Sparing of perceptual implicit memory despite suppression of the electrophysiological word repetition effect: a study with general anesthetic isoflurane.

OBJECTIVE: Much effort has been devoted to the search for the neurophysiological correlates of implicit memory. A commonly held view is that the early portion (250-500 ms) of the event-related potential (ERP) word repetition effect reflects processes important for perceptual implicit memory whereas the latter portion reflects processes implicated in explicit memory. It is, however, difficult to disentangle with certainty the relative contributions of each form of memory on ERPs since both forms co-exist in normal subjects. To dissociate ERP effect related to implicit and explicit memory, we used isoflurane sedation in normal subjects to suppress explicit remembering while sparing implicit memory. These ERPs were compared with those of non-medicated control subjects. METHODS: Thirteen subjects performed an incidental encoding task for words presented auditorily during the inhalation of a subanesthetic dose of isoflurane. After termination of isoflurane administration, we assessed free recall and recorded ERPs during a syllable completion task (implicit memory) and during a passive listening task (ERP repetition effect). Eleven non-medicated control subjects were tested in a similar manner. RESULTS: The controls showed robust early and late ERP repetition effect. The isoflurane group had implicit memory without free recall and showed no ERP repetition effect. CONCLUSIONS: These findings failed to show an association between any part of the repetition effect and perceptual implicit memory. The results are consistent with the view that processes linked to explicit memory contribute to the ERP repetition effect since there was a marked difference in free recall between the control and isoflurane groups. SIGNIFICANCE: The present study shows that the reversible alterations of memory by general anesthetics can be used to study the neurophysiological correlates of memory processes.     

Malignant glioma-derived soluble factors regulate proliferation of normal adult human astrocytes.

Malignant gliomas are characteristically surrounded by marked gliosis. To assess whether glioma-derived products contribute to the proliferation of astrocytes, a feature of the gliosis response, we evaluated the influence of culture supernatants from malignant human glioma lines and tumor cyst fluids collected from two patients with glioblastoma multiforme on the proliferation of non-transformed adult human astrocytes. Both the culture supernatants and cyst fluids significantly increased DNA synthesis in astrocytes as assessed by a double immunofluorescence glial fibrillary acidic protein-bromodeoxyuridine technique. The net proliferative effect mediated by glioma cell line supernatants was tumor growth phase-dependent, being preferentially expressed during the logarithmic phase of glioma cell growth. Specific growth factor molecules and cytokines known to be secreted by gliomas (epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, transforming growth factor-beta, interleukin-6, and tumor necrosis factor-alpha) could not reproduce the mitogenic effects of the glioma-derived soluble factors. Cytokines which can induce DNA synthesis by adult human astrocytes in vitro, gamma-interferon and interleukin-1, were not detected in the culture supernatant of glioma lines used in this study. In conjunction with the documented effects of glioma products on endothelial and lymphoid cells, the current study suggests that soluble glioma products can contribute to the production of surrounding gliosis observed in vivo.     

Opposite effects of internal globus pallidus stimulation on pallidal neurones activity.

Besides clinical efficacy, the mechanisms of action of deep brain stimulation (DBS) are still debated. To shed light on this complex issue, we have taken the opportunity to record the response of globus pallidus internus (GPi) neurones to 100 Hz stimulations in a case of Lesch-Nyhan syndrome (LNS) where four pallidal electrodes were implanted. Three types of response were observed, 2/19 neurones were unaffected by DBS. About 7/19 neurones were inhibited during DBS stimulation and 10/19 neurones were excited during DBS stimulation. Both effects ceased when DBS was turned off. Inhibited neurones were situated lower that exited ones on the trajectory (1.25 and 4.65 mm above the center of GPi respectively). These observations suggest that locally DBS induces a reversible inhibition of neurone firing rate while at the same time distantly exciting the main afferents to and/or efferents from the GPi. Both actions would result in a strong GPi inhibition that does not preclude increased outflow from the GPi.     

Bicuculline-induced epileptogenesis in the human neocortex maintained in vitro

Summary Intracellular and extracellular recordings were made from human neocortical slices of the temporal lobe maintained in vitro. The slices were treated with bicuculline methiodide to reduce synaptic inhibition mediated by tha gamma-aminobutyric acid A (GABA_A) receptor. Spontaneously occurring epileptiform activity was never observed in over 60 slices examined. All epileptiform discharges were elicited by single-shock stimuli delivered in the underlying white matter or within the cortical layers. Intracellularly, the stimulus-induced epileptiform discharge resembled the paroxysmal depolarization shift (PDS). This potential was observed in neurons located between 200 and 2200 m from the pia. It was characterized by a 100–1800 ms long depolarization which triggered burst firing of action potentials, and was at times followed by an afterdischarge. Simultaneous intracellular and extracellular recordings showed that each PDS was reflected by the synchronous discharge of a neuronal aggregate. The voltage behaviour of the PDS and its preceding EPSP was analyzed in cells that were injected with the lidocaine derivative QX-314. The amplitudes of the PDS depolarizing envelope measured at its peak and during its falling phase both behaved as a monotonic function of the membrane potential by increasing in amplitude during hyperpolarization. In addition, the PDS peak amplitude showed a much greater rate of increase than the early EPSP peak amplitude, thus suggesting that the synaptic conductance underlying the PDS was much greater. Perfusion of the neocortical slices with the N-Methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-phosphonovaleric acid (APV) reduced both the duration and the amplitude of the paroxysmal field discharge in a dose related fashion. The effects of APV were reflected intracellularly by an attenuation of the PDS's late phase and a blockade of the afterdischarge. Similar findings were also obtained by using the NMDA receptor antagonist 3-((±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid. These data indicate that reduction or blockade of the GABA_A receptor is sufficient to elicit epileptiform discharges in the human neocortex maintained in vitro. Mechanisms dependent upon the NMDA receptor contribute to this type of epileptiform response mainly by prolonging the stimulus-induced depolarizing potential and the associated burst of firing.     

Fractionated stereotactic radiation therapy for intracranial tumors

In stereotactic radio surgery, a single, large dose of radiation is delivered to a small, well-defined, stereotactically localized intracranial lesion. In contrast to conventional radiation therapy, in radio surgery no attempt is made to spare normal cells within the target volume by fractionating the tumor dose. In 1987, the authors began a program of fractionated stereotactic radiation therapy for selected tumors involving sensitive brain structures. Their objective was to improve the therapeutic index and study the feasibility of the fractionated technique. Fifteen patients were treated with a multifraction regimen typically consisting of six fractions of 700 cGy each, given on alternate days for 2 weeks (total tumor dose, 4200 cGy). All patients were treated with the dynamic stereotactic radio surgical technique. A head ring ("halo frame") was used for immobilization and setup during radiation treatments. At a median follow-up time of 27 months, the symptoms of the majority of the patients improved clinically; this improvement usually occurred within a few weeks after completion of the treatment. The radiologic response was much slower. Currently, only two patients have had complete radiologic disappearance of their lesions; the majority of the patients have only had a decrease in tumor size. The treatments were well tolerated by the patients and no acute complications were observed. One patient who had a vasogenic edema 11 months after treatment fully recovered after steroid therapy. Fractionated stereotactic radiation therapy is a feasible treatment technique and may prove to be useful for selected patients with intracranial tumors. Although the preliminary data are encouraging, this technique should still be considered experimental. A larger number of patients and a longer follow-up time are necessary to determine whether the results of this technique are actually better than those of conventional radiation therapy.     

Static Compressive Loading Reduces the mRNA Expression of Type II and X Collagen in Rat Growth-Plate Chondrocytes During Postnatal Growth

The mechanisms by which chondrocytes modulate longitudinal bone growth are not well understood. This in vitro study investigated the effects of loading on the mRNA expression pattern of key molecular components of the growth-plate related to the extracellular matrix (type II and type X collagen) and the PTH-PTHrP feedback loop. Short-term static compressive loading was applied to rat proximal tibial growth-plate explants. Four age groups at specific developmental stages were investigated. The spatial variation in the mRNA expression was compared among loaded explants, their contralateral sham controls, and uncultured growth plates from normal animals. Basic cell metabolism (18S rRNA) was unaffected by load. Results indicated a narrower spatial distribution of mRNA expression of type II collagen throughout the growth plate; similarly, a narrowed distribution of expression of type X collagen was noted in the lower hypertrophic zone of the growth-plate. This suggests that mechanical compression influences chondrocytes of the hypertrophic zone to alter their expression of specific genes encoding proteins of the extracellular matrix, while PTH-PTHrP receptor mRNA, a regulatory protein, remained unaffected by loading. The effects of compression were similar at the different stages of growth, suggesting that additional factors may be involved in the clinical progression of skeletal deformities observed during growth spurts. Although this study was done in vitro and limited to static loading, it furthers our understanding of growth-plate mechanobiology as a first step toward providing a scientific rationale for treating progressive musculoskeletal deformities.     

Inhibitory effects of Serenoa repens on the kinetic of pig prostatic microsomal 5α-reductase activity

The pathogenesis of benign prostatic hyperplasia is linked to the accumulation of dihydrotestosterone (DHT), the active form of testosterone (T), in prostatic tissue. We have defined characteristics of 5α-reductase enzyme which catalyzes the conversion of T into DHT in prostatic microsomes of growing pigs. Peaks for the 5α-reductase activity were found at pH 5.5 and 8.0, which indicates the presence of both type 1 and type 2 isozymes. Kinetic parameters of porcine 5α-reductase in the presence of Serenoa repens extracts revealed uncompetitive, noncompetitive, and mixed types of inhibitions. Our results show the inhibitory action of S. repens on prostate porcine microsomal 5α-reductase activity.     

Management and treatment of hepatitis C virus in patients with HIV and hepatitis C virus coinfection: A practical guide for health care professionals

Concomitant HIV and hepatitis C virus (HCV) is a common yet complex coinfection. The present document is a practical guide for treating HCV infection in people coinfected with HIV. Effective antiretroviral therapies have prolonged survival rates for HIV-infected people over the past decade, which have made latent complications of HCV major causes of morbidity and mortality in these patients. Advances in the treatment of HCV (eg, combined pegylated interferon and ribavirin) offer the possibility of eradicating HCV infection in coinfected persons. The treatment of HCV must be considered in all cases. Intensive management of the adverse effects of HCV treatment is one of the factors for the success of these therapies. HCV eradication is predicted to decrease the mortality associated with coinfection and reduce the toxicity of HIV treatment.     

Static and dynamic compression application and removal on the intervertebral discs of growing rats

Fusionless implants are used to correct pediatric progressive spinal deformities, most of them spanning the intervertebral disc. This study aimed at investigating the effects of in vivo static versus dynamic compression application and removal on discs of growing rats. A microloading device applied compression. 48 immature rats (28 d.o.) were divided into two groups (43d, 53d). Each group included four subgroups: control (no surgery), sham (device installed without loading), static (0.2 MPa) and dynamic compressions (0.2 MPa ± 30% with 0.1 Hz). In 43d subgroups, compression was applied for 15 days. In 53d subgroups, compression was followed by 10 days without loading. Disc heights, nucleus/annulus volumetric proportions and nucleus proteoglycan contents were analyzed using one‐way ANOVA and post‐hoc Tukey comparisons (p < 0.05). Disc heights of 43d and 53d static and dynamic loading rats were lower than shams (p < 0.05). Volumetric proportions remained similar. At 43d, nucleus proteoglycan contents increased in both static and dynamic loading rats. However, at 53d, static loading rats had lower proteoglycan content than dynamic loading rats (p < 0.05). Disc structure is altered following static compression removal, but nucleus proteoglycan content remaining elevated in dynamic group. Dynamic fusionless implants would better preserve disc integrity. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:290–298, 2016.     

A Population WB-PBPK Model of Colistin and its Prodrug CMS in Pigs: Focus on the Renal Distribution and Excretion

Purpose

The objective was the development of a whole-body physiologically-based pharmacokinetic (WB-PBPK) model for colistin, and its prodrug colistimethate sodium (CMS), in pigs to explore their tissue distribution, especially in kidneys.

Methods

Plasma and tissue concentrations of CMS and colistin were measured after systemic administrations of different dosing regimens of CMS in pigs. The WB-PBPK model was developed based on these data according to a non-linear mixed effect approach and using NONMEM software. A detailed sub-model was implemented for kidneys to handle the complex disposition of CMS and colistin within this organ.

Results

The WB-PBPK model well captured the kinetic profiles of CMS and colistin in plasma. In kidneys, an accumulation and slow elimination of colistin were observed and well described by the model. Kidneys seemed to have a major role in the elimination processes, through tubular secretion of CMS and intracellular degradation of colistin. Lastly, to illustrate the usefulness of the PBPK model, an estimation of the withdrawal periods after veterinary use of CMS in pigs was made.

Conclusions

The WB-PBPK model gives an insight into the renal distribution and elimination of CMS and colistin in pigs; it may be further developed to explore the colistin induced-nephrotoxicity in humans.