short-term visual-motor training in pediatric posterior fossa tumor survivors.

BACKGROUND: Pediatric posterior fossa tumor (PFT) survivors experience a range of cognitive and motor impairments that require timely rehabilitation of these functions. In Russia, rehabilitation services are only just beginning to be formed; therefore, it is necessary to test rehabilitation protocols for children surviving cancer. AIM: To evaluate the efficacy of short-term cognitive and motor training (CMT) aimed on visual-motor integration in PFT survivors using training devices. DESIGN: "Single center" quasi randomized controlled experiment. SETTING: Outpatients of the Russkoe Pole Rehabilitation Center. POPULATION: The 63 children cancer survivors between the ages of 6 and 17 years. METHODS: The baseline level of cognitive and motor functions was assessed in all participants. Then the sample of patients split into two subgroups of equal sex, age, and diagnosis. The intervention subgroup received six sessions of CMT for two weeks, and the other subgroup underwent 'empty' two weeks with no intervention. Reassessment of motor and cognitive functions was conducted in all participants. Then the subgroups changed: the first subgroup underwent 'empty' two weeks, and the second subgroup completed the CMT, and further reassessment was provided. RESULTS: The primary results demonstrate an increase in gross and fine motor skills, motor coordination, visual-motor integration, and visual processing after CMT. Secondary results show that the age at onset is an important factor in the subsequent decline in cognitive, motor functions, and eye movements. Children with medulloblastoma perform worse on motor tests than children with astrocytoma. A tumor in the IV ventricle is the most harmful, and a tumor in the cerebellar hemispheres is the least harmful to a child's cognitive and motor development. CONCLUSIONS: This study shows the effectiveness of a short-term CMT program for children who survived PFT. The study also found that cognitive, motor, and visual-motor functions are affected by the tumor's localization, malignancy, and the child's age at onset. CLINICAL REHABILITATION IMPACT: Short-term rehabilitation methods can be useful in pediatric oncological practice. Reconstruction of cognitive functions can occur during the training of more "simple" functions, such as hand-eye integration. The study makes a significant contribution to the methods of short-term rehabilitation in children who survived cancer.

Potential of Chemically Synthesized Oligosaccharides To Define the Carbohydrate Moieties of the Fungal Cell Wall Responsible for the Human Immune Response, Using Aspergillus fumigatus Galactomannan as a Model.

Methodologies to identify epitopes or ligands of the fungal cell wall polysaccharides influencing the immune response of human pathogens have to date been imperfect. Using the galactomannan (GM) of Aspergillus fumigatus as a model, we have shown that synthetic oligosaccharides of distinct structures representing key fragments of cell wall polysaccharides are the most precise tools to study the serological and immunomodulatory properties of a fungal polysaccharide.

Importance of Candida Antigenic Factors: Structure-Driven Immunomodulation Properties of Synthetically Prepared Mannooligosaccharides in RAW264.7 Macrophages.

The incidence and prevalence of serious fungal infections is rising, especially in immunosuppressed individuals. Moreover, co-administration of antibiotics and immunosuppressants has driven the emergence of new multidrug-resistant pathogens. The significant increase of multidrug-resistant pathogens, together with their ability to form biofilms, is associated with morbidity and mortality. Research on novel synthetically prepared immunomodulators as potential antifungal immunotherapeutics is of serious interest. Our study demonstrated the immunobiological activity of synthetically prepared biotinylated mannooligosaccharides mimicking Candida antigenic factors using RAW264.7 macrophages. Macrophage exposure to the set of eight structurally different mannooligosaccharides induced a release of Th1, Th2, Th17, and Treg cytokine signature patterns. The observed immune responses were tightly associated with structure, dose, exposure time, and selected signature cytokines. The viability/cytotoxicity of the mannooligosaccharide formulas was assessed based on cell proliferation. The structure-based immunomodulatory activity of the formulas was evaluated with respect to the length, branching and conformation of the various formulas. Glycoconjugate formulas with terminal ß-mannosyl-units tended to be more potent in terms of Candida relevant cytokines IL-12 p70, IL-17, GM-CSF, IL-6, and TNFα induction and cell proliferation, and this tendency was associated with structural differences between the studied glycoconjugate formulas. The eight tested mannooligosaccharide conjugates can be considered potential in vitro immunomodulative agents suitable for in vitro Candida diagnostics or prospectively for subcellular anti-Candida vaccine design.

Magnetic resonance imaging of changes in the brain of children cured of acute lymphoblastic leukemia.

This study was aimed to systematize magnetic resonance imaging (MRI) presentation of toxic leukoencephalopathy, to find the correlation between method of central nervous system (CNS) leukemia prevention and changes on MRI, to find relationship between existence leukoencephalopathy on imaging and neurocognitive deficits in pediatric patients after anti-leukemic therapy. Brain MRI data of 48 children, who underwent a therapy course according to the ALL-MB intermediate risk protocol, was evaluated. In accordance with two arms of this protocol, they received either radiation therapy, or additional intrathecal administration of chemotherapeutic agents as a prevention of CNS leukemia. Also, neurocognitive tests were performed. According to the results of the performed investigation, 10 (50%) out of 20 children, who received cranial irradiation and 18 (66.6%) out of 27 patients, who received only intrathecal therapy demonstrated abnormal brain changes (leukoencephalopathy) according to MRI data. Leukoencephalopathy was mostly presented by diffuse zones and localized predominantly in the frontal and temporal lobes. There was no correlation between method of CNS prevention and the existence of leukoencephalopathy on MRI. The analysis of our data did not show significant differences in brain damage and severity of cognitive impairment depending on the type of prevention of CNS leukemia. Moreover, in this study no statistical correlation was found between leukoencephalopathy on MRI and neurocognitive impairment according to clinical tests data. Further long-term prospective studies and examinations should be performed to assess late neurotoxic effects.

Novel mouse monoclonal antibodies specifically recognizing ß-(1→3)-D-glucan antigen.

ß-(1→3)-D-Glucan is an essential component of the fungal cell wall. Mouse monoclonal antibodies (mAbs) against synthetic nona-ß-(1→3)-D-glucoside conjugated with bovine serum albumin (BSA) were generated using hybridoma technology. The affinity constants of two selected mAbs, 3G11 and 5H5, measured by a surface plasmon resonance biosensor assay using biotinylated nona-ß-(1→3)-D-glucan as the ligand, were approximately 11 nM and 1.9 nM, respectively. The glycoarray, which included a series of synthetic oligosaccharide derivatives representing ß-glucans with different lengths of oligo-ß-(1→3)-D-glucoside chains, demonstrated that linear tri-, penta- and nonaglucoside, as well as a ß-(1→6)-branched octasaccharide, were recognized by mAb 5H5. By contrast, only linear oligo-ß-(1→3)-D-glucoside chains that were not shorter than pentaglucosides (but not the branched octaglucoside) were ligands for mAb 3G11. Immunolabelling indicated that 3G11 and 5H5 interact with both yeasts and filamentous fungi, including species from Aspergillus, Candida, Penicillium genera and Saccharomyces cerevisiae, but not bacteria. Both mAbs could inhibit the germination of Aspergillus fumigatus conidia during the initial hours and demonstrated synergy with the antifungal fluconazole in killing C. albicans in vitro. In addition, mAbs 3G11 and 5H5 demonstrated protective activity in in vivo experiments, suggesting that these ß-glucan-specific mAbs could be useful in combinatorial antifungal therapy.

Reduced vs. standard dose native E. coli-asparaginase therapy in childhood acute lymphoblastic leukemia: long-term results of the randomized trial Moscow-Berlin 2002.

PURPOSE: Favorable outcomes were achieved for children with acute lymphoblastic leukemia (ALL) with the first Russian multicenter trial Moscow-Berlin (ALL-MB) 91. One major component of this regimen included a total of 18 doses of weekly intramuscular (IM) native Escherichia coli-derived asparaginase (E. coli-ASP) at 10000 U/m2 during three consolidation courses. ASP was initially available from Latvia, but had to be purchased from abroad at substantial costs after the collapse of Soviet Union. Therefore, the subsequent trial ALL-MB 2002 aimed at limiting costs to a reasonable extent and also at reducing toxicity by lowering the dose for standard risk (SR-) patients to 5000 U/m2 without jeopardizing efficacy. METHODS: Between April 2002 and November 2006, 774 SR patients were registered in 34 centers across Russia and Belarus, 688 of whom were randomized. In arm ASP-5000 (n = 334), patients received 5000 U/m2 and in arm ASP-10000 (n = 354) 10 000 U/m2 IM. RESULTS: Probabilities of disease-free survival, overall survival and cumulative incidence of relapse at 10 years were comparable: 79 ± 2%, 86 ± 2% and 17.4 ± 2.1% (ASP-5000) vs. 75 ± 2% and 82 ± 2%, and 17.9 ± 2.0% (ASP-10000), while death in complete remission was significantly lower in arm ASP-5000 (2.7% vs. 6.5%; p = 0.029). CONCLUSION: Our findings suggest that weekly 5000 U/m2E. coli-ASP IM during consolidation therapy are equally effective, more cost-efficient and less toxic than 10000 U/m2 for SR patients with childhood ALL.

Synthesis of a biotinylated probe from biotechnologically derived ß-d-mannopyranosyl-(1 → 2)-d-mannopyranose for assessment of carbohydrate specificity of antibodies.

The disaccharide ß-d-mannopyranosyl-(1 → 2)-d-mannopyranose obtained by chemical cleavage and enzymatic dephosphorylation of biotechnologically available phosphomannan was transformed over six steps into a biotinylated probe suitable for assessment of carbohydrate specificity of antibodies induced by yeast cell wall preparations.

Synthesis of 3-aminopropyl ß-(1 → 6)-d-glucotetraoside and its biotinylated derivative.

3-Aminopropyl ß-(1 â†’ 6)-d-glucotetraoside has been synthesized from 3-benzyloxycarbonylaminopropanol and 6-O-acetyl-2,3,4-tri-O-benzoyl-d-glucopyranosyl trichloroacetimidate by successive attachment of one monosaccharide unit in total yield of 22%. Free aminopropyl glycoside was converted into a biotin derivative that can be used for controlled immobilization of the oligosaccharide on streptavidin-coated ELISA plates and for tracing carbohydrate binding molecules.

The evaluation of ß-(1 → 3)-nonaglucoside as an anti-Candida albicans immune response inducer.

Synthetically prepared bovine serum albumin (BSA) conjugate of linear ß-(1 → 3)-nonaglucoside ligand (G9) has been applied as a biological response immunomodulator in vivo and ex vivo. Active immunization of Balb/c mice revealed effective induction of specific humoral responses in comparison with Candida ß-D-glucan and Candida whole cells. Induced post-vaccination serum exhibited a growth-inhibition effect on the multi-azole-resistant clinical strain Candida albicans CCY 29-3-164 in experimental mucocutaneous infection ex vivo. Evaluation of immune cell proliferation and the cytotoxic potential of the G9-ligand has revealed its bioavailability and an immunostimulative effect in vaccination-sensitized Balb/c mice splenocytes and RAW 264.7 macrophages.

Immune cell response to Candida cell wall mannan derived branched α-oligomannoside conjugates in mice.

BACKGROUND: Constructs composed of cell wall mannan-derived moieties conjugated to immunogenic proteins could be promising agents for induction of protective anti-Candida immune responses. METHODS: This report is focused on the cellular immune response differences induced by BSA-based conjugates bearing synthetic α-1,6-branched oligomannosides. For monitoring of the immune responses following active immunization we evaluated changes in the frequencies of T and B lymphocytes and their activation status in the blood and spleen. We compared the immunization-induced changes of co-stimulatory molecules CD80 and CD86 expression on blood neutrophils and Th1/Th2 polarization of the immune response based on IFN-γ, TNF-α (pro-Th1), IL-4, and IL-10 (pro-Th2) cytokines levels and induction of IL-17. RESULTS: The results pointed out a comparable effect of the conjugates on the modulation of T and B lymphocytes frequencies in blood and spleen. Both conjugates induced upregulation of CD25 surface antigen on CD4(+) T lymphocytes, independently on the structural differences of oligosaccharides. The differences in structure of oligomannoside antigens or conjugate constructs were reflected in the increase of co-stimulatory molecules CD80 and CD86 expression on neutrophils, and in induced cytokine response. M5-BSA conjugate induced only a slight increase in CD80 expression but a significant increase in IFN-γ, TNF-α, and IL-10. M6-BSA conjugate induced a significant increase of CD80 expression and increase of TNF-α, IL-4, and IL-10. CONCLUSION: Obtained data demonstrate the importance of cellular immune response analysis for investigation of immunomodulatory properties of oligomannoside-protein conjugates.

Synthetically prepared glycooligosaccharides mimicking Candida albicans cell wall glycan antigens--novel tools to study host-pathogen interactions.

The immunobiological efficacy of synthetically prepared mannooligosaccharides and a glucooligosaccharide mimicking the structure of Candida albicans cell wall glycans was assessed in vivo and in vitro to exploit immune responses. The exposure of mice splenocytes to BSA-based conjugates of synthetic oligomannosides and oligoglucoside revealed intense influence on T-cell subset polarization. The conjugates biased the immune responses towards Th1 and Th17 with respect to the prevalence of interferon-gamma (IFN-γ) and interleukin (IL)-17 (IL-17) over IL-4 and IL-10 levels. The inflammatory activity of the conjugates has been evaluated based on the induction of pro-inflammatory cytokines. Postvaccination, antimannooligosaccharide and antiglucooligosaccharide antisera were subjected to an evaluation of the structure-immunomodulation activity relationship. Clinical isolates of C. albicans CCY 29-3-32 and C. albicans CCY 29-3-164 were applied to study interactions between Candida cells and anti-oligosaccharide antibodies. In situ recognition of parietal oligomannosyl and oligoglucosyl sequences in C. albicans cell wall by the antisera raised against BSA-based conjugates of synthetic oligomannosides and oligoglucoside revealed the effective recognition of specific distribution of natural oligosaccharide sequences in the cell wall of C. albicans serotype A. With respect to these results, it can be concluded that new, synthetically prepared oligosaccharides mimicking Candida cell wall structures represent prospective immunobiologically effective components for further immunopharmacologically relevant Candida vaccine design.

Humoral and cell-mediated immunity following vaccination with synthetic Candida cell wall mannan derived heptamannoside-protein conjugate: immunomodulatory properties of heptamannoside-BSA conjugate.

Chemically defined glycoprotein conjugate composed of synthetically prepared mannan-derived heptamannoside with terminal ß-1,2-linked mannose residue attached to the α-1,3-linked mannose residues and BSA as carrier protein (M7-BSA conjugate) was analysed for the capacity to induce protective humoral immunity and appropriate alteration cellular immunity. To identify protective antigenic structure of Candida cell wall mannan M7-BSA conjugate was used for BALB/c mice immunization. The obtained results were compared with placebo group and with heat-inactivated C. albicans whole cells immunization. The administration route of M7-BSA conjugate secondary booster injection significantly affected the intensity of humoral immune response and the specificity of produced antibodies. All prepared sera were able to elevate candidacidal activity of polymorphonuclear leukocytes (PMN) in cooperation with complement. Moreover, polyclonal sera obtained after secondary subcutaneous (s.c.) booster injection of M7-BSA conjugate were able to induce candidacidal activity of PMN also in complement independent manner. M7-BSA conjugate immunization induced increases of phagocytic activity and respiratory burst of granulocytes, caused a raise of the proportion of CD3(+) T lymphocytes and increased the CD4(+)/CD8(+) T lymphocyte ratio. We observed also an increasing proportion of CD4(+)CD25(+) T cells compared to immunization with heat inactivated whole C. albicans cells, which in turn promoted an increase of the CD8(+)CD25(+) cell proportion. Immunization with M7-BSA conjugate induced Th1, Th2 and Th17 immune responses as indicated by the elevation of relevant cytokines levels. These data provide some insights on the immunomodulatory properties of oligomannosides and contribute to the development of synthetic oligosaccharide vaccines against fungal diseases.

Model alpha-mannoside conjugates: immunogenicity and induction of candidacidal activity.

The effect of Candida cell wall mannan-derived alpha-oligomannoside structural components on the modulation of the immune system and their role in protective immunity are studied here. Semi-synthetic alpha-mannoside-bovine serum albumin conjugates were used for immunization of rabbits. Dimeric alpha-mannoside, representing Candida antigenic factor 1, was used as a model of linear alpha-mannoside, and pentameric alpha-mannoside was used as a model of branched oligomannoside side chain structure. The induction of humoral immune response and the functionality of the serum tested by induction of peripheral blood leukocyte (PBL) candidacidal activity are documented. Anti-Candida albicans serotype B immunoglobulins (IgG and IgM) levels were higher than anti-serotype A following immunization with both conjugates. Dimer-conjugate postimmunization sera evidently enhanced C. albicans killing activity of PBLs in candidacidal assay. The study shows the importance of alpha-mannoside structures in perspective anti-Candida vaccine with a broad spectrum of effectiveness.

Synthesis of 3,6-branched oligomannoside fragments of the mannan from Candida albicans cell wall corresponding to the antigenic factor 4.

3-Aminopropyl glycosides of 3,6-branched penta- and hexamannoside fragments of the cell wall mannan from Candida albicans, corresponding to the antigenic factor 4, have been synthesized. Subsequent coupling of both oligosaccharides with BSA using the squarate procedure provided corresponding neoglycoconjugates.

Synthesis of a heptasaccharide fragment of the mannan from Candida guilliermondii cell wall and its conjugate with BSA.

The 3-aminopropyl glycoside of a heptasaccharide fragment of the cell wall mannan from Candida guilliermondii 18, which corresponds to the antigenic Factor 9, has been synthesized by a convergent approach based on glycosylation of a tetrasaccharide acceptor with a trisaccharide donor as the key step to give a protected heptasaccharide 17. Subsequent two-step deprotection of 17 afforded the heptamannoside 18, which was then conjugated with BSA using the squarate procedure.