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Biomedical subjects

R Regev

Publications and source records attributed to R Regev.

At least 19 recordsLinked to original sources
PubMed2002

Glu274Lys/Gly309Arg mutation of the tissue-nonspecific alkaline phosphatase gene in neonatal hypophosphatasia associated with convulsions.

We describe a patient diagnosed with lethal perinatal hypophosphatasia with a unique clinical presentation of convulsions that responded to vitamin B6. Genomic DNA sequence analysis of the tissue-nonspecific alkaline phosphatase (TNSALP) gene revealed two missense mutations: a G-to-A transition resulting in a Glu to Lys at codon 274 (E274K), and a G-to-C transversion resulting in a Gly to Arg at codon 309 (G309R). The first mutation was maternally transmitted and was previously characterized as a moderate one, whereas the latter was paternally transmitted and has not been previously reported. Phenotype/genotype correlation indicates that G309R is a deleterious mutation that can lead to seizures and a lethal outcome, as was demonstrated in our patient.

Alkaline Phosphatase↗
PubMed2001

Cells from chronic myelogenous leukaemia patients at presentation exhibit multidrug resistance not mediated by either MDR1 or MRP1.

Tetramethylrosamine (TMR) is excluded from P-glycoprotein (MDR1)-enriched cell lines, but it stains efficiently MDR1-poor parent lines. Application of the TMR resistance assay to cells obtained from chronic myelogenous leukaemia (CML) patients revealed, in all individuals, a significant resistance compared with healthy donors (P < 0.001). Cells from the same patients at later phases exhibited a further increase in TMR resistance. Doxorubicin was excluded from all cell samples obtained from CML patients at presentation. The resistance to TMR and doxorubicin was energy-dependent, and was not modulated by inhibitors of MDR1 and multidrug-resistance protein-1 (MRP1). Transcription of mRNAs suspected as relevant to multidrug resistance was assessed using comparative reverse transcription polymerase chain reaction. All cells from the CML patients transcribed high levels of MRP3, MRP4 and MRP5 compared with healthy donors. Low levels of MDR1, MRP1, MRP2, MRP6, lung resistance-related protein and anthracycline resistance-associated protein were equally transcribed in cells from healthy donors and CML patients. These results indicated that neither MDR1 nor MRP1 mediate the resistance in these cells. Our results shed light on a resistance mechanism operative in CML patients, which, together with the resistance to apoptosis, is responsible for the lack of response of CML patients to induction-type protocols used to treat acute myeloid leukaemia patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Preterm labour at 34--36 weeks of gestation: should it be arrested?

Currently, preterm labour is treated with tocolytic agents and prenatal steroids until the 34th week of gestation only. Our objective in this study was to assess this practice. Seven-year records of all preterm infants born in our institution at 34--36 weeks of gestation, were evaluated retrospectively. All babies, born in singleton well-dated pregnancies, without maternal, medical or obstetric complications, and by normal vaginal delivery, were included. Their length of hospital stay and perinatal complications were compared across gestational age groups of 34, 35 and 36 weeks. Of the 207 babies included, statistically significant reductions in the rates of respiratory distress syndrome (15.0% vs. 3.2%), nosocomial sepsis (5.0% vs. 0%) and apnoea of prematurity (11.7% vs. 2.2%), and consequently, in length of hospital stay (16 +/- 2.7 vs. 4 +/- 0.3 days) occurred between 34 and 36 weeks of gestation. The severity of respiratory distress syndrome also declined significantly. The changes were most noticeable after 35 weeks of gestation, and it was concluded that neonatal complications are still prevalent at 34 and 35 weeks. Therefore, we propose that labour should not be induced at 34 and 35 weeks of gestation and that tocolytic agents and maternal prenatal steroids may be considered in preterm labour during this period.

Adrenal Cortex Hormones↗
PubMed2000

Prenatal sonographic detection of a lipomeningocele as a sacral lesion.

We present a case of a lipomeningocele in a newborn. Prenatal sonography revealed dysraphia and a 3.8 x 4.3 cm, semisolid, echogenic mass that was continuous with the sacral area and bulged posteriorly under the skin. The mass was diagnosed after birth as a lipomeningocele based on the results of MRI. This diagnosis was confirmed histologically.

Adult↗
PubMed1999

Optimality score for the neurologic examination of the infant at 12 and 18 months of age.

The aim of this study was to develop and validate a simple, quantifiable, neurologic examination for infants between 2 and 24 months of age. The assessment consists of 37 items, divided into 3 sections. The first section includes 26 items assessing cranial nerve function, posture, movements, tone, and reflexes; the second section of 8 items documents the development of motor function, and the third section of 3 items evaluates the state of behavior. We applied this assessment to a cohort of ninety-two 12-month-old infants and forty-three 18-month-old infants, with no known perinatal risk factors. The proforma presented has been designed according to the frequency distribution of the neurologic findings in this cohort. Each item is scored individually, and a global score is the sum of all individual scores. The quantitative score enhances the value of this examination, both in clinical practice and in research settings.

Behavior↗
PubMed1999

Membrane fluidization by ether, other anesthetics, and certain agents abolishes P-glycoprotein ATPase activity and modulates efflux from multidrug-resistant cells.

The anesthetics benzyl alcohol and the nonaromatic chloroform and diethyl ether, abolish P-glycoprotein (Pgp) ATPase activity in a mode that does not fit classical competitive, noncompetitive, or uncompetitive inhibition. At concentrations similar to those required for inhibition of ATPase activity, these anesthetics fluidize membranes leading to twofold acceleration of doxorubicin flip-flop across lipid membranes and prevent photoaffinity labeling of Pgp with [125I]-iodoarylazidoprazosin. Similar concentrations of ether proved nontoxic and modulated efflux from Pgp-overexpressing cells. A similar twofold acceleration of doxorubicin flip-flop rate across membranes was observed with neutral mild detergents, including Tween 20, Nonidet P-40 and Triton X-100, and certain Pgp modulators, such as verapamil and progesterone. Concentrations of these agents, similar to those required for membrane fluidization, inhibited Pgp ATPase activity in a mode similar to that observed with the anesthetics. The mode of inhibition, i.e. lack of evidence for classical enzyme inhibition and the correlation of Pgp ATPase inhibition with membrane fluidization over a wide range of concentrations and structures of drugs favors the direct inhibition of Pgp ATPase activity by membrane fluidization. The unusual sensitivity of Pgp to membrane fluidization, as opposed to acceleration of ATPase activity of ion transporters, could fit the proposed function of Pgp as a 'flippase', which is in close contact with the membrane core.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Familial perinatal hemochromatosis: a disease that causes recurrent non-immune hydrops.

Perinatal hemochromatosis is a rare disorder with an enormous iron overload in the parenchymal organs, especially the liver, pancreas, heart and endocrine glands. Elements of the reticuloendothelial system are relatively spared. The clinical course is rapidly progressive and the disease is invariably fatal. Several siblings are described in the literature. Herein, we describe one pair of full siblings affected by the disease, wherein the clinical presentation was hydrops. We suggest that hemochromatosis should be considered in the differential diagnosis of hydrops fetalis.

Adult↗
PubMed1997

Flip-flop of doxorubicin across erythrocyte and lipid membranes.

Doxorubicin, an anticancer drug, is extruded from multidrug resistant (MDR) cells and from the brain by P-glycoprotein located in the plasma membrane and the blood-brain barrier, respectively. MDR-type drugs are hydrophobic and, as such, enter cells by diffusion through the membrane without the requirement for a specific transporter. The apparent contradiction between the presumably free influx of MDR-type drugs into MDR cells and the efficient removal of the drugs by P-glycoprotein, an enzyme with a limited ATPase activity, prompted us to examine the mechanism of passive transport within the membrane. The kinetics of doxorubicin transport demonstrated the presence of two similar sized drug pools located in the two leaflets of the membrane. The transbilayer movement of doxorubicin occurred by a flip-flop mechanism of the drug between the two membrane leaflets. At 37 degrees, the flip-flop exhibited a half-life of 0.7 min, in both erythrocyte membranes and cholesterol-containing lipid membranes. The flip-flop was inhibited by cholesterol and accelerated by high temperatures and the fluidizer benzyl alcohol. The rate of doxorubicin flux across membranes is determined by both the massive binding to the membranes and the slow flip-flop across the membrane. The long residence-time of the drug in the inner leaflet of the plasma membrane allows P-glycoprotein a better opportunity to remove it from the cell.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Efficiency of P-glycoprotein-mediated exclusion of rhodamine dyes from multidrug-resistant cells is determined by their passive transmembrane movement rate.

The aim of the present study was to examine the relationship between the rate of the passive transmembrane movement of multidrug resistance (MDR)-type substrates and the ability of P-glycoprotein to extrude them from MDR cells. For this purpose, seven rhodamine dyes were examined for their P-glycoprotein-mediated exclusion from MDR cells, their localization in wild-type drug-sensitive cells, their capacity to stimulate the ATPase activity of P-glycoprotein reconstituted in proteoliposomes, and their transmembrane movement rate in artificial liposomes. All these rhodamine dyes were accumulated in wild-type drug-sensitive cells and were localized mainly in the mitochondria. All the dyes tested were substrates of reconstituted P-glycoprotein and cellular P-glycoprotein and were excluded to a variable degree from MDR cells. The transmembrane movement rate proved the major factor determining the efficacy of the P-glycoprotein-mediated exclusion of rhodamine dyes from MDR cells. Thus, rhodamine B, the poorest cellular P-glycoprotein substrate, exhibited a high affinity toward reconstituted P-glycoprotein, but was the fastest membrane-traversing dye. In contrast, tetramethylrosamine, the best cellular MDR probe, exhibited high affinity toward reconstituted P-glycoprotein and slow transmembrane movement rate. Therefore, an anticancer drug with a fast transmembrane movement rate is expected to overcome the MDR phenomenon. Furthermore, the widely used MDR marker, rhodamine 123, was a poor cellular MDR substrate compared with other rhodamine dyes, especially tetramethylrosamine, which was a superior cellular MDR substrate for functional dye-exclusion studies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Birth weight and physical ability in 5- to 8-yr-old healthy children born prematurely.

Recent advances in perinatal care have resulted in increased survival rates of extremely small and immature newborns. This has resulted in some neurodevelopmental impairment. The purpose of this study was to quantitatively evaluate and compare neuromuscular performance in children born prematurely at various levels of subnormal birth weight (BW). Subjects were 5- to 8-yr-old children born prematurely at different levels of subnormal BW (535-1760 g, N = 22, PM), and age-matched controls born at full term (> 2500 g, N = 15, CON). None of the subjects had any clinically defined neuromuscular disabilities. Body mass (BM) of PM was lower than that of CON (18.3 +/- 2.7 vs 21.7 +/- 3.8 kg) with no difference in height or sum of 4 skinfolds. Peak mechanical power output determined with a 15-s modified Wingate Anaerobic Test and corrected for BM was lower (P = 0.07) in PM than in CON (5.11 +/- 1.07 vs 5.94 +/- 1.00 W.kg-1). This was especially noticeable in children born at extremely low BW (ELBW, < 1000 g, 4.49 +/- 1.04 W.kg-1, P < 0.01). Peak power, determined in a force-plate vertical jump, corrected for BM was lower in PM vs CON (25.5 +/- 5.4 vs 30.8 +/- 5.2 W.kg-1, respectively P = 0.01), especially in the ELBW group (20.0 +/- 5.5 W.kg-1). Similarly, the elapsed time between peak velocity and actual jump take-off was longer in PM than in CON (41.2 +/- 9.4 vs 35.8 +/- 5.8 ms, respectively, P = 0.04). No differences were observed in peak force. The results suggest that performance deficiencies of prematurely-born children may be a result of inferior inter-muscular coordination. The precise neuromotor factors responsible for this should be identified by future research.

Birth Weight↗
PubMed1997

The development of the complement system after 28 weeks' gestation.

OBJECTIVE: To assess the levels and development of the various complement components in preterm infants, particularly among those born before 34 weeks' gestation. SUBJECTS AND METHODS: We measured the complement system's activities (CH50 and AP50) as well as its various components (C1q,r,s, C2-C9, Factor B, and properdin) in 25 preterm infants [gestational age (GA) 28-33 weeks], 35 preterm infants (GA 34-36 weeks), 50 full-term newborn infants (GA 37-42 weeks), and 49 healthy adults as control subjects. RESULTS AND CONCLUSIONS: The results of these studies are: (i) complement levels and activity were significantly reduced in preterm and full-term neonates when compared with adult levels, with the exception of C7 which was within the normal range in most infants. C8 and C9 were the most markedly reduced at all gestational ages. (ii) Complement levels correlated significantly with gestational age, but not with birth-weight, type of delivery, or gender. (iii) Between 28 and 33 weeks' gestation, there appeared to be almost no development of the complement system.

Adult↗
PubMed1996

The role of passive transbilayer drug movement in multidrug resistance and its modulation.

The successful lowering of the intracellular concentration of multidrug resistance (MDR)-type drugs by P-glycoprotein (Pgp) relies on its ability to overcome the passive influx rate of each MDR-type drug. Thus, the aim of the present work was to study the effect of passive transbilayer drug movement on the multidrug resistance and its modulation. Fluorescence quenching studies indicated that whereas the Pgp substrate rhodamine 123 traverses an artificial lipid membrane with a lifetime of 3 min, the transbilayer movement rate of the MDR modulators, quinidine and quinine, was too fast to be detected with present methods. Transbilayer movement rates of drugs and modulators were estimated from their equilibration rate throughout artificial multilamellar vesicles. The equilibration rate of five selected modulators was faster than the equilibration rate of five representative MDR-type drugs tested, which was comparable with the rate of rhodamine 123 equilibration. Moreover, the carrier-type peptide ionophore, valinomycin, which is freely mobile in the membrane, inhibited Pgp-mediated efflux of rhodamine 123 from MDR cells. In contrast, the channel-forming ionophore gramicidin D, a Pgp substrate that flip-flops slowly across the membrane, did not modulate cellular Pgp activity. Pgp, with a turnover number of about 900 min-1 can keep pace with the influx of an MDR-drug like rhodamine 123 exhibiting a transbilayer movement with a lifetime of minutes. On the other hand, Pgp would fail to protect MDR cells against cytotoxic drugs that are freely mobile through biological membranes and that re-enter cells faster than their Pgp-mediated active efflux rate. The relatively fast transbilayer movement exhibited by MDR modulators suggest that in contrast to MDR-type drugs, MDR modulators traverse the plasma membrane faster than the maximal expulsion rate of Pgp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Functional reconstitution of P-glycoprotein reveals an apparent near stoichiometric drug transport to ATP hydrolysis.

We have recently described an ATP-driven, valinomycin-dependent 86Rb+uptake into proteoliposomes reconstituted with mammalian P-glycoprotein (Eytan, G. D., Borgnia, M. J., Regev, R., and Assaraf, Y. G. (1994) J. Biol. Chem. 269, 26058-26065). P-glycoprotein mediated the ATP-dependent uptake of 86Rb+-ionophore complex into the proteoliposomes, where the radioactive cation was accumulated, thus, circumventing the obstacle posed by the hydrophobicity of P-glycoprotein substrates in transport studies. Taking advantage of this assay and of the high levels of P-glycoprotein expression in multidrug-resistant Chinese hamster ovary cells, we measured simultaneously both the ATPase and transport activities of P-glycoprotein under identical conditions and observed 0.5-0.8 ionophore molecules transported/ATP molecule hydrolyzed. The amount of 86Rb+ ions transported within 1 min via the ATP- and valinomycin-dependent P-glycoprotein was equivalent to an intravesicular cation concentration of 8 mM. Thus, this stoichiometry and transport capacity of P-glycoprotein resemble various ion-translocating ATPases, that handle millimolar substrate concentrations. This constitutes the first demonstration of comparable rates of P-glycoprotein-catalyzed substrate transport and ATP hydrolysis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Survival rate and 2 year outcome in very low birthweight infants.

The purpose of this study was to determine the mortality rate of 282 infants with a birthweight (BW) of < 1,500 g during a 5 year period (1987-92), and to evaluate 2 year neurodevelopmental outcome in 114 infants (born 1987-90) and its correlation with intracranial pathologies diagnosed by ultrasonography. Overall survival rate was 76.6% (216/282). With the introduction of exogenous surfactant therapy in 1991 a significant increase in survival was noted in the 751-1,000 g BW infants (from 20/36 to 20/22, P < 0.002). Two year evaluation was performed in 114 of 119 infants (95.7%) who survived this age. Twenty-two children (22/114, 19.3%) were functionally disabled, of whom 15 (13%) had a major disability. Of these 15 infants, 5/28 weighed < 1,000 g and 10/86 weighed 1,001-1,500 g (P = 0.6). Severe intraventricular hemorrhage (IVH) and cystic periventricular leukomalacia (PVL) were significantly associated with adverse outcome at 2 year (5/11 and 10/10 respectively were handicapped, P < 0.001). We therefore conclude that every effort should be made to save the extremely premature infants (< 1,000 g BW). Since adverse outcome was significantly associated with severe brain pathologies (large IVH and cystic PVL) rather than with lower BW, brain ultrasonography as a diagnostic mode should be taken into clinical consideration.

Cerebral Hemorrhage↗
PubMed1994

Transport of polypeptide ionophores into proteoliposomes reconstituted with rat liver P-glycoprotein.

The aim of this study was to examine the peptide transport activity of a naturally occurring P-glycoprotein such as that present in rat liver canalicular membrane vesicles. The peptide ionophores valinomycin and gramicidin D, which are known substrates of P-glycoprotein, served to monitor the P-glycoprotein activity indirectly as the ATP-dependent uptake of 86Rb+ mediated by these ionophores. Canalicular membrane vesicles proved inherently permeable to K+ ions, which prevented assay of transport ionophore activity. Therefore, P-glycoprotein was extracted from canalicular membrane vesicles and reconstituted into proteoliposomes that are relatively impermeable to cations. P-glycoprotein activity in the proteoliposomes was dependent on ATP hydrolysis since it was not observed with non-hydrolyzable analogs of ATP. Maximal ATP-dependent 86Rb+ uptake occurred at 50 nM gramicidin D and at 500 nM valinomycin thus possibly reflecting higher affinity of P-glycoprotein for gramicidin D. Nigericin, which does not participate in the multidrug resistance phenomenon, did not support an ATP-dependent uptake of 86Rb+. ATP hydrolysis increased the amount of 86RB+ transported into the proteoliposomes. Furthermore, preincubation of the proteoliposomes in the presence of gramicidin D and 86Rb+, allowing for maximal ATP-independent 86Rb+ uptake to occur, did not interfere with subsequent ATP-dependent uptake, indicating the latter to constitute an active transport mechanism. The ATP-dependent component of 86Rb+ uptake occurred neither with liposomes nor with proteoliposomes reconstituted with proteins extracted from sinusoidal vesicles that lack P-glycoprotein. The ATP-dependent uptake was blocked by the known inhibitors of the ATPase activity associated with P-glycoprotein, oligomycin and vanadate, as well as by its established substrates, daunorubicin, doxorubicin, vinblastine, and the tripeptide N-acetyl-leucyl-leucyl-norleucinal. Thus, the reconstituted P-glycoprotein catalyzes the ATP-dependent 86Rb+ uptake that appears to occur by an energy-dependent translocation of the 86Rb(+)-ionophore complex. In this case, the actual substrate of P-glycoprotein is the ionophore-cation complex, which is both hydrophobic and positively charged as are most of the substrates of P-glycoprotein. This is the first demonstration of transport of a naturally occurring polypeptide by proteoliposomes reconstituted with physiologically expressed P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

A holistic transition programme for persons with learning disabilities in Israel.

This paper describes a two year holistic transition programme for persons with a learning disability in Israel and a follow-up of the first cohort of trainees. The programme which was initiated by the National Insurance Institution and 'Nitzan' a parent voluntary organization was developed to provide these persons with the vocational, personal and social skills required for successful independent living and vocational adjustment. The training was carried out in a residential setting and included vocational training, activities of daily living, educational activities and personal adjustment counselling. The results indicated that two years after completing the programme the trainees were generally meeting the expectations of the goals of the project.

Activities of Daily Living↗
PubMed1994

Effect of surfactant replacement therapy on the outcome of premature infants with respiratory distress syndrome.

Lung surfactant replacement has been tested clinically in recent years. In this study the outcome of 31 premature infants with moderate to severe neonatal respiratory distress syndrome (RDS) treated with surfactant was compared to that of 74 prematures with RDS treated conventionally by positive pressure ventilation and supportive care. The groups were well matched for gestational age, birthweight, sex, and Apgar scores at 1 and 5 min. Surfactant treatment resulted in a significant decrease in mortality--from 36.6% in the untreated group to 12.9% in the surfactant-treated group (P < 0.04). This improvement in survival was seen also in prematures with a birthweight < 1,000 g; in the untreated group mortality was 57.6% compared to 23.5% in the treated group (P < 0.05). The incidence of pneumothorax was lower in the treated group--42% vs. 13% (P < 0.01). Surfactant treatment resulted in a trend of more survivors without bronchopulmonary dysplasia or intraventricular hemorrhage, even though surfactant therapy did not change the incidence of either.

Bronchopulmonary Dysplasia↗