Beta-thalassemia in Yugoslavia

This study concerned the evaluation of beta-thalassemia alleles in nearly 50 patients with beta-thalassemia major and in 130 -thalassemia heterozygotes using gene amplification and dot-blot hybridization with synthetic probes. Fourteen different mutations were observed; of these, three (IVS-I-110; IVS-I-6; IVS-I-1) account for some 75% of all beta-thalassemia alleles. Newly discovered variants, i.e. T----C in the initiation codon and AATAAA----AATGAA in the poly A site were observed in a few patients. The poly A mutation with classical beta-thalassemia alleles result in thalassemia intermedia. Hb Lepore is a rather common abnormality and combinations of this variant with beta-thalassemia often result in severe disease; a search for beta-thalassemia mutations among patients affected with this disease should include an analysis to detect this hemoglobin abnormality.     

Comprehensive characterization of IGHV3-21-expressing B-cell chronic lymphocytic leukemia: an Italian multicenter study

IGHV3-21-using chronic lymphocytic leukemia (CLL) is a distinct entity with restricted immunoglobulin gene features and poor prognosis and is more frequently encountered in Northern than Southern Europe. To further investigate this subset and its geographic distribution in the context of a country (Italy) with both continental and Mediterranean areas, 37 IGHV3-21 CLLs were collected out of 1076 cases enrolled by different institutions from Northern or Central Southern Italy. Of the 37 cases, 18 were identified as homologous (hom)HCDR3-IGHV3-21 CLLs and were found almost exclusively (16 of 18) in Northern Italy; in contrast, 19 nonhomHCDR3-IGHV3-21 cases were evenly distributed throughout Italy. Clinically, poor survivals were documented for IGHV3-21 CLLs as well as for subgroups of mutated and homHCDR3-IGHV3-21 CLLs. Negative prognosticators CD38, ZAP-70, CD49d, and CD79b were expressed at higher levels in homHCDR3 than nonhomHCDR3-IGHV3-21 cases. Differential gene expression profiling (GEP) of 13 IGHV3-21 versus 52 non-IGHV3-21 CLLs identified, among 122 best-correlated genes, TGFB2 and VIPR1 as down- and up-regulated in IGHV3-21 CLL cases, respectively. Moreover, GEP of 7 homHCDR3 versus 6 nonhomHCDR3-IGHV3-21 CLLs yielded 20 differentially expressed genes, with WNT-16 being that expressed at the highest levels in homHCDR3-IGHV3-21 CLLs. Altogether, IGHV3-21 CLLs, including those with homHCDR3, had a peculiar global phenotype in part explaining their worse clinical outcome.     

Sexual Function in Adult Male Rats after Prenatal Modulation of the Cholinergic System

Prenatal administration of the n-cholinolytic ganglerone to pregnant female rats at different periods of gestation was found to lead to long-term changes in sexual behavior in pubescent offspring: there was a reduced dynamic of acquiring sexual experience and a very low level of sexual activity, with significant impairment to the motivational and ejaculatory components of sexual behavior. The number of males with reduced sexual activity in the experimental groups was significantly greater than that in control offspring. The results obtained here provide evidence that impairments of sexual function in adult offspring induced by prenatal administration of the n-cholinolytic ganglerone at 9–11 and 12–14 days of gestation and, to a lesser extent, the m-cholinolytic metamyzil at 9–11 days of gestation, were due to impairment to the central mechanisms regulating sexual function due to stable changes in neurotransmitter activity in the hippocampus and hypothalamus, along with a significant reduction in the blood testosterone level. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 94, No. 5, pp. 581–591, May, 2008.     

Pilot experience in using adjustable suburethral sling in the treatment of anatomic stress urinary incontinence in females

Adjustable suburethral prolen sling (Agency for Medical Innovations) was set up during surgery via transobturatory approach in 21 females with stress urinary incontinence (SUI). Mean age of the patients was 58.5 years (32-76 years). Only 3 (14%) women failed to retain urine on postoperative day 1, the other 18 of 21 (86%) women no longer showed SUI. Obstructive urination was observed in 4 of 21 (19%) patients, residual urine was present in 3 of these 4 patients (120, 170 and 220 ml). Correction of the sling position was made in early postoperative period in 7 (33.3%) patients. Under local anesthesia of the paraurethral channels with 0.5% novocain solution, the sling was displaced in the direction from the urethra to obturatory opening in 3 women with residuary SUI, from the urethra to the vagina - in 4 women. After regulation of the sling position all the patients retained urine and had no residual urine after urination. Thus, the suburethral prolen sling the position of which can be adjusted in early postoperative period is an effective method of treating females with anatomic SUI.     

Molecular and clinical features of chronic lymphocytic leukaemia with stereotyped B cell receptors: results from an Italian multicentre study

A fraction of chronic lymphocytic leukaemia (CLL) cases carry highly homologous B-cell receptors (BCR), i.e. characterized by non-random combinations of immunoglobulin heavy-chain variable ( IGHV ) genes and heavy-chain complementarity determining region-3 (HCDR3), often associated with a restricted selection of IGVK/L light chains. Such 'stereotyped' BCR occur more frequently in CLL with unmutated (UM) than mutated (M) IGHV genes. We analysed 1426 IG rearrangements (from 1398 CLL cases) by a clustering driven by HCDR3 similarities. Molecular findings were correlated to time-to-treatment (TTT) and presence of known prognosticators. Sixty-nine clusters (319 IG-rearrangements, 22·4%) with stereotyped BCR were identified. Among 30 confirmed clusters (≥3 IG-rearrangements/cluster), we found 14 novel clusters, of which 11 had M IG rearrangements (M clusters) and predominantly (8/11) used IGHV3 subgroup genes. Recurrent cluster-biased amino acid changes were found throughout IGHV sequences of these 'M clusters'. Regarding clinical outcome: (i) UM CLL from the IGHV1-2/1-3/1-18/1-46/7-4-1/IGKV1-39 cluster had poorer prognosis than UM/M cases, or UM cases using the same IGHV genes but not in clusters; (ii) M CLL from the IGHV3-21/IGLV3-21 cluster had TTT similar to UM CLL, and shorter than M CLL expressing IGHV3-21 but not in cluster. Altogether, our analysis identified additional molecular and clinical features for CLL expressing stereotyped BCR.     

Thalassemias and other hemoglobinopathies in the Republic of Macedonia

This paper summarizes the results on the epidemiology and molecular basis of thalassemias and other hemoglobinopathies in the Republic of Macedonia. Over the past 40 years, population surveys of more than 22,000 participants (school children and workers) from all over the country, have shown that the average incidence of beta-thalassemia (thal) trait is 2.6%, ranging from less than 1% in the northeast to 10% in the south. The frequency of deltabeta-thal is 0.2%, while the frequency of the Swiss type of hereditary persistence of fetal hemoglobin (HPFH) is 0.3%. Screening of 9,619 newborns has shown that the frequency of alpha-thal trait is 1.5%, of which alpha-thal-2 is 1.45% and alpha-thal-1 is 0.05%. The molecular basis of the different forms of beta-thal and other hemoglobinopathies has been completely defined. Among the Macedonians, over 450 beta-thal chromosomes have been studied. Fifteen different beta-thal mutations have been detected, four of which [IVS-I-110 (G-->A), IVS-I-6 (T-->C), IVS-I-1 (G-->A), codon 39 (C-->T)] account for 85% of all beta-thal chromosomes. Among the Albanians, 48 beta-thal chromosomes have been studied. Eight different mutations have been detected, four of which [codon 39, -30 (T-->A), IVS-I-110, IVS-I-1] account for 85% of all beta-thal chromosomes. Four new mutations [-101 (C-->A), -87 (C-->G), -30, polyadenylation signal (poly A) (AATAAA-->AATGAA)] have been characterized. Molecular analyses of DNA from over 20 unrelated cases with deltabeta-thal have shown that this condition is caused by a 13 kb deletion (Sicilian type); in two families a deletion of 18 to 23 kb (Macedonian type of deltabeta-thal) was discovered. Molecular analyses of alpha-thal in the Republic of Macedonia have shown the following types of molecular defects: 20.5 kb deletion, 17.5 kb deletion, 3.7 kb deletion, poly A mutation (AATAAA-->AATGAA), and Hb Icaria [alpha142, Term-->Lys, TAA-->AAA (alpha2)]. The incidence of abnormal hemoglobins (Hbs) in the Republic of Macedonia is 0.4%. Three different alpha chain variants among 10 families, seven different beta chain variants among 33 families, two gamma chain variants in two newborns, one variant with an extended alpha chain, and Hb Lepore among 105 families, have been observed. Structural analysis of numerous cases with Hb Lepore showed that the variant was of the Washington-Boston type.     

Synthesis and antimicrobial activity of pyrimidinophanes with two uracil units and bridging nitrogen atoms

A series of pyrimidinophanes containing two uracil units and nitrogen atoms in bridging polymethylene chains –(CH₂) _n N(Et)(CH₂) _m – (n, m = 5, 6) have been synthesized. The uracil moieties are represented by 6-methyl-, 5-decyl-6-methyl-, and 5-fluorouracils. Quaternization of the bridging N atom with ethylbromide or n-decylbromide yielded amphiphilic pyrimidinophanes, which were evaluated for their antibacterial and antifungal activity in terms of minimal inhibiting concentration (MIC) against Gram-positive and Gram-negative bacteria and fungi. It has been found that MICs of the amphiphilic pyrimidinophanes decrease with increasing lipophilicity of the alkyl substituents at the bridging N atoms and with increasing polymethylene N(pyr)–N chain length (in some cases MIC against Staphylococcus aureus is below 1 ìg/mL). The MICs increase dramatically upon introduction of lipophilic n-decyl substituents at C(5) atoms of the uracil moiety. The results can be used in the search for new highly effective antimicrobial agents.     

Effect of some imidazole-4,5-dicarboxylic acid derivatives on the activity of N-methyl-D-aspartate (NMDA) receptors

The results of experiments on mice showed that some imidazole-4,5-dicarboxylic acid derivatives injected into lateral cerebral ventricles produce a dose-dependent convulsant or anticonvulsant effects, that is, possess the properties of partial NMDA receptor agonists. The most promising partial NMDA receptor agonist selected for further investigation is 2-propylimidazole-4,5-dicarboxylic acid.