Mucoepidermoid Carcinoma of the Lung Arising at the Primary Site of A Bronchogenic Cyst: Clinical, Cytogenetic, and Molecular Findings

Primary lung tumors are rare in children, and mucoepidermoid carcinoma (MEC) represents less than 10% of them. Additionally, MEC arising from bronchogenic cysts (BC) is particularly unusual. We describe the clinical and genetic findings on a MEC occurring within a previous location of a BC in an adolescent. This particular association has not been previously reported. The lesion revealed normal karyotype without the typical t(11;19)(q21;p13) translocation. Cyclin D1 overexpression (165-fold increase) was demonstrated by real-time PCR although FISH assessment showed normal hybridization at 11q13. Information on these unusual clinical presentations may present relevant insight on tumorigenesis of infrequent pediatric pulmonary tumors. Pediatr Blood Cancer 2011;56:311-313. (C) 2010 Wiley-Liss, Inc.

Liver HLA-G expression is associated with multiple clinical and histopathological forms of chronic hepatitis B virus infection

As the mechanisms leading to the persistence of hepatitis B virus (HBV) infection are poorly understood and as the histocompatibility leucocyte antigen (HLA)-G is well described as a tolerogenic molecule, we evaluated HLA-G expression in 74 specimens of HBV liver biopsies and in 10 specimens obtained from previously healthy cadaver liver donors. HBV specimens were reviewed and classified by the METAVIR score, and HLA-G expression was assessed by immunohistochemistry. No HLA-G expression was observed in control hepatocytes. In contrast, 57 (77%) of 74 HBV specimens showed soluble and membrane-bound HLA-G expression in hepatocytes, biliary epithelial cells or both. No associations between the intensity of HLA-G expression and patient age or gender, HBeAg status, severity of liver fibrosis, and grade of histological findings were observed. Although significance was not reached (P = 0.180), patients exhibiting HLA-G expression presented a higher median HBV DNA viral load (105 copies/mL) than those who did not express HLA-G (103.7 copies/mL). These results indicate that HLA-G is expressed in most cases of chronic HBV infection in all stages and may play a role in the persistency of HBV infection.

Clinical Evaluation of the NS1 Antigen-Capture ELISA for Early Diagnosis of Dengue Virus Infection in Brazil

The fact that the diagnosis of infection with dengue virus is usually made by detecting IgM antibodies during the convalescent phase of the disease interferes with disease management and, consequently, with reducing mortality rates. This study evaluated the sensitivity and specificity of detection of NS1 in samples of patients suspected of acute dengue virus infection in Brazil. The results were used to institute treatment and the sensitivity and specificity of detection of NS1 were compared to the results of detection of IgM, virus isolation, and RT-PCR. Detection of NS1 yielded better results than RTPCR and virus isolation. When considering IgM detection and RT-PCR positive results as ""gold standards,"" the sensitivity and specificity of the NS1 assay were 95.9% and 81.1%, respectively. All patients enrolled in the study were treated promptly and had an uneventful course of the disease. The detection of NS1 provided better results than the diagnostic techniques used currently during the acute phase of disease (RT-PCR and virus isolation). Detection of NS1 is an important tool for the diagnosis of acute dengue infection, particularly in highly endemic areas, allowing for rapid treatment of patients and reduction of disease burden. J. Med. Virol. 82: 1400-1405, 2010. (C) 2010 Wiley-Liss, Inc.

The Kinin System in Patients with Systemic Lupus Erythematosus Exhibiting Mucocutaneous Lesions: A Clinical Study

In the present study, we evaluated the kinin system components in the plasma of patients with systemic lupus erythematosus exhibiting mucocutaneous lesions. Fifteen women with active cutaneous lupus (P) and 15 normal healthy women (C) were studied. Low molecular (LKg) and high molecular (HKg) weight kininogen were determined by ELISA (expressed mu g Bk/ml). The activities of tissue kallikrein (TKal), plasma kallikrein (PKal) and kininase II were assayed by their action on selective substrates. Statistical analysis was performed using the Mann-Whitney test. The patients presented increased plasma levels of LKg (P = 2.98, C = 0.79) and HKg (P = 1.78, C = 0.5) associated with the increased activity of PKal (P = 2.50, C = 1.63 U/ml), TKal (P = 1.87, C = 1.30 mu M pNa/ml) and kininase II (P = 1.50, C = 0.51 mu M Hys-Leu/ml), when compared to the values observed in the control group (P < 0.0001 for each comparison). Thus, the increased concentration of all parameters of the kinin system in these patients indicate an overactivity of the kinin system in the acute phase of lupus, corroborating with the participation of these mediators in lupus pathogenesis.

Anti-aversive effects of the atypical antipsychotic, aripiprazole, in animal models of anxiety

Aripiprazole is a unique antipsychotic that seems to act as a partial agonist at dopamine D2-receptors, contrasting with other drugs in this class, which are silent antagonists. Aripiprazole may also bind to serotonin receptors. Both neurotransmitters may play major roles in aversion-, anxiety-and panic-related behaviours. Thus, the present work tested the hypothesis that this antipsychotic could also have anti-aversive properties. Male Wistar rats received injections of aripiprazole (0.1-10 mg/kg) and were tested in the open field, in the elevated plus and T mazes (EPM and ETM, respectively) and in a contextual fear conditioning paradigm. Aripiprazole (1mg/kg) increased the percentage of entries onto the open arms of the EPM and attenuated escape responses in the ETM. In the latter model, the dose of 0.1 mg/kg also decreased the latency to leave the enclosed arm, suggesting anxiolytic- and panicolytic-like properties. This dose also decreased the time spent in freezing in a contextual fear conditioning. No significant motor effects were observed at these doses. The present data support the hypothesis that aripiprazole could inhibit anxiety-related responses. Acting as a partial agonist at dopamine receptors, this drug could effectively treat schizophrenia and, in contrast with most antipsychotic drugs, alleviate aversive states.

Modulation of anxiety-like behaviour by Transient Receptor Potential Vanilloid Type 1 (TRPV1) channels located in the dorsolateral periaqueductal gray

The endocannabinoid anandamide is a possible agonist at the Transient Receptor Potential Vanilloid Type 1 (TRPV1) channel, in addition to its agonist activity at cannabinoid type 1 (CB1) receptor. In the midbrain dorsolateral periaqueductal gray (dlPAC) our previous data showed that CB1 activation induces anxiolytic-like effects. However, the rote of TRPV1 has remained unclear. Thus, in the present study we tested the hypothesis that this channel would contribute to the modulation of anxiety-like behaviour in the dlPAG. Mate Wistar rats received local injections of the TRPV1 antagonist capsazepine (10-60 nmol) and were submitted to the elevated plus-maze (EPM) and to the Vogel test. In addition, animals received local injections of capsaicin (0.01-1nmol), a TRPV1 agonist, and were tested in the same models. In accordance with our hypothesis, capsazepine produced anxiolytic-like effects both in the EPM and in the Vogel test. Capsaicin mimicked these results, which might be attributed to its ability to quickly desensitize the channel. Altogether, our data suggest that, while CB1 receptors seem to inhibit aversive responses in the dlPAG, TRPV1 could facilitate them. Thus, CB1 and TRPV1 may have opposite functions in modulating anxiety-like behaviour in this region. (C) 2008 Elsevier B.V. and ECNP. All rights reserved.

Involvement of the lateral habenula in the regulation of generalized anxiety- and panic-related defensive responses in rats

Recently obtained evidence points to the involvement of the lateral habenular nuclei (LHb) in the mediation of coping defensive responses to threatening/stressful stimuli. Nevertheless, the role of this brain area in the regulation of defensive responses that have been associated with specific subtypes of anxiety disorders recognized in clinical settings is presently unknown. To address this question, we investigated the effects of either electrolytic lesions or chemical stimulation of the LHb on the defensive behaviors generated in rats by the elevated T-maze. This experimental model allows the measurement, in a same rat, of two defensive behaviors, inhibitory avoidance and escape, that have been related in terms of psychopathology to generalized anxiety and panic disorders, respectively. Bilateral electrolytic lesions of the LHb (1 mA, 10 s) impaired inhibitory avoidance acquisition and facilitated escape performance. On the other hand, chemical stimulation of the LHb by bilateral microinjection of kainic acid (30-60 pmol/0.2 mu L) had the opposite effect, i.e., facilitated inhibitory avoidance and impaired escape. The present results indicate that the LHb exerts an opposed regulatory control on generalized anxiety- and panic-related defensive responses in rats. (c) 2008 Elsevier Inc. All rights reserved.

5-HT1A receptors in the dorsal hippocampus mediate the anxiogenic effect induced by the stimulation of 5-HT neurons in the median raphe nucleus

We evaluated the involvement of dorsal hippocampus (DH) 5-HT1A receptors in the mediation of the behavioral effects caused by the pharmacological manipulation of 5-HT neurons in the median raphe nucleus (MRN). To this end, we used the rat elevated T-maze test of anxiety. The results showed that intra-DH injection of the 5-HT1A/7 agonist 8-OH-DPAT facilitated inhibitory avoidance, an anxiogenic effect, without affecting escape. Microinjection of the 5-HT1A antagonist WAY-100635 was ineffective. In the elevated T-maze, inhibitory avoidance and escape have been related to generalized anxiety and panic disorders, respectively. Intra-MRN administration of the excitatory aminoacid kainic acid, which non-selectively stimulates 5-HT neurons in this brain area facilitated inhibitory avoidance and impaired escape performance, but also affected locomotion. Intra-MRN injection of WAY-100635, which has a disinhibitory effect on the activity of 5-HT neurons in this midbrain area, only facilitated inhibitory avoidance. Preadministration of WAY-100635 into the DH blocked the behavioral effect of intra-MRN injection of WAY-100635, but not of kainic acid. These results indicate that DH 5-HT1A receptors mediate the anxiogenic effect induced by the selective stimulation of 5-HT neurons in the MRN. (c) 2007 Elsevier B.V. and ECNP. All rights reserved.

Involvement of dorsal raphe nucleus and dorsal periaqueductal gray 5-HT receptors in the modulation of mouse defensive behaviors

Previous findings point to the involvement of the dorsal raphe nucleus (DRN) and dorsal periaqueductal gray (dPAG) serotonergic receptors in the mediation of defensive responses that are associated with specific subtypes of anxiety disorders. These studies have mostly been conducted with rats tested in the elevated T-maze, an experimental model of anxiety that was developed to allow the measurement, in the same animal, of two behaviors mentioned: inhibitory avoidance and one-way escape. Such behavioral responses have been respectively related to generalized anxiety disorder (GAD) and panic disorder (PD). In order to assess the generality of these findings, in the current study we investigated the effects of the injection of 5-HT-related drugs into the DRN and dPAG of another rodent species, mouse, on the mouse defense test battery (MDTB), a test of a range of defensive behaviors to an unconditioned threat, a predator. Male CD-1 mice were tested in the MDTB after intra-DRN administration of the 5-HT(1A) receptor antagonist WAY-100635 or after intra-dPAG injection of two serotonergic agonists, the 5-HT1A receptor agonist 8-OH-DPAT and the 5-HT(2A/2C) receptor agonist DOI. Intra-DRN injection of WAY-100635 did not change behavioral responses of mice confronted with a rat in the MDTB. In the dPAG, both 8-OH-DPAT and DOI consistently impaired mouse escape behavior assessed in the MDTB. Intra-dPAG infusion of 8-OH-DPAT also decreased measures of mouse risk assessment in the rat exposure test. In conclusion, the current findings are in partial agreement with previous results obtained with rats tested in the elevated T-maze. Although there is a high level of similarity between the behavioral effects obtained in rats (elevated T-maze) and mice (MDTB and RET) with the infusion of 5-HT agonists into the dPAG, the same is not true regarding the effects of blockade of DRN 5-HT(1A) receptors in these rodent species. These data suggest that there may be differences between mice and rats regarding the involvement of the DRN in the mediation of defensive behaviors. (C) 2010 Elsevier B.V. and ECNP. All rights reserved.

Cannabinoid CB(1) receptors in the medial prefrontal cortex modulate the expression of contextual fear conditioning

The ventral portion of the medial prefrontal cortex (vMPFC) has been related to the expression of contextual fear conditioning. This study investigated the possible involvement of CB(1) receptors in this aversive response. Male Wistar rats were submitted to a contextual aversive conditioning session and 48 h later re-exposed to the aversive context in which freezing and cardiovascular responses (increase of arterial pressure and heart rate) were recorded. The expression of CB(1) receptor-mRNA in the vMPFC was also measured using real time-PCR. In the first experiment intra-vMPFC administration of the CB(1) receptor agonist anandamide (AEA, 5 pmol/200 nl) or the AEA transport inhibitor AM404 (50 pmol/200 nl) prior to re-exposure to the aversive context attenuated the fear-conditioned responses. These effects were prevented by local pretreatment with the CB(1) receptor antagonist AM251 (100 pmol/200 nl). Using the same conditioning protocol in another animal group, we observed that CB(1) receptor mRNA expression increased in the vMPFC 48 h after the conditioning session. Although AM251 did not cause any effect by itself in the first experiment, this drug facilitated freezing and cardiovascular responses when the conditioning session employed a lesser aversive condition. These results indicated that facilitation of cannabinoid-mediated neurotransmission in the vMPFC by local CB(1) receptor activation attenuates the expression of contextual fear responses. Together they suggest that local endocannabinoid-mediated neurotransmission in the vMPFC can modulate these responses.

Panicolytic-like effect of BDNF in the rat dorsal periaqueductal grey matter: the role of 5-HT and GABA

A wealth of evidence suggests a role for brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) in the aetiology of depression and in the mode of action of antidepressant drugs. Less clear is the involvement of this neurotrophin in other stress-related pathologies such as anxiety disorders. The dorsal periaqueductal grey matter (DPAG), a midbrain area rich in BDNF and TrkB receptor mRNAs and proteins, has been considered a key structure in the pathophysiology of panic disorder. In this study we investigated the effect of intra-DPAG injection of BDNF in a proposed animal model of panic: the escape response evoked by the electrical stimulation of the same midbrain area. To this end, the intensity of electrical current that needed to be applied to DPAG to evoke escape behaviour was measured before and after microinjection of BDNF. We also assessed whether 5-HT- or GABA-related mechanisms may account for the putative behavioural/autonomic effects of the neurotrophin. BDNF (0.05, 0.1, 0.2 ng) dose-dependently inhibited escape performance, suggesting a panicolytic-like effect. Local microinjection of K252a, an antagonist of TrkB receptors, or bicuculline, a GABA(A) receptor antagonist, blocked this effect. Intra-DPAG administration of WAY-100635 or ketanserin, respectively 5-HT(1A) and 5-HT(2A/2c) receptor antagonists, did not alter BDNF`s effects on escape. Bicuculline also blocked the inhibitory effect of BDNF on mean arterial pressure increase caused by electrical stimulation of DPAG. Therefore, in the DPAG, BDNF-TrkB signalling interacts with the GABAergic system to cause a panicolytic-like effect.

Non-N-methyl-d-aspartate glutamate receptors in the lateral hypothalamus modulate cardiac baroreflex responses in conscious rats

P>In the present study, we investigated the effects of inhibition of the lateral hypothalamus (LH) neurotransmission with bilateral microinjection of CoCl(2), a non-selective blocker of neurotransmission, on modulation of cardiac baroreflex responses in conscious rats as well as the involvement of LH glutamatergic neurotransmission in this modulation. Reflex bradycardiac and tachycardiac responses to blood pressure increases (following i.v. infusion of phenylephrine) or decreases (following i.v. infusion of sodium nitroprusside) were investigated in conscious male Wistar rats. Responses were evaluated before and after microinjection of 1 nmol/100 nL CoCl(2), 2 nmol/100 nL 1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzoquinoxaline-7-sulphonamide (NBQX; a selective non-N-methyl-d-aspartate (NMDA) glutamate receptor antagonist) or different doses (2, 4 or 8 nmol/100 nL) of the selective NMDA glutamate receptor antagonist LY235959. Microinjection of CoCl(2) into the LH had no effect on the tachycardiac baroreflex response, but did evoke a decrease in the reflex bradycardia caused by increases in blood pressure. Microinjection of NBQX into the LH had a similar effect on reflex bradycardia as CoCl(2), but had no effect on the tachycardiac response. Microinjection of increasing doses of LY235959 into the LH had no effect on the cardiac baroreflex response. In conclusion, the data suggest that the LH has a tonic facilitatory influence on the parasympathetic component of the baroreflex. The results also indicate that this facilitatory influence is mediated by local LH glutamatergic neurotransmission through non-NMDA glutamatergic receptors.

Increased cardiac sympathetic drive and reduced vagal modulation following endothelin receptor antagonism in healthy conscious rats

1. The present study evaluated changes in autonomic control of the cardiovascular system in conscious rats following blockade of endothelin (ET) receptors with bosentan. 2. Rats were treated with bosentan or vehicle (5% gum arabic) for 7 days by gavage. 3. Baseline heart rate (HR) was higher in the bosentan-treated group compared with the control group (418 +/- 5 vs 357 +/- 4 b.p.m., respectively; P < 0.001). This baseline tachycardia was associated with a lower baroreflex sensitivity of the bradycardiac and tachycardiac responses in the bosentan-treated group compared with the control group. Sequential blockade of the parasympathetic and sympathetic autonomic nervous system with methylatropine and propranolol showed a higher intrinsic HR in the bosentan-treated group compared with the control group (411 +/- 5 vs 381 +/- 4 b.p.m., respectively; P < 0.05). This was accompanied by a higher cardiac sympathetic tone (31 +/- 1 vs 13 +/- 1%, respectively; P < 0.01) and a lower vagal parasympathetic tone (69 +/- 2 vs 87 +/- 2%, respectively; P < 0.01) in the bosentan-treated group compared with the control group. Variance and high-frequency oscillations of pulse interval (PI) variability in absolute and normalized units were lower in the bosentan-treated group than in the control group. Conversely, low-frequency (LF) oscillations of PI variability in absolute and normalized units, as well as variance and LF oscillations of systolic arterial pressure variability, were greater in the bosentan-treated group than the control group. 4. Overall, the data indicate an increased cardiac sympathetic drive, as well as lower vagal parasympathetic activity and baroreflex sensitivity, in conscious rats after chronic blockade of ET receptors with bosentan.

Antimicrobial Activities of Ethanol Extract and Coumestans from Eclipta alba (L.) Hassk (Asteraceae)

Ethanol extract and fractions from aerial parts of Eclipta alba (L.) Hassk (Asteraceae) were screened for the antibacterial and antifungal activities against different species of human pathogenic bacterial ATCC, antibiotic-resistant clinical isolates and strains of the dermatophyte Trichophyton rubrum (wild and mutant for TruMDR2 gene) using a microdilution method. Demethylwedelolactone/wedelolactone (DWL/WL) and only wedelolactone (WL), both in a high homogeneity degree, were efficient to inhibit the ATCC strains of Staphylococus aureus (Minimal Inhibitory Concentration MIC = 75 mu g/mL), Staphylococcus epidemidis (MIC = 125 mu g/mL) and Escherichia coli (MIC = 125 mu g/mL) as well as antibiotic-resistant clinical isolates of Enterococcus spp (MIC = 250 mu g/mL) and S. aureus (MIC = 125 mu g/mL). Ethanol extract was more effective than the purified fractions against Trichophyton rubrum strains (MIC = 125 mu g/mL), suggesting that anti-fungal activity is not only related to demethylwedelolactone and wedelolactone, but also to a synergistic action between these coumestans and other compounds found in that extract. Thus, this work suggests that E. alba possesses a significant antimicrobial activity, including that against multi-drug resistant microorganisms, which could be of relevance for the treatment of infectious diseases.