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Circadian rhythms, rhythms of about 24 h in various physiological functions, are getting extensively characterized at the molecular level. The generation of circadian rhythms is acknowledged to originate from oscillations in the expression of several clock genes as well as in the regulation of their protein products. While the general entrainment of organisms to the light-dark cycle of the environment is mainly achieved through the master clock of the suprachiasmatic nucleus in mammals, the molecular clockwork is functional in various organs and tissues. The molecular components of the circadian system have been found to be essential for a diversity of basic and homeostatic systems ranging from the control of cell cycle, the regulation of cardiac and metabolic function, to the fine-tuning of sleep and mental health. The present review will focus on the involvement of clock genes in human health and diseases.

Apigenin is a member of the flavone family of flavonoids and possesses anti-inflammatory, free radical scavenging and anti-carcinogenic properties. Hydrogen peroxide, which is generated during oxidative stress, is known to damage proteins, nucleic acids and cell membranes and also has been implicated in cancer, ageing and several chronic neurogenerative diseases. The present study focuses on the protective effect of apigenin against genotoxic doses of hydrogen peroxide (H₂O₂) using sister chromatid exchanges (SCEs) and cytokinesis blocked micronucleus (CBMN) assay. The treatment with 50, 100 and 150 μM of H₂O₂ results in a significant dose dependent increase in the frequency of SCEs and MN. The treatment with 100 μM of H₂O₂ along with 5, 10 and 20 μM of apigenin results in a dose dependent significant decrease in the frequency of SCEs and MN on cultured human lymphocytes. A similar result was obtained with treatment with 150 μM of H₂O₂ along with 5, 10 and 20 μM of apigenin. The results of the present study suggest a protective effect of apigenin against hydrogen peroxide induced genotoxic damage on cultured human lymphocytes.

The ubiquitous polyamines putrescine, spermidine and spermine fulfil an array of physiological roles in man. In particular, their participation in cell growth and proliferation has been of great interest in relation to their roles in tumour growth and in wound healing. Both endogenous and dietary polyamines take part in such processes. The deprivation of exogenous polyamines emerges as a promising strategy in tumour therapy. Thus, reliable information on their content in foods is needed for dieticians. This review continues our previous comprehensive review on the topic, summarising data on the polyamine content in foods published from 2005 to April 2009. Some new data has appeared. Bovine, porcine and chicken liver, kidney, spleen and heart all have a high content of spermine; bovine liver also of spermidine. Losses of spermidine and spermine up to one half of their original levels occur during both cold and frozen storage and during various thermal treatments. Cultivated mushrooms were reported to contain very high levels of spermidine. Recent results have proved that polyamine content varies widely within a food item, and this complicates the application of available data for the controlled nutrition of patients.

The present study was undertaken to provide more information of the translocation of AgNORs to the nucleolar periphery in human early granulocyte progenitors such as myeloblasts and promyelocytes. The bone marrow smears of patients untreated or treated with the cytostatic therapy appeared to be a convenient model for such study because they possessed a satisfactory number of these cells. The translocation of AgNORs to the nucleolar periphery in early granulocytic progenitors was observed in all studied patients but with different incidence. Since the translocation of AgNORs to the nucleolar periphery was induced in experimental studies in vitro by the cell ageing, it seems to be likely that even some granulocyte progenitors in patients suffering from chronic myeloid leukaemia might age without a further differentiation. In addition, the incidence of such cells was markedly and significantly increased by the targeted cytostatic therapy with imatinib. At this occasion it should be noted that these patients were also characterised by a significantly decreased granulopoiesis.

Six clinically healthy blood donor dogs were used to evaluate the effect of desmopressin (DDAVP) on haemochromocytometric and clotting parameters,. They received subcutaneously a physiological solution (placebo) and DDAVP (1μg/kg) with a two-weeks wash-out period between treatments. Blood samples were collected immediately before the injection, after 30 minutes, then after 1, 2, 3, 4, 5 and 6 hours. Two-way repeated measure analysis of variance (ANOVA) showed no significant effect of DDAVP vs placebo, except for white blood cell (WBC) count, and in particular on neutrophils. In conclusion, DDAVP administration in healthy donor dogs does not induce modification in blood cell count and clotting parameters, except of WBC.

Estrogen replacement therapy (ERT) engenders much debate since several studies contradict its efficacy as a palliative therapy for cognitive decline and neurodegenerative diseases. Signaling transduction pathways alter brain cell activity, survival, and morphology by facilitating transcription factor activation and protein production. The steroidal hormone estrogen and the anti-depressant drug lithium can interact also through these signaling transduction pathways resulting in transcription factor activation. The transcription factor cAMP response element binding protein (CREB) is affected by both estrogen and lithium, and CREB regulates genes involved in learning, memory and neuronal survival. CREB is activated upon phosphorylation at serine 133 by protein kinases and, estrogen and its receptors (ER) facilitate this phosphorylation. Glycogen synthase kinase-3beta (GSK-3β) attenuates CREB's transcriptional properties via subsequent phosphorylation of its serine 129, and lithium is known as a negative regulator of GSK-3β, thus facilitating CREB response element binding. Interestingly, ERα function and DNA-binding properties are facilitated by GSK-3β. In this review we include protein modeling depicting the interaction of CREB/GSK-3β and ERα/GSK-3β using I-TASSER and PatchDock web servers. Understanding the molecular pathways of estrogen will assist in identifying a palliative therapy for menopause-related dementia, and lithium may serve this purpose by acting as a selective estrogen-mediated signaling modulator.

The nucleolus is a large nuclear domain generated by the act of building ribosomes. It illustrates the compartmentation of the nuclear functions, since it is in the nucleolus that transcription of the ribosomal genes, maturation and processing of the 47S ribosomal RNAs (rRNAs) into 18S, 5.8S and 28S rRNA, and almost complete assembly of the 40S and 60S ribosome subunits take place. The shape, size and organization of the nucleoli vary with their activity. Nuleolar activity is a cell cycle dependent-process. In electron microscopy, the nucleolus exhibits three main components: fibrillar centers (FCs), a dense fibrillar component (DFC) and a granular component (GC), corresponding to different steps of ribosome biogenesis. The steady state between transcription, processing and export of ribosomal subunits engenders this organization. Conversely, inactivation or blockage of one of these processes modifies the organization of the nucleolus and ultimately induces nucleolar disassembly. The nucleolus is also a plurifunctional domain, a key partner of chromatin architecture in the nucleus and it plays a crucial role in several cellular functions in addition to ribosome production.
The nucleolus is assembled at the end of mitosis, is active during interphase, and disassembled in prophase. The nucleolar transcription and processing machineries are inherited from parental to daughter cells through mitosis. The polymerase I (pol I) transcription machinery is repressed during mitosis although assembled with ribosomal genes. Repression of pol I transcription is achieved at the end of prophase and is maintained during mitosis through phosphorylation of transcription factors by the cyclin-dependent kinase (CDK) 1. The nucleolar processing machineries relocalize from the nucleolus towards the periphery of all chromosomes until telophase and this chromosome association depends on CDK1 activity. As a consequence of natural inhibition of CDK1 activity, pol I transcription is restored in telophase. The processing machineries are recruited to the sites of rDNA transcription after a temporary transit in foci known as prenucleolar bodies.
In conclusion, the behavior of the nucleolus illustrates the fact that the dynamics of nuclear organization are integrated in a network of interactions and controls that is largely dependent on the coordination of cell cycle controls.

Nitric oxide (NO) is a free radical endogenously produced by nitric oxide synthase. This molecule possesses many important functions in the mammalian organism. The role of NO in regulating cell death and proliferation is now widely recognized. In cultured primary hepatocytes both proapoptotic and antiapoptotic NO effects have been reported. However, most reports support its role in the inhibition of apoptosis. NO has been shown to suppress apoptosis in a model of inflammation and cholestasis, and inhibits spontaneous apoptosis. NO antiapoptotic function was exerted via inhibition of both activity and activation of caspases either directly by nitrosylation, or indirectly via an cGMP-dependent pathway. Both spontaneous and induced hepatocyte apoptosis can be determined by biochemical and morphological methods, which cover various aspects of the apoptotic process, and have a different specificity for detection of apoptotic cell death.

The effects of irradiation (200kV X-ray, 5 Gy), extremely low frequency electromagnetic fields (ELF-EMF, 50 Hz, 60±0.2 μT) and/or heat shock (HS, 41°C for 30 min) on the expression of several heat shock genes (HSP27, HSP60, HSP70, HSP75, HSP78, HSP90) in human HL-60 leukaemia cells was studied by RT-PCR. In addition, the effects of these stressors on cell cycle progression in exponentially and asynchronously growing cell cultures were studied by flow cytometry. The dynamics of cell division during successive cell cycles was monitored by fluorescence-labelling of the cells with carboxyfluorescein succinimidyl ester (CFSE). Finally, the cell cycle distribution was studied by staining with propidium iodide (PI). With respect to HSP gene expression the three stressors produced similar effects. The combination of stressors (ELF-EMF and HS or Radiation and HS) strongly induced transcription of the HSP70 gene above the level induced by each stressor alone. The cell cycle analysis, however, revealed striking differences in the cellular response to each stressor. Of particular interest was the observed thermoprotective effect of ELF-EMF in heat shocked cells, an effect that was not seen in cells which were exposed to X-rays in the presence of thermal stress.

A significant aspermatogenic activity, ascertained by microscopic studies of seminiferous tubules and interstitial tissue, and by the observation of the entrance of immunity and fibrocytic cells in mice injected with polyspermine (PS) or polyspermine conjugated to monomeric or dimeric RNase A (PS-RNase A or PS-dimeric RNase A, respectively), was found either in mice injected or in non-injected testes. Polyspermine and its complexes with RNase A destroyed all spermatogenic and intertestitial tissue, including Leydic cells, as well as their ability to secrete testosterone. The total loss of spermatogenic activity in injected testes is irreversible because spermatogonia cells also were destroyed. The injection of PS into both mice testes determined the total degeneration of testicle tissue in 50% of injected testes. The second half of testes was also partly degenerated, and if they were re-injected, almost all testes were fully destroyed. PS-dimeric RNase A injected once into both testicles produced a stronger degeneration and also the interruption of testosterone secretion in comparison with the effects due to injection of mice with PS or PS-RNase A. In all mice treated with these substances, as well as in rats in which PS was injected twice into their testes, we detected polymorfonucleates, monocytes, plasma cells, lymphocytes and fibrocytic cells. Antibodies against PS, PS-RNase A or PS-dimeric RNase A did not influence the aspermatogenic activity. Animals in which a repeated intra-peritoneal injection was carried out did not lose body mass and remained in good condition, with the exception of mice injected with spermine.

The epidermal stem cell plays a pivotal role in the function of squamous epithelia in physiological as well as in pathological conditions such as cancer. This review summarizes data about the glycobiology of normal squamous epithelia and related tumors with respect to epithelial cell differentiation and search for a glycophenotype specific for epidermal stem cells using labeled plant and endogenous lectins. Although the glycophenotype typical for epithelial cells at the stage of low differentiation level were found, no typical cell surface saccharidic markers of stem cells were detected. The nuclear binding of galectin-1 seems to be specific for the keratinocyte population prepared from hair follicles enriched for multipotent stem cells. The close topographical relationship of nuclear galectin-1 binding sites with SC35 splicing factor suggests some role for these glycoepitopes in pre-mRNA splicing. The data shown in this paper can be employed for diagnostic purposes and for cell therapy of skin defects and indicate the importance of the use of endogenous lectins as probes in biology and medicine.

Down syndrome (DS) is often accompanied by autoimmune diseases. Among those, autoimmune thyroid disease, type 1 diabetes and celiac disease are the most common. The major cause of enhanced vulnerability of DS patients to a variety of autoimmune diseases is impaired immune response, with multiple abnormalities in all components of the immune system, especially in cell-mediated immunity. This could explain a significantly higher frequency of autoimmune disorders in DS compared to the general population. The diagnosis of autoimmune diseases accompanying DS could be complicated by masking effects of the underlying features of the syndrome such as failure to thrive, short stature and delayed puberty. However, screening for immunological signs of coexistent autoimmunity such as tissue-specific antibodies and monitoring insulin secretion, glucose levels, thyroid function and other metabolic parameters should help in early diagnosis of coexistent autoimmunity in DS patiens.

Phenylhydrazine (PHZ) and its derivatives were first given a medical application at the end of the 19^th century but with very little benefit. However, this compound seems to be very useful in models studying mechanisms of haemolytic anaemia. Phenylhydrazine induces a reactive oxygen species formation, peroxidation of lipids and oxidative degradation of spectrin in the membrane skeleton. PHZ-induced haemolytic injury seems to be derived from oxidative alternations to red blood cell proteins. This compound can modulate immune reactions.

The editorial boards with responsible reviewers in scientific journals might play a very important role and should be of a great help for authors. It is a reasonable hope that the journals with such reviewers might be very much respected as well as and highly evaluated without overestimation of the impact factor.

As more information accumulates on the detailed dynamics of life processes, emphasis on steady state behaviour gives way to the recognition that the organism is a multi-oscillator. Systems biology takes account of the controls and balances on inputs and outputs between the environment and the open system of the functioning organism. The matching of the system to its periodic environment performed by biological clocks (circadian, tidal, lunar, annual) is belatedly acknowledged and exploited in applied biomedicine, even as detailed mechanisms continue to be elucidated. Ancestral shorter-period (ultradian) oscillations, rhythms and clocks are all-pervasive in intracellular regulation and control. Yeast in continuous culture shows all these characteristics as well as population coherence. Temporal organisation of tissues, organs and of the whole organism; its construction, operation and maintenance are extensions of these dynamic principles.

For the psychiatrist, lithium is an effective drug for both the treatment and prophylaxis of bipolar disorder. The molecular mechanisms underlying its therapeutic actions have not yet been fully explained. The effects of lithium on a number of enzymes and biological processes have been studied. Inositol monophosphatase and glycogen synthase kinase-3 (GSK-3) have been suggested as the relevant intracellular targets for lithium action. The discovery of the role of GSK-3, the Wnt signalling system, and the anti-apoptotic factor Bcl-2 has led to the suggestion that there could be a therapeutic use for lithium in neurodegenerative disorders, such as Alzheimer's disease.

Calreticulin is a Ca²⁺-binding protein of the ER/SR, from where it acts as a chaperone, and affects calcium homeostasis, gene expression and cell adhesion. Cell adhesion to the extracellular matrix can generate transmembrane signals important for cell survival and migration. In a variety of cell types, integrin stimulation by ECM proteins, such as fibronectin, leads to changes in intracellular protein tyrosine phosphorylation. Tyrosine phosphorylation leads to the co-localization of focal adhesion kinase, vinculin and paxillin at focal contacts. Interaction between focal adhesion kinase and paxillin is critical for the activation of signaling cascades involved in cell survival and motility. Fibroblasts either over- or underexpressing calreticulin show differences in their adhesive properties, which are related to the calmodulin/CaMKII pathway. Inhibition of these pathways causes the weekly adhesive calreticulin underexpressing cells to behave like the calreticulin overexpressers, through increased spreading and increased levels of focal adhesion kinase, paxillin and fibronectin. We propose that calreticulin, via its Ca²⁺-homeostatic effects, may affect fibronectin synthesis and matrix assembly by modulating fibronectin gene expression, and by influencing formation of cellular adhesions, both of which are instrumental in matrix assembly and remodelling. Interestingly, it appears that besides the calmodulin/CaMKII pathway, differential calreticulin expression also modulates the c-src pathway.

We tested the potency to reactivate AChE inhibited by diisopropyl fluorophosphates (DFP) by using bis-pyridinium oxime reactivators connected with CH₂CH₂OCH₂CH₂ linkers between two pyridinium rings. The potency was strongly dependent on oxime functional groups, and the bis-oxime derivatives 1,1-[Oxybis(ethylene)]-bis[4-(hydroxyimino)methyl]pyridinium dibromide (1) and 1,1-[Oxybis(ethylene)]-bis[2-(hydroxyimino)methyl]pyridinium dichloride (2) are more potent than mono-oxime compounds 1-(4-hydroxyiminomethyl-1-pyridino)-5-(4-carbamoyl-1-pyridino)-3-oxapentane dibromide (3) and 1-(3-hydroxyiminomethyl-1-pyridino)-5-(4-carbamoyl-1-pyridino)-3-oxapentane dibromide (4). Not only is the number of oxime groups an important structural factor, but also their position. The in vitro reactivation ability of the most potent bis-pyridinium oxime 2 was further evaluated for the housefly (HF) AChE inhibited by DFP and the bovine red blood cell (RBC) AChE inhibited by paraoxon. The reactivation ability of oxime 2 at 5x10^-3M concentration was almost 80% for HF-AChE inhibited by DFP and 82.1% for RBC-AChE inhibited by paraoxon.

B-chronic lymphocytic leukemia (B-CLL) is the most common form of leukemia in the western world. It results from a relentless accumulation of small mature monoclonal lymphocytes. Following a recent demonstration of a significant increase in the proliferative pool of CLL cells in vivo, the gradual accumulation of malignant B-CLL cells seems to be primarily the consequence of their selective survival advantages relative to their normal B-cell counterparts. As the disease is mainly caused by defective apoptosis it is thus a good candidate for treatment by proapoptotic agents. Even though a large amount of research has been done during the last past years, the prognosis has not changed. Because of this, new therapeutic strategies are urgently needed, especially those that could switch on new apoptotic responses. In order to test the ability of parthenolide, a sesquiterpene lactone, to induce apoptosis and cytotoxicity of B-CLL cells in vitro, we cultured these cells in the presence of this substance. Incubations were continued for 3 days. Samples of cells were taken from cultures at 0, 24, 48 and 72 hours to measure apoptosis and cell viability. Peripheral Blood Mononuclear Cells (PBMCs) from five normal donors were submitted to the same techniques and served as control samples. In this study we show for the first time that parthenolide has a potent apoptotic and cytotoxic effect on B-CLL. It is noteworthy that this substance has almost no impact on normal PBMCs. This evidence suggests that parthenolide might be a promising therapy for B-CLL.

Rhythmic changes in a number of haematological characteristics have been described in many published papers during the 20^th and at the beginning of the 21^st century. The best known are circadian rhythms, which are mostly correlated with the light/dark regime, inducing rhythmic changes in levels of melatonin, synchronised by a suprachiasmatic nucleus and the retinohypothalamic input. These circadian rhythms in men and diurnal animals have an inverse relationship to rhythms in nocturnal beings. Some haematological rhythms are modified by other synchronisers. Knowledge of circadian rhythms in haematological characteristics is important for both the faultless clinical interpretation of laboratory data and the search for mechanisms participating in rhythm regulation.

Hodgkin's Disease (HD) is one of the malignant diseases with good chances for a cure. The prognosis for cure depends on the initial stages and the outcome after initial treatment. Stages I or II at diagnosis, or a complete remission after initial treatment are good indicators for the best prognosis to patients.
A frequent problem faced by clinicians is met at the post-therapy stage because of the difficulty of distinguishing between dead tissue and disease activity in residual masses. Considering that these two situations include therapy options that run from treatment abstention to autologous stem cell transplantation, it is extremely important to distinguish them accurately.
Classical Tomography Scan (CT Scan), Gallium scintigraphy, Magnetic Resonance Imaging (MRI) or Positron Emission Tomography (PET) are used to investigate residual masses. In order to clarify the best way to confirm the post-treatment status of patients affected by HD, we describe in this paper our experience of using PET to solve those problem situations where a CT Scan or MRI were not conclusive and Gallium was negative.

Quality control of the endoplasmic reticulum plays a critical role in protein folding, modification and modification of a secretory pathway. As endoplasmic reticulum chaperones, calreticulin and calnexin have similar substrate specificity and share several common features. Yet, surprisingly, mice bearing a disruption in the calreticulin gene die from a lesion in cardiac development and develop significant metabolic problems whereas calnexin-deficient mice are born alive with, yet not understood, neurological problems. Studies with calreticulin and calnexin gene knockout mice and calreticulin- and calnexin-deficient cell lines indicate that calnexin is unable to compensate for the loss of calreticulin and conversely, calreticulin cannot compensate for the loss of calnexin. Calreticulin or calnexin deficiency or reduction in the level of ERp57 protein (ERp57 heterozygote mice) leads to development of metabolic disorders as documented by sever changes serum lipids and carbohydrates composition in these animals. These observations indicate that calreticulin, calnexin and ERp57, in addition of being involved in maturation of glycoproteins in the endoplasmic reticulum, perform other distinct functions including affecting energy metabolism.

The present study was undertaken to provide more information on the nucleolar size, number and distribution of AgNORs (silver stained nucleolus organizer regions) in nucleolar bodies of aging leukemic granulocytic progenitor cells represented by cultured K562 cells. In these aging and starving cells without further differentiation and with translocated AgNORs to the nucleolar periphery, the diameter of the nucleolar size was reduced together with a reduction in the number of these nucleolar compartments. However, after re-feeding cell cultures, the nucleolar size increased again. Similarly, the number of AgNORs also increased and was distributed in the whole nucleolar body as in control cells. Such cells apparently entered into the cycle and proliferation documented by the re-occurrence of mitotic divisions in studied cultures, an increased number of AgNORs and increased nuclear size. This observation suggests that early granulocytic precursors with translocated nucleolar AgNORs might represent a transitionally quiescent population of cells which may return to a fully proliferating state.

The human circadian system is evidently regulated by components which can be found in the retina (light input), a suprachiasmatic nucleus in the hypothalamus (clock genes) and the pineal gland (melatonin synthesis). Clock genes are interdependent through two intracellular feedback loops. The pineal gland is not the single important producer of melatonin, as immune cells can also produce this hormone. Immune cells contain active clock genes as SCN cells and we can suggest that the regulation of the circadian system is a component of the neuroimmune regulation of the organism. The endogenous character is dominant in SCN, which is modulated by darkness and which synchronizes organisms to the light/dark regime including immunity. The exogenous character seems to be dominant in the immune system which synchronizes the organism including SCN cells to other environmental stimuli. The mathematical theory of chaos shows that the circadian activity of a cell is derived from ultradian metabolic rhythms; these rhythms support the stability of living systems which can be changed by a limited repertoire of interventions. The complexity of neuroimmune interactions perhaps explains why we are far from knowing the mechanism concerning the regulation of biorhythms despite the vast number of related scientific publications.

Our research group has previously studied the role of melatonin in the immune system of birds and mice, finding that incubation with both pharmacological and physiological doses of melatonin augmented the activity of phagocytes from these animals, and that this activity was lowered in pinealectomized animals. Since melatonin is synthesized from the amino acid tryptophan, the aim of the present work was to determine whether the administration of tryptophan might affect the plasma levels of melatonin and the phagocytic activity of peritoneal macrophages over the course of a circadian cycle. The study animals were 14-week-old male Wistar rats. They were administered tryptophan orally in a daily single dose of 125 mg/kg at 19:00 h for 21 days. Prior to beginning this treatment, the circadian rhythms of plasma melatonin and phagocytic activity were evaluated under basal conditions over a 24-h period, taking blood and cell suspension samples each 2 hours during the light period (08:00-20:00) and each hour during the dark period (20:00-08:00), since it is during this latter period that the secretion of melatonin is maximum. The results showed that, under basal conditions, the rats' plasma melatonin levels and phagocytic activity peaked at 02:00. After the tryptophan administration, there were increases in plasma melatonin levels with respect to basal and control-group values, with a peak at 21:00, and in the phagocytic activity of the peritoneal macrophages, which peaked at 02:00. This suggests that the tryptophan administration stimulated melatonin synthesis, leading to increased and earlier peaking plasma levels of this hormone, and augmented the innate immune response carried out by the peritoneal macrophages as a result of the immunoregulatory action of melatonin.

Excitatory amino acids (EAA) represent major brain neurotransmitters. They are present in numerous neuronal systems and thus are involved in almost all aspects of normal and pathological brain activity. Changes in EAA transmission have been associated with the functional impairments characterizing major neurological disorders, including epilepsy and schizophrenia. There is also a suspicion that EAA systems underlie the neuronal death associated not only with acute CNS insults, such as in ischemia or post-traumatic lesions, but also with neurodegenerative diseases such as ALS, Huntington's disease and Parkinson's disease. The neurotoxicity of EAA, referred to as excitotoxicity, is presumably mediated primarily through an excess of EAA synaptic receptor stimulation. Indeed, overstimulation of the ionotropic NMDA or AMPA/kainate receptor subtypes has been shown to produce an intense membrane depolarisation and further a massive increase in intracellular calcium leading to cell damage. The extreme diversity and specific pattern of expression of EAA receptor subunits could account for the differential vulnerability of certain brain areas to such excitotoxic processes. In addition, it is now believed that besides abnormalities in receptor functioning or in release processes, alterations in EAA transmission may result from dysfunction of the EAA uptake system, which represents the mechanism for EAA removal from the synapse. From the five transporter proteins cloned, termed EAAT1-5, the primarily glial transporters EAAT1 and EAAT2 have been shown to mediate the bulk of EAA uptake in the brain and it has then been suggested that they play a major role in the prevention of excitotoxic processes. In this respect, the degeneration of motor neurons in ALS has been associated with altered expression or inactivation of EAAT2. Moreover, recent evidence has been provided that pharmacological alteration of glutamate transport can also induce astrocyte degeneration, as observed in neurodegenerative insults, but through a mechanism independent of stimulation of EAA receptors. Thus, one can obviously consider that these EAATs can represent a key target for further development of new neuroprotective agents.

Circadian biorhythms change with age and such changes are caused by the loss of both the time and the space structure. These alterations of biorhythms are associated with poor health and the end of life but we do not know the extent to which they represent cell clock system injury. It seems that ageing of biorhythms in mammals, i.e. including humans, is caused by the ability of suprachiasmatic nuclei to drive oscillations in other tissues. Social synchronization extending photic stimuli, which diminishes during degeneration of nerve and optic system, enhances the quality of life and therefore further studies of the influence of health and social care systems on circadian rhythms could contribute to the lengthening of life.