Evidence for metaplasticity in the human visual cortex

The threshold and direction of excitability changes induced by low- and high-frequency repetitive transcranial magnetic stimulation (rTMS) in the primary motor cortex can be effectively reverted by a preceding session of transcranial direct current stimulation (tDCS), a phenomenon referred to as “metaplasticity”. Here, we used a combined tDCS–rTMS protocol and visual evoked potentials (VEPs) in healthy subjects to provide direct electrophysiological evidence for metaplasticity in the human visual cortex. Specifically, we evaluated changes in VEPs at two different contrasts (90 and 20 %) before and at different time points after the application of anodal or cathodal tDCS to occipital cortex (i.e., priming), followed by an additional conditioning with low- or high-frequency rTMS. Anodal tDCS increased the amplitude of VEPs and this effect was paradoxically reverted by applying high-frequency (5 Hz), conventionally excitatory rTMS (p < 0.0001). Similarly, cathodal tDCS led to a decrease in VEPs amplitude, which was reverted by a subsequent application of conventionally inhibitory, 1 Hz rTMS (p < 0.0001). Similar changes were observed for both the N1 and P1 component of the VEP. There were no significant changes in resting motor threshold values (p > 0.5), confirming the spatial selectivity of our conditioning protocol. Our findings show that preconditioning primary visual area excitability with tDCS can modulate the direction and strength of plasticity induced by subsequent application of 1 or 5 Hz rTMS. These data indicate the presence of mechanisms of metaplasticity that keep synaptic strengths within a functional dynamic range in the human visual cortex.     

Subcutaneous inverse vaccination with PLGA particles loaded with a MOG peptide and IL-10 decreases the severity of experimental autoimmune encephalomyelitis

“Inverse vaccination” refers to antigen-specific tolerogenic immunization treatments that are capable of inhibiting autoimmune responses. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), initial trials using purified myelin antigens required repeated injections because of the rapid clearance of the antigens. This problem has been overcome by DNA-based vaccines encoding for myelin autoantigens alone or in combination with “adjuvant” molecules, such as interleukin (IL)-4 or IL-10, that support regulatory immune responses. Phase I and II clinical trials with myelin basic protein (MBP)-based DNA vaccines showed positive results in reducing magnetic resonance imaging (MRI)-measured lesions and inducing tolerance to myelin antigens in subsets of MS patients. However, DNA vaccination has potential risks that limit its use in humans. An alternative approach could be the use of protein-based inverse vaccines loaded in polymeric biodegradable lactic-glycolic acid (PLGA) nano/microparticles (NP) to obtain the sustained release of antigens and regulatory adjuvants. The aim of this work was to test the effectiveness of PLGA-NP loaded with the myelin oligodendrocyte glycoprotein (MOG)_35–55 autoantigen and recombinant (r) IL-10 to inverse vaccinate mice with EAE. In vitro experiments showed that upon encapsulation in PLGA-NP, both MOG_35-55 and rIL-10 were released for several weeks into the supernatant. PLGA-NP did not display cytotoxic or proinflammatory activity and were partially endocytosed by phagocytes. In vivo experiments showed that subcutaneous prophylactic and therapeutic inverse vaccination with PLGA-NP loaded with MOG_35-55 and rIL-10 significantly ameliorated the course of EAE induced with MOG_35-55 in C57BL/6 mice. Moreover, they decreased the histopathologic lesions in the central nervous tissue and the secretion of IL-17 and interferon (IFN)-γ induced by MOG_35-55 in splenic T cells in vitro. These data suggest that subcutaneous PLGA-NP-based inverse vaccination may be an effective tool to treat autoimmune diseases.     

G protein-coupled receptor binding and pharmacological evaluation of indole-derived thiourea compounds

Four 2-(1H-indol-3-yl)ethylthiourea derivatives were prepared by condensation of 2-(1H-indol-3-yl)ethanamine with the corresponding aryl/alkylisothiocyanates in a medium-polarity solvent. Their structures were confirmed by spectral techniques, and the molecular structure of 3 was determined by X-ray crystal analysis. For all derivatives, the binding affinities at the 5-HT_2A and 5-HT_2C receptors, as well as their functional activities at the 5-HT_1A and D₂ receptors, were determined. The arylthioureas 1 and 4 were the most active at the 5-HT_1A receptor, showing, at the same time, significant selectivity over the studied 5-HT₂ and D₂ receptor subtypes. The compounds were tested for their pharmacological activities within the central nervous system in relevant mouse models. The involvement of the serotonergic system in the activity of 1 and 4 was indicated. The antinociceptive action of 4 was linked to its anti-inflammatory activity.     

Content of methylhistidines in normal and pathological human skeletal muscles

The content of 3-methylhistidine (3-MH) and 1-methylhistidine (1-MH) was measured in muscle biopsy specimens from 13 normal controls, 19 patients with Duchenne muscular dystrophy, 8 limb-girdle disease patients, and 23 disease controls with different forms of muscular pathology. 3-MH and 1-MH concentrations in normal human muscle did not appear to be influenced by sex, body weight, and age, at least for subjects in the 10–60 year age group examined. Skeletal muscle 1-MH levels did not significantly differ from mean control values in any of the pathologies investigated. In the patient population examined, the mean 3-MH level per unit of noncollagen protein (NCP) was significantly lower than normal in Duchenne dystrophy only, the reduction being related to disease severity. The significantly lower concentrations of 3-MH in muscle of Duchenne patients indicate the importance of measuring 3-MH in diseased muscle to obtain reliable estimates of the myofibrillar protein catabolic rate.     

Excretion of aminoglycosides in a rat kidney model

Dactimicin is a new aminoglycoside antibiotic with an interesting low nephrotoxicity in animal experimental models. In order to establish if a correlation exists between the nephrotoxic effect and renal pharmacokinetic behaviour of aminoglycosides, tobramycin, sisomicin and dactimicin were studied in a model of isolated and perfused rat kidney. Concentrations in venous and urinary effluent during a continuous perfusion of a constant concentration of drugs were evaluated. The influence of active transport was studied comparing excretion data obtained with perfusion buffer with or without glucose. In the present experimental model the renal excretions of the aminoglycosides tested are quite similar and cannot account for the different nephrotoxicity observed in animals.     

Noncontrast conventional computed tomography in the evaluation of acute stroke

The advantages of CT scanning in the assessment of hyperacute stroke patients include convenience, accuracy, speed, and low cost. CT scanning is presently considered to be the standard of care for the detection of acute extra-axial and parenchymal hemorrhage, although newer MRI techniques are challenging this claim. The accuracy of CT scanning for stroke detection can be optimized by the use of appropriate scanning technique, as well as interactive image review at a picture archiving and communication system workstation using narrow window and level settings. More importantly, CT scanning has prognostic value for patients receiving thrombolytic treatment by helping to predict both responses to treatment and hemorrhage risk. Finally, as will be discussed in other articles in this issue, CT angiography can be performed in the same imaging session as noncontrast CT scanning without substantially increasing the time required for patient evaluation. This provides data regarding vascular patency and tissue perfusion, which are valuable in the triage of stroke patients.     

Bilateral ganglion cyst of the common peroneal nerve

Ganglion cysts of the common peroneal nerve are rarely described in the literature and a bilateral lesion has not been previously reported. We present a case of a 41-year-old man with a bilateral cyst of the common peroneal nerve diagnosed with ultrasound and magnetic resonance imaging. Electronic Publication     

Isolated Agenesis of the Gallbladder: Report of a Case

We report the rare case of an isolated gallbladder with cystic duct agenesis that was misdiagnosed as acute alithiasic cholecystitis. We underline the inaccuracy of currently used diagnostic tests and the importance of making a correct preoperative diagnosis to avoid a needless surgical procedure. Based on the rare and incidental nature of this congenital anomaly, we discourage an extensive routine diagnostic workup, but rather, suggest a careful clinical and diagnostic evaluation of the patient who has symptoms suggestive of biliary tract disease. We conclude that in patients with gallbladder and cystic duct agenesis surgery might be useless and risky when performed by the laparoscopic approach. On the other hand, the awareness of the laparoscopic surgeon of the problems posed by this anomaly and a careful review of currently available diagnostic tests can prevent unnecessary laparotomy and minimize the risk of complications. Received: June 5, 2000 / Accepted: May 15, 2001