Verbal paired-associate learning by APOE genotype in non-demented older adults: fMRI evidence of a right hemispheric compensatory response

Previous studies of episodic memory report a greater extent of blood-oxygenation-level-dependent (BOLD) response in non-demented older adults with the apolipoprotein E epsilon-4 (APOE epsilon4) allele than in those without the allele. We conducted a functional MRI study to investigate whether APOE genotype is related to brain response to verbal paired-associate encoding and consolidation, particularly in the right hemisphere, among non-demented older adults. Structurally segmented volumes and BOLD response were measured in 13 non-epsilon4 and 12 epsilon4 subjects. The epsilon4 group displayed greater activation than the non-epsilon4 group in multiple right hemisphere regions for previously encoded word pairs relative to fixation. Activation within manually outlined hippocampal regions of interest also displayed genotype-specific dissociations consistent with whole brain analyses. Furthermore, this differential BOLD response occurred in the presence of equivalent behavioral and neuropsychological performances as well as comparable hippocampal and overall structural segmentation volumes between groups. Results implicate a widely distributed and interconnected network of right hemisphere brain regions that may be involved in compensating for APOE epsilon4-related deficiencies associated with verbal episodic memory encoding and consolidation.     

Factors and processes modulating phenotypes in neuronopathic lysosomal storage diseases

Lysosomal storage diseases are inherited metabolic disorders caused by genetic defects causing deficiency of various lysosomal proteins, and resultant accumulation of non-degraded compounds. They are multisystemic diseases, and in most of them (>70 %) severe brain dysfunctions are evident. However, expression of various phenotypes in particular diseases is extremely variable, from non-neuronopathic to severely neurodegenerative in the deficiency of the same enzyme. Although all lysosomal storage diseases are monogenic, clear genotype-phenotype correlations occur only in some cases. In this article, we present an overview on various factors and processes, both general and specific for certain disorders, that can significantly modulate expression of phenotypes in these diseases. On the basis of recent reports describing studies on both animal models and clinical data, we propose a hypothesis that efficiency of production of compounds that cannot be degraded due to enzyme deficiency might be especially important in modulation of phenotypes of patients suffering from lysosomal storage diseases.     

The role of drug timing and histoincompatibility barrier in prolongation of cardiac graft survival in mice treated with donor-specific blood and cyclophosphamide

In the H-2-compatible donor-recipient combination (BALB/c----DBA/2), pretransplant donor-specific blood transfusion (DST) significantly prolonged graft survival. Concomitant use of immunosuppression by cyclophosphamide (CY) brought about potentiation of DST effect, resulting in long-term graft survival. In contrast, in the 'strong' H-2-incompatible combination (BALB/c----CBA/H) pretreatment of the recipients with donor-specific blood resulted in hyperacute graft rejection or in impairment of drug-induced immunosuppression when DST was used with a single dose of CY. In this model however, combination of DST with both pre- and posttransplant CY immunosuppression interacted beneficially to produce significant donor-specific prolongation of graft survival.     

Intrarater and interrater reliability of the MS functional composite outcome measure

OBJECTIVE: To assess practice effects, and intrarater and interrater reliability of the MS functional composite (MSFC) outcome measure. BACKGROUND: To address the poor reliability and insensitivity to change of available MS clinical rating scales, the National MS Society's Clinical Outcomes Assessment Task Force developed the MSFC, a multidimensional quantitative clinical outcome measure that includes tests of leg function/ambulation (Timed 25-Foot Walk), arm function (Nine-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). METHODS: Ten patients with secondary progressive MS underwent six testing sessions over a 2-week period. The MSFC was administered by the same examining technician in the first five sessions and by the other technician in the sixth. Patients were reassessed by both technicians after 6 months (sessions 7 and 8). The MSFC score was calculated as the mean of the Z scores of the three components. A pooled dataset derived from secondary progressive MS patients in the placebo arms of previous clinical trials and natural history studies served as the reference population to standardize scores. RESULTS: Practice effects were evident initially but stabilized by the fourth administration. The intraclass correlation coefficient (ICC) was 0.97 for the MSFC for session 4 versus session 5 (intrarater reliability). The ICC was 0.95 for session 5 versus session 6 (interrater reliability), and was 0.96 for session 7 versus session 8 when patients were reassessed 6 months later. CONCLUSIONS: The MS functional composite (MSFC) outcome measure had excellent intrarater and interrater reliability when standardized procedures were used to train examining technicians and to assess patients. Prebaseline testing sessions should be included in clinical trials employing the MSFC to compensate for practice effects.     

Potentiation of the anti-tumour effects of Photofrin-based photodynamic therapy by localized treatment with G-CSF

Photofrin-based photodynamic therapy (PDT) has recently been approved for palliative and curative purposes in cancer patients. It has been demonstrated that neutrophils are indispensable for its anti-tumour effectiveness. We decided to evaluate the extent of the anti-tumour effectiveness of PDT combined with administration of granulocyte colony-stimulating factor (G-CSF) as well as the influence of Photofrin and G-CSF on the myelopoiesis and functional activity of neutrophils in mice. An intensive treatment with G-CSF significantly potentiated anti-tumour effectiveness of Photofrin-based PDT resulting in a reduction of tumour growth and prolongation of the survival time of mice bearing two different tumours: colon-26 and Lewis lung carcinoma. Moreover, 33% of C-26-bearing mice were completely cured of their tumours after combined therapy and developed a specific and long-lasting immunity. The tumours treated with both agents contained more infiltrating neutrophils and apoptotic cells then tumours treated with either G-CSF or PDT only. Importantly, simultaneous administration of Photofrin and G-CSF stimulated bone marrow and spleen myelopoiesis that resulted in an increased number of neutrophils demonstrating functional characteristics of activation. Potentiated anti-tumour effects of Photofrin-based PDT combined with G-CSF observed in two murine tumour models suggest that clinical trials using this tumour therapy protocol would be worth pursuing.     

Renal transplantation in insulin-treated diabetics.

In our view, renal transplantation in the uremic diabetic patient is justified. Recipients should be selected with caution. Patients with both loss of vision and heart disease will only rarely benefit from renal transplantation. Living related donor should be preferred if possible.     

Second cancers in hematologic malignancies (epidemiologic observations from a 20-year period)

INTRODUCTION: The incidence of malignant tumours have increased steadily worldwide. Prior reports indicate that patients with some hematologic malignancies (for example chronic lymphocytic leukemia, non-Hodgkin's lymphoma) may be at increased risk of second neoplasms. AIM: The aim of the authors was to explore the possible association between hematologic malignancies and subsequent solid tumours. PATIENTS, METHODS: Between January 1, 1983 and December 31, 2002, in the county of Szabolcs-Szatmár-Bereg 151 cases with both malignant hematologic diseases and cancers were registered by the authors. In their 60 patients (50 with lymphoid and 10 with myeloid malignancies) the first tumour was the hematologic malignancy. Among these cases the number of second cancers was 64. RESULTS: The most common kind of second tumours was lung cancer. There was a significant connection between lymphoid malignancies and second cancers as compared to myeloid malignancies and subsequent cancers (p < 0.05). CONCLUSIONS: Analysing the epidemiologic data the authors established the following conclusions: the association of second cancers with hematologic malignancies in most of the cases is not accidental. The age of patients with second cancers seemed to be not too important, but it was of crucial importance in patients with Hodgkin's disease and non-Hodgkin's lymphoma. The role of immunodeficiency in the development of second cancers may be important in patients with Hodgkin's disease, non-Hodgkin's lymphoma and chronic lymphocytic leukemia (the number of second cancers in their patients with multiple myeloma and hairy cell leukemia was too small do draw a conclusion).     

Complex cytogenetics in a case of probably work related MDS/AML

In the majority of cases of overt acute myeloid leukemia (AML), there is no knowledge about a preleukemic phase of myelodysplastic syndrome (MDS). A few recent case-control studies suggest an association between MDS and several occupations. We report a unique case of MDS/AML related to the patient’s work condition with numerous cytostatic agents. The karyotype revealed a spectrum of genetic rearrangements identified by conventional cytogenetics, fluorescence in situ hybridization (FISH) and spectral karyotyping (SKY). We suggest that amplification of chromosomal material may play a greater role in leukemogenesis than has been recognized previously.