The pentose phosphate pathway and pyruvate carboxylation after neonatal hypoxic-ischemic brain injury

The neonatal brain is vulnerable to oxidative stress, and the pentose phosphate pathway (PPP) may be of particular importance to limit the injury. Furthermore, in the neonatal brain, neurons depend on de novo synthesis of neurotransmitters via pyruvate carboxylase (PC) in astrocytes to increase neurotransmitter pools. In the adult brain, PPP activity increases in response to various injuries while pyruvate carboxylation is reduced after ischemia. However, little is known about the response of these pathways after neonatal hypoxia-ischemia (HI). To this end, 7-day-old rats were subjected to unilateral carotid artery ligation followed by hypoxia. Animals were injected with [1,2-¹³C]glucose during the recovery phase and extracts of cerebral hemispheres ipsi- and contralateral to the operation were analyzed using ¹H- and ¹³C-NMR (nuclear magnetic resonance) spectroscopy and high-performance liquid chromatography (HPLC). After HI, glucose levels were increased and there was evidence of mitochondrial hypometabolism in both hemispheres. Moreover, metabolism via PPP was reduced bilaterally. Ipsilateral glucose metabolism via PC was reduced, but PC activity was relatively preserved compared with glucose metabolism via pyruvate dehydrogenase. The observed reduction in PPP activity after HI may contribute to the increased susceptibility of the neonatal brain to oxidative stress.     

Multidetector-row computed tomography and magnetic resonance imaging of atherosclerotic lesions in human ex vivo coronary arteries

In the present study, we tested the ability of multidetector-row computed tomography (MDCT) and magnetic resonance imaging (MRI) to identify and retrospectively characterize atherosclerotic lesions in human ex vivo coronary arteries. Thirteen ex vivo hearts were studied with MDCT and MRI. MDCT-images were obtained with an isotropic voxel size of 0.6mm(3). MR images were obtained with an in-plane resolution of 195 microm and 3mm slice thickness. All images were matched with histopathology sections. For both modalities, the sensitivity for the detection of any atherosclerotic lesion was evaluated, and a retrospective analysis of plaque morphology according to criteria defined by the American Heart Association (AHA) was performed. At histopathology, 28 atherosclerotic lesions were found. 21 and 23 of these lesions were identified by MDCT and MRI, respectively. Both modalities detected a small number of false-positive lesions. After retrospective matching with histopathology, MDCT as well as MRI were able to differentiate typical morpholocigal features for fatty, fibrous or calcified plaque components. Using the information presented in this study, in vivo coronary artery wall imaging using MDCT as well as MRI could be facilitated and supported for future investigations on this subject.     

TEL gene is involved in myelodysplastic syndromes with either the typical t(5;12)(q33;p13) translocation or its variant t(10;12)(q24;p13)

A t(5;12)(q33;p13) translocation is a recurrent chromosome abnormality in a subgroup of myeloid malignancies with features of both myeloproliferative disorders and myelodysplastic syndromes (MDSs). The molecular consequence of a t(5;12) is a fusion between the platelet- derived growth factor receptor-B gene on chromosome 5 and a novel ETS- like gene, TEL, on chromosome 12. We report on three patients with a t(5;12)(q33;p13) diagnosed as chronic myelomonocytic leukemia, and one case of a t(10;12)(q24;p13) in a progressive MDS, with eosinophilia and monocytosis. Involvement of the TEL gene in these chromosome translocations was investigated by fluorescence in situ hybridization (FISH) with cosmid probes containing selectively the 5' end or 3' end of TEL. Hybridization of these cosmids to the der(5)/der(10) or a der(12), respectively, demonstrated a rearrangement of TEL in both translocations, showing that the t(10;12) is a variant translocation of the t(5;12). Cloning of the fusion cDNA of one case of t(5;12) showed that the breakpoint occurred at the RNA level at exactly the same position as reported by Golub et al (Cell 77:307, 1994). In addition, the TEL gene on chromosome 12 could be localized between two probes previously mapped to 12p13, namely PRB1 and D12S178, leading to a better definition of the position of TEL in this chromosome region. Moreover, in the case involving chromosome 10, the breakpoint occurred between cKTN206 and cKTN312/LYT-10 at 10q24. Clinicohematological data in these studies as well as the restriction mapping of chromosomal breakpoints strongly suggest that (1) common features in MDSs involving the TEL gene are monocytosis and eosinophilia, (2) chromosomes other than no. 5 may be involved and at least a t(10;12)(q24;p13) variant chromosome translocation does exist in these MDSs, and (3) both standard and variant 12p/TEL translocations may be identified by FISH with appropriate probes.     

Hepatosplenic T-cell lymphoma: sinusal/sinusoidal localization of malignant cells expressing the T-cell receptor gamma delta

Peripheral T-cell lymphomas consist of a clinically heterogeneous group of malignant disorders whose immunophenotype usually corresponds to that of normal mature T cells. We describe and correlate the clinical, histopathologic, phenotypic, and genotypic findings in two patients with malignant lymphoma presenting with hepatosplenic disease. The morphologic pattern of lymphoma was that of a sinusal/sinusoidal infiltration in spleen, marrow, and liver. This morphologic characteristic was associated with the presence of a productive clonal rearrangement of the T-cell receptor (TCR) delta gene. Lymphoma cells expressed a CD3-TCR-gamma delta- phenotype. They were also double negative (ie, CD4-CD8-) and lacked the CD5 and CD7 antigens. In one patient, tumor progression was associated with phenotypic changes that resulted in a CD3-TCR-gamma delta- phenotype with the same delta-gene rearrangement as initially. These observations suggest the existence of a new type of peripheral T-cell lymphoma characterized by its hepatosplenic presentation, and by the sinusal/sinusoidal tropism and the TCR-gamma delta phenotype of the malignant cells.     

Further specificity characterization of von Willebrand factor inhibitors developed in two patients with severe von Willebrand disease

Circulating inhibitors against von Willebrand factor (vWF) that show the properties of heterologous IgG antibodies have been described in a few patients with severe von Willebrand disease (vWD). The present study provides further characterization of inhibitors from two patients with severe vWD. Inhibitors in both, like polyclonal rabbit antibody, detected all sizes of multimers and the complex structure of each multimer from platelets and plasma of normal individuals as well as from plasma of patients with IIA, IIB, and IIC vWD. Both inhibitors and the rabbit antibody reacted mainly with the intact 225-Kd vWF subunit and the 189-H and 140-Kd fragments in contrast to monoclonal antibodies specific for vWF fragments that detected a higher relative proportion of 176-Kd fragment. Furthermore, all these antibodies recognized fragment III, although one inhibitor and rabbit polyclonal antibody reacted poorly and the other inhibitor did not react at all with reduced fragment II of vWF digested with Staphylococcus aureus V-8 protease. These data suggest that although human inhibitors from severe vWD patients may behave, to some extent, as polyclonal heterologous antibodies against native vWF, the former show striking differences in their target specificity as well as a much broader specificity than that described for human factor VIII inhibitors.     

Functional factors that are important correlates to physical activity in people with multiple sclerosis: a pilot study

Purpose: Identify functional factors that are important correlates to physical activity levels among people with multiple sclerosis.

Methods: A total of eight functional tests were conducted and physical activity was objectively measured (Actigraph GT3X accelerometer) for one week in 34 people with multiple sclerosis. A corrected Akaike Information Criterion analysis was performed to identify the strongest correlates with moderate-to-vigorous physical activity, total activity and sedentary time.

Results: The multiple regression analysis converged on a model for moderate-to-vigorous physical activity (R²?=?0.31, F?=?6.97, p=?0.003) that included total strength of the less-affected leg (partial r?=?0.46, p?=?0.007) and average peg test performance (partial r?=??0.30, p?=?0.087). The model for total activity (R²?=?0.40, F?=?10.51, p?<?0.001) included five times sit-to-stand performance (partial r=??0.44, p?=?0.010) and total strength of the less-affected leg (partial r?=?0.31, p?=?0.077). The model for sedentary time (R²=0.22, F?=?9.23, p?=?0.005) only included total strength of the more affected leg (r=??0.47, p?=?0.005).

Conclusion: These results suggest that leg strength, manual dexterity and the ability to perform functional tasks may be important correlates with physical activity levels in people with multiple sclerosis. The findings of this pilot study can inform future investigations aiming to increase physical activity levels or develop improved rehabilitation protocols for people with multiple sclerosis.

• Implications for Rehabilitation

• Physical activity is an effective means of improving the symptoms associated with multiple sclerosis.

• Participation in physical activity by people with multiple sclerosis may be affected by functional factors such as leg strength, manual dexterity and the ability to rise from a seated position.

• Bilateral leg strength differences should be assessed and addressed in people with multiple sclerosis.