Regional variations in intramyocellular lipid concentration correlate with muscle fiber type distribution in rat tibialis anterior muscle.

1H MR spectroscopy (MRS) has proved to be a valuable noninvasive tool to measure intramyocellular lipids (IMCL) in research focused on insulin resistance and type II diabetes in both humans and rodents. An important determinant of IMCL is the muscle fiber type, since oxidative type I fibers can contain up to three times more IMCL than glycolytic type II muscle fibers. Because these different muscle fiber types are inhomogeneously distributed in rodent muscle, in the present study we investigated the distribution of IMCL within the rat tibialis anterior muscle (TA) in vivo using single-voxel 1H MRS along with the muscle fiber distribution in the TA ex vivo determined from immunohistological assays. IMCL levels in the TA differed by up to a factor of 3 depending on the position of the voxel. The distribution of IMCL over the TA cross section was not random, but emerged in a pattern similar to the distribution of the predominantly oxidative muscle fiber types. Dietary interventions, such as high-fat feeding and 15 hr of fasting, did not significantly change this typical fiber type-dependent pattern of IMCL content. These results stress the importance of voxel positioning when single-voxel 1H MRS is used to study IMCL in rodent muscle.     

Electrodynamics and ultimate SNR in parallel MR imaging.

The purpose of this article is to elucidate inherent limitations to the performance of parallel MRI. The study focuses on the ultimate signal-to-noise ratio (SNR), which refers to the maximum SNR permitted by the electrodynamics of the signal detection process. Using a spherical model object, it is shown that the behavior of the ultimate SNR imposes distinct limits on the acceleration rate in parallel imaging. For low and moderate acceleration, the ultimate SNR performance is nearly optimal, with geometry factors close to 1. However, for high reduction factors beyond a critical value, the ultimate performance deteriorates rapidly, corresponding to exponential growth of the geometry factor. The transition from optimal to deteriorating performance depends on the electrodynamic characteristics of the detected RF fields. In the near-field regime, i.e., for low B0 and small object size, the critical reduction factor is constant and approximately equal to four for 1D acceleration in the sphere. In the far-field wave regime the critical reduction factor is larger and increases both with B0 and object size. Therefore, it is concluded that parallel techniques hold particular promise for human MR imaging at very high field.     

Array compression for MRI with large coil arrays.

Arrays with large numbers of independent coil elements are becoming increasingly available as they provide increased signal-to-noise ratios (SNRs) and improved parallel imaging performance. Processing of data from a large set of independent receive channels is, however, associated with an increased memory and computational load in reconstruction. This work addresses this problem by introducing coil array compression. The method allows one to reduce the number of datasets from independent channels by combining all or partial sets in the time domain prior to image reconstruction. It is demonstrated that array compression can be very effective depending on the size of the region of interest (ROI). Based on 2D in vivo data obtained with a 32-element phased-array coil in the heart, it is shown that the number of channels can be compressed to as few as four with only 0.3% SNR loss in an ROI encompassing the heart. With twofold parallel imaging, only a 2% loss in SNR occurred using the same compression factor.     

Gliotoxin non-selectively induces apoptosis in fibrotic and normal livers.

BACKGROUND: Liver fibrosis is the common response to chronic liver injury, ultimately leading to cirrhosis. Several lines of evidence indicate that inducing apoptosis of hepatic stellate cells (HSC) may lead to regression of liver fibrosis. Recently, it was shown that gliotoxin (GTX) induces apoptosis of HSC. However, the clinical use of GTX may be limited because of the lack of cell and tissue specificity, causing a high risk of potentially severe adverse effects. The aim of this study, therefore, was to study the effect of GTX on different cells of the liver. METHODS: We used normal and fibrotic precision-cut rat liver slices to study the effect of GTX on the various resident liver cell types. In these slices, the complex cell-cell interactions are preserved, which closely mimics the in vivo situation. RESULTS: GTX exhibited a potent apoptosis-inducing activity in these slices. Both immunohistochemical stainings and real-time mRNA techniques showed that this apoptosis-inducing effect was seen in HSC. However, Kupffer cells and liver endothelial cells were also affected by GTX, whereas hepatocytes were only mildly affected. CONCLUSIONS: This study indicates that the apoptosis-inducing strategy to treat liver fibrosis has high potential, but it will be necessary to develop an HSC-specific therapy to prevent adverse effects.     

Attitudes toward male fertility control: results of a multinational survey on four continents

BACKGROUND: Following extensive research activity to develop an effective agent to control male fertility, such a product may be available for use within approximately 5 years. However, little is known concerning contraceptive knowledge, desires and attitudes of men in different countries, and their acceptance of male fertility control (MFC). METHODS: A survey of >9000 males aged 18-50 years was performed in nine countries on four continents in 2002. The objective was to compare, on a cross-cultural basis, the knowledge, attitudes and acceptability of MFC among men and assess their willingness to use such a method. RESULTS: Between 50 and 83% of the male respondents currently use contraceptive methods, and 55-81.5% reported that both partners participate in selecting the method of contraception employed. Overall acceptance of hormonal MFC was high (>55%), with 28.5-71.4% of survey participants of various nationalities expressing the willingness to use such a method. CONCLUSION: While MFC appears to be well accepted overall, the willingness to use this type of contraception varies widely between differing population groups. The specific characteristics and profile of any MFC product will have to be carefully evaluated to accurately assess its acceptance, both by men and their female partners.     

Molecular mechanisms that set the stage for DC-T cell engagement

The unsurpassed capacity of dendritic cells (DC) to prime naive T cells is thought to depend on the formation of an immunological synapse. DC-SIGN, a C-type lectin exclusively expressed at the cell surface of DC, functions as an adhesion receptor facilitating T cell binding and priming through recognition of glycosylated ICAM-3 on naive T cells. Yet, DC-SIGN also mediates binding to pathogens such as HIV by recognizing glycosylated gp120. The scope of the present study was to investigate whether DC-SIGN upon recognition of its cellular ligand and pathogenic ligand affects DC synapse formation and activation/mobilization of other adhesion receptors such as LFA-1 to the cell contact site. Using a DC-SIGN deletion mutant, we show that DC-SIGN is a constitutively active receptor that mediates ligand binding independent of signaling through the cytoplasmic domain. Surprisingly, initial binding of gp120 to DC-SIGN did not result in increased adhesion levels of LFA-1 to its ligand ICAM-1 in both immature DC and Raji-DC-SIGN cells. However, ligand binding to DC-SIGN induced recruitment of LFA-1 to the adhesion site. Moreover, we could demonstrate that activation of LFA-1 results in DC-SIGN-LFA-1 co-clustering in the cell membrane. This triggers binding of ligands to LFA-1 that are shared with DC-SIGN, such as ICAM-3, but not of ligands that are not shared with DC-SIGN, such as ICAM-1. Thus, we propose that upon ligand binding DC-SIGN recruits LFA-1 to the contact site, resulting in the formation of DC-SIGN-LFA-1 co-clusters, in which the initial DC-SIGN-mediated interactions with ligand are transient and eventually shift to more stable LFA-1-dependent interactions.     

Application of a comprehensive subtelomere array in clinical diagnosis of mental retardation

In 2-8% of patients with mental retardation, small copy number changes in the subtelomeric region are thought to be the underlying cause. As detection of these genomic rearrangements is labour intensive using FISH, we constructed and validated a high-density BAC/PAC array covering the first 5 Mb of all subtelomeric regions and applied it in our routine screening of patients with idiopathic mental retardation for submicroscopic telomeric rearrangements. The present study shows the efficiency of this comprehensive subtelomere array in detecting terminal deletions and duplications but also small interstitial subtelomeric rearrangements, starting from small amounts of DNA. With our array, the size of the affected segments, at least those smaller than 5 Mb, can be determined simultaneously in the same experiment. In the first 100 patient samples analysed in our diagnostic practice by the use of this comprehensive telomere array, we found three patients with deletions in 3p, 10q and 15q, respectively, four patients with duplications in 9p, 12p, 21q and Xp, respectively, and one patient with a del 6q/dup 16q. The patients with del 3p and 10q and dup 12p had interstitial rearrangements that would have been missed with techniques using one probe per subtelomeric region chosen close to the telomere.     

The Effect of Parenterally Administered Cyclodextrins on Cholesterol Levels in the Rat

The inclusion complex formation of intravenously administered hydroxypropyl--cyclodextrin and -cyclodextrin with endogenous lipids was studied. We tested the hypothesis that complex formation of endogenous cholesterol with cyclodextrins in the bloodstream leads to extraction of cholesterol from the large lipoprotein particles. The relatively small cholesterol–cyclodextrin complexes then leave the bloodstream via capillary pores, and dissociation of the complex in the extravascular compartment finally causes redistribution of cholesterol from blood to tissue. This hypothesis is supported by the following experimental findings. Intravenous administration of cyclodextrins led to a transient decrease in plasma cholesterol levels in a dose-dependent manner, and in vitro cholesterol-cyclodextrin complexes passed dialysis membranes with a molecular weight cutoff of 6000–8000. Further, cyclodextrins increased protein binding of the steroidal drug spironolactone, probably through removal of cholesterol from plasma protein binding sites. Finally, extravascular redistribution was directly demonstrated in histological studies of the kidneys. Glomerular filtration of the cholesterol–cyclodextrin complex is followed by dissociation of the complex in the ultrafiltrate, resulting in cholesterol accumulation in the proximal tubule cells. The cholesterol--cyclodextrin complex has a limited aqueous solubility. Crystallization of this complex in renal tissue might explain the nephrotoxicity of parenterally administered -cyclodextrin. The absence of such crystallization might explain the lower nephrotoxicity of hydroxypropyl--cyclodextrin after intravenous administration.