Effective inhibition of copper-catalyzed production of hydroxyl radicals by deferiprone.

Copper ions can catalyze the production of free oxygen radicals (•OH and •OOH) similar to iron ions. The capacity to initiate oxidative damage is most commonly attributed to Cu-induced toxicity in copper-related diseases where there is an increase in copper levels and also when Cu homeostasis and regulation are disrupted. An antioxidant/chelator inhibiting Cu-induced oxidative damage could play a significant role in the treatment of such Cu-related diseases. Deferiprone has high affinity for copper binding and can be considered for the potential treatment of copper toxicity and overloading conditions, such as Wilson's disease. In the present study, the ability of deferiprone to inhibit the production of hydroxyl radicals catalyzed by copper ions was elucidated using an Electron Paramagnetic Resonance (EPR) spin trapping technique. The values of g-factors and hyperfine splitting constants were calculated for Cu(II)-deferiprone 1:1 complex: (a = 58.5 G, g = 2.1667) and 1:2 complex: (a = 73.0 G, g = 2.1378). The TMIO spin trap (2,2,4-trimethyl-2H-imidazole-1-oxide) was used for the detection of free radicals formed in Fenton-like copper-catalyzed reactions. It was demonstrated that the interaction of deferiprone with Cu2+ ions completely inhibited hydroxyl radical (•OH) production in the presence of hydrogen peroxide. It was found also that deferiprone inhibits Cu-induced oxidation of linoleic acid in micellar solution. In addition to existing data for water solutions, the affinity of deferiprone for copper binding in non-aqueous environment has been elucidated.

Inhibition of Fe(2+)- and Fe(3+)- induced hydroxyl radical production by the iron-chelating drug deferiprone.

Deferiprone (L1) is an effective iron-chelating drug that is widely used for the treatment of iron-overload diseases. It is known that in aqueous solutions Fe(2+) and Fe(3+) ions can produce hydroxyl radicals via Fenton and photo-Fenton reactions. Although previous studies with Fe(2+) have reported ferroxidase activity by L1 followed by the formation of Fe(3+) chelate complexes and potential inhibition of Fenton reaction, no detailed data are available on the molecular antioxidant mechanisms involved. Similarly, in vitro studies have also shown that L1-Fe(3+) complexes exhibit intense absorption bands up to 800nm and might be potential sources of phototoxicity. In this study we have applied an EPR spin trapping technique to answer two questions: (1) does L1 inhibit the Fenton reaction catalyzed by Fe(2+) and Fe(3+) ions and (2) does UV-Vis irradiation of the L1-Fe(3+) complex result in the formation of reactive oxygen species. PBN and TMIO spin traps were used for detection of oxygen free radicals, and TEMP was used to trap singlet oxygen if it was formed via energy transfer from L1 in the triplet excited state. It was demonstrated that irradiation of Fe(3+) aqua complexes by UV and visible light in the presence of spin traps results in the appearance of an EPR signal of the OH spin adduct (TMIO-OH, a(N)=14.15G, a(H)=16.25G; PBN-OH, a(N)=16.0G, a(H)=2.7G). The presence of L1 completely inhibited the OH radical production. The mechanism of OH spin adduct formation was confirmed by the detection of methyl radicals in the presence of dimethyl sulfoxide. No formation of singlet oxygen was detected under irradiation of L1 or its iron complexes. Furthermore, the interaction of L1 with Fe(2+) ions completely inhibited hydroxyl radical production in the presence of hydrogen peroxide. These findings confirm an antioxidant targeting potential of L1 in diseases related to oxidative damage.

[Possibility of using microbiological data in epidemiological analysis of hospital pneumonias]. / Vozmozhnosti ispol'zovaniia mikrobiologicheskikh dannykh pri épidemiologicheskom analize vnutribol'nichnykh pnevmonii.

A total of 528 patients with nosocomial pneumonias were examined by bacteriological methods during 4 years. The data on the patients and on 2468 bacterial strains isolated from them were computer processed using original software "Hospital Infection". Special attention was paid to hospital strains of pneumonia agents of the same taxonomic position with identical markers of antibacterial resistance. Tendencies and seasonal fluctuations in the prevalence of hospital serovars were detected. Special bacteriological studies helped detect differences in the translocation capacity of different biological variants of the agents. Routine bacteriological studies and their adequate statistical computer processing yield information needed for epidemiological analysis of the development of nosocomial pneumonias in patients of clinical wards of different profile.

[Tasks and possibilities of bacteriological laboratories in computer-assisted control of hospital infections]. / Zadachi i vozmozhnosti bakteriologicheskikh laboratorii pri komp'iuternom kontrole vnutribol'nichnykh infektsii.

The authors discuss the organization of epidemiological surveillance of hospital infections, carried out by bacteriological laboratories. The principal tasks of epidemiological surveillance of pyoseptic infections in surgical hospitals are formulated. The potentialities of using the data of computer monitoring of nosocomial infections are discussed. This method helps adopt epidemiologically justified decisions.

[Hirschsprung's disease in newborns]. / Bolezn Girshprunga u novorozhdennykh.

The authors examined and treated 52 newborn babies and infants with Hirschsprung's disease. The total form was encountered in 25%, the subtotal in 23.1%, the rectosigmoid in 36.5%, the rectal in 9.6%, and the supraanal in 5.8% of cases. The clinical picture was characterized by retention of meconium (94.2%), regurgitation or vomiting (75%), abdominal distention (100%). Irrigography with calculation of the rectosigmoid ratio was conducted in 35 children, histochemical examination in 46, and histological examination in 38 children. Twenty-four (68.5%) children had the third phase of disturbed proportion of the intestinal bacteria with clinical manifestations of enterocolitis. Emergency decompression of the intestine for low acute intestinal obstruction was carried out in 27 newborn babies. Twenty children were subjected to radical surgery in the first 2-4 months of life. The choice of the operative method was guided by the form of the disease and the length of the aganglionic zone.

[Study of large intestinal microflora in newborns with Hirschsprung disease]. / Issledovanie mikroflory tolstoi kishki pri bolezni girshprunga u novorozhdënnykh.

In 35 newborns and children at the age under 4 mos with Hirschsprung's disease, colonic microflora was studied. Disbacteriosis at phase 1 was revealed in 1 (2.9%) child, at phase 2--in 7 (20%), at phase 3--in 27 (77.1%). In acute form of Hirschsprung's disease, in 68.5% of cases, disbacteriosis at phase 3 with the signs of enterocolitis causing acute ileus was revealed. Intestinal perforation against background of enterocolitis developed in 8 cases.

[Characteristics of histochemical diagnosis of Hirschsprung disease in newborn infants]. / Osobennosti gistokhimicheskoi diagnostiki bolezni Girshprunga u novorozhdennykh.

The authors had 52 newborns and infants with Hirschsprung's disease under observation. The activity of tissue acetylcholinesterase (ASE) was tested by the Karnovsky-Ruts method in 35 cases. ACE activity was evaluated according to 5 types and a specific "newborn" type was set apart. A positive (42.9%) and weakly positive (28.6%) types of ACE activity prevailed in the neonatal period. Test for ACE activity performed in dynamics in 15 newborns showed gradual accumulation of ACE in the mucosa of the large intestine. In 6 (17.1%) babies a false-negative ACE activity was found, which was encountered in hypogangliosis and long-segmental forms. False-positive reactions were not encountered. Histochemical diagnosis made it possible to recognise Hirschprung's disease of the newborn in 82.9% of cases.

[Characteristics of clinical manifestations and diagnosis in Hirschsprung disease in newborn infants and young children]. / Osobennosti klinicheskikh proiavlenii i diagnostiki bolezni Girshprunga u novorozhdennykh i detei rannego vozrasta.

Twenty two newborns and 10 young children with acute form of the Hirschsprung's disease were observed. In 1/3 of the patients, the Hirschsprung's disease was associated with congenital anomalies. The patients were treated by means of the performance of histochemical (15 cases), histologic (23) investigations and irrigography (19). A complex of the diagnostic measures used permitted to establish a reliable diagnosis.

[Clinico-morphologic parallels in acute forms of Hirschsprung disease in newborns and infants]. / Kliniko-morfologicheskie paralleli pri ostrykh formakh bolezni girshprunga u novorozhdennykh i detei rannego vozrasta.

39 newborns with an acute form of Hirschsprung's disease were under observation: rectal form 18%, recto-sigmoid 28.2%, subtotal 25.6%, total 28.2%. Clinical manifestations appeared soon after the birth and were characterized by the impediment of the meconium discharge, vomiting or eructations, abdominal swelling. The evaluation of the validity of histochemical and histological diagnostic methods in infants and morphologic description of the tissue acetylcholinesterase activity are presented. Hypoganglionic form of the disease was found in 4 cases. Clinical and morphologic picture of the hypogangliosis in newborns is described.

[Diagnostic and therapeutic tactics in various forms of cholangiopathies in children]. / Diagnosticheskaia i lechebnaia taktika pri razlichnykh formakh kholangiopatii u detei.

Seventy children with obstructive cholangopathy were examined in the clinic in the recent 15 years: 48 children had "cholangiopathy of the newborn" and 22 had a cyst of the common bile duct. A total of 44 operations were carried out: on 22 infants with cholangiopathy of the newborn and on 22 with cysts of the common bile duct. The most informative methods for the diagnosis of cholangiopathy in children are as follows: ultrasonic scanning, laparoscopy, ERCPG, aspiration biopsy of the liver, and aspiration cholangiography under control of a laparoscope. Kasai's operation is the operation of choice in obstructive cholangiopathy of the newborn. The operation of choice in cysts of the common bile duct is cystectomy with choledocho- or hepaticojejunostomy on an isolated loop after Roux.

[Electrophysiologic and anatomic parallels in the status of the external rectal sphincter in healthy children and in those with anorectal developmental abnormalities]. / Elektrofiziologicheskie i anatomicheskie paralleli sostoianiia naruzhnogo sfinktera priamoi kishki zdorovykh detei s anorektal'nymi porokami razvitiia.

Electromyography was used to examine the external rectal sphincter in 44 neonate patients and in 24 patients aged 2 months to 3 years with different anorectal developmental abnormalities. The same examinations were performed in the control groups: in 30 normal neonates, in 15 premature (grade I-II) neonates, and in 64 normal children aged 1 to 14 years. According to the data of comparative morphometry, a study was made of the autopsy material of the external rectal sphincter from 15 full-term stillborns and 16 premature (grade I-II) stillborns as well as from 11 infants with anorectal developmental abnormalities who died within the first days after birth without any surgical intervention. It is concluded that in patients with anorectal developmental abnormalities, the contractility of the external rectal sphincter is considerably lower than in the respective weight groups of normal children and that such patients demonstrated the lack of the normal time-course of changes in its increase with age.