A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117 (Pro117Ser): Comparison of clinical, neuropathological and cell culture phenotypes of Pro117Leu and Pro117Ser mutations

A novel presenilin-1 (PS1) mutation (P117S) in an American pedigree is described. We compare clinical, neuropathological and cell culture phenotypes produced by this mutation with another codon 117 mutation that was earlier discovered by our group in a Polish kindred. Both mutations are associated with an unusually severe Alzheimer disease (AD) phenotype, with the onset starting before the third decade of life, rapid disease progression and acute presentation of clinical symptoms. The severity of clinical phenotype was closely correlated with the abundance of pathology: massive deposition of Abeta42 in plaques, severe neurofibrillary degeneration and neuronal loss. When overexpressed in mouse neuroblastoma N2a cells, both mutations caused loss of an ability to promote neurite outgrowth and produced an increase in the ratio of secreted Abeta42/40 amyloid peptides. In stably transfected N2a cell lines only mutant proteins were endoproteolytically cleaved indicating some dependability of this process on the presence of mutation. Taken together, our results show that clinical and cell culture phenotypes produced by these 2 codon 117 mutations are closely related suggesting that the pathogenic action of PS1 may involve effect on neurite outgrowth and endoproteolytic cleavage of the full-length protein. Given the high potency in vivo and in vitro of both codon 117 mutations, this site of PS1 must be particularly important for its normal/pathogenic function.     

The cellular composition and macrophage phenotype in induced sputum in smokers and ex-smokers with COPD

STUDY OBJECTIVES: The relationship between smoking and COPD has been well-documented. We investigated the impact of cigarette smoking on airway inflammation in COPD patients. DESIGN: Changes in cell profiles in induced sputum (IS) samples from smokers with COPD and patients who ceased smoking were compared. SETTING: Department of pneumonology in a university hospital. PATIENTS: IS samples were collected from 17 smokers and 17 ex-smokers with COPD. INTERVENTIONS: We examined IS samples for differential cell counts and macrophage phenotypes determined by immunocytochemistry with monoclonal antibodies anti-CD11b, anti-CD14, anti-CD54, and anti-CD71. MEASUREMENTS AND RESULTS: The median IS volume was greater and the total cell count was higher in smokers than in ex-smokers. The difference, however, was not significant. We did not find any significant differences in the proportions of cells and in the phenotypes of macrophages between the two groups, with the proportion of eosinophils being slightly higher in the group of smokers. We found, however, a significant positive correlation between the decrease in pulmonary function parameters and the number of pack-years smoked, an inverse correlation of pulmonary function test results with the number of lymphocytes in IS, and a correlation between some changes in the expression of macrophage surface markers and smoking history. There was no correlation between the time from smoking cessation and any cellular component found in IS samples. CONCLUSIONS: The analysis of IS samples in patients with COPD revealed no significant differences in cell count and macrophage phenotypes between active smokers and ex-smokers.     

Assessment of the midwives preparation to take care of patients with cervical cancer

INTRODUCTION: The success of the cervical cancer treatment depends not the only on the early diagnosis, but also on the immediate initiation of the appropriate treatment and proper nursing care, which should be adequate with the present knowledge. OBJECTIVE: The objective of the research was the assessment of the theoretical preparation of nurses taking care of patients with cervical cancer. MATERIALS AND METHOD: 50 nurses, working in the departments of gynecological diseases, have been interviewed. All the nurses graduated from College of Nursing, 3 of them additionally studied in the Pedagogical Graduate School. 60% of the nurses had 10-20 years of professional experience. We used special questionnaire made of 3 parts: describing the objective of the research/test, characteristics of the patient, specific questions. There were 18 questions: 5-closed, 1-open, 12-semiopen. They were checking the knowledge about the diagnostics, preparation of the patient to the operation using Wertheim-Meigs-Valle method, postoperative care until the discharge from the hospital and then oncological care. RESULTS: Almost all of them (88%-92%) have known the sequence of the diagnosis and treatment of the cervical cancer. 90% of them have been knowledgeable what kind of diagnostic and nursing procedures were required before the surgery using Wertheim-Meigs-Valle method. Almost all of the tested nurses (96%-100%) have known the procedure of postoperative care. They had a practical knowledge how to assess the patient condition and components of care that the patients require during the first few days after the surgery. According to the tested nurses, 90% of the patients operated because of cervical cancer, should follow up in oncological centers. CONCLUSION: 1. The nurses' preparation to take care of patients with cervical cancer is sufficient and it affects the effectiveness of the treatment. 2. The nurses have knowledge about pre- and postoperative procedures that the patients require, as well as assessment of general condition and patients' care, which are so important in the first few days after the surgery.     

Complex management of osteoporotic vertebral fracture

Background. Compression fractures of the thoraco-lumbar spine are the most common form of damage to the skeletal system caused by osteoporosis. These fractures are stable and do not produce neurological deficits. The intensity of the clinical symptoms depends on the degree of kyphotic distortion of the spine and the number of fractured vertebrae. Among the most serious consequences of such injuries are chronic pain, habituated poor body posture (deeper thoracic kyphosis with compensatory hyperlordosis in the lumbar spine), motor and functional limitations, reduced quality of life, and heightened risk of subsequent spinal fractures.
Material and methods. We analyzed a group of 26 patients treated for spinal fractures associated with osteoporosis, in order to evaluate the effectiveness of the treatment methods applied.
Conclusions. Our results indicate that the best outcomes are obtained when the period of immobility is reduced to a minimum and rehabilitation is commenced as early as possible.     

Trimethyltin-evoked neuronal apoptosis and glia response in mixed cultures of rat hippocampal dentate gyrus: a new model for the study of the cell type-specific influence of neurotoxins

We investigated the effects of a potent neurotoxin, trimethyltin (TMT), on mixed neuronal/glial cultures derived from rat hippocampal dentate gyrus. We found that TMT induced neuronal cell death in a concentration dependent manner, which was estimated by microtubule degeneration, hematoxylin histological staining and the TUNEL method. This cell death is most probably of an apoptotic type as suggested by Hoechst staining. In parallel to studies the effects of TMT on neurons, its concentration dependent actions on astroglia and microglia were also examined using GFAP and GS-B4 isolectin as immunocytochemical markers, respectively. We found that neurotoxic concentrations of TMT evoked astrocytic swelling, whereas low, non-cytotoxic concentrations caused changes in microglia morphology characteristic of their active form. The combined results of our studies provide new data concerning the cell type-specific influence of TMT and indicate that the culture of dentate gyrus cells is a feasible in vitro modelforfurther studies of neuronal-glial interaction in response to toxic injury.     

Synthesis and pharmacological activity of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine: part 2. Synthesis and pharmacological activity of 1,6-diaryl-5,7(1H)dioxo-2,3-dihydroimidazo[1,2-a][1,3,5]triazines

Synthesis and pharmacological activity of 1,6-diaryl-5,7(1H)dioxo-2,3-dihydroimidazo-[1,2-a][1,3,5]triazines (C) are presented. The title compounds were obtained from 1-arylimidazolinurea derivatives in cyclization reaction with difunctional carbonyl reagents--phosgene (method I) or carbonyldiimidazole (CDI) (method II). Their molecular structures were confirmed by the X-ray analysis of 1-phenyl-6-(4-chlorophenyl)-5,7(1H)-dioxo-2,3-dihydroimidazo[1,2-a][1,3,5]triazine (C2) crystals. Compounds C exhibited significant depressive action on the central nervous system (CNS) of the laboratory animals, correlated with very low acute toxicity (LD(50) > 2000 mg kg(-1) i.p.), and showed antinociceptive activity in behavioural models. Reversion of this effect by small dose of naloxone (5 mg kg(-1)) can suggest opioid-like mechanism of antinociception produced by these and other carbonyl derivatives of 1-aryl-2-iminoimidazolidine. Additionally, an effect on the serotonin neurotransmission pathway was also observed. The receptor mechanism of activity for investigated compounds was confirmed only for the opioid mu receptor in binding affinity assay test. Same tests performed for the serotonin 5-HT(2) and benzodiazepine BZD receptors showed no affinity for tested compounds. The opioid-like and serotonergic activities are similar to these described earlier for chain carbonyl 1-aryl-2-iminoimidazolidine derivatives containing urea moiety, mainly due to similar chemical structure, although compounds C are not able to adopt any of the higher energy conformations of urea derivatives. Rigid location of aromatic ring (Ar') at N6, acting as a spacer blocking any direct access to the carbonyl groups (e.g. through the hydrogen bonding), could be responsible for lack of affinity toward 5-HT(2) expressed in the binding assay test.     

Evaluation of different mannan polysaccharide usage in enzyme-linked immunosorbent assay for specific antibodies determination

Polysaccharides as antigens impose the problem of the proper ELISA assay. The indirect coating using biotin-avidin or lectins are therefore used. We tried to clarify the efficiency of different approaches to this problem. Our experiments clearly demonstrate that direct coating with mannan polysaccharide on high binding ELISA plates is superior to any other combination using any intermediate protein. On the other hand, the direct coating of the normal ELISA plate with mannan was of significantly lower (P=0.008) efficiency. The use of protein cannot be avoided in normal microplates. All previous statements are supported by experimental data in the paper.     

Molecular mechanisms of levodopa action in animal models of Parkinson's disease

Parkinson's disease is a progressive neurodegenerative movement disorder, affecting mainly the elderly. One of the most important hallmarks of Parkinson's disease is the loss of neuronal cell bodies containing neuromelanin in the substantia nigra zona compacta, and subsequently, loss of dopamine terminals in basal ganglia nuclei of the brain. The discovery by Hornykiewicz and co-workers that levodopa could successfully treat Parkinson's disease in humans was one of the most important events of medicine in the 20th century. Since loss of nigrostriatal dopaminergic function is the basic underlying pathophysiology of this disease, drugs that enhance dopaminergic function in the striatum, including the exogenous precursor levodopa, remain the most effective symptomatic agents in the treatment of Parkinson's disease. However, there are some areas of controversy about levodopa-evoked motor complications (dyskinesias, on-off phenomena) as well as neuroprotective or neurotoxic activity of this drug, etc. In this article the authors try to clarify the molecular mechanisms involved in levodopa action, such as volume transmission - a crucial process for successful levodopa therapy, evidence that serotoninergic neurons may accumulate levodopa and convert it into dopamine as well as some aspects of neuroprotective action of levodopa.     

Flicker perimetry (CFF) in patients with lens opacities--first report

PURPOSE: Comparison of standard W/W and CFF perimetry in patients with cataract and lens opacities. MATERIAL AND METHODS: Visual field was measured on Octopus 301 perimeter with option flicker perimetry. W/W and CFF perimetry (Program G1 in TOP strategy) was performed in 44 eyes with cataract and lens opacities. RESULTS: Defects in visual field with CFF perimetry were found in 24% of cases but with W/W perimetry in 100% of cases. CONCLUSIONS: Perimetry CFF is a new tool for early detection and follow up of visual field defects in patients with cataract and lens opacities.