Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties.

BACKGROUND AND PURPOSE: ABC multidrug transporters (MDR-ABC proteins) cause multiple drug resistance in cancer and may be involved in the decreased anti-cancer efficiency and modified pharmacological properties of novel specifically targeted agents. It has been documented that ABCB1 and ABCG2 interact with several first-generation, small-molecule, tyrosine kinase inhibitors (TKIs), including the Bcr-Abl fusion kinase inhibitor imatinib, used for the treatment of chronic myeloid leukaemia. Here, we have investigated the specific interaction of these transporters with nilotinib, dasatinib and bosutinib, three clinically used, second-generation inhibitors of the Bcr-Abl tyrosine kinase activity. EXPERIMENTAL APPROACH: MDR-ABC transporter function was screened in both membrane- and cell-based (K562 cells) systems. Cytotoxicity measurements in Bcr-Abl-positive model cells were coupled with direct determination of intracellular TKI concentrations by high-pressure liquid chromatography-mass spectrometry and analysis of the pattern of Bcr-Abl phosphorylation. Transporter function in membranes was assessed by ATPase activity. KEY RESULTS: Nilotinib and dasatinib were high-affinity substrates of ABCG2, and this protein mediated an effective resistance in cancer cells against these compounds. Nilotinib and dasatinib also interacted with ABCB1, but this transporter provided resistance only against dasatinib. Neither ABCB1 nor ABCG2 induced resistance to bosutinib. At relatively higher concentrations, however, each TKI inhibited both transporters. CONCLUSIONS AND IMPLICATIONS: A combination of in vitro assays may provide valuable preclinical information for the applicability of novel targeted anti-cancer TKIs, even in multidrug-resistant cancer. The pattern of MDR-ABC transporter-TKI interactions may also help to understand the general pharmacokinetics and toxicities of new TKIs.

Birth weight discordance in spontaneous versus induced twins: impact on perinatal outcome.

PURPOSE: To compare the rate of birth weight discordance and perinatal outcome of twin pregnancies after assisted reproduction with that of spontaneous twins. METHOD: A total of 12,920 deliveries were analyzed retrospectively. Seventy-five twin pregnancies after ART were compared to the 94 spontaneous counterparts. Birth weight discordance was defined as a difference of 20% or more. RESULTS: Discordance rate was elevated (25.3% vs. 17.0%) among ART twins. SGA was increased and NICU admission was more frequent in discordant group. Unlike-sexed twins were more prevalent (73.7% vs. 37.5%) among discordants after ART. CONCLUSIONS: ART can increase discordance rate which can elevate perinatal risk.

Vein of Galen malformation combined with atrial septal defect in a neonate.

An arteriovenous fistula (AVF) is an abnormal connection between an artery and a vein, whereby the interconnecting capillary network is missing. Such a malformation frequently occurs in the deep midline regions of the brain, and the subsequent increased flow into the draining vein of Galen substantially dilates in an aneurysmal manner. Congenital forms of the aneurysmal dilatation of the vein of Galen (AVG) often lead to death in the neonatal period, predominantly due to cardiac failure caused by the increased venous inflow as a consequence of the intracerebral arteriovenous shunting. In the presented case a male baby suffered from a rare combination of a cerebral AVF and an atrial septal defect (ASD). He was born at week 38 of pregnancy and subsequently developed tachydyspnoe. Ultrasound (US) and CT scans revealed a large bilateral AVF with dilated basal venous sinuses, hydrocephalus and brain atrophy. In the heart, severe right ventricular hypertrophy, patent ductus arteriosus and an ASD were detectable by US. Neurosurgical consultation rejected the possibility of an operative treatment due to size and localization of the lesion and the existing irreversible brain damage. The child died because of cardiac failure 6 days after birth. Autopsy examination in the brain demonstrated a large conglomerate of dilated blood vessels predominantly in the midline and left occipital lobe, edema and hydrocephalus. In the heart, the ASD detected by US proved to be an ostium secundum-type lesion. Histologically, the conglomerate of vessels revealed features of an AVF and matched the characteristics of AVG. Consequences of chronic ischemic brain injury were also present, with ferruginated neurons suggesting intrauterine damage caused by a congenital AVF. Based on data in the literature, we assume that the left-to-right shunt due to increased venous influx into the heart caused not only cardiomegaly, but may have also interfered with the normal development of the atrial septum leading to an ASD, contributing to the rapid progression of the cardiac failure.

Dilemma of increased obstetric risk in pregnancies following IVF-ET.

PURPOSE: To determine the rates of pregnancy complications following in vitro fertilization in comparison with those in a matched control group. METHODS: A total of 13,543 deliveries at the Department of Obstetrics and Gynecology, University of Szeged, between January 1, 1995 and February 28, 2002 were subjected to retrospective analysis The 230 (1.7%) pregnancies following IVF-ET were evaluated and matched with spontaneous pregnancies concerning age, parity, gravidity, and previous obstetric outcome. Demographic and selected maternal characteristics, pregnancy and labor complications, and neonatal outcome were compared in the two groups RESULTS: The pregnancy complication rate was partly significantly higher among the singleton IVF-ET pregnancies. The obstetric risk was elevated, though not significantly concerning twin pregnancies. CONCLUSIONS: IVF-ET presents an additional obstetric risk. The neonatal outcome displays a significant difference only concerning an increased premature birth rate of singleton pregnancies. Triplet IVF-ET pregnancies involve a much higher risk of both pregnancy complications and neonatal outcome.

The incidence of major birth defects following in vitro fertilization.

PURPOSE: To evaluate the risk of congenital malformations in newborns delivered after IVF-ET in comparison with matched controls from spontaneous pregnancies. METHODS: A total of 12,920 deliveries were subjected to retrospective analysis. A total of 301 neonates were evaluated. The incidence of major birth defects was compared with controls matched with regard to age, gravidity, parity, and previous obstetric outcome after spontaneous pregnancies. RESULTS: The incidence of major congenital abnormalities was not significantly higher (p > 0.05) among the cases (1.90%) than among the controls (1.15%). CONCLUSION: The risk of major birth defects following IVF-ET is comparable with that of spontaneously conceived, matched pregnancies.

Perinatal outcome of induced and spontaneous pregnancies of primiparous women aged 35 or over.

OBJECTIVES: To compare the neonatal and maternal morbidity data associated with induced or naturally conceived pregnancies of primiparous women aged 35 years and older. METHODS: We recruited primiparous women aged 35 years and older, who delivered between January 1995 and December 2000. The outcomes of the induced (n=62) and naturally conceived (n=132) pregnancies were compared. The Fisher exact test was used for univariate analysis in order to compare the delivery and pregnancy characteristics in the two groups. RESULTS: Cesarean section featured with a 0.76 times lower prevalence among the induced pregnant women, than among the spontaneous ones, but the difference was not significant statistically. The induced pregnancies were not associated with a significantly higher rate of perinatal complications. CONCLUSIONS: Induced pregnancy does not involve a higher risk of maternal complications. The incidence of premature newborns and intrauterine growth retardation was high in both subgroups, but without a statistically significant difference.

[Increased sensitivity to balsams and fragrances among our patients]. / A balzsamokkal és az illatanyagokkal szembeni érzékenység növekedése betegeink között.

Allergic contact dermatitis caused by fragrances and balsams play an increasingly important role in the daily practice of dermatology. Based on county tests, the authors have found high increase in 1999, which is in accordance with observations made abroad and the prognosis of earlier tests. The balsam of Peru and the fragrance mix are among the leader allergens, and this should be considered during treatment. Irrespective of age, scentless and hypoallergen cosmetics are to be used.

Age differences in decision making: to take a risk or not?

A controlled laboratory experiment was used to assess the efficacy of the cognitive processes that underlie risk taking decision making in young and elderly people. Thirty-six participants took part in the study: half the subjects were elderly (mean age of 74) and the other half were young adults (mean age of 19). The elderly participants made equivalent decisions to those of the control young adults. Both age-groups of participants systematically and comparably changed their behavior as a function of risk levels. Furthermore, the elderly participants, relative to young adults, did not exhibit any slowing down in the speed of processing the information involved in making risk taking decisions, reflecting that healthy elderly people are cognitively apt to making risk taking decisions. Both age-groups took comparably less time on the easy trials (trials with either low or high levels of risk) and comparably more time on the difficult trials (trials with medium levels of risk).

Human ingestion of chromium (VI) in drinking water: pharmacokinetics following repeated exposure.

Regulatory agencies have established safe drinking water concentrations for hexavalent chromium [Cr(VI)] based in part on the presumed capability of human gastric juices to rapidly reduce Cr(VI) to nontoxic trivalent chromium [Cr(III)] prior to systemic absorption. This study examines dose-related pharmacokinetics in humans following repeated oral exposure to Cr(VI) in drinking water. In particular, we sought to examine whether plausible drinking water exposures to Cr(VI) caused a sustained increase in red blood cell chromium levels, a specific marker for systemic uptake of Cr(VI). Adult male volunteers ingested a liter (in three volumes of 333 ml, at approximate 6-hr intervals) of deionized water containing Cr(VI) concentrations ranging from 0.1 to 10.0 mg/liter. Samples of urine, plasma, and red blood cells were collected and analyzed for chromium. A dose-related increase in urinary chromium excretion was observed in all volunteers. Red blood cell and plasma chromium concentrations became elevated in certain individuals at the highest doses. The RBC chromium profiles suggest that the ingested Cr(VI) was reduced to Cr(III) before entering the bloodstream, since the chromium concentration in the RBCs dropped rapidly postexposure. These findings suggest that the human gastrointestinal tract has the capacity to reduce ingested Cr(VI) following ingestion of up to 1 liter of water containing 10.0 mg/liter of Cr(VI), which is consistent with USEPA's position that the Cr(VI) drinking water standard of 0.10 mg Cr(VI)/liter is below the reductive capacity of the stomach.

[Resuscitation of neonates in the delivery room. Recommendations by the American Heart Association and American Academy of Pediatrics]. / Ujszülöttek szülöszobai resuscitatiója.

According to the recommendation of the American Heart Association and the American Academy of Pediatrics 43 newborn babies with mean birth weight 3300 g (range 610-5100 g) were resuscitated. One-minute Apgar score was 0:1, 1:22, 2:11, 3:7, 4:2 cases. Mask and bag ventilation were needed in 43, heart compression in 7, tracheal intubation in 2, drugs in 2 cases. Five-minute Apgar values were 8:39, 5:1, 7:1 case. All resuscitations were successful. The resuscitation program is a great advance in the field of neonatology. Nationwide application of it might be helpful to decrease neonatal mortality in Hungary.

Modified Blalock-Taussig shunt using allograft saphenous vein: six years' experience.

BACKGROUND: The occurrence of life-threatening late infectious complications after the use of expanded polytetrafluoroethylene conduits as modified Blalock-Taussig shunts prompted us to apply allograft saphenous veins instead. METHODS: In 23 cyanotic patients (age, 1 week to 18 years) allograft saphenous veins were used for performing Blalock-Taussig shunts from July 1989 onward. Veins stored in Hank's solution were implanted in 8 patients and cryopreserved ones in 15. All patients were followed up regularly up to 15 months. RESULTS: There were two early and two late deaths: none were related to shunt occlusion. Clinical, angiographic, and echocardiographic studies proved that, except for one early occlusion, all shunts were patent and functioning well after an average of 41 months. Donor cells disappeared 1 to 3 days after implantation, and several months after the operation both the wall and the luminal surface of the grafts were repopulated with cells possibly of recipient origin. No difference was found between veins stored in Hank's solution only and cryo-preserved grafts, concerning clinical outcome and histology. CONCLUSIONS: Allograft saphenous veins function well as modified Blalock-Taussig shunts at least up to 6 years. Owing to the good results and lack of complications their clinical use is recommended.

[Modified Blalock-Taussig shunt using a saphenous vein allograft. Five-year experience]. / Módosított Blalock-Taussig-shuntök allograft vena saphena alkalmazásával. Ot év tapasztalatai.

From July 1989 to June 1994 23 modified Blalock-Taussig shunts were performed using allograft saphenous veins. Veins stored in Hank's solution were implanted in 8, and cryopreserved ones were used in 15 cases. No operative death, bleeding, or infectious complication has occurred. There were 2 early and 2 late deaths, none was related to shunt occlusion. Clinical, angiographic and echocardiographic investigations proved that the rest of the shunts are still patent and functioning well after an average of 30 months follow up. Histological studies showed that donor cells have been replaced after several months with recipient cells both in the wall and at the luminal surface of the grafts. No difference was found between veins stored in Hank's solution and cryopreserved grafts concerning clinical outcome and histology.

[Preparing dental radiographs without film. Radiovisiography]. / Fogröntgenfelvétel készítése film nélkül. A radioviziográfiás rendszer.

In dental practice it was with the Radiovisiography system that a dental X-ray picture can be made without film and development time. The radiation load of patients decreases from 62%- to 94% compared to dental film. The regulation of the contrast and the light intensity of the electronic picture makes the further evaluation of the exposure possible.

[Neonatal hypoxic myocardial lesion]. / Ujszülöttkori hypoxiás myocardialis laesio.

Five patients suffering from transient myocardial ischemia of the newborn are discussed. The role of two-dimensional doppler-echocardiography is emphasized in establishing the diagnosis. Tricuspid insufficiency due to perinatal asphyxia can be detected easier by ultrasound than by any other cardiac examination. Cardiac failure as a result of hypoxic myocardial ischemia is usually reversible and responds well to anticongestive treatment and administration of oxygen. On the other hand some cases can be fatal, histopathologic examination on the heart shows similarity to myocardial infarction.

[The importance of Doppler echocardiography in the differential diagnosis of causes of neonatal cyanosis]. / Az echo-Doppler-vizsgálat jelentösége az újszülöttkori cyanosisok elkülönítö diagnózisában.

The authors report 329 dopplerechocardiographic examinations performed on 167 term and preterm newborn babies presenting cyanosis. Seventy-six congenital heart defects were detected among their patients, 12 of whom were operated without heart catheterization, according to the ultrasound finding. The diagnosis of ten inoperable heart diseases established without hemodynamic examination was confirmed by autopsy. Cyanosis due to cardiac and pulmonary abnormalities without congenital heart defect was diagnosed in 38 patients. Persistent ductus arteriosus was found in 45 very lowbirth-weight premature babies. Doppler echocardiography proved to be a major advance in the differential diagnosis of newborn cyanosis and in choosing appropriate therapy.

HLA investigations in cardiomyopathies.

Typization of HLA A, B and C antigens of peripheral lymphocytes was performed in 14 patients suffering from cardiomyopathy and in 10 family members from 10 families. Among the antigens of locus A, the most frequent were the subgroups of HLA A9 (A23 and A24) in 7/14, and those of HLA A10 (A25 and A26) in 3/14; frequent antigens of locus B were the types B5, B7, B12 and B35. In 2 of 10 families the cardiomyopathy was transmitted by autosomal dominant genes, while the other cardiomyopathy cases were sporadic. The HLA B8 antigen was not observed in any case of cardiomyopathy.