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Tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) is one of the highly toxic organophosphorus compounds misused as chemical warfare agents for military as well as terroristic purposes. It differs from other highly toxic organophosphates in its chemical structure and by the fact that the commonly used antidotes (atropine in combination with an oxime) are not able to sufficiently eliminate its acute toxic effects.
The neuroprotective effects of the newly developed oximes (K027, K048) or trimedoxime in combination with atropine (atropine, K027/atropine, K048/atropine and trimedoxime/atropine mixtures) on rats poisoned with tabun at a lethal dose (270 mg/kg i.m.; 120% of LD₅₀ value) were studied. The tabun-induced neurotoxicity was monitored using a functional observational battery and an automaticmeasurement of motor activity. The neurotoxicity of tabun was monitored at 24 hours and 7 days following tabun challenge. The results indicate that atropine alone is not able to protect rats from the lethal effects of tabun. Five non-treated tabun-poisoned rats and five tabun-poisoned rat treated with atropine alone died within 24 hours. On the other hand, atropine combined with all tested oximes allows most tabun-poisoned rats to survive within 7 days following tabun challenge. All three oximes tested combined with atropine seem to be sufficiently effective antidotes for a decrease in tabun-induced neurotoxicity in the case of lethal poisonings, although they are not able to eliminate tabun-induced neurotoxicity completely. Due to their neuroprotective effects, all the tested oximes appear to be more suitable oximes for the antidotal treatment of acute tabun exposure than the currently used oximes (pralidoxime, obidoxime, HI-6).

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.

Oxidative stress may cause free radical reactions to produce deleterious modifications in membranes, proteins, enzymes and DNA. Valproic acid is a major anti-epileptic drug with a broad spectrum of anti-epileptic activity. Chronic treatment with valproic acid can lead to elevated serum ammonia levels and specific oxidative metabolites of valproic acid have been associated with the drug's toxicity. The influence of sodium valproate treatment on lipid peroxidation and lipid profiles and the detoxifying effects of α-ketoglutarate on sodium valproate induced toxicity were studied in rats. The levels of thiobarbituric acid reactive substances, hydroperoxides and lipid profile variables (cholesterol, phospholipids, triglycerides and free fatty acids) were significantly increased in sodium valproate treated rats. Further, non-enzymic antioxidants (reduced glutathione) and the activities of the enzymic (superoxide dismutase, catalase, glutathione peroxidase) antioxidants were significantly decreased in sodium valproate treated rats. The levels were observed to be normal in α-KG + sodium valproate treated rats. These biochemical alterations during α-KG treatment could be due to (i) its ubiquitous collection of amino groups in body tissues, (ii) the participation of α-KG in non-enzymatic oxidative decarboxylation of the hydrogen peroxide decomposition process and (iii) its role in the metabolism of fats which could suppress oxygen radical generation and thus prevent lipid peroxidative damage.

Benzalkonium bromides (BAK) are an important class of cationic surfactants with both industrial and commercial uses. They are used as preservatives for ophthalmic, nasal and parenteral products and they are also used as a topical antiseptic and medical equipment disinfectant. In this work a universal method for the preparation of these compounds is described. Using quaternization of N,N-dimethylbenzylamines with long-chain n-alkylbromides we have prepared C₈, C₁₀, C₁₂, C₁₄, C₁₆, C₁₈ and C₂₀ homologues of the benzalkonium bromides (BAK).

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.

The biochemical and haematological parameters of nutritional interest were determined in the serum of opiate addicts in order to compare them with those obtained in healthy subjects. The blood of 106 opiate addicts in detoxification treatment (n=19) or in Methadone Maintenance Treatment Program (MMTP) (n=87) was studied. Opiate addicts presented lower levels in the number of red cells, cholesterol, albumin, retinol, α-tocopherol, folic acid, K and Se and higher levels in the number of leukocytes, GOT, GPT and Na, than the control group. The opiate addicts in MMTP had higher levels of glucose, triglycerides, Mg and P than the opiate addicts in the detoxification treatment and control groups. Significant correlations between the three vitamins (folic acid, retinal and α-tocopherol) were observed and the graphic representations suggest a biochemical differentiation between opiate addicts and healthy subjects. Factor analysis made it possible to select seven factors explaining 66.2% of the total variance, and representing the first and fourth factor, opiate addicts tended to separate from the control group.

First described by Alois Alzheimer in 1907, Alzheimer's disease (AD) is the most common dementia type, affecting approximately 20 million people worldwide. As the population is getting older, AD is a growing health problem. AD is characterized by the presence of neuritic plaques containing the amyloid-beta peptide (Abeta) and an intraneuronal accumulation of tubule-associated protein called tau. Currently available treatment used in AD is based on acetylcholinesterase inhibitors, since in the course of AD there is a substantial loss in cholinergic neurons. Another registered drug used in more severe AD is the NMDA antagonist-memantine. From a drug development point of view, some potential new AD therapeutics include neuroprotective peptides that may act in a variety of different ways, e.g. they help to break the amyloid plaque formation, modulate peptide processing enzymes (secretases) or are able to degrade Abeta toxic peptide. In this review, we present an overview of the new classes of compounds in use against AD.

Changes in the expression and cellular localization of abundant nucleolar proteins: C23/nucleolin, upstream binding factor (UBF), B23/nucleophosmin, and fibrillarin were examined in human lymphocytes subjected to the control of nucleolar activity by phytohemagglutinin and actinomycin D. Data suggest that the up-regulation of ribosomal RNA transcription induced by phytohemagglutinin was accompanied by a significant increase in the nucleolar content of C23/nucleolin, UBF, B23/nucleophosmin, whilst the nucleolar content of fibrillarin had a relatively low-variable. An unraveling of the multicopy ribosomal gene accompanying the mitogenic stimulation was detected through the immunofluorescence of UBF permanently associated with rDNA. Down-regulation of RNA polymerase I activity induced by actinomycin D, 24 hrs after initiating stimulation, did not influence the expression of C23/nucleolin, UBF, and fibrillarin, and up-regulated the expression of B23/nucleophosmin. This inhibition resulted in the translocation of chaperons C23/nucleolin and B23/nucleophosmin to the nucleoplasm, while UBF and fibrillarin persisted in the nucleolus. The re-clustering of dispersed transcription units of rDNA, induced by actinomycin D, despite the persistence of UBF in the nucleolus, contradicts the hypothesis that neo-synthesis of UBF is the main drive for unraveling a multicopy rDNA gene. The translocations of C23/nucleolin and B23/nucleophosmin are discussed in relation to the cellular stress response caused by the genotoxic activity of actinomycin D. It is suggested that the reannealing activity of nucleolin and nucleophosmin helps to drive the genotoxic agent to the nucleolus, diminishes the diversity of genotoxic damage and inhibits the growth-division activity of cells.

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.

There are no doubts about the benefits of non-invasive laser therapy in treating surgical wounds, thanks to its anti-inflammatory, stimulating and analgesic effects. Systemic enzymotherapy is particularly employed due to its thrombolytic, fibrinolytic and antiedema effects. Concurrent use of the two above mentioned treatment modalities exerts a synergistic action. Thus, it is possible to reduce the persistence of the pain as well as the duration of the post-operation period after surgical interventions in the mouth cavity at a statistically highly significant level. Thus, this approach can be recommended for achieving a favourable outcome in most post-operation conditions.

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.

The purpose of this preliminary, double-blind, placebo-control study was to evaluate the effect of GaAlAs diode laser on wound healing and pain reduction in patients after extraction of impacted lower third molars by infrared thermography. Material and methods: The study population of two patients was divided into group A treated by GaAlAs diode laser with a wavelength 830 nm and maximal output power of 100 mW and group B treated by placebo laser. Therapeutic Schedule: The energy density per point was 12 J, treatment time 2 minutes, the total energy density for one treatment session was 36 J. Treatment intervals were 10 minutes after extraction, 1 and 3 days after extraction. Patients in group B were treated with a placebo probe in the same schedule. Patients evaluated the level of pain and swelling on 100 mm Visual Analog Scale. Thermographic measurements were performed by ThermaCAM™ SC 2000 before extraction, 30 minutes after extraction and on the 1^st, 3^rd, 5^th, 8^th days. Results: The patient treated by active laser reported more pain and swelling during the first week after tooth extraction than the patient treated by placebo laser. However, the comparison of thermograms of patients treated by placebo and active laser showed the acceleration of wound healing after extraction in the patient treated with GaAsAl diode laser. Conclusion: The treatment by GaAlAs diode laser, 830 nm and total energy density for one treatment session 36 J had a stimulation effect on the healing process but did not lead to reduction of pain and swelling in the patient after dental surgery.