Cell-specific inhibitory modulation of sound processing in the auditory thalamus.

Inhibition along the auditory pathway is crucial for processing of acoustic information. Within the auditory thalamus, a key region in the central auditory pathway, inhibition is provided by the thalamic reticular nucleus (TRN), comprised of two large classes of inhibitory neurons, parvalbumin (PV TRN ) and somatostatin (SST TRN ) positive. In the auditory cortex, PV and SST neurons differentially shape auditory processing. We found that the ventral MGB, the thalamic region in the direct ascending auditory pathway, receives inputs predominantly from PV TRN neurons, whereas SST TRN neurons project to the dorso-medial regions of MGB. Consistently, inactivating PV TRN neurons increased sound-evoked activity in over a third of neurons in the vMGB, with another large fraction of neurons being suppressed. By contrast, inactivating SST TRN neuronal activity largely reduced tone-evoked activity in vMGB neurons. Cell type-specific computational models revealed candidate circuit mechanisms for generating the bi-directional effects of TRN inactivation on MGB sound responses. These differential inhibitory pathways within the auditory thalamus suggest a cell-specific role for thalamic inhibition in auditory computation and behavior.

The effect of self-sampled HPV testing on participation to cervical cancer screening in Italy: a randomised controlled trial (ISRCTN96071600).

BACKGROUND: In Italy, cervical cancer screening programmes actively invite women aged 25-64 years. Programmes are hindered by low participation. METHODS: A sample of non-responder women aged 35-64 years, belonging to three different programmes (in Rome, Florence and Teramo), was randomly split into four arms: two control groups received standard recall letters to perform either Pap-test (first group) or human papillomavirus (HPV) test (second group) at the clinic. A third arm was sent letters offering a self-sampler for HPV testing, to be requested by phone, whereas a fourth group was directly sent the self-samplers home. RESULTS: Compliance with standard recall was 13.9% (N619). Offering HPV test at the clinic had a nonsignificant effect on compliance (N616, relative risk (RR)=1.08; 95% CI=0.82-1.41). Self-sampler at request had the poorest performance, 8.7% (N622, RR=0.62; 95% CI=0.45-0.86), whereas direct mailing of the self-sampler registered the highest compliance: 19.6% (N616, RR=1.41; 95% CI=1.10-1.82). This effect on compliance was observed only in urban areas, Florence and Rome (N438, RR=1.69; 95% CI=1.24-2.30), but not in Abruzzo (N178, RR=0.95; 95% CI=0.61-1.50), a prevalently rural area. CONCLUSIONS: Mailing self-samplers to non-responders may increase compliance as compared with delivering standard recall letters. Nevertheless, effectiveness is context specific and the strategy costs should be carefully considered.

Contextual modulation of sound processing in the auditory cortex.

In everyday acoustic environments, we navigate through a maze of sounds that possess a complex spectrotemporal structure, spanning many frequencies and exhibiting temporal modulations that differ within frequency bands. Our auditory system needs to efficiently encode the same sounds in a variety of different contexts, while preserving the ability to separate complex sounds within an acoustic scene. Recent work in auditory neuroscience has made substantial progress in studying how sounds are represented in the auditory system under different contexts, demonstrating that auditory processing of seemingly simple acoustic features, such as frequency and time, is highly dependent on co-occurring acoustic and behavioral stimuli. Through a combination of electrophysiological recordings, computational analysis and behavioral techniques, recent research identified the interactions between external spectral and temporal context of stimuli, as well as the internal behavioral state.

Role of quercetin and its in vivo metabolites in protecting H9c2 cells against oxidative stress.

The aim of this study was to investigate the potential of quercetin and two of its "in vivo" metabolites, 3'-O-methyl quercetin and 4'-O-methyl quercetin, to protect H9c2 cardiomyoblasts against H(2)O(2)-induced oxidative stress. As limited data are available regarding the potential uptake and cellular effects of quercetin and its metabolites in cardiac cells, we have evaluated the cellular association/uptake of the three compounds and their involvement in the modulation of two pro-survival signalling pathways: ERK1/2 signalling cascade and PI3K/Akt pathway. The three flavonols associated with cells to differing extents. Quercetin and its two O-methylated metabolites were able to reduce intracellular ROS production but only quercetin was able to counteract H(2)O(2) cell damage, as measured by MTT reduction assay, caspase-3 activity and DNA fragmentation assays. Furthermore, only quercetin was observed to modulate pro-survival signalling through ERK1/2 and PI3K/Akt pathway. In conclusion we have demonstrated that quercetin, but not its O-methylated metabolites, exerts protective effects against H(2)O(2) cardiotoxicity and that the mechanism of its action involves the modulation of PI3K/Akt and ERK1/2 signalling pathways.

Green tea modulation of inducible nitric oxide synthase in hypoxic/reoxygenated cardiomyocytes.

Hypoxia/reoxygenation (H/R) is one of the causes of the increased expression of inducible nitric oxide synthase (iNOS) in cardiomyocytes. Since an aberrant NOS induction has detrimental consequences, we evaluated the effect of a green tea extract (GTE) on the NOS induction and activity in H/R-cardiomyocytes to define a nutritional strategy. Cultured rat cardiomyocytes were exposed to H/R in the presence of two concentrations of a green tea extract (GTE), which is reported to inhibit NOS expression and activity in different cells. In cultured cardiomyocytes two NOS isoforms were constitutively expressed, but only iNOS was induced by H/R. GTE supplementation at the lowest concentration, comparable to that in human plasma after dietary consumption, was ineffective, while the highest, comparable to that achievable by dietary supplements, counteracted the effect of H/R on iNOS induction and activity. It is necessary to verify in humans the relationship between the modulation of NO production and green tea dietary consumption.

Green tea extracts can counteract the modification of fatty acid composition induced by doxorubicin in cultured cardiomyocytes.

Doxorubicin cardiotoxicity is associated with the generation of free radicals, and involves not only lipid peroxidation but also a decreased biosynthesis of highly unsaturated fatty acids, leading to significant modification in cardiomyocyte fatty acid composition. We have evaluated whether naturally occurring antioxidants could counteract this side-effect. Green tea is an excellent source of catechins; we supplemented cultured rat cardiomyocytes with different green tea extracts to relate their catechin content and composition to their ability in protecting cells against doxorubicin-induced damage. The determination of total lipid fatty acid composition, of conjugated diene production (indicator of lipid peroxidation), and of lactate dehydrogenase release revealed that supplementation with tea extracts could counteract significant modifications in the fatty acyl pattern due to doxorubicin exposure, although to different extents. These differences could be ascribed to the different total catechin content and to qualitative differences among the tea extracts, determined by HPLC analysis.

Cystamine-tacrine dimer: a new multi-target-directed ligand as potential therapeutic agent for Alzheimer's disease treatment.

Alzheimer's disease (AD) is the most common cause of dementia, clinically characterized by loss of memory and progressive deficits in different cognitive domains. An emerging disease-modifying approach to face the multifactorial nature of AD may be represented by the development of Multi-Target Directed Ligands (MTDLs), i.e., single compounds which may simultaneously modulate different targets involved in the neurodegenerative AD cascade. The structure of tacrine, an acetylcholinesterase (AChE) inhibitor (AChEI), has been widely used as scaffold to provide new MTDLs. In particular, its homodimer bis(7)tacrine represents an interesting lead compound to design novel MTDLs. Thus, in the search of new rationally designed MTDLs against AD, we replaced the heptamethylene linker of bis(7)tacrine with the structure of cystamine, leading to cystamine-tacrine dimer. In this study we demonstrated that the cystamine-tacrine dimer is endowed with a lower toxicity in comparison to bis(7)tacrine, it is able to inhibit AChE, butyrylcholinesterase (BChE), self- and AChE-induced beta-amyloid aggregation in the same range of the reference compound and exerts a neuroprotective action on SH-SY5Y cell line against H(2)O(2)-induced oxidative injury. The investigation of the mechanism of neuroprotection showed that the cystamine-tacrine dimer acts by activating kinase 1 and 2 (ERK1/2) and Akt/protein kinase B (PKB) pathways. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Role of quercetin in modulating rat cardiomyocyte gene expression profile.

Despite extensive studies, the fundamental mechanisms responsible for the development and progression of cardiovascular diseases have not yet been fully elucidated. Recent experimental and clinical studies have suggested that reactive oxygen species play a major pathological role. Oxidative stress reduction induced by flavonoids has been regarded by many as the most likely mechanism in the protective effects of these compounds; however, there is an emerging view that flavonoids may also exert modulatory actions on protein kinase and lipid kinase signaling pathways. Quercetin, a major flavonoid present in the human diet, has been widely studied, and its biological properties are consistent with its protective role in the cardiovascular system. However, it remains unknown whether the cardioprotective effects of quercetin may also occur through the modulation of genes involved in cell survival. The main goal of this study was to examine the gene expression profiling of cultured rat primary cardiomyocytes treated with quercetin using DNA microarrays and to relate these data to functional effects. Results showed distinct temporal changes in gene expression induced by quercetin and a strong upregulation of phase 2 enzymes, highlighting quercetin ability to act also with an indirect antioxidant mechanism.

Antioxidant effectiveness of organically and non-organically grown red oranges in cell culture systems.

BACKGROUND: Consumers consider plant food products from organic origin healthier than the corresponding conventional plant foods. Clear experimental evidence supporting this assumption is still lacking. AIM OF THE STUDY: To determine if the organic red oranges have a higher phyto-chemical content (i. e., phenolics, anthocyanins and ascorbic acid), total antioxidant activity and in vitro bioactivity, in terms of protective effect against oxidative damage at cellular level, than nonorganic red oranges. METHODS: Total phenolics were measured using the Folin Ciocalteau assay, while total anthocyanins and ascorbic acid levels were determined by spectrophotometric and HPLC analysis, respectively. In addition, the total antioxidant activity of red orange extracts was measured by the ABTS(*+) test. The ability of red orange extracts to counteract conjugated diene containing lipids and free radical production in cultured rat cardiomyocytes and differentiated Caco-2 cells, respectively, was assessed. RESULTS: Organic oranges had significantly higher total phenolics, total anthocyanins and ascorbic acid levels than the corresponding non-organic oranges (all p < 0.05). Moreover, the organic orange extracts had a higher total antioxidant activity than non-organic orange extracts (p < 0.05). In addition, our results indicate that red oranges have a strong capacity of inhibiting the production of conjugated diene containing lipids and free radicals in rat cardiomyocytes and differentiated Caco-2 cells, respectively. Statistically higher levels of antioxidant activity in both cell models were found in organically grown oranges as compared to those produced by integrated agriculture practice. CONCLUSIONS: Our results clearly show that organic red oranges have a higher phytochemical content (i. e., phenolics, anthocyanins and ascorbic acid), total antioxidant activity and bioactivity than integrated red oranges. Further studies are needed to confirm whether the organic agriculture practice is likely to increase the antioxidant activity of other varieties of fruits and vegetables.

[Cardiac tumors]. / I tumori cardiaci.

Primary cardiac tumors are rare and their subdivision often difficult because of their unknown origin. In the most recent classification, cardiac tumors are divided into benign (about 75% and malignant neoplasms in relationship to their tissue differentiation (rhabdomyoma, haemangioma, etc.) or uncertain aetiology (myxoma, papillary fibroelastoma). Primary malignant tumors are maimly represented by sarcomas. The most frequent tumor is cardiac myxoma, which by itself represents about 50% of all primary cardiac neoplasms. Although non-invasive technologies as trans-esophageal ecocardiography allow the detection and exact localization of cardiac mass, clinical diagnosis is often tardive. This is due, besides the intrinsic rarity, to two main factors: first, the tumor is often asymptomatic (incidental autopic finding) or; alternatively, it may show aspecif symptoms mimicking heart failure or other pathologies. In this article, clinicopathological features of main primary cardiac tumors are presented. Investigation of the histogenesis of some of these neoplasms is still a primary field of research.

Topical treatment of basal cell carcinoma with tazarotene: a clinicopathological study on a large series of cases.

BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer in humans. Medical treatment modalities offer cost reductions and clinical advantages in selected cases such as low-risk areas, surgically inaccessible sites, patients with multiple neoplasms, and older, infirm or anticoagulated subjects. Tazarotene has been proposed for the treatment of BCC; however, data on its efficacy are lacking. OBJECTIVES: To investigate the efficacy of tazarotene in a large series of BCCs, better to define the clinical advantages and the mechanisms of action in vivo. METHODS: Tazarotene 0.1% gel was applied daily for 24 weeks to 154 small superficial and nodular BBCs. Clinicopathological changes were followed during the therapy by dermoscopic and histological examination. Proliferation, retinoic acid receptors and apoptosis were investigated by immunohistochemistry and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling on biopsies. RESULTS: At 24 weeks of therapy, 70.8% of the BCCs showed > 50% clinical and dermoscopic regression, and 30.5% healed without recurrences after 3 years of follow-up. At 12 weeks, biopsies showed that regression was associated with reduced proliferation and increased apoptosis of basaliomatous cells. Most unresponsive tumours displayed a keratotic differentiation. CONCLUSIONS: Tazarotene was effective in the majority of superficial and nodular undifferentiated BCCs treated, possibly by antiproliferative and proapoptotic actions in vivo. Keratotic BCCs were the major type among the unresponsive tumours, and were characterized by overexpression of p53 and cellular retinol binding protein-1 in comparison with undifferentiated tumours. Topical tazarotene represents an alternative medical choice for selected cases of BCC.