A comparative neuropsychological test battery differentiates cognitive signatures of Fragile X and Down syndrome.

BACKGROUND: Standardised neuropsychological and cognitive measures present some limitations in their applicability and generalisability to individuals with intellectual disability (ID). Alternative approaches to defining the cognitive signatures of various forms of ID are needed to advance our understanding of the profiles of strengths and weaknesses as well as the affected brain areas. AIM: To evaluate the utility and feasibility of six non-verbal comparative neuropsychological (CN) tasks administered in a modified version of the Wisconsin General Test Apparatus (WGTA) to confirm and extend our knowledge of unique cognitive signatures of Fragile X syndrome (FXS) and Down syndrome (DS). METHOD: A test battery of CN tasks adapted from the animal literature was administered in a modified WGTA. Tasks were selected that have established or emerging brain-behaviour relationships in the domains of visual-perceptual, visual-spatial, working memory and inhibition. RESULTS: Despite the fact that these tasks revealed cognitive signatures for the two ID groups, only some hypotheses were supported. Results suggest that whereas individuals with DS were relatively impaired on visual-perceptual and visual-spatial reversal learning tasks they showed strengths in egocentric spatial learning and object discrimination tasks. Individuals with FXS were relatively impaired on object discrimination learning and reversal tasks, which was attributable to side preferences. In contrast, these same individuals exhibited strengths in egocentric spatial learning and reversal tasks as well as on an object recognition memory task. Both ID groups demonstrated relatively poor performance for a visual-spatial working memory task. CONCLUSION: Performance on the modified WGTA tasks differentiated cognitive signatures between two of the most common forms of ID. Results are discussed in the context of the literature on the cognitive and neurobiological features of FXS and DS.

Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice.

BACKGROUND AND PURPOSE: High resting heart rate is a predictor for total and cardiovascular mortality independent of other risk factors in patients with coronary artery disease. We tested the hypothesis that a reduction of resting heart rate with the cardiac pacemaker I(f) current inhibitor ivabradine prevents the endothelial dysfunction associated with dyslipidaemia. EXPERIMENTAL APPROACH: Three-month-old dyslipidaemic (DL) male mice expressing the human ApoB-100 were assigned or not (DL, n=16), to treatment for 3 months with ivabradine (10 mg kg(-1) d(-1), n=17). Wild-type C57Bl/6 mice (WT, n=15) were used as controls. Heart rate was measured at 3, 4.5 and 6 months. Dilatation to acetylcholine (ACh) of isolated cerebral and renal arteries was investigated at 6 months. KEY RESULTS: Heart rate remained stable in anaesthetized WT mice, increased (25%, P<0.05) with age in DL mice but was limited (11%, P<0.05) by ivabradine. At 6 months, left ventricular maximal pressure was similar in all groups. The minimal and end-diastolic left ventricular pressures were increased (P<0.05) in DL (10.2+/-1.0 and 18.7+/-1.4 mm Hg) compared to WT (-0.4+/-0.7 and 6.3+/-1.0 mm Hg) and reduced (P<0.05) by ivabradine (4.2+/-1.3 and 11.5+/-1.5 mm Hg). ACh-induced maximal dilatation was impaired (P<0.05) in renal and cerebral arteries isolated from DL compared to WT (56+/-7 versus 83+/-3% in renal arteries; 22+/-2 versus 42+/-2% in cerebral arteries). Ivabradine completely prevented (P<0.05) this dysfunction in renal and cerebral arteries. CONCLUSIONS AND IMPLICATIONS: Selective heart rate reduction with ivabradine limits cardiac dysfunction and prevents the renovascular and cerebrovascular endothelial dysfunction associated with dyslipidaemia.

[Negative D-dimers and peripheral pulmonary embolism]. / D-dimères négatifs et embolies pulmonaires périphériques.

The measurement of D-dimers is a recent addition to the diagnostic strategy of pulmonary embolism and has been shown to be a valuable tool with excellent sensitivity. However, there have been rare reports of patients with pulmonary embolism but negative D-dimer tests. The object of this study was to study patients with pulmonary embolism but negative D-dimers and to compare them with a population of patients with pulmonary embolism and raised D-dimers. One hundred and fifty consecutive patients admitted for pulmonary embolism were included in this study. All underwent measurement of D-dimers (normal <500 ng/ml) by an ELISA technique. The data of clinical examination and complementary investigations were analysed with respect to the D-dimers result. The sensitivity of raised D-dimers for pulmonary embolism was 96% (6 patients had results <500 ng/ml). The finding of chest pain was statistically greater in the group with negative D-dimers (p=0.01). In these cases, the emboli were all distal (p=0.0003), the average Miller index was significantly lower than in patients with high D-dimers (p=0.04) and the diagnostic value of ultrasound investigations (echocardiography, ultrasonography of lower limb veins) was less (p<0.0001). The authors conclude that measurement of D-dimers by the ELISA method may be non-diagnostic in distal pulmonary embolism and one explanation could be the less extensive thromboembolic process. In cases with negative D-dimers, a strong clinical suspicion of pulmonary embolism should lead to the request for further investigations.

Identification of PML oncogenic domains (PODs) in human megakaryocytes.

Megakaryocytes (Mks) are unique cells in the human body in that they carry a single and polyploid nucleus. It is therefore of interest to understand their nuclear ultrastructure. PML oncogenic domains (PODs) were described in several types of eukaryotic cells using human autoantibodies which recognize nuclear antigens with a specific speckled pattern (dots) in indirect immunofluorescence (IF). Two main antigens, PML and Sp 100, usually colocalize and concentrate in these nuclear subdomains. We investigated the presence of PODs using IF and immunoelectron microscopy (IEM) in cells from megakaryocytic lineage: the HEL cell line and human cultured Mks. Antibodies against PML, Sp100, and anti-nuclear dots were used in single and double labeling. PODs were identified in HEL cells and in human Mks, and their ultrastructure was characterized. We then used IF to quantify PODs within Mks and showed that their number increased proportionally to nuclear lobularity. In summary, we report the identification of PODs in human Mks at an ultrastructural level and an increase in PODs number in parallel with Mk ploidy. We show that endomitosis not only leads to DNA increase but also to the multiplication of at least one of the associated nuclear structures.

Newly recognized cellular abnormalities in the gray platelet syndrome.

The gray platelet syndrome (GPS) is a rare congenital bleeding disorder in which thrombocytopenia is associated with increased platelet size and decreased alpha-granule content. This report describes 3 new pediatric cases presenting with the classical platelet abnormalities of GPS within one family with normal parents. Examination of blood smears of the 3 patients demonstrated not only gray platelets, but also gray polymorphonuclear neutrophils (PMNs) with decreased or abnormally distributed components of secretory compartments (alkaline phosphatase, CD35, CD11b/CD18). Secondary granules were also decreased in number as assayed by immunoelectron microscopy. These data confirm that the secretory compartments in neutrophils were also deficient in this family. Megakaryocytes (MKs) were cultured from the peripheral blood CD34+ cells of the 3 patients for 14 days, in the presence of thrombopoietin and processed for immunoelectron microscopy. Although von Willebrand factor (vWF) was virtually undetectable in platelets, vWF immunolabeling was conspicuous in cultured maturing MKs, particularly within Golgi saccules, but instead of being packaged in alpha-granules, it was released into the demarcation membrane system. In contrast, P-selectin followed a more classical pathway. Double-labeling experiments confirmed that vWF was following an intracellular pathway distinct from the one of P-selectin. In these 3 new cases of GPS, the MKs appeared to abnormally process vWF, with secretion into the extracellular space instead of normal alpha-granule packaging. Furthermore, the secretory compartment of another blood cell line, the neutrophil, was also affected in this family of GPS.

Pathologic interaction between megakaryocytes and polymorphonuclear leukocytes in myelofibrosis.

Idiopathic myelofibrosis (MF) is a myeloproliferative syndrome characterized by an increase in bone marrow collagen. Megakaryocytes (Mks), which store growth factors in their alpha granules, are known to be involved in the pathogenesis of MF. Previously, mice given bone marrow grafts infected with a retrovirus carrying murine thrombopoietin (TPO) complementary DNA developed a disease resembling human idiopathic MF. In this study, we used this murine model (TPO mice) to determine whether release of alpha granules is responsible for fibroblast activation and development of fibrosis. The intracellular trafficking of several alpha-granule proteins (von Willebrand factor, fibrinogen, and transforming growth factor beta (TGF beta), which are stored in the granule matrix; and alpha(IIb)beta(3) integrin and P-selectin (CD62p), which are located in the alpha-granule membrane) was studied with immune electron microscopy in bone marrow Mks from TPO mice. P-selectin immunolabeling increased consistently and was occasionally found lining the demarcation membrane system. Evidence of extensive emperipolesis was also found in TPO mouse Mks, involving almost exclusively neutrophil and eosinophil polymorphonuclear (PMN) cells with altered morphologic features. In parallel, the host Mks had myeloperoxidase-positive granules scattered in their cytoplasm, associated with marked ultrastructural cytoplasmic alterations and ruptured alpha-granule membranes. Similar observations were made in bone marrow biopsy specimens from 12 patients with idiopathic MF; indeed, there was an increased rate of emperipolesis involving mostly PMN cells, abnormal P-selectin expression, and mutual subcellular PMN and Mk alterations. This study indicates that in idiopathic MF, abnormal P-selectin distribution in Mks induces selective sequestration of PMN cells. This results in a release of alpha-granular proteins and growth factors, which in turn induces fibroblast activation and fibrosis deposition. (Blood. 2000;96:1342-1347)

IGF-1 or insulin, and the TSH cyclic AMP cascade separately control dog and human thyroid cell growth and DNA synthesis, and complement each other in inducing mitogenesis.

The regular doubling of cell mass, and therefore of cell protein content, is required for repetitive cell divisions. Preliminary observations have shown that in dog thyrocytes insulin induces protein accumulation but not DNA synthesis, while TSH does not increase protein accumulation but triggers DNA synthesis in the presence of insulin. We show here that EGF and phorbol myristate ester complement insulin action in the same way. HGF is the only factor activating both protein accumulation and DNA synthesis. The effects of insulin on protein accumulation and in permitting the TSH effect are reproduced by IGF-1 and are mediated, at least in part by the IGF-1 receptor. The concentration effect curves are similar for both effects. Similar results are obtained in human thyrocytes. They reflect true cell growth, as shown by increases in RNA content and cell size. Carbachol and fetal calf serum also stimulate protein synthesis and accumulation without triggering DNA synthesis, but they are not permissive for the mitogenic effects of TSH or of the general adenylate cyclase activator, forskolin. Moreover the mitogenic effect of TSH greatly decreased in cells deprived of insulin for 2 days although these cells remain hypertrophic. Hypertrophy may therefore be necessary for cell division, but it is not sufficient to permit it. Three different mechanisms can therefore be distinguished in the mitogenic action of TSH: (1) the increase of cell mass (hypertrophy) induced by insulin or IGF-1; (2) the permissive effect of insulin or IGF-1 on the mitogenic effect of TSH which may involve both the increase of cell mass and the induction of specific proteins such as cyclin D3 and (3) the mitogenic effect of the TSH cyclic AMP cascade proper.