Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats

Background: Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is being investigated as a treatment for major depression. We report on the effects of ventromedial prefrontal cortex (vmPFC) DBS in rats, focusing on possible mechanisms involved in an antidepressant-like response in the forced swim test (FST). Methods: The outcome of vmPFC stimulation alone or combined with different types of lesions, including serotonin (5-HT) or nore-pineprhine (NE) depletion, was characterized in the FST. We also explored the effects of DBS on novelty-suppressed feeding, learned helplessness, and sucrose consumption in animals predisposed to helplessness. Results: Stimulation at parameters approximating those used in clinical practice induced a significant antidepressant-like response in the FST. Ventromedial PFC lesions or local muscimol injections did not lead to a similar outcome. However, animals treated with vmPFC ibotenic acid lesions still responded to DBS, suggesting that the modulation of fiber near the electrodes could play a role in the antidepressant-like effects of stimulation. Also important was the integrity of the serotonergic system, as the effects of DBS in the FST were completely abolished in animals bearing 5-HT, but not NE, depleting lesions. In addition, vmPFC stimulation induced a sustained increase in hippocampal 5-HT levels. Preliminary work with other models showed that DBS was also able to influence specific aspects of depressive-like states in rodents, including anxiety and anhedonia, but not helplessness. Conclusions: Our study suggests that vmPFC DES in rats maybe useful to investigate mechanisms involved in the antidepressant effects of SCG DBS.

THE ANTERIOR CINGULATE CORTEX IS A TARGET STRUCTURE FOR THE ANXIOLYTIC-LIKE EFFECTS OF BENZODIAZEPINES ASSESSED BY REPEATED EXPOSURE TO THE ELEVATED PLUS MAZE AND FOS IMMUNOREACTIVITY

Prior experience with the elevated plus maze (EPM) increases the avoidance of rodents to the open arms and impairs the anxiolytic-like effects of benzodiazepines on the traditional behaviors evaluated upon re-exposure to the maze, a phenomenon known as one-trial tolerance. Risk assessment behaviors are also sensitive to benzodiazepines. During re-exposure to the maze, these behaviors reinstate the information-processing initiated during the first experience, and the detection of danger generates stronger open-arm avoidance. The present study investigated whether the benzodiazepine midazolam alters risk assessment behaviors and Fos protein distribution associated with test and retest sessions in the EPM. Naive or maze-experienced Wistar rats received either saline or midazolam (0.5 mg/kg i.p.) and were subjected to the EPM. Midazolam caused the usual effects on exploratory behavior, increasing exploratory activity of naive rats in the open arms and producing no effects on these conventional measures in rats re-exposed to the maze. Risk assessment behaviors, however, were sensitive to the benzodiazepine during both sessions, indicating anxiolytic-like effects of the drug in both conditions. Fos immunohistochemistry showed that midazolam injections were associated with a distinct pattern of action when administered before the test or retest session, and the anterior cingulate cortex, area 1 (Cg1), was the only structure targeted by the benzodiazepine in both situations. Bilateral infusions of midazolam into the Cg1 replicated the behavioral effects of the drug injected systemically, suggesting that this area is critically involved in the anxiolytic-like effects of benzodiazepines, although the behavioral strategy adopted by the animals appears to depend on the previous knowledge of the threatening environment. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.

Activity of the medial prefrontal cortex and amygdala underlies one-trial tolerance of rats in the elevated plus-maze

The anxiolytic effects of benzodiazepines are reduced after a single exposure of rats to elevated plus-maze test (EPM). Midazolam showed an anxioselective profile in animals submitted to one session (T1) but did not change the usual exploratory behavior of rats exposed twice (T2) to the EPM. In this study we examined further the one-trial tolerance by performing a factor analysis of the exploratory behavior of rats injected with saline before both trials as well as an immunohistochemistry study for quantification of Fos expression in encephalic structures after these sessions. Factor analysis of all behavioral categories revealed that factor I consisted of anxiety-related categories in T1 whereas these same behavioral categories loaded on factor 2 in T2. Risk assessment was also dissociated as it loaded stronger on T2 (factor 3) than on T1 (factor 4). Locomotor activity in T1 loaded on factor 5. Immunohistochemistry analyses showed that Fos expression predominated in limbic structures in T1 group. The medial prefrontal cortex and amygdala were the main areas activated in T2 group. These data suggest that anxiety and risk assessment behaviors change their valence across the EPM sessions. T2 is characterized by the emergence of a fear factor, more powerful risk assessment and medial prefrontal cortex activation. The amygdala functions as a switch between the anxiety-like patterns of T1 to the cognitive control of fear prevalent in T2. The EPM retest session is proposed as a tool for assessing the cognitive activity of rodents in the control of fear. (c) 2007 Elsevier B.V. All rights reserved.

Midazolam reduces the selective activation of the rhinal cortex by contextual fear stimuli

Independent brain circuits appear to underlie different forms of conditioned fear, depending on the type of conditioning used, such as a context or explicit cue paired with footshocks. Several clinical reports have associated damage to the medial temporal lobe (MTL) with retrograde amnesia. Although a number of studies have elucidated the neural circuits underlying conditioned fear, the involvement of MTL components in the aversive conditioning paradigm is still unclear. To address this issue, we assessed freezing responses and Fos protein expression in subregions of the rhinal cortex and ventral hippocampus of rats following exposure to a context, light or tone previously paired with footshock (Experiment 1). A comparable degree of freezing was observed in the three types of conditioned fear, but with distinct patterns of Fos distribution. The groups exposed to cued fear conditioning did not show changes in Fos expression, whereas the group subjected to contextual fear conditioning showed selective activation of the ectorhinal (Ect), perirhinal (Per), and entorhinal (Ent) cortices, with no changes in the ventral hippocampus. We then examined the effects of the benzodiazepine midazolam injected bilaterally into these three rhinal subregions in the expression of contextual fear conditioning (Experiment 2). Midazolam administration into the Ect, Per, and Ent reduced freezing responses. These findings suggest that contextual and explicit stimuli endowed with aversive properties through conditioning recruit distinct brain areas, and the rhinal cortex appears to be critical for storing context-, but not explicit cue-footshock, associations. (C) 2010 Elsevier B.V. All rights reserved.

Serotonergic mechanisms of the median raphe nucleus-dorsal hippocampus in conditioned fear: Output circuit involves the prefrontal cortex and amygdala

Independent studies have shown that the median raphe nucleus (MRN) and dorsal hippocampus (DH) are involved in the expression of contextual conditioned fear (CFC). However, studies that examine the integrated involvement of serotonergic mechanisms of the MRN-DH are lacking. To address this issue, a CFC paradigm was used to test whether the serotonergic projections from the MRN to DH can influence CFC. Serotoninergic drugs were infused either into the MRN or DH prior to testing sessions in which freezing and startle responses were measured in the same context where 6 h previously rats received footshocks. A reduction of serotonin (5-HT) transmission in the MRN by local infusions of the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) decreased freezing in response to the context but did not reduce fear-potentiated startle. This pattern of results is consistent with the hypothesis that MRN serotonergic mechanisms selectively modulate the freezing response to the aversive context. As for the DH, a decrease in postsynaptic 5-HT receptor activity at projection areas has been proposed to be the main consequence of 5-HT(1A) receptor activation in the MIRN. Intra-DH injections of 8-OH-DPAT inhibited both the freezing and fear-potentiated startle response to the context. To reconcile these findings, an inhibitory mechanism may exist between the incoming 5-HT pathway from the MRN to DH and the neurons of the DH output to other structures. The DH-amygdala or medial prefrontal cortex projections could well be this output circuit modulating the expression of CFC as revealed by measurements of Fos immunoreactivity in these areas. (C) 2009 Elsevier B.V. All rights reserved.

Francoist Primary education: the schoolbook as an instrument of child indoctrination

The Francoist rule, mainly in its first decades, exerted a strong control upon education, which was left in the hands of the Catholic nationalist. Innumerous children`s schoolbooks were published driven by strong patriotic and religious bias. The authors aimed to shape the children`s minds based on the premises that supported the regimen: authority, hierarchy, order, abeyance, fear and devotion to God and the leader Francisco Franco. This paper analyzes the content of the elementary education books and shows how they were important instruments of child indoctrination marked by intolerance. The content and the images of the books contributed to construct an excluding national identity based on a heightened Catholic patriotism, stimulated heroism, martyrdom, child sacrifice, and hatred for the enemies of the religion and of ""mother Spain"".

Three-monthly intravitreal bevacizumab injections for neovascular age-related macular degeneration: short-term visual acuity results

PURPOSE. To evaluate the change in vision after 3 monthly consecutive intravitreal injections of 1.25 mg of bevacizumab for neovascular age-related macular degeneration (AMD). METHODS. A retrospective analysis of 35 eyes was performed. Visual acuity (VA) at initial visit and at each follow-up visit was compared. The injection of bevacizumab was performed at 30-day intervals and patients were observed for 5 months after the last injection. RESULTS. Of the 35 eyes, 9 had received previous treatment with photodynamic therapy with or without 4 mg of intravitreal triamcinolone. VA was measured in Snellen table and transformed into logMAR for statistical purposes. Mean age was 76.66 years (range, 49-90 years). There were 24(69%) women and 11(31%) men. Mean VA at the initial visit was 0.92 +/- 0.50. At month 1, mean VA was 0.84 +/- 0.51 and at month 2 was 0.74 +/- 0.51. At month 3, mean VA remained 0.74 +/- 0.49. Six and 8 months after the initial visit, VA was 0.79 +/- 0.49 and 0.77 +/- 0.50, respectively. The improvement in VA was statistically significant at month 2 and at the end of the follow-up (8 months) compared with the baseline VA. CONCLUSIONS. Three consecutive monthly injections of intravitreal bevacizumab to treat neovascular AMD is effective in improving VA in the short term. Longer prospective studies should be performed to confirm VA stability after the third injection. (Eur J Ophthalmol 2010; 20: 740-4)

Primary Antiphospholipid Syndrome and Thyroid Involvement

Background: Data on thyroid involvement in primary antiphospholipid syndrome are scarce and inconclusive. Objectives: The aim of this study was to evaluate the frequency of thyroid dysfunction and antibodies in patients with primary antiphospholipid syndrome ( PAPS) and the association of these alterations with clinical and immunologic features. Methods: The study group included 50 PAPS patients (44 females) with a mean age of 39.7 +/- 11.5 years and mean disease duration of 77.3 +/- 63.5 months. Clinical data related to thyroid dysfunction and PAPS were obtained by chart review, patient interview, and clinical examination. Serum levels of TSH, free T4, antithyroglobulin antibody (TgAb), antithyroperoxidase antibody (TPOAb), thyroid receptor antibody (TRAb), and antiphospholipid autoantibodies were analyzed by standard techniques. Results: We found no hyperthyroidism among patients and found 22% (11 patients) with hypothyroidism in this sample. There were no differences between the latter patients and the euthyroid group about demographic findings, disease duration, thrombotic or obstetric events, and frequency of antiphospholipid antibodies as well as prevalence of thyroid auto antibodies. The prevalence of thyroid autoantibodies found was 6 patients (12%) with TgAb, 5 with TPOAb (10%), and 2 patients (4%) with both TgAb and TPOAb, comprising 18% of positivity of at least one of the auto antibodies. Conclusion: Hypothyroidism is present among 22% of PAPS patients and thyroid autoantibodies in 18% of them. These findings suggest a common pathophysiologic mechanism between antiphospholipid syndrome and autoimmune thyroid diseases.

Prostatic Artery Embolization as a Primary Treatment for Benign Prostatic Hyperplasia: Preliminary Results in Two Patients

Symptomatic benign prostatic hyperplasia (BPH) typically occurs in the sixth and seventh decades, and the most frequent obstructive urinary symptoms are hesitancy, decreased urinary stream, sensation of incomplete emptying, nocturia, frequency, and urgency. Various medications, specifically 5-alpha-reductase inhibitors and selective alpha-blockers, can decrease the severity of the symptoms secondary to BPH, but prostatectomy is still considered to be the traditional method of management. We report the preliminary results for two patients with acute urinary retention due to BPH, successfully treated by prostate artery embolization (PAE). The patients were investigated using the International Prostate Symptom Score, by digital rectal examination, urodynamic testing, prostate biopsy, transrectal ultrasound (US), and magnetic resonance imaging (MRI). Uroflowmetry and postvoid residual urine volume complemented the investigation at 30, 90, and 180 days after PAE. The procedure was performed under local anesthesia; embolization of the prostate arteries was performed with a microcatheter and 300- to 500-mu m microspheres using complete stasis as the end point. One patient was subjected to bilateral PAE and the other to unilateral PAE; they urinated spontaneously after removal of the urethral catheter, 15 and 10 days after the procedure, respectively. At 6-month follow-up, US and MRI revealed a prostate reduction of 39.7% and 47.8%, respectively, for the bilateral PAE and 25.5 and 27.8%, respectively, for the patient submitted to unilateral PAE. The early results, at 6-month follow-up, for the two patients with BPH show a promising potential alternative for treatment with PAE.

Functional mapping of the motor cortex of the rat using transdural electrical stimulation

Motor cortex stimulation oriented by functional cortical mapping is used mainly for treating otherwise intractable neurological disorders, however. its mechanism of action remains elusive. Herein, we present a new method for functional mapping of the rat motor cortex using non-invasive transdural electrical stimulation. This method allows a non-invasive mapping of the surface of the neocortex providing a differentiation of representative motor areas. This Study may facilitate further investigation about the mechanisms mediating the effects of electrical stimulation, possibly benefiting patients who do not respond to this neuromodulation therapy. (c) 2009 Elsevier B.V. All rights reserved.

Primary antiphospholipid syndrome with thrombotic thrombocytopenic purpura: a very unusual association

This report considers the rare situation in which primary antiphospholipid syndrome (PAPS) is linked with thrombotic thrombocytopenic purpura (TTP). It describes the case of a young lady with PAPS, characterized by recurring cerebro-vascular abnormalities and marked livedo reticularis, combined with circulating anticardiolipin and lupus anticoagulant antibodies. On follow-up, while on oral anticoagulation, she developed severe thrombocytopenia associated with hematuria, microangiophatic anaemia and neurological manifestations consistent with a diagnosis of TTP. The patient was treated with pulses of methylprednisolone and plasmapheresis with plasma exchange. The result was a favourable outcome. To our knowledge, this is the seventh report on this rare association in the English-language literature of this field. Lupus (2009) 18, 841-844.

Antinociception induced by epidural motor cortex stimulation in naive conscious rats is mediated by the opioid system

Epidural motor cortex stimulation (MCS) has been used for treating patients with neuropathic pain resistant to other therapeutic approaches. Experimental evidence suggests that the motor cortex is also involved in the modulation of normal nociceptive response, but the underlying mechanisms of pain control have not been clarified yet. The aim of this study was to investigate the effects of epidural electrical MCS on the nociceptive threshold of naive rats. Electrodes were placed on epidural motor cortex, over the hind paw area, according to the functional mapping accomplished in this study. Nociceptive threshold and general activity were evaluated under 15-min electrical stimulating sessions. When rats were evaluated by the paw pressure test, MCS induced selective antinociception in the paw contralateral to the stimulated cortex, but no changes were noticed in the ipsilateral paw. When the nociceptive test was repeated 15 min after cessation of electrical stimulation, the nociceptive threshold returned to basal levels. On the other hand, no changes in the nociceptive threshold were observed in rats evaluated by the tail-flick test. Additionally, no behavioral or motor impairment were noticed in the course of stimulation session at the open-field test. Stimulation of posterior parietal or somatosensory cortices did not elicit any changes in the general activity or nociceptive response. Opioid receptors blockade by naloxone abolished the increase in nociceptive threshold induced by MCS. Data shown herein demonstrate that epidural electrical MCS elicits a substantial and selective antinociceptive effect, which is mediated by opioids. (C) 2008 Elsevier B.V. All rights reserved.

Evaluate of the efficacy and safety of tacrolimus ointment 0,03% to treat atopic dermatitis in pediatric patients

BACKGROUND: Tacrolimus ointment has been shown to be effective in treatment of atopic dermatitis. OBJECTIVES: To evaluate the efficacy and safety of 0.03% tacrolimus ointment (Protopic(R)) in pediatric patients with mild, moderate and severe atopic dermatitis. METHODS.. Open, non-comparative, multicentric study carried out in Brazil. 174 patients (ages from two to 10) with mild to severe atopic dermatitis were included. Patients were instructed to apply Protopic(R) twice a day for six weeks. Primary efficacy criterion was clinical improvement >= 90% assessed by the pbysician (Clinical Response Global Evaluation Scale). Other efficacy criteria included reduction of the Eczema Area Severity Index (EASI), decrease of the affected body surface area (%BSA) and evaluation of the itching by the patients or their guardians (visual analogical scale). Safety was evaluated by adverse events reported by patients and/or guardians or by investigators. RESULTS: Thirty-three percent of patients showed clinical improvement 90%. 45.5% of patients (1st week) decreased EASI and 61.8% (6th week) (p<0,001). %BSA decreased 30.4% and 55.5% in the first and sixth week. improvement was also significant when measured by itching (p<0, 001). Most frequent adverse effects were: burning and itching. CONCLUSION: 0.03% tacrolimus ointment is a safe and effective therapy for mild to severe atopic dermatitis in pediatric patients.

Influence of gender on the clinical and laboratory spectra of patients with primary antiphospholipid syndrome

The objectives of this cross-sectional study were to evaluate the differences between males and females in the clinical and biochemical manifestations of primary antiphospholipid antibody syndrome (PAPS). The method involved 49 patients (38 premenopausal females and 11 males) diagnosed with PAPS (according to the Sapporo criteria) and their demographic data, clinical data, medications used and antiphospholipid antibodies were analyzed. The results of this study are as follows. Both the groups of patients were statistically similar regarding age, race, weight and body mass index. However, males were significantly taller than females (172 +/- A 8.9 vs. 159.2 +/- A 6.2 cm, p < 0.0001). The duration of disease was similar for females and males. The prevalence of pulmonary thromboembolism was higher in females than in males (34.2 vs. 0.0%, p = 0.024). Regarding other PAPS manifestations (arterial events, venous events, deep venous thrombosis, thrombocytopenia, acute myocardial infarction, angina, cerebrovascular accidents and Sneddon syndrome), comorbidities (arterial hypertension and dyslipidemia), lifestyle (physical activity, previous smoking and current smoking) and the use of medications (current and previous use of corticosteroids, as well as the use of statins or chloroquine), both groups were statistically similar (p > 0.05). More females than males tested positive for IgM anticardiolipin antibodies (76.3 vs. 36.4%, p = 0.025) or for at least one of the antiphospholipid antibodies tested (either IgM anticardiolipin or IgG anticardiolipin 84.2 vs. 45.5%, p = 0.016). However, both groups were similar regarding the frequency of positivity for lupus anticoagulant and isolated IgG anticardiolipin, as well as regarding mean levels of IgG and IgM anticardiolipin (p > 0.05). We concluded that, among PAPS patients, the frequency of pulmonary thromboembolism and of positivity for IgM anticardiolipin is higher in females than in males. Our findings show that there are gender differences in PAPS, differences that might be related to alterations in sex hormones.