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Biomedical subjects

G Leo

Publications and source records attributed to G Leo.

At least 19 recordsLinked to original sources
PubMed2006

Intramembrane receptor-receptor interactions: a novel principle in molecular medicine.

In 1980/81 Agnati and Fuxe introduced the concept of intramembrane receptor-receptor interactions and presented the first experimental observations for their existence in crude membrane preparations. The second step was their introduction of the receptor mosaic hypothesis of the engram in 1982. The third step was their proposal that the existence of intramembrane receptor-receptor interactions made possible the integration of synaptic (WT) and extrasynaptic (VT) signals. With the discovery of the intramembrane receptor-receptor interactions with the likely formation of receptor aggregates of multiple receptors, so called receptor mosaics, the entire decoding process becomes a branched process already at the receptor level in the surface membrane. Recent developments indicate the relevance of cooperativity in intramembrane receptor-receptor interactions namely the presence of regulated cooperativity via receptor-receptor interactions in receptor mosaics (RM) built up of the same type of receptor (homo-oligomers) or of subtypes of the same receptor (RM type1). The receptor-receptor interactions will to a large extent determine the various conformational states of the receptors and their operation will be dependent on the receptor composition (stoichiometry), the spatial organization (topography) and order of receptor activation in the RM. The biochemical and functional integrative implications of the receptor-receptor interactions are outlined and long-lived heteromeric receptor complexes with frozen RM in various nerve cell systems may play an essential role in learning, memory and retrieval processes. Intramembrane receptor-receptor interactions in the brain have given rise to novel strategies for treatment of Parkinson's disease (A2A and mGluR5 receptor antagonists), schizophrenia (A2A and mGluR5 agonists) and depression (galanin receptor antagonists). The A2A/D2, A2A/D3 and A2A/mGluR5 heteromers and heteromeric complexes with their possible participation in different types of RM are described in detail, especially in the cortico-striatal glutamate synapse and its extrasynaptic components, together with a postulated existence of A2A/D4 heteromers. Finally, the impact of intramembrane receptor-receptor interactions in molecular medicine is discussed outside the brain with focus on the endocrine, the cardiovascular and the immune systems.

Animals↗
PubMed2006

Semiconductor waveguide source of counterpropagating twin photons.

We experimentally demonstrate an integrated semiconductor source of counterpropagating twin photons in the telecom range. A pump beam impinging on top of an AlGaAs waveguide generates parametrically two counterpropagating, orthogonally polarized signal/idler guided modes. A 2 mm long waveguide emits at room temperature one average photon pair per pump pulse, with a spectral linewidth of 0.15 nm. The twin character of the emitted photons is ascertained through a time-correlation measurement. This work opens a route towards new guided-wave semiconductor quantum devices.

Journal Article↗
PubMed2006

Abeta peptides as one of the crucial volume transmission signals in the trophic units and their interactions with homocysteine. Physiological implications and relevance for Alzheimer's disease.

Amyloid peptides (Abeta) can operate as volume transmission (VT) signals since they are continuously released from cells of the central nervous system and diffuse in the extra-cellular space of the brain. They have both regulatory and trophic functions on cellular networks. In agreement with Abeta regulatory actions on glial-neuronal networks, the present paper reports new findings demonstrating that intrastriatal injections of Abeta peptides reduce striatal tyrosine hydroxylase, increase striatal GFAP immunoreactivities and lower pain threshold in experimental rats. Furthermore, it has been demonstrated that exogenous homocysteine (Hcy) binds Abeta(1-40) favouring its beta-sheet conformation both in vitro and in vivo and hence the formation of beta-fibrils and development of neurotoxicity. Thus, the hypothesis is discussed that Abeta peptides represent crucial VT-signals in the brain and their action is altered by dysmetabolic signals such as high Hcy extra-cellular levels, known to be an important risk factor for Alzheimer's disease.

Alzheimer Disease↗
PubMed2006

A boolean network modelling of receptor mosaics relevance of topology and cooperativity.

In the last five years data have been obtained showing that a functional cross-talk among G Protein Coupled receptors (GPCR) exists at the plasma membrane level where they can dimerise and are able to generate high order oligomers. These findings are in agreement with the receptor mosaic (RM) hypothesis that claims the existence of clusters of receptor proteins at the plasma membrane level, where they establish mutual interactions and work as 'intelligent interfaces' between the extra-cellular and the intra-cellular environments. Individual receptor dimers can be considered to have two stable conformational states with respect to the macromolecular effectors: one active, one inactive. Owing to receptor-receptor interactions, however, a state change of a given receptor will change the probability of changing the state for the adjacent receptors in the RM and the effect will propagate throughout the cluster, leading to a complex cooperative behaviour. In this study we explore the properties of a RM on the basis of an equivalence with a Boolean network, a mathematical framework able to describe how complex properties may emerge from systems characterized by deterministic local interactions of many simple components acting in parallel. Computer simulations of receptor clusters arranged according to topologies consistent with available experimental ultrastructural data were performed. They indicated that RMs after a stimulation can achieve a limited number of specific temporary equilibrium configurations (attractors), characterized by the presence of receptor units frozen in the active state. They could be interpreted as a form of information storage and a role of RM in learning and memory could be hypothesized. Moreover, they seem to be at the basis of very common 'macroscopical' properties of a receptor system, such as a sigmoidal response curve to an extracellular ligand, the sensitivity of the mosaic being modulated by changes in the topology and/or in the level of cooperativity among receptors.

Allosteric Regulation↗
PubMed2006

Nuclear maspin detection in renal cell tumours: possible diagnostic role and correlation with p53 status.

AIMS: To investigate the presence of maspin in renal tumours in an attempt to improve our understanding of the underlying mechanism of renal carcinogenesis and for diagnostic purposes. METHODS AND RESULTS: We examined 122 renal neoplasms of varying histological types and immunohistochemically investigated maspin and p53 expression. All clear cell carcinomas (CC) were negative for maspin, whereas oncocytomas (OC), papillary renal cell carcinomas (PC), chromophobe carcinomas (CPC) and, at least focally, collecting duct carcinomas (CDC) stained positively. We found that p53 positivity had a statistically significant correlation with metastasis (P=0.009) in CC and maspin showed a significant inverse correlation with the presence of metastasis in PC and CDC (P=0.02). CONCLUSIONS: The detection of maspin may be useful for differential diagnostic purposes and suggests a different underlying mechanism in the development of the various histological types of renal carcinomas.

Adenoma, Oxyphilic↗
PubMed2006

Urinary iodine concentration and availability of iodated salt in school children in a goitre-endemic district of Tanzania.

OBJECTIVES: To determine the iodine status of school children and document the availability, price, use and storage of iodated salt in Ludewa District, Tanzania. DESIGN: A cross-sectional descriptive study. SUBJECTS: One hundred parents and their fifty school children aged eight to ten years. SETTING: Ludewa District of Iringa region, Tanzania in January 2003. RESULTS: Median urinary iodine concentration of the school children was 86.76 microg/L (range: 21.69 microg/L - 273.36 microg/L). The prevalence of mild iodine deficiency was 44% while that of moderate iodine deficiency was 18%. Thirty-eight percent of the school children had normal iodine status and no child was found to be severely iodine deficient. Household salt samples were found to be non-iodated (12%), insufficiently iodated (58%) and 30% were adequately iodated. For 500 gm, fine salt was sold at US dollar 0.14 (TSh. 100.00) while coarse salt was sold at US dollar 0.07 (TSh. 50.00). Once bought salt was stored in covered containers (55%), uncovered containers (13%), or folded newspapers (32%). With most foods, salt was added at the beginning of a cooking process (1%), during cooking (80%), at the end of cooking (13%) or at the table (6%). CONCLUSION: With 62% of the school children having mild and moderate forms of iodine deficiency, results of the present study demonstrate that iodine deficiency is a public health problem in the District. Consumption of iodated salt and foods rich in iodine is low. Education and communication strategies to different stakeholders need to be strengthened to effectively communicate the message on iodine nutrition. There is a need for renewed efforts to reinforce regular monitoring of iodine content of salt especially in the rural areas where informal re-packing of iodated salt and sale of non-iodated salt are common.

Child↗
PubMed2005

Nuclear expression of maspin is associated with a lower recurrence rate and a longer disease-free interval after surgery for squamous cell carcinoma of the larynx.

AIMS: Maspin, a protein belonging to the serpin superfamily, is the product of a tumour suppressor gene. Tissue distribution studies have shown maspin expression in normal mammary epithelial cells, in the placenta, prostate, thymus, testis, oral cavity, small intestine, skin, and cornea. Maspin is expressed but down-regulated in human breast, prostatic, and colonic cancers but apparently up-regulated in pancreatic, ovarian, and gastric cancers. Only two studies concerning maspin expression in head and neck carcinomas are available. The present study is the first attempt to determine maspin expression in laryngeal carcinoma. METHODS AND RESULTS: Maspin expression was evaluated in 21 cases of laryngeal carcinoma consecutively treated with an exclusively surgical approach with a follow-up period longer than 24 months. The expression of p53, p27 and MIB-1 was also studied. Two patterns of distribution of maspin in laryngeal neoplastic cells were found. Cytoplasmic expression of maspin was identified in 47.6% of the cases. Nuclear maspin positivity was determined in 47.6% of the cases. A statistically significant difference in nuclear maspin expression between the group of patients without carcinoma recurrence and the group with evidence of recurrence was demonstrated (P = 0.039). Log rank test analysis showed a statistically significant direct correlation between nuclear maspin expression and disease-free intervals after surgical treatment calculated in months (P = 0.028). A significant inverse correlation was disclosed between nuclear maspin staining and MIB-1 (P = 0.028). A trend of increasing p27 expression was noted in cases with positive nuclear maspin expression. Nuclear maspin expression was not statistically correlated with p53 expression. A trend towards direct correlation between cytoplasmic maspin expression and squamous cell carcinoma histological grade (G) was apparent. Cytoplasmic maspin expression did not correlate with p53, MIB-1 or p27 expression. CONCLUSIONS: These preliminary results suggest that nuclear location of maspin is a good prognostic factor in laryngeal carcinoma.

Adult↗
PubMed2004

Energy gradients for the homeostatic control of brain ECF composition and for VT signal migration: introduction of the tide hypothesis.

The present paper enlightens a new point of view on brain homeostasis and communication, namely how the brain takes advantage of different chemical-physical phenomena such as pressure waves, and temperature and concentration gradients to allow the renewal of the extra-cellular fluid (i.e., the homeostasis of the brain internal milieu) as well as some forms of intercellular communications (Volume Transmission) at an energy cost much lower than the classical synaptic transmission (the prototype of Wiring Transmission). In particular, the possible functional meaning of the intracranial pressure waves is discussed in the frame of the so called "tide hypothesis" which maintains that the pressure waves, created by the cardiac pump, modulate the cerebro-spinal fluid flow from and towards the subarachnoid space as well as towards and from the Virchow-Robin spaces. These fluid push-pull movements favor both the migration of signals and the extra-cellular fluid renewal, especially in the cerebral cortex.

Animals↗
PubMed2004

Dynamics of volume transmission in the brain. Focus on catecholamine and opioid peptide communication and the role of uncoupling protein 2.

This review focuses on transmitter-receptor mismatches in the brain, which is one of the hallmarks of the Volume Transmission (VT) concept, and how this phenomenon may be related to local temperature gradients created by brain uncoupling protein 2 (UCP2), which uncouples oxidative phosphorylation from ATP synthesis, hereby generating heat. Recent studies on transmitter-receptor mismatches have revealed dopamine and opioid peptide receptor mismatches in the intercalated islands of the amygdala, which are GABAergic cell clusters regulating amygdaloid output. Such mismatches have also been found in regions belonging to the extended amygdala and the nucleus accumbens shell. Now substantial UCP2 immunoreactivity has been found within the above transmitter-receptor mismatch regions, suggesting that UCP2 may enhance diffusion and convection of DA and opioid peptides in such regions by generation of local temperature gradients, thereby contributing to a dynamic regulation of VT.

Animals↗
PubMed2004

Energy gradients for VT-signal migration in the CNS: studies on melanocortin receptors, mitochondrial uncoupling proteins and food intake.

The present paper enlightens a new point of view on brain homeostasis and communication, namely how the brain takes advantage of different chemical-physical phenomena such as pressure waves, and temperature and concentration gradients to allow the homeostasis of the brain internal milieu as well as some forms of intercellular communications (volume transmission, VT) at an energy cost much lower than the classical synaptic transmission (the prototype of wiring transmission, WT). The possible melanocortin control of uncoupling protein 2 (UCP2) expression (hence of local brain temperature gradients) has been studied in relation to food intake in male Wistar rats. Osmotic minipumps were subcutaneously (sc) implanted in the midscapular region for intracerebroventricular (icv) infusion. The control rats received an icv infusion of 0.5 microl/h of artificial cerebrospinal fluid (ACSF), while experimental rats received either an icv infusion of 0.16 nmol/h of HS024 or of 0.16 nmol/h of adrenocorticotropin-(1-24) [ACTH-(1-24)]. The ACTH-treated group ate significantly less than the ACSF-treated group during the first three days of infusion, while, subsequently, food intake of the two groups was similar. On the other hand, the HS024-treated group ate significantly more (up to 153% of the control value) than ACSF- and ACTH-treated rats during the entire period. UCP2 mRNA analysis in arcuate nuclei of ACTH, HS024 and ACSF-treated animals showed a significant 75% decrease (p<0.05 vs saline) of the total specific mRNA level in the HS024-treated group vs ACSF-treated animals (control group), while no significant change was observed between ACTH- and ACSF-treated animals. Melanocortin antagonist HS024 via blockade of MCR4 increases food intake and via a reduction of UCP2 expression enhances the food consumption ratio. This result underlines the fact that UCP2 expression and food intake can be differentially regulated. In other words, via a peptidergic control the central nervous system (CNS) can modulate the energy stored from the amount of the food that the animal has eaten and also uncouple the thermal micro-gradients (dependent on UCP2 expression) and hence the VT-signal micro-migrations from the food intake. It should also be noticed that the control of the thermal gradients affects also the neuronal firing rate and hence the transmitter release (likely above all the release of peptides such as neuropeptide Y (NPY), melanin-concentrating hormone (MCH) and beta-endorphin, e.g., in the arcuate nucleus representing signals relevant to energy homeostasis). Thus, WT and VT are both modulated by peptidergic signals that affect thermal gradients.

Adrenocorticotropic Hormone↗
PubMed2003

Receptor heteromerization in adenosine A2A receptor signaling: relevance for striatal function and Parkinson's disease.

Recently evidence has been presented that adenosine A2A and dopamine D2 receptors form functional heteromeric receptor complexes as demonstrated in human neuroblastoma cells and mouse fibroblast Ltk- cells. These A2A/D2 heteromeric receptor complexes undergo coaggregation, cointernalization, and codesensitization on D2 or A2A receptor agonist treatments and especially after combined agonist treatment. It is hypothesized that the A2A/D2 receptor heteromer represents the molecular basis for the antagonistic A2A/D2 receptor interactions demonstrated at the biochemical and behavioral levels. Functional heteromeric complexes between A2A and metabotropic glutamate 5 receptors (mGluR5) have also recently been demonstrated in HEK-293 cells and rat striatal membrane preparations. The A2A/mGluR5 receptor heteromer may account for the synergism found after combined agonist treatments demonstrated in different in vitro and in vivo models. D2, A2A, and mGluR5 receptors are found together in the dendritic spines of the striatopallidal GABA neurons. Therefore, possible D2/A2A/mGluR5 multimeric receptor complexes and the receptor interactions within them may have a major role in controlling the dorsal and ventral striatopallidal GABA neurons involved in Parkinson's disease and in schizophrenia and drug addiction, respectively.

Animals↗
PubMed2003

Possible role of intramembrane receptor-receptor interactions in memory and learning via formation of long-lived heteromeric complexes: focus on motor learning in the basal ganglia.

Learning in neuronal networks occurs by instructions to the neurons to change their synaptic weights (i.e., efficacies). According to the present model a molecular mechanism that can contribute to change synaptic weights may be represented by multiple interactions between membrane receptors forming aggregates (receptor mosaics) via oligomerization at both pre- and post-synaptic level. These assemblies of receptors together with inter alia single receptors, adapter proteins, G-proteins and ion channels form the membrane bound part of a complex three-dimensional (3D) molecular circuit, the cytoplasmic part of which consists especially of protein kinases, protein phosphatases and phosphoproteins. It is suggested that this molecular circuit has the capability to learn and store information. Thus, engram formation will depend on the resetting of 3D molecular circuits via the formation of new receptor mosaics capable of addressing the transduction of the chemical messages impinging on the cell membrane to certain sets of G-proteins. Short-term memory occurs by a transient stabilization of the receptor mosaics producing the appropriate change in the synaptic weight. Engram consolidation (long-term memory) may involve intracellular signals that translocate to the nucleus to cause the activation of immediate early genes and subsequent formation of postulated adapter proteins which stabilize the receptor mosaics with the formation of long-lived heteromeric receptor complexes. The receptor mosaic hypothesis of the engram formation has been formulated in agreement with the Hebbian rule and gives a novel molecular basis for it by postulating that the pre-synaptic activity change in transmitter and modulator release reorganizes the receptor mosaics at post-synaptic level and subsequently at pre-synaptic level with the formation of novel 3D molecular circuits leading to a different integration of chemical signals impinging on pre- and post-synaptic membranes hence leading to a new value of the synaptic weight. Engram retrieval is brought about by the scanning of the target networks by the highly divergent arousal systems. Hence, a continuous reverberating process occurs both at the level of the neural networks as well as at the level of the 3D molecular circuits within each neuron of the network until the appropriate tuning of the synaptic weights is obtained and, subsequently, the reappearance of the engram occurs. Learning and memory in the basal ganglia is discussed in the frame of the present hypothesis. It is proposed that formation of long-term memories (consolidated receptor mosaics) in the plasma membranes of the striosomal GABA neurons may play a major role in the motivational learning of motor skills of relevance for survival. In conclusion, long-lived heteromeric receptor complexes of high order may be crucial for learning, memory and retrieval processes, where extensive reciprocal feedback loops give rise to coherent synchronized neural activity (binding) essential for a sophisticated information handling by the central nervous system.

Animals↗
PubMed2003

Factors affecting washout in intermittently feed upflow anaerobic reactors: experimental tests and modelling.

This paper reports the results of experimental investigations carried out on a full-scale ABR and on a pilot UASB to determine biomass washout for various intermittent feed conditions. Particularly, the tests aimed to determine the extent to which sludge washout is affected by such factors as: daily flow distribution; upflow velocity; concentration and sedimentation properties of the biomass. Moreover, in order to obtain a tool to estimate sludge washout in different influent flow conditions, a simulation model of the sludge transport phenomena in the uplow anaerobic reactors is proposed. The results showed that when the influent flow is interrupted for long periods (above 1 hour), once it is resumed considerable losses of biomass into the effluent were found, independent of the upflow velocity. In contrast with shorter periods, regular sludge expansion took place even with very high upflow velocities (up to 4 m h(-1)), giving rise to limited sludge washout and high removal efficiencies.

Bacteria, Anaerobic↗
PubMed2003

The long term outcome of gastric non-invasive neoplasia.

BACKGROUND: The cancer risk associated with gastric non-invasive neoplasia (formerly dysplasia) is debated. This prospective long term follow up study investigates the clinicopathological behaviour of non-invasive gastric neoplasia (and related lesions), focusing on the cancer risk associated with each different histological phenotype. PATIENTS AND METHODS: A total of 118 consecutive cases (nine indefinite for non- invasive neoplasia; 90 low grade non-invasive neoplasia; 16 high grade non- invasive neoplasia; and three suspicious for invasive adenocarcinoma) with a histological follow up of more than 12 months (average 52 months; range 12-206) were prospectively followed up with a standardised protocol. Patients in whom gastric cancer was detected within 12 months from the initial diagnosis of non-invasive neoplasia were excluded, assuming that invasive carcinoma had been missed at the initial endoscopy procedure. RESULTS: Non-invasive neoplasia was no longer detectable in 57/118 cases (48%), was unchanged in 32 (30%), and evolved into gastric cancer in 20 patients (17%). Evolution to invasive adenocarcinoma was documented in both low and high grade non-invasive neoplastic lesions (8/90 low grade; 11/16 high grade) and correlated with histological severity (low versus high grade) at baseline (p<0.001). Seventy five per cent of cancers occurring during the long term follow up were stage I. CONCLUSIONS: The risk of invasive gastric cancer increases with the histological grade of the non-invasive neoplasia. Following up non-invasive gastric neoplasia increases the likelihood of gastric cancer being detected in its early stages.

Adenocarcinoma↗
PubMed2002

Pharmacological manipulation of brain galaninergic system and sexual behavior in male mice.

RATIONALE: Available data suggest a complex role for the brain galaninergic system in male sexual behavior; however, the results so far obtained in animals with either galanin or galanin antagonists are conflicting. OBJECTIVE: To define the better influence of galanin on male sexual behavior by studying, in mice, (i) the effect of galanin and of the chimeric galanin peptide M40 on the copulatory performance, and (ii) galanin mRNA levels in hypothalamic arcuate and dorso-medial nuclei. METHODS: For the behavioral testing, only sexually sluggish male mice were used. Galanin mRNA levels were studied in both sexually potent and impotent mice by means of in situ hybridization. Standard behavioral parameters for sexual behavior were recorded or calculated. Synthetic galanin (0.05, 0.1 or 1 microg/mouse) and M40 (5 or 20 microg/mouse) were intracerebroventricularly (ICV) injected, 15 min before the copulatory test. Galanin mRNA levels were evaluated. RESULTS: In sexually sluggish male mice, both galanin (0.1 and 1 microg/mouse ICV) and M40 (20 microg/mouse ICV), significantly increased intromission frequency and ejaculation latency; M40 also improved copulatory efficacy. On the other hand, in the hypothalamic arcuate and dorso-medial nuclei, the levels of galanin mRNA were not significantly different in sexually potent and impotent male mice. CONCLUSIONS: These results show that in sexually sluggish male mice the ICV injection of either galanin or the chimeric analogue M40 greatly prolongs the duration of the copulation; without a reduction of the sexual drive or of the copulatory performance. On the other hand, the hybridization experiments seem to rule out an important physiological role of the brain galaninergic system in the regulation of male sexual behavior, at least in mice.

Animals↗
PubMed2001

Poly(L-lactide)acid/alginate composite membranes for guided tissue regeneration.

The barrier membranes for guided tissue regeneration (GTR) to treat bone defects have to satisfy the criteria of biocompatibility, cell-occlusiveness, space-making, tissue integration and clinical manageability. In this study a system constituted of a poly(L-lactide) acid (PLLA) asymmetric membrane combined with an alginate film was prepared. The PLLA membrane functions to both support the alginate film and separate the soft tissue; the alginate film is intended to act as potential vehicle for the growth factors to promote osteogenesis. The structural, morphological, and mechanical properties of the bilamellar membrane and its stability in culture medium were evaluated. Moreover, the feasibility of using the alginate membranes as controlled-release delivery vehicles of TGF-beta was monitored. Finally, the bacterial adhesion and permeability of Streptococcus mutans, selected for the high adhesive affinity, were monitored. The results showed that the surfaces of the alginate side, to be used in contact with the bone defect, were rougher than PLLA ones. When in contact with complete culture medium, the PLLA-alginate membrane retained its mechanical and structural properties for more than 100 days. Then, the degradation processes occurred but the membrane continued to be stable and manageable for 6 months. Growth factors such as TGF-beta can be incorporated into alginate membranes functioning as drug delivery vehicle, and retain the biological activity when tested in an in vitro model system. The obtained membrane acted as a barrier to the passage of S. mutans bacteria and showed to promote a lower bacterial adhesion with respect to commercial GTR membranes.

Alginates↗