Immunosuppressive immunophilin ligands attenuate damage in cultured rat astrocytes depleted of glutathione and exposed to simulated ischemia in vitro. Comparison with N-acetylcysteine

The aim of the present study was to test the hypothesis that exposure of astrocytes depleted of glutathione (GSH) to simulated ischemia conditions in vitro and treated with immunosuppressant immunophilin ligands (cyclosporin A (CsA) and FK506) can increase intracellular GSH levels and that such mechanism may be responsible, at least in part, for their protective effects. In addition, we also compared the antioxidant properties of these immunosuppressants with N-acetylcysteine (NAC), a precursor of GSH synthesis. GSH depletion was induced by 24 h pretreatment with L-buthionine sulfoximine (BSO). Cultures of rat astrocytes were exposed to CsA (1-50 microM) and FK506 (1-1000 nM) and NAC (100 or 200 microM). We examined the effects of these compounds on apoptosis, cell viability, reactive oxygen species production and GSH content. Our study demonstrated that toxicity of simulated ischemia conditions were enhanced when intracellular GSH was depleted, and immunosuppressants (especially 100 nM FK506 and 10 microM CsA) effectively prevented ischemia toxicity in GSH depleted astrocytes. In addition, we have shown that interfering with the generation of GSH and attenuation, the rise of oxidative stress level by NAC may be a powerful tool for prevention of ischemia-induced glial cell damage.     

Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases

Commensal microflora (normal microflora, indigenous microbiota) consists of those micro-organisms, which are present on body surfaces covered by epithelial cells and are exposed to the external environment (gastrointestinal and respiratory tract, vagina, skin, etc.). The number of bacteria colonising mucosal and skin surfaces exceeds the number of cells forming human body. Commensal bacteria co-evolved with their hosts, however, under specific conditions they are able to overcome protective host responses and exert pathologic effects. Resident bacteria form complex ecosystems, whose diversity is enormous. The most abundant microflora is present in the distal parts of the gut; the majority of the intestinal bacteria are Gram-negative anaerobes. More than 50% of intestinal bacteria cannot be cultured by conventional microbiological techniques. Molecular biological methods help in analysing the structural and functional complexity of the microflora and in identifying its components. Resident microflora contains a number of components able to activate innate and adaptive immunity. Unlimited immune activation in response to signals from commensal bacteria could pose the risk of inflammation; immune responses to mucosal microbiota therefore require a precise regulatory control. The mucosal immune system has developed specialised regulatory, anti-inflammatory mechanisms for eliminating or tolerating non-dangerous, food and airborne antigens and commensal micro-organisms (oral, mucosal tolerance). However, at the same time the mucosal immune system must provide local defense mechanisms against environmental threats (e.g. invading pathogens). This important requirement is fulfilled by several mechanisms of mucosal immunity: strongly developed innate defense mechanisms ensuring appropriate function of the mucosal barrier, existence of unique types of lymphocytes and their products, transport of polymeric immunoglobulins through epithelial cells into secretions (sIgA) and migration and homing of cells originating from the mucosal organised tissues in mucosae and exocrine glands. The important role of commensal bacteria in development of optimally functioning mucosal immune system was demonstrated in germ-free animals (using gnotobiological techniques). Involvement of commensal microflora and its components with strong immunoactivating properties (e.g. LPS, peptidoglycans, superantigens, bacterial DNA, Hsp) in etiopathogenetic mechanism of various complex, multifactorial and multigenic diseases, including inflammatory bowel diseases, periodontal disease, rheumatoid arthritis, atherosclerosis, allergy, multiorgan failure, colon cancer has been recently suggested. Animal models of human diseases reared in defined gnotobiotic conditions are helping to elucidate the aetiology of these frequent disorders. An improved understanding of commensal bacteria-host interactions employing germ-free animal models with selective colonisation strategies combined with modern molecular techniques could bring new insights into the mechanisms of mucosal immunity and also into pathogenetic mechanisms of several infectious, inflammatory, autoimmune and neoplastic diseases. Regulation of microflora composition (e.g. by probiotics and prebiotics) offers the possibility to influence the development of mucosal and systemic immunity but it can play a role also in prevention and treatment of some diseases.     

New composite implant for tracheal reconstruction--preliminary study

Stenosis of trachea's diameter occurs the most often as complications after intubation and tracheotomy. Among the other reasons of narrowing of this organ the following are being named: mechanical injuries, chemical damages, primary and metastasis tumors. The therapy of trachea's stenosis includes both alternative and radical treatments. The radical treatment consists of surgical excision of the narrowed segment followed by reconstruction of trachea (anastomosing of free ends or filling of lost segment with use of auto- or allogenic material). There is no appropriate alloplastic material developed to date, the use of which in reconstructive surgery of large segment trachea defects would bring about positive long-term experimental results. The success of alloplastic material implantation in the reconstruction of large tracheal defects is limited by the fact that the biomechanical characteristics of replaced tissue are distinctly different from synthetic material. The work is devoted to evaluation of complex mechanical characteristic of natural sheep trachea before designing the proper synthetic material for large tracheal defects reconstruction. Various mechanical tests were conducted to study the mechanical behavior of total trachea. Samples of tissue cut out from trachea were also examined. The results revealed strong directional--dependent mechanical properties of trachea. Composite constituents, namely carbon fibers and biocompatible and biostable polysulfone were used to manufacture the implant.     

Synthesis and in vitro cytostatic activity of some new 1,3-(oxytetraethylenoxy)-cyclotriphosphazatriene derivatives

A series of cyclophosphazene crown ether derivatives bearing aziridinyl (ethylene imine) units and also 2-naphthyl or anthraquinone groups as co-substituents has been synthesized and their cytostatic activity against the panel of eight cancer cells in vitro has been studied. The substituents used exhibit different activities: alkylation (aziridinyl groups) and intercalation (naphtyl, anthraquinone groups) against DNA. These both interactions are supposed to enhance the efficiency of the cyclophosphazene crown ether derivatives studied as cytotoxic agents.     

Therapeutic doses of topiramate are not toxic to the developing rat brain

Antiepileptic drugs (AEDs) used to treat seizures in pregnant women, infants, and young children may cause cognitive impairment. One of the implicated mechanisms is enhancement of apoptotic neuronal death, which occurs physiologically in the developing brain. We investigated whether topiramate, one of the newer antiepileptic drugs, has neurotoxic properties in the developing rat brain. Topiramate slightly but significantly enhanced apoptotic neuronal death in the 7-day-old rat brain at doses of 50 mg/kg and above. These doses are several folds higher than reported ED(50) doses in infant rodent seizure models that respond to topiramate. Electron microscopy confirmed that dying neurons following topiramate treatment displayed the same morphological features as neurons undergoing physiological cell death during development. When compared to the neurotoxicity profile of phenytoin, valproate, and phenobarbital, the separation between the effective anticonvulsant dose and the neurotoxic dose was greater for topiramate and the neurotoxic effect was lower.     

Effects of Vision herbicide on mortality, avoidance response, and growth of amphibian larvae in two forest wetlands

The effects of Vision (glyphosate, 356 mg acid equivalents (a.e.)/L) on mortality, avoidance response, and growth of larval amphibians (Rana clamitans and Rana pipiens) were investigated using in situ enclosures deployed in two forest wetlands of northern Ontario, Canada. In addition to untreated controls, Vision was applied to yield initial concentrations ranging from 0.29 to 14.3 mg a.e./L (0.94-46.1 mg/L of Vision). Resultant 96-h median lethal concentration (LC50) values ranged from 2.70 to 11.5 mg a.e./L (8.71-37.1 mg/L of Vision) depending on the species or site involved. Substantial mortality and incidences of abnormal avoidance response occurred only at concentrations exceeding the expected environmental concentrations (EEC) (1.43 mg a.e./L, or 4.61 mg/L of Vision) as calculated by Canadian regulatory authorities. The concentration dependence of larval growth rate and maximum size varied depending on site and species. Mean growth rates and maximum sizes exposed to 1.43 mg a.e./L (EEC) treatments were the same or greater than controls. Experimental site and biotic/abiotic factors therein, such as pH and suspended sediments, substantially affected the expression of Vision herbicide toxicity in the amphibian larvae tested. Overall, results suggest that the silvicultural use of Vision herbicide in accordance with the product label and standard Canadian environmental regulations should have negligible adverse effects on sensitive larval life stages of native amphibians.     

Nephroblastoma in children aged less than 6 months at diagnosis

We present the results of treatment of kidney tumours in newborns and infants aged less than 6 months, in the years 1993-2000, from the Nephroblastoma Committee of the Polish Paediatric Group of Solid Tumours (PPGGL). We have analysed the diagnostic and treatment results in the group of 31 children aged 0 to 6 months. For 19 children registered between 1993 and 1996, event-free survival (EFS) and overall survival (AS) were assessed. Among 450 children registered between 1993 and 2000 by PPGGL and treated for kidney tumours, there were 31 (7.1%) newborns and infants aged below 6 months. The accuracy of diagnosis based on imaging studies was 97%. Only in one child the initial diagnosis of kidney tumour was not confirmed; cystic degeneration of kidney was finally established. The tumours removed during surgery were small, with average size 213 cm3, and in half of the cases the size of the tumour did not exceed 165 cm3. Primary complete excision of the tumour was performed in 21 children (67.7%). In 10 cases histopathology confirmed mesoblastic nephroma, in 19 cases nephroblastoma and in 2 cases sarcoma clarocellulare. In 10 infants (32.2%) with nephroblastoma delayed surgery preceded by chemotherapy was performed. Indications for initial preoperative chemotherapy comprised: tumour in a single kidney, tumour in a horseshoe kidney, preoperative diagnostic biopsy of the tumour and large tumour in neonates older than 3 months. In almost 70% of the children the stage of advancement was low (stage I and IIN-). Histopathology of excised tumours confirmed in 42% of cases low risk, and in 51.6% intermediate risk. Intraoperative complications occurred in 5 infants (16%). The tolerance of reduced chemotherapy by the infants was good. AS was 100%. ESF for the 19 children registered for nephroblastoma between 1993 and 1996 for all stages of advancement and types of histology was 94.75%. Conclusions: 1) Mesoblastic nephroma and low risk nephroblastoma are the most common tumours in children within the first three years of life. 2) The results of treatment of nephroblastoma in the youngest children (below 6 months of age) are the most favourable and represent world standards.3) Surgical complications in children operated primarily for nephroblastoma indicate the need of performing such operations in academic centres, specialised in newborn surgery. 4) In infants with extensive kidney tumours older than 3 months, primarily considered as inoperative, individual induction chemotherapy should be taken into account.     

Effects of simvastatin only or in combination with continuous combined hormone replacement therapy on lipid levels in hypercholesterolemic women

OBJECTIVE: To evaluate the effects of simvastatin only or combined with continuous transdermal hormone replacement therapy (HRT) on the serum lipid profile in hypercholesterolaemic women. MATERIAL AND METHODS: The study population consisted of 75 women after menopause, ranging in age from 45 to 62. The patients were divided into five groups: group I--women receiving HRT (Systen Sequi, Cilag); group II--HRT + statin (Systen Sequi, Cilag + Zocor, MSD); group III--HRT (Systen Conti, Cilag); group IV--HRT + statin (Systen Conti, Cilag + Zocor, MSD) and group V--statin only (Zocor, MSD). Before and after 3 and 6 months therapy serum total cholesterol (TC), triglycerides (TG), HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C) was measured. RESULTS: The combination of simvastatin + HRT or simvastatin only decreased significantly TC and LDL-C, and increased HDL-C levels at 3 months (groups II, IV and V). A comparative analysis revealed that HRT effect on TC, LDL-C and HDL-C was significantly observed after 6 months (group I and III). TG levels significantly decreased after 6 months of therapy (simvastatin + HRT) in groups II and IV. CONCLUSIONS: The combination of simvastatin and HRT seems to be more effective than simvastatin only in the treatment of hypercholesterolaemia in women.     

Four main reasons of maternal death in Poland between 1991-2000

Maternal death during pregnancy, labour and puerperium constitutes the main problem of prenatal medicine and still a major public health topic. In this work we analyses maternal deaths in Poland between 1991-2000. There were 4,404,641 live births and 462 maternal deaths. Among them there were 402 direct ("true") maternal deaths with mortality rate 9.1 per 100,000 live births and 60 indirect maternal deaths (rate 1.4). There were 218 cases of pregnancy associated deaths (rate 4.9). The main causes of direct maternal deaths were as follows: haemorrhage--33.6% (rate 3.1), sepsis--27.3% (rate 2.5), amniotic fluid embolism--22.4% (rate 2.0) and pregnancy induced hypertension 16.7% (rate 1.5). Increasing maternal age is one of important risk factor for mortality. Over 30% of direct pregnancy related deaths were noted within women above 35 years. Unsatisfactory antenatal care, management deficiency and patient's neglect were main risk factor foe fatal outcome. Practical conclusions should be issued as general rules, instructions and recommendations. Between one third to one half of the maternal deaths are considered to have been preventable.