Influence of enantiomers of 1-naphthylalanine in position 2 of VAVP and dVAVP on their pharmacological properties

In this study, we described the synthesis and some pharmacological properties of four new analogues of arginine vasopressin (AVP). Two peptides are substituted in position 2 with L-1-naphthylalanine (L-1-Nal) or its D-enantiomer and in position 4 with valine. In the further two compounds, we combined the above modifications with placement into position 1 of 3-mercaptopropionic acid residue (Mpa). All new peptides were tested for vasopressor and antidiuretic activities. We also estimated the uterotonic activities of these compounds in vitro. Urine samples prior and after peptide administration were analyzed for electrolytes excretion. All analogues are potent oxytocin antagonists. One of them, namely [L-1-Nal2,Val4]AVP, which appears practically not to interact with V1a and V2 receptors, is exceptionally selective. Our results open new possibilities for the design of very potent and selective oxytocin antagonists in vitro.     

Coexistence of Addison-Biermer's anaemia with endocrine glands' dysfunctions

Addison-Biermer's anaemia is an autoimmune disease. It may coexist with other auto-aggressive diseases, precede them or join the other existing autoimmune diseases. It most often accompanies the Hashimoto disease but also may coexist polyglandular autoimmune syndrome (PGA). Three types of PGA are distinguished: PGA1--Blizzard's Syndrome, PGA2--Schmidt's Syndrome, and PGA3. The latter, unlike the remaining ones, is characterized by normal function of adrenal glands. Addison-Biermer's anaemia occurrence may be often difficult to diagnose as coexisting illnesses might ouflage its clinical symptoms. The aim of this paper was to analyse patients with different types of PGA with coexisting Addison-Biermer's anaemia. Group of 24 individuals was analysed: 2 women with PGA1, 10 patients with PGA2, 10 patients with PGA3. In 2 remaining ones PGA was not confirmed. Addison-Biermer's anaemia occurred in 7 patients (2 with PGA2 and 5 with PGA3 syndrome). Decreased concentration of vitamin B12 was diagnosed in 3 individuals among 24 examined patients (1 with type 3 and 2 with type 2), as well in 2 patients with unconfirmed PGA. Addison-Biermer's anaemia was not observed in patients with PGA1. We observed that megaloblastic anaemia occurred characteristic schedule depending on appearance of autoimmune diseases: in PGA2--many years after other immunopathies were found, in PGA3--as first auto-aggressive disease. Our analysis suggests the necessity of detailed check-ups on patients with Addison-Biermer's anaemia, as with time they may develop other diseases, especially hypothyroidism and/or PGA failure. On the contrary, in individuals with thyroid gland diseases and PGA syndromes further checkups should be megaloblastic anaemia-sensitive. In both cases it is important to consider substitutive treatment. The possibility of family coexisting both pernicious anaemia and autoimmune endocrinopathies needs diagnostics of members of the patient's family.     

Clinical course of toxocarosis in children

The aim of the study was to monitor the clinical course of T. canis infection in children with particular consideration of the estimation of infected children's immune system. The study comprised 52 children, aged 3 to 18 years, diagnosed and treated at the I Department of Paediatrics and Gastroenterology, Institute Polish Mother Health Centre, in whom infection with Toxocara canis larva was confirmed with serologic test. The control group included 38 children, aged 3 to 16 years in whom no infection with this parasite was detected in serologic test. In the investigated children subjective and physical examinations were performed, clinical symptoms, changes in organs, haematological, biochemical investigations and selected parameters of humoral and cellular immunity were analysed. In children with toxocarosis most frequently not localized abdominal pain, subfebrile body temperature and generalized lymphadenitis were observed. Significantly higher percentage of eosinophil cells and immunoglobulin E serum concentration with decreased percentage of lymphocytes CD3+, CD4+ and CD4/CD8 ratio were found in the investigated children. Toxocarosis diagnosis is difficult because its clinical symptoms are differentiated and not characteristic, what requires broadening of differential diagnosis concerning numerous entities.     

Some aspects of pharmacotherapy of tinnitus. Compound therapy with Xylocaine and directive counseling--long-term results

29 out of 49 patients, who were treated in 1996-1998 with Xylocaine and directive counselling for their tinitus, were reevaluated. Non of the patients used any other pharmacological treatment of the tinnitus or underwent full tinnitus retraining therapy (TRT) since 10-days treatment with Xylocaine had been completed. Initially 65.3% of patients declared improvement in their tinnitus. After over 5 years of observation success rate decreased to only 41.3%. Since the positive effect of 10-days treatment with Xylocaine and directive counselling was not stable we concluded that tinnitus patients should receive full TRT.     

Cysteine proteases as disease markers

This review comprises issues concerning cysteine cathepsins (CCs): human peptidases belonging to papain family (C1) of clan CA of cysteine proteases: cathepsins B, L, H, S, K, F, V, X, W, O and C. The involvement of these enzymes in physiological and pathological processes is described, especially with respect to their application as diagnostic and prognostic markers. They participate in precursor protein activation (including proenzymes and prohormones), MHC-II-mediated antigen presentation, bone remodeling, keratinocytes differentiation, hair follicle cycle, reproduction and apoptosis. Cysteine cathepsins upregulation has been demonstrated in many human tumors, including breast, lung, brain, gastrointestinal, head and neck cancer, and melanoma. Besides cancer diseases, they have been implied to participate in inflammatory diseases, such as inflammatory myopathies, rheumatoid arthritis, and periodontitis. Also, certain hereditary disorders are connected with mutations in CCs genes, what is observed in pycnodysostosis resulted from catK gene mutation and Papillon-Lefevre and Haim-Munk syndrome caused by catC gene defect. The potential application of cysteine cathepsins in diagnosis and/or prognosis is discussed in cancer diseases (breast, lung, head and neck, ovarian, gastrointestinal cancers, melanoma), as well as other disorders (periodontitis, rheumatoid arthritis, osteoarthritis).     

Incidence of congenital malformations and neonatal mortality in children born at the Regional Hospital in Brzeziny in years 1990-2001

The aim of the study was to estimate the incidence of congenital malformations and neonatal mortality rate in children born in our hospital from 1990 to 2001, taking into account the effects of low birth weight and premature delivery. We investigated medical documentation of 5496 children born during the analyzed period. Presence of major and minor malformations and survival through the neonatal period were determined for each subject. Among newborns with low birth weight 8.3% were born with congenital malformations, among those born preterm--12.1%. The major malformations were 3 times more often in children with low birth weight and 4 times more often in children born prematurely. In our cohort the mortality of 0.2% was observed. Congenital defects, followed by the complications of preterm delivery, were the predominant causes of natal death. Deaths due to congenital defects occurred twice as often as the deaths caused by prematurity complications. The congenital malformations mortality in newborns with congenital malformations reached 4.8%. The majority of congenital defects deaths were caused by central nervous system defects, chromosomal aberrations and multiple congenital malformations.     

Expected change of direction in Polish law regarding cosmetics

In connection with adaptation of Polish law to UE regulations, new Polish Act on cosmetics was published. There were also prepared regulations concerning: lists the substances forbidden to be used in cosmetics, permitted to be used in cosmetics only with restrictions, allowed colouring agents, preservatives and UV filters, rules of non-inclusion of one or more ingredients on the list used for the labelling, establishing National System for Informing about Cosmetics and methods of analysis necessary for checking the composition of cosmetic products. Publication in Official Journal of the European Union L. 66/26 Directive 2003/15/EC shows direction necessary changes in Polish Act on cosmetics.     

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.     

BRCA1 and BRCA2 mutation analysis in breast-ovarian cancer families from northeastern Poland

Sixty high-risk breast and/or ovarian cancer families from North-Eastern Poland were screened for germline mutations in BRCA1 (MIM# 113705) and BRCA2 (MIM# 600185), using a combination of protein truncation test, denaturing high-performance liquid chromatography and direct sequencing. Sixteen (27%) of the families were found to carry nine different BRCA mutations, including 14 families with BRCA1 mutation and two families with BRCA2 mutation. The results suggest the presence of two strong BRCA1 founder mutations in the Polish population - 5382insC (6 families) and 300T>G (Cys61Gly; 3 families). The remaining seven mutations were found in single families and included three previously reported BRCA1 mutations (185delAG, 2682C>T [Gln855Ter] and 3819del5), a novel BRCA1 mutation (IVS14+1G>A), as well as two BRCA2 mutations (4088delA and 7985G>A [Trp2586Ter]) not previously observed in Polish families. We confirm the strong influence of two Central-Eastern European BRCA1 founder mutations in familial breast and/or ovarian cancer in Poland. We also conclude that the Polish population has a more dispersed BRCA mutation spectrum than had been earlier thought. This warrants further careful BRCA mutation screening in order to optimise genetic counselling and disease prevention in affected families.