Brain Glioma and Human Leukocyte Antigens (HLA) – is There an Association

Expression of human leukocyte antigens (HLA) is important for the immune response against infectious agents and malignant cells. Association of single HLA antigens or HLA haplotypes with disease has been investigated previously, and positive correlations between HLA and some cancers, such as cervical or nasopharyngeal carcinomas have been reported. In the present study, HLA antigen frequencies of 65 adult Caucasian patients with low-grade, anaplastic, or malignant astrocytic glioma (WHO grades II–IV) were compared with 157 racially similar, asymptomatic control individuals. Both standard serologic and PCR techniques for HLA typing were employed for all patients and controls.Our results suggest a positive association between single HLA antigens and presence of symptomatic cerebral glioma. Compared with the control population, patients positive for HLA-A*25 had a 3.0-fold increased risk of glioma (p = 0.04), patients positive for HLA-B*27, a 2.7-fold risk (p = 0.03), and patients positive for HLA-DRB1*15, a 2.2-fold risk (p = 0.03), whereas HLA-DRB1*07 was associated with a 0.4-fold decreased risk of glioma (p = 0.02). Occurrence rate of some HLA antigen combinations and estimated haplotypes was also different in glioma patients. Thus, HLA-DRB1*15:DRB5*(51) occurrence in combination with HLA-DRB1*11 was associated with a 13.4-fold increased risk of glioma (p = 0.001), and the incidence of HLA-Cw*6:DRB1*07 with a 0.2-fold decreased risk of glioma (p = 0.03).In conclusion, single HLA antigens and their combinations and estimated haplotypes are possibly significantly more or less frequent in persons developing symptomatic cerebral glioma during their adult life, compared with asymptomatic individuals.     

Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity

The VHL tumor suppressor gene has previously been reported to encode a protein of 213 amino acid residues. Here we report the identification of a second major VHL gene product with an apparent molecular weight of 18 kD, pVHL18, which appears to arise from alternate translation initiation at a second AUG codon (codon 54) within the VHL open reading frame. In vitro and in vivo studies indicate that the internal codon in the VHL mRNA is necessary and sufficient for production of pVHL18. pVHL18 can bind to elongin B, elongin C, and Hs-CUL2. When reintroduced into renal carcinoma cells that lack a wild-type VHL allele, pVHL18 suppresses basal levels of VEGF expression, restores hypoxia-inducibility of VEGF expression, and inhibits tumor formation in nude mice. These data strongly support the existence of two distinct VHL gene products in VHL tumor suppression.     

Transgenic pigs as models for translational biomedical research

The translation of novel discoveries from basic research to clinical application is a long, often inefficient, and thus costly process. Accordingly, the process of drug development requires optimization both for economic and for ethical reasons, in order to provide patients with appropriate treatments in a reasonable time frame. Consequently, “Translational Medicine” became a top priority in national and international roadmaps of human health research. Appropriate animal models for the evaluation of efficacy and safety of new drugs or therapeutic concepts are critical for the success of translational research. In this context rodent models are most widely used. At present, transgenic pigs are increasingly being established as large animal models for selected human diseases. The first pig whole genome sequence and many other genomic resources will be available in the near future. Importantly, efficient and precise techniques for the genetic modification of pigs have been established, facilitating the generation of tailored disease models. This article provides an overview of the current techniques for genetic modification of pigs and the transgenic pig models established for neurodegenerative diseases, cardiovascular diseases, cystic fibrosis, and diabetes mellitus.     

Hardware Failures in Spinal Cord Stimulation for Failed Back Surgery Syndrome

Spinal cord stimulation (SCS) is an efficient means for treatment of the postsurgical lumbar spine condition known as failed back surgery syndrome (FBSS). Although the devices and the implantation techniques are well established and the technology is sophisticated, there are some complications caused by hardware failures. This study was aimed at identifying the most frequent types of hardware failures and their causes in FBSS patients treated with SCS. In a retrospective analysis, a group of 42 FBSS patients using single lead SCS for 6–74 months was evaluated. Only hardware failures were considered in the analysis, and parameters such as occurrence of failure after primary implantation of the device, frequency and site of failure, stimulation time to failure (TF), and overall time of SCS usage were recorded. In the patient group studied, 12 surgical corrections of the hardware were carried out in 10 patients. In eight patients there was a single corrective procedure, in two additional cases there were two surgically corrected hardware failures each. The most often encountered type of hardware failure was lead breakage or disruption of insulation (percutaneously placed Quad leads only) leading to short circuiting and dysfunction (n= 8). Second in frequency were receiver (model 3470) failures due to insulation leakage at the plug connection site (n= 2). In one case, extension cable breakage caused dysfunction of the system, and another dysfunction was caused by distal extension cable disconnection. In conclusion, SCS is a low‐complication procedure for treatment of benign low‐back pain, but seems to be prone to lead and insulation failures.     

Electrochemical recognition properties of 13- and 16-membered azo- and azoxycrowns in solution

The voltammetric reduction of 13- and 16-membered azo- and azoxycrowns is investigated in the presence of alkali metal cations (Na⁺ or K⁺ for 13- or 16-membered azocrowns, respectively). Two types of recognition behaviour have been observed. The first type consists in a positive shift of the redox potential (100–150 mV) upon addition of metal cation (single peak behaviour). The second type consists in the appearance of two separated redox peaks (150–320 mV more positive, two-wave situation). Better electrochemical recognition results were obtained using SW voltammetry with the peak potential for the complex up to 0.32 V (for the azoxycrown derivative) more positive of the original azocrown compound. For azo- and azoxycrowns exhibiting ‘two-wave’ behaviour, the binding enhancement (ratio of binding constants for reduced and neutral species) was 10²–10⁵ M^?1. For other azocrown compounds with single peak recognition behaviour the binding constants for reduced species were estimated to be 10⁴–10⁵ M^?1. In general, K⁺ binds to 16-membered neutral azocrowns more strongly than Na⁺ to 13-membered ones, whilst binding to the anion-radical has the opposite trend.     

Axo–axonic GABA-immunopositive synapses on the primary afferent fibers in frogs

In three frog species Rana esculenta, Rana temporaria and Xenopus laevis, the contacts established by γ-aminobutyric acid and glutamate decarboxylase immunoreactive (-ir) terminals upon primary afferent fibers were studied using confocal and electron microscopy. For confocal microscopy, the primary afferent fibers were labeled through the dorsal root with Dextran–Texas Red, whereas γ-aminobutyric acid and glutamate decarboxylase immunoreactivity were revealed with fluorescein isothiocyanate. Appositions of γ-aminobutyric acid and glutamate decarboxylase immunoreactive profiles onto primary afferent fibers were observed and were considered as putative axo–axonic contacts of GABAergic terminals upon primary afferents. The latter was confirmed by the ultrastructural finding of axo–axonic synapses from γ-aminobutyric acid immunopositive boutons upon the HRP-labeled primary afferent fibers in postembedding immunoelectron microscopic study. Such synapses may represent the morphological basis of GABAergic presynaptic inhibition of primary afferent fibers.     

The biomechanics of the lumbar multifidus

The possible actions of the lumbar multifidus were determined by plotting the points of attachment and orientation of each of its component fascicles on radiographs of 5 cadavers and 21 living subjects. Subsequent analysis revealed that the principal action of multifidus is posterior sagittal rotation (extension without posterior translation) of the lumbar vertebrae. It has no translatory action. Any axial rotation exerted by the lumbar multifidus is only a minor, secondary action which must be coupled with posterior sagittal rotation. This extension balances the flexion moment generated by the abdominal muscles which rotate the trunk. The constancy of the sites of attachment of the multifidus allows each of its fascicles to be plotted accurately on radiographs or computer diagrams which can be used to produce highly detailed analyses or models of the forces exerted by the multifidus on the lumbar spine.     

Stabilization of synaptic membranes by α-tocopherol against the damaging action of phospholipases. Possible mechanism of biological action of vitamin E

Using fluorescent and ESR-spin probes, the effects of phospholipases A₂, C and D on rat brain synaptosomal membranes were investigated. It was shown that the exposure of synaptosomal membranes to phospholipases A₂, C and D results in their depolarization and an increase of the negative surface potential. In the case of phospholipases A₂ and C, these changes are associated with a decrease of the microviscosity of the membrane lipid bilayer. α-Tocopherol stabilizes synaptosomal membranes against the damaging action of the phospholipases. This stabilization consists in the reconstitution of the transmembrane potential and an increase of microviscosity of the phospholipase-treated membranes. The stabilizing effect of α-tocopherol is due to the binding of phospholipid hydrolysis products, but not to the inhibition of phospholipases. The observed stabilization of synaptosomal membranes by α-tocopherol is regarded as a possible mechanism of biological action of vitamin E on biomembranes.     

Deafferentation of neighbouring motor cortex areas does not further enhance saturated practice-dependent plasticity in healthy adults

OBJECTIVE: To assess effects of deafferentation of the arm representation of primary motor cortex (M1) on practice-dependent plasticity in healthy adults. METHODS: Twelve healthy, right-handed adults (18-48 years, median 20.2 years) performed two consecutive experiments (exp. 1 and exp. 2). Exp. 1 consisted of a motor practice (MP) of repeated ballistic flexion movements of the left thumb. This was followed by exp. 2 consisting of selective anaesthesia of the upper brachial plexus (SPA) to disinhibit the training M1 and a second period of the same MP. Peak acceleration of the trained thumb movement and the motor evoked potential (MEP) amplitude in the flexor pollicis brevis muscle elicited by single-pulse transcranial magnetic stimulation of the training M1 were studied before and after exp. 1 and after exp. 2. RESULTS: After exp. 1 all subjects demonstrated an increase of peak acceleration (baseline: 19.23+/-3.81ms(-2); after exp. 1: 43.28+/-17.63ms(-2), p=0.008) and MEP amplitude (from 0.46+/-0.23mV to 1.26+/-0.77mV, p=0.03). There was no additional increase of these measures after exp. 2 (44.37+/-19.56ms(-2), p=0.78, 1.69+/-1.21mV (p=0.07)). CONCLUSIONS: Training of ballistic thumb movements leads to behavioural improvement as well as to an increased excitability of the corresponding M1 representation. These effects do not increase further during deafferentation of the training M1. In contrast to stroke patients [Muellbacher W, Richards C, Ziemann U, Wittenberg G, Weltz D, Boroojerdi B, et al. Improving hand function in chronic stroke. Arch Neurol 2002;59:1278-82], practice-dependent plasticity in healthy subjects cannot be enhanced by deafferentation of neighbouring motor cortex areas. SIGNIFICANCE: Healthy subjects, in contrast to patients with central motor lesions, are capable of saturating practice-dependent plasticity to a level that cannot be further enhanced by experimental manipulation.     

Ca2+-dependent histaminergic regulation of proenkephalin mRNA levels in cultured adrenal chromaffin cells

The effect of histamine on messenger ribonucleic acid levels encoding proenkephalin A (mRNA(enk)) was studied in serum-free cultures of bovine adrenal chromaffin cells. Histamine (10(-7)-10(-4) M) stimulated mRNA(enk), with a maximum response (5-fold) at 10(-5) M, an effect which could be abolished by the H1 receptor antagonist clemastine (10(-7) M) but not by the H2 receptor antagonist cimetidine (10(-7)-10(-5) M). The histamine stimulation was partially reduced by the Ca++ channel blockers D600 (10(-5) M) and nifedipine (10(-7) M). On the other hand, muscarinic receptor stimulation, which similarly to histamine is known to stimulate phosphoinositide hydrolysis in chromaffin cells, did not alter mRNA(enk) in these cells. These data show that mRNA(enk) levels may be modulated by activation of the H1 receptor and that this effect is partially dependent on the activation of voltage-dependent Ca2+ channels.