Dysferlin is a new marker for leaky brain blood vessels in multiple sclerosis

Dysferlin is a muscle protein involved in cell membrane repair and its deficiency is associated with muscular dystrophy. We describe that dysferlin is also expressed in leaky endothelial cells. In the normal central nervous system (CNS), dysferlin is only present in endothelial cells of circumventricular organs. In the inflamed CNS of patients with multiple sclerosis (MS) or in animals with experimental autoimmune encephalomyelitis, dysferlin reactivity is induced in endothelial cells and the expression is associated with vascular leakage of serum proteins. In MS, dysferlin expression in endothelial cells is not restricted to vessels with inflammatory cuffs but is also present in noninflamed vessels. In addition, many blood vessels with perivascular inflammatory infiltrates lack dysferlin expression in inactive lesions or in the normal-appearing white matter. In vitro, dysferlin can be induced in endothelial cells by stimulation with tumor necrosis factor-alpha. Hence, dysferlin is not only a marker for leaky brain vessels, but also reveals dissociation of perivascular inflammatory infiltrates and blood-brain barrier disturbance in multiple sclerosis.

Overexpression of gastrin-releasing peptide receptors in tumor-associated blood vessels of human ovarian neoplasms

BACKGROUND: Peptide receptors, overexpressed in specific cancers, represent new diagnostic and therapeutic targets. In this study, receptors for the gastrin-releasing peptide (GRP), and other members of the bombesin-family of peptides, were evaluated in ovarian neoplasms. METHODS: 75 primary, secondary and metastatic ovarian tumors were investigated for their bombesin-receptor subtype expression, incidence, localization and density using in vitro autoradiography on tissue sections with the universal radioligand (125)I-[D-Tyr(6), beta-Ala(11), Phe(13), Nle(14)]-bombesin(6-14) and the GRP-receptor subtype-preferring (125)I-[Tyr(4)]-bombesin. RESULTS: GRP-receptors were detected in 42/61 primary ovarian tumors; other bombesin-receptor subtypes (BB1, bb3) were rarely present (3/61). Two different tissue compartments expressed GRP-receptors: the tumoral vasculature was the predominant site of GRP-receptor expression (38/61), whereas neoplastic cells more rarely expressed GRP-receptors (14/61). GRP-receptor positive vessels were present in the various classes of ovarian tumors; generally, malignant tumors had a higher incidence of GRP-receptor positive vessels compared to their benign counterparts. The prevalence of such vessels was particularly high in ovarian carcinomas (16/19) and their metastases (5/5). The GRP-receptors were expressed in high density in the muscular vessel wall. Normal ovary (n=10) lacked GRP-receptors. CONCLUSIONS: The large amounts of GRP-receptors in ovarian tumor vessels suggest a role in tumoral vasculature and possibly angiogenesis. Further, these vessels might be targeted in vivo with bombesin analogs for diagnosis or for therapy.

Ultrastructural changes in diaphragm neuromuscular junctions in a severe mouse model for Spinal Muscular Atrophy and their prevention by bifunctional U7 snRNA correcting SMN2 splicing

In Spinal Muscular Atrophy (SMA), the SMN1 gene is deleted or inactivated. Because of a splicing problem, the second copy gene, SMN2, generates insufficient amounts of functional SMN protein, leading to the death of spinal cord motoneurons. For a "severe" mouse SMA model (Smn -/-, hSMN2 +/+; with affected pups dying at 5-7 days), which most closely mimicks the genetic set-up in human SMA patients, we characterise SMA-related ultrastructural changes in neuromuscular junctions (NMJs) of two striated muscles with discrete functions. In the diaphragm, but not the soleus muscle of 4-days old SMA mice, mitochondria on both sides of the NMJs degenerate, and perisynaptic Schwann cells as well as endoneurial fibroblasts show striking changes in morphology. Importantly, NMJs of SMA mice in which a modified U7 snRNA corrects SMN2 splicing and delays or prevents SMA symptoms are normal. This ultrastructural study reveals novel features of NMJ alterations - in particular the involvement of perisynaptic Schwann cells - that may be relevant for human SMA pathogenesis.

Brain metabolite composition in relation to cognitive function and dystrophin mutations in boys with Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a hereditary X-linked recessive disorder affecting the synthesis of dystrophin, a protein essential for structural stability in muscle. Dystrophin also occurs in the central nervous system, particularly in the neocortex, hippocampus and cerebellum. Quantitative metabolic analysis by localized (1) H MRS was performed in the cerebellum (12 patients and 15 controls) and a temporo-parietal location (eight patients and 15 controls) in patients with DMD and healthy controls to investigate possible metabolic differences. In addition, the site of individual mutations on the dystrophin gene was analyzed and neuropsychological cognitive functions were examined. Cognitive deficits in the patient group were found in line with earlier investigations, mainly concerning verbal short-term memory, visuo-spatial long-term memory and verbal fluency, but also the full-scale IQ. Causal mutations were identified in all patients with DMD. Quantitative MRS showed consistent choline deficits, in both cerebellar white matter and temporo-parietal cortex, as well as small, but significant, metabolic abnormalities for glutamate and total N-acetyl compounds in the temporo-parietal region. Compartment water analysis did not reveal any abnormalities. In healthy subjects, choline levels were age related in the cerebellum. The choline deficit contrasts with earlier findings in DMD, where a surplus of choline was postulated for the cerebellum. In patients, total N-acetyl compounds in the temporo-parietal region were related to verbal IQ and verbal short-term memory. However, choline, the putative main metabolic abnormality, was not found to be associated with cognitive deficits. Furthermore, in contrast with the cognitive performance, the metabolic brain composition did not depend significantly on whether or not gene mutations concerned the expression of the dystrophin isoform Dp140, leading to the conclusion that the effect of the missing Dp140 isoform on cognitive performance is not mediated through the observed metabolite composition, or is caused by local effects beyond the resolution accessible to MRS investigations.

Neuropsychological impairments and the impact of dystrophin mutations on general cognitive functioning of patients with Duchenne muscular dystrophy

Mutations in the dystrophin gene have long been recognised as a cause of mental retardation. However, for reasons that are unclear, some boys with dystrophin mutations do not show general cognitive deficits. To investigate the relationship between dystrophin mutations and cognition, the general intellectual abilities of a group of 25 boys with genetically confirmed Duchenne muscular dystrophy were evaluated. Furthermore, a subgroup underwent additional detailed neuropsychological assessment. The results showed a mean full scale intelligence quotient (IQ) of 88 (standard deviation 24). Patients performed very poorly on various neuropsychological tests, including arithmetics, digit span tests and verbal fluency. No simple relationship between dystrophin mutations and cognitive functioning could be detected. However, our analysis revealed that patients who lack the dystrophin isoform Dp140 have significantly greater cognitive problems.

Time-referenced effects of an internal vs. external focus of attention on muscular activity and compensatory variability

The paralysis-by-analysis phenomenon, i.e., attending to the execution of one's movement impairs performance, has gathered a lot of attention over recent years (see Wulf, 2007, for a review). Explanations of this phenomenon, e.g., the hypotheses of constrained action (Wulf et al., 2001) or of step-by-step execution (Masters, 1992; Beilock et al., 2002), however, do not refer to the level of underlying mechanisms on the level of sensorimotor control. For this purpose, a “nodal-point hypothesis” is presented here with the core assumption that skilled motor behavior is internally based on sensorimotor chains of nodal points, that attending to intermediate nodal points leads to a muscular re-freezing of the motor system at exactly and exclusively these points in time, and that this re-freezing is accompanied by the disruption of compensatory processes, resulting in an overall decrease of motor performance. Two experiments, on lever sequencing and basketball free throws, respectively, are reported that successfully tested these time-referenced predictions, i.e., showing that muscular activity is selectively increased and compensatory variability selectively decreased at movement-related nodal points if these points are in the focus of attention.

Concomitant vascular GRP-receptor and VEGF-receptor expression in human tumors: molecular basis for dual targeting of tumoral vasculature

Gastrin-releasing peptide (GRP) and GRP receptors (GRPR) play a role in tumor angiogenesis. Recently, GRPR were found to be frequently expressed in the vasculature of a large variety of human cancers. Here, we characterize these GRPR by comparing the vascular GRPR expression and localization in a selection of human cancers with that of an established biological marker of neoangiogenesis, the vascular endothelial growth factor (VEGF) receptor. In vitro quantitative receptor autoradiography was performed in parallel for GRPR and VEGF receptors (VEGFR) in 32 human tumors of various origins, using ¹²⁵I-Tyr-bombesin and ¹²⁵I-VEGF₁₆₅ as radioligands, respectively. Moreover, VEGFR-2 was evaluated immunohistochemically. All tumors expressed GRPR and VEGFR in their vascular system. VEGFR were expressed in the endothelium in the majority of the vessels. GRPR were expressed in a subpopulation of vessels, preferably in their muscular coat. The vessels expressing GRPR were all VEGFR-positive whereas the VEGFR-expressing vessels were not all GRPR-positive. GRPR expressing vessels were found immunohistochemically to co-express VEGFR-2. Remarkably, the density of vascular GRPR was much higher than that of VEGFR. The concomitant expression of GRPR with VEGFR appears to be a frequent phenomenon in many human cancers. The GRPR, localized and expressed in extremely high density in a subgroup of vessels, may function as target for antiangiogenic tumor therapy or angiodestructive targeted radiotherapy with radiolabeled bombesin analogs alone, or preferably together with VEGFR targeted therapy.

Corticospinal output during muscular fatigue differs in multiple sclerosis patients compared to healthy controls

In multiple sclerosis (MS), fatigue is a common and often disabling symptom. It has multiple causes with central motor fatigue playing an important role.

Six-month clinical outcomes following implantation of the bioresorbable everolimus-eluting vascular scaffold in vessels smaller or larger than 2.5 mm

We investigated the 6-month clinical outcomes after implantation of second-generation 3.0-mm bioresorbable everolimus-eluting vascular scaffolds (BVS) in small coronary vessels (<2.5 mm).

Transposition of the supra-aortic vessels before stent grafting the aortic arch and descending aorta

Thoracic endovascular aortic repair has broadened the spectrum of treatment options for various acute and chronic thoracic aortic diseases. In clinical practice, aneurysms of the descending aorta are rarely limited to 1 segment. Thus, various surgical and endovascular options have been developed to offer treatment to those patients with more extended descending thoracic aortic disease. We have summarized the most common methods of arch rerouting, depending on the aortic involvement, emphasizing that these techniques should be used very selectively by experienced cardiovascular surgery teams.

Determinants of preformed collateral vessels in the human heart without coronary artery disease

Coronary collaterals protect myocardium jeopardized by coronary artery disease (CAD). Promotion of collateral circulation is desirable before myocardial damage occurs. Therefore, determinants of collateral preformation in patients without CAD should be elucidated.