Involvement of the human thalamus in relational and non-relational memory

Damage to the human thalamus has been associated with selective anterograde recognition memory impairments. Recently, recognition memory has been subdivided into relational and non-relational memory. The aim of the present study was to assess the potentially differential involvement of the human thalamus in relational and non-relational memory. Ten patients with focal ischemic thalamic lesions were compared to individualized control groups of healthy subjects matched to each individual patient on age and IQ. Six patients showed poorer relational memory than their respective control samples. None of the 10 patients showed a significant deficit on the non-relational memory task. These observations suggest an involvement of the thalamus in relational memory, and are discussed in terms of disruption of mediotemporal-thalamic and thalamic-fronto-striatal circuits.     

Lymphoma stem cells: enough evidence to support their existence?

While leukemia-originating stem cells are critical in the initiation and maintenance of leukemias, the existence of similar cell populations that may generate B-cell lymphoma upon mutation remains uncertain. Here we propose that committed lymphoid progenitor/precursor cells with an active V-D-J recombination program are the initiating cells of follicular lymphoma and mantle cell lymphoma when targeted by immunoglobulin (IG)- gene translocations in the bone marrow. However, these pre-malignant lymphoma-initiating cells cannot drive complete malignant transformation, requiring additional cooperating mutations in specific stem-cell programs to be converted into the lymphoma-originating cells able to generate and sustain lymphoma development. Conversely, diffuse large B-cell lymphoma and sporadic Burkitt’s lymphoma derive from B lymphocytes that acquire translocations through IG-hyper-mutation or class-switching errors within the germinal center. Although secondary reprogramming mutations are generally required, some cells such as centroblasts or memory B cells that have certain stem cell-like features, or lymphocytes with MYC rearrangements that deregulate self-renewal pathways, may bypass this need and directly function as the lymphoma-originating cells. An alternative model supports an aberrant epigenetic modification of gene sets as the first occurring hit, which either leads to retaining stem-cell features in hematopoietic stem or progenitor cells, or reprograms stemness into more committed lymphocytes, followed by secondary chromosomal translocations that eventually drive lymphoma development. Isolation and characterization of the cells that are at the origin of the different B-cell non-Hodgkin’s lymphomas will provide critical insights into the disease pathogenesis and will represent a step towards the development of more effective therapies.     

Determination of <Emphasis Type="Italic">arylsulfatase A pseudodeficiency</Emphasis> allele and haplotype frequency in the Tunisian population

Arylsulfatase A (ASA) is a lysosomal enzyme involved in the catabolism of cerebroside sulfate. ASA deficiency is associated with metachromatic leukodystrophy (MLD). Low ASA activities have also been reported in a more common condition with no apparent clinical consequences termed ASA pseudo-deficiency (ASA-PD) which is associated with two linked mutations in the ASA gene (c.1049A>G and c.*96A>G). This study aimed to investigate the frequency of the two ASA-PD variants and their linkage disequilibrium (LD) among Tunisians. ASA-PD variants were detected in 129 healthy Tunisians and their frequencies were compared to those described worldwide. The frequency of the PD allele was estimated at 17.4 % for the overall sample, with c.1049A>G and c.*96A>G frequencies of 25.6 and 17.4 %, respectively. This study also revealed a high LD between the two ASA-PD variants (r ² = 0.61). Inter-population analysis revealed similarities in the ASA-PD genetic structure between Tunisians and populations from Middle East with c.*96A>G frequencies being the highest in the world. A significant North vs. South genetic differentiation in the ASA-PD frequency was also observed in Tunisian population who seems genetically intermediate between Africans, Middle-Easterners and Europeans. This is the first report on the allele frequency of the ASA-PD in North Africa, revealing a relatively high frequency of the PD allele among Tunisians. This study gives also evidence on the importance of discriminating ASA-PD allele from pathological mutations causing MLD and supporting enzymatic activity testing with both sulfatiduria determination and genetic testing in the differential diagnosis of MLD in the Tunisian population.     

Lower CSF HVA and 5-HIAA in bipolar disorder type 1 with a history of childhood ADHD

Bipolar disorder with childhood attention-deficit hyperactivity disorder (ADHD) is a subphenotype characterized by earlier age of onset, more frequent mood episodes, more suicide attempts, and more interpersonal violence than pure bipolar patients. The aim of this study was to test the biological validity of using childhood ADHD to subgroup bipolar disorder. The monoamine metabolites, homovanillinic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were determined in the cerebrospinal fluid (CSF) of 53 euthymic patients with bipolar disorder type 1, with (N = 17) and without (N = 36) a history of childhood ADHD. In addition to structured clinical interviews, childhood ADHD was assessed by a next of kin using the Autism-Tics, ADHD and other comorbidities questionnaire (A-TAC), and by patients themselves using the Wender Utah rating scale (WURS-25). Current ADHD symptoms were assessed by the Brown attention-deficit disorder scale (Brown ADD). Bipolar patients with childhood ADHD had significantly lower CSF concentration (mean ± SD nmol/l) of HVA (89.0 ± 32.5 vs. 115.8 ± 47.1, P = 0.039) and 5-HIAA (88.7 ± 38.5 vs. 116 ± 47.9, P = 0.021) than pure bipolar patients. CSF MHPG did not differ between the groups. The WURS-25 score correlated negatively with both HVA (r = −0.27, P = 0.048) and 5-HIAA (r = −0.30, P = 0.027). Likewise, the Brown ADD total score correlated negatively with both HVA (r = −0.34, P = 0.013) and 5-HIAA (r = −0.35, P = 0.011). These findings indicate different monoaminergic function in patients with and without childhood ADHD in bipolar disorder type 1. This lends biological support to the notion that those with childhood ADHD represent a valid subphenotype of bipolar disorder.     

Is transketolase like 1 a target for the treatment of differentiated thyroid carcinoma? A study on thyroid cancer cell lines

Summary  Radioactive iodine-refractory [¹⁸F] fluorodeoxy-glucose-positron emission tomography-positive thyroid carcinomas represent especially aggressive tumors. Targeting glucose metabolism by the transketolase isoenzyme transketolase like 1 (TKTL-1) which is over-expressed in various neoplasms, may be effective. The correlation of TKTL-1 expression and the response to oxythiamine as the currently best-characterized inhibitor of transketolases was studied in differentiated thyroid cancer cell lines. We determined TKTL-1 expression, proliferation, glucose uptake and GLUT-1 expression in non-treated thyroid cells and recorded the effect of oxythiamine on iodide uptake and on thymidine uptake. TKTL 1 was highest expressed in cell lines derived from more invasive tumors but the expression level was not strongly correlated to proliferation rate, to GLUT-1 expression or to the response to oxythiamine. Oxythiamine showed only a weak effect in the TKTL-1 expressing cell lines. Over-expression of TKTL-1 is not an indicator for responsiveness to oxythiamine. More specific inhibitors should be tested.     

Role of pharmacogenetics in chemotherapy of colorectal cancers

SCOPE: Clinical implications associated with polymorphisms in drug-metabolizing genes involved in the chemotherapy of colorectal cancers (5-flurorouracil, oxaliplatin and irinotecan) are reviewed. CURRENT SITUATION AND SALIENT POINTS: Treatments of colorectal cancers have been greatly improved last years but patients respond differently to identical medication. Genetic polymorphisms are one of the major causes of these individual responses to drugs associated with sometimes severe adverse effects. Pharmacogenetics is based on all polymorphisms that determine genetic human diversity associated with variable response to anticancer drugs. PERSPECTIVES: Morbidity and mortality related to toxicity or inefficacy of these drugs could be reduced by analyzing the pharmacogenetic profile of patients before treatment. Results should be integrated in protocols for monitoring and assessment the dosage of drugs.