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M Morad

Publications and source records attributed to M Morad.

At least 19 recordsLinked to original sources
PubMed2006

Fetal alcohol syndrome and its long-term effects.

Ancient scripture and paintings together with several medical reports on the effect of alcohol on the newborn over the past 300 years finally led to the description of the fetal alcohol syndrome in the 1970s by French and American research groups. Maternal alcohol abuse during pregnancy can result in the specific pattern of malformations and neurocognitive deficits characteristic of this syndrome. Diagnostic criteria and classifications have been developed and in the 1990s reports showed the long-term consequences for these children. In recent years several studies from different countries have shown that prenatal alcohol exposure will lead to life-long consequences on physical development, intellectual development, behavior, social development, occupation, independence, sexuality or sexual behavior and increased risk of suicidality. In this review of long-term observation studies we found that the prenatal exposure to alcohol have permanent and life-long damage, which impair both the social and occupational future of the person exposed with a need for life-long assistance in order for that person to function at an optimal level. Primary prevention and early intervention with general public health educational efforts seems to be the best way forward.

Adolescent↗
PubMed2003

Molecular determinants of cAMP-mediated regulation of the Na+-Ca2+ exchanger expressed in human cell lines.

The cardiac Na+-Ca2+ exchanger (NCX1) is one of the major sarcolemmal Ca2+ transporters of cardiomyocytes. Structure-function studies suggest that beta-adrenergic inhibition of NCX1, as reported for frog, but not mammalian hearts, may be associated with a unique splice variant of frog cardiac NCX1 where insertion of an extra exon completes the coding of a nucleotide binding P-loop. To test the involvement of the P-loop in cAMP-mediated regulation of NCX1 we used four stably transfected human cell lines (a previously established line of baby hamster kidney (BHK) cells and three new lines of human embryonic kidney (HEK) cells) expressing: (1) wild-type dog NCX1 (dog NCX1); (2) wild-type frog NCX1 (frog NCX1); (3) chimeric frog-dog NCX1 incorporating the completed P-loop from the frog NCX1 into the dog NCX1 sequence (frog/dog NCX1); and (4) a mutated frog NCX1 where a putative protein kinase A (PKA) site was disrupted by substitution of a single serine residue with glycine (S374G frog NCX1). Structural expression of these NCX1 constructs was confirmed using Western blot analysis of extracted proteins and immunofluorescence imaging. The NCX1-generated current (INa-Ca) was reliably measured in cells expressing dog (2.0 +/- 0.15 pA pF-1), frog (0.6 +/- 0.1 pA pF-1) and frog/dog (0.6 +/- 0.1 pA pF-1) NCX1, but less so in those expressing S374G frog NCX1 (0.3 +/- 0.1 pA pF-1). Addition of 100 microM 8-bromoadenosine 3',5' cyclic monophosphate (8-Br-cAMP) suppressed INa-Ca of frog and frog/dog NCX1 by 60-80 %. The suppression of INa-Ca was smaller and transient in cells expressing S374G frog NCX1, and absent in cells expressing dog NCX1. Intracellular Ca2+ (Ca2+i)-transients, activated by rapid withdrawal of Na+, were also downregulated in the frog and frog/dog NCX1 and to a smaller and transient extent in S374G frog NCX1. Our findings suggest that the suppressive effect of beta-adrenergic agonists requires the presence of the P-loop domain of the frog NCX1, and provide evidence that the putative PKA site, present in both dog and frog NCX1, might also be critical in the cAMP-mediated regulation of the exchanger.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2003

Voltage-gated calcium channels in adult rat inferior colliculus neurons.

The inferior colliculus (IC) plays a key role in the processing of auditory information and is thought to be an important site for genesis of wild running seizures that evolve into tonic-clonic seizures. IC neurons are known to have Ca(2+) channels but neither their types nor their pharmacological properties have been as yet characterized. Here, we report on biophysical and pharmacological properties of Ca(2+) channel currents in acutely dissociated neurons of adult rat IC, using electrophysiological and molecular techniques. Ca(2+) channels were activated by depolarizing pulses from a holding potential of -90 mV in 10 mV increments using 5 mM barium (Ba(2+)) as the charge carrier. Both low (T-type, VA) and high (HVA) threshold Ca(2+) channel currents that could be blocked by 50 microM cadmium, were recorded. Pharmacological dissection of HVA currents showed that nifedipine (10 microM, L-type channel blocker), omega-conotoxin GVIA (1 microM, N-type channel blocker), and omega-agatoxin TK (30 nM, P-type channel blocker) partially suppressed the current by 21%, 29% and 22%, respectively. Since at higher concentration (200 nM) omega-agatoxin TK also blocks Q-type channels, the data suggest that Q-type Ca(2+) channels carry approximately 16% of HVA current. The fraction of current (approximately 12%) resistant to the above blockers, which was blocked by 30 microM nickel and inactivated with tau of 15-50 ms, was considered as R-type Ca(2+) channel current. Consistent with the pharmacological evidences, Western blot analysis using selective Ca(2+) channel antibodies showed that IC neurons express Ca(2+) channel alpha(1A), alpha(1B), alpha(1C), alpha(1D), and alpha(1E) subunits. We conclude that IC neurons express functionally all members of HVA Ca(2+) channels, but only a subset of these neurons appear to have developed functional LVA channels.

Animals↗
PubMed2002

Prevalence of Helicobacter pylori in people with intellectual disability in a residential care centre in Israel.

In 1982, Helicobacter pylori (formerly Campylobacter pylori) was identified as a pathogenic factor in peptic ulcer disease by researchers from Australia. Because only a small number of studies of H. pylori infection have been conducted in people with intellectual disability (ID), and none of these were done in Israel, the present authors decided to conduct a pilot study on its prevalence in this population. The Israeli Division for Mental Retardation provides services to over 6000 people in 54 residential care centres (or institutions), and one centre in the south of the country with kibbutz-style living arrangements was selected for this pilot study. The study was performed as part of the yearly routine medical examination of all residents, and blood specimens were drawn for IgG antibodies to H. pylori (ELISA). Out of the 47 individuals screened, 75% (n=36) were seropositive. In addition to the reported high rates of H. pylori infection in residents with ID living in large facilities, the present pilot study suggests that people with ID living in smaller, kibbutz-style arrangements are also at high risk.

Adult↗
PubMed2001

Bimodal regulation of Na(+)--Ca(2+) exchanger by beta-adrenergic signaling pathway in shark ventricular myocytes.

In shark heart, the Na(+)--Ca(2+) exchanger serves as a major pathway for both Ca(2+) influx and efflux, as there is only rudimentary sarcoplasmic reticulum in these hearts. The modulation of the exchanger by a beta-adrenergic agonist in whole-cell clamped ventricular myocytes was compared with that of the Na(+)--Ca(2+) exchanger blocker KB-R7943. Application of 5 microM isoproterenol and 10 microM KB-R7943 suppressed both the inward and the outward Na(+)--Ca(2+) exchanger current (I(Na--Ca)). The isoproterenol effect was mimicked by 10 microM forskolin. Isoproterenol and forskolin shifted the reversal potential (E(rev)) of I(Na--Ca) by approximately -23 mV and -30 mV, respectively. An equivalent suppression of outward I(Na--Ca) by KB-R7943 to that by isoproterenol produced a significantly smaller shift in E(rev) of about --4 mV. The ratio of inward to outward exchanger currents was also significantly larger in isoproterenol- than in control- and KB-R7943-treated myocytes. Our data suggest that the larger ratio of inward to outward exchanger currents as well as the larger shift in E(rev) with isoproterenol results from the enhanced efficacy of Ca(2+) efflux via the exchanger. The protein kinase A-mediated bimodal regulation of the exchanger in parallel with phosphorylation of the Ca(2+) channel and enhancement of its current may have evolved to satisfy the evolutionary needs for accelerated contraction and relaxation in hearts of animals with vestigial sarcoplasmic Ca(2+) release stores.

Adrenergic beta-Agonists↗
PubMed2000

Inotropic stimulation induces cardiac dysfunction in transgenic mice expressing a troponin T (I79N) mutation linked to familial hypertrophic cardiomyopathy.

The cardiac troponin T (TnT) I79N mutation has been linked to familial hypertrophic cardiomyopathy and a high incidence of sudden death, despite causing little or no cardiac hypertrophy. In skinned fibers, I79N increased myofilamental calcium sensitivity (Miller, T., Szczesna, D., Housmans, P. R., Zhao, J., deFreitas, F., Gomes, A. V., Culbreath, L., McCue, J., Wang, Y., Xu, Y., Kerrick, W. G., and Potter, J. D. (2001) J. Biol. Chem. 276, 3743-3755). To further study the functional consequences of this mutation, we compared the cardiac performance of transgenic mice expressing either human TnT-I79N or human wild-type TnT. In isolated hearts, cardiac function was different depending on the Ca(2+) concentration of the perfusate; systolic function was significantly increased in Tg-I79N hearts at 0.5 and 1 mmol/liter. At higher Ca(2+) concentrations, systolic function was not different, but diastolic dysfunction became manifest as increased end-diastolic pressure and time to 90% relaxation. In vivo measurements by echocardiography and Doppler confirmed that base-line systolic function was significantly higher in Tg-I79N mice without evidence for diastolic dysfunction. Inotropic stimulation with isoproterenol resulted only in a modest contractile response but caused significant mortality in Tg-I79N mice. Doppler studies ruled out aortic outflow obstruction and were consistent with increased chamber stiffness. We conclude that in vivo, the increased myofilament Ca(2+) sensitivity due to the I79N mutation enhances base-line contractility but leads to cardiac dysfunction during inotropic stimulation.

Animals↗
PubMed2000

New molecular determinant for inactivation of the human L-type alpha1C Ca2+ channel.

Molecular cloning of the human fibroblast Ca2+ channel pore-forming alpha1C subunit revealed (Soldatov, 1992. Proc. Natl. Acad. Sci. USA 89:4628-4632) a naturally occurring mutation g2254 --> a that causes the replacement of the conservative alanine for threonine at the position 752 at the cytoplasmic end of transmembrane segment IIS6. Using stably transfected HEK293 cell lines, we have compared electrophysiological properties of the conventional alpha(1C,77) human recombinant L-type Ca2+ channel with those of its mutated isoform alpha(1C,94) containing the A752T replacement. Comparative quantification of steady-state availability of the current carried by alpha(1C,94) and alpha(1C,77) showed that A752T mutation prevented a large (approximately 25%) fraction of the current carried by Ca2+ or Ba2+ from fully inactivating. This mutation, however, did not appear to alter significantly the Ca2+-dependence and kinetics of decay of the inactivating fraction of the current or its voltage-dependence. The data suggests that Ala752 at the cytoplasmic end of IIS6 might serve as a molecular determinant of the Ca2+ channel inactivation, possibly regulating the voltage-dependence of its availability.

Alanine↗
PubMed2000

Remodelling of ionic currents in hypertrophied and failing hearts of transgenic mice overexpressing calsequestrin.

Overexpression of cardiac calsequestrin (CSQ) impairs Ca2+ signalling in murine myocytes, leading to marked cardiac hypertrophy. Here we report on contractile, histological and electrophysiological changes accompanying the development of cardiac hypertrophy and failure in CSQ-overexpressing mice. CSQ mice developed contractile dysfunction after 60 days of age, with only 40% survival at 6 months. Four- to 6-month-old CSQ mice revealed biventricular dilatation, cardiomyocyte hypertrophy, patchy interstitial fibrosis and tissue calcifications. Cardiac hypertrophy of CSQ mice was accompanied by progressive P-R and Q-T interval prolongation, conduction blocks, 2-fold prolongation of the ventricular action potential and increased cellular membrane capacitance. Remodelling of ionic currents included marked reduction of both density and absolute magnitude of transient outward (Ito) and inward rectifying (IK1) K+ currents. The density, but not the absolute magnitude, of basal and isoproterenol (isoprenaline)-stimulated Ca2+ current (ICa) was decreased by 42% and the inactivation kinetics of ICa were significantly slowed. Na+ current density was suppressed by 50%, but its steady-state activation and inactivation were shifted to more positive potentials. The density of Na+-Ca2+ exchange current was increased by 35%. In CSQ but not in control myocytes dialysed with cAMP, isoproterenol continued to enhance ICa. This apparent lower responsiveness of ICa to cAMP could be reversed by the non-hydrolysable cAMP analogue 8-Br-cAMP or the phosphodiesterase inhibitor IBMX, suggesting high phosphodiesterase activity of CSQ myocytes. In young CSQ mice (< 60 days) with compensated cardiac hypertrophy, only Ito was significantly suppressed. All other currents remained relatively intact. An increase in cardiac Ca2+-storage capability by overexpression of CSQ results in a dilated cardiomyopathy with tissue fibrosis, calcifications, impaired beta-adrenergic signalling and progressive remodelling of ionic currents. The extent of the changes in ionic currents was age dependent.

Action Potentials↗
PubMed2000

Modulation of focal and global Ca2+ release in calsequestrin-overexpressing mouse cardiomyocytes.

1. Focal and global Ca2+ releases were monitored in voltage-clamped control and hypertrophied calsequestrin (CSQ)-overexpressing mouse cardiomyocytes, dialysed with fluo-3, using rapid (120-240 frames s-1) two-dimensional confocal imaging. 2. Spontaneous focal Ca2+ releases (Ca2+ sparks) were absent or significantly reduced in frequency in hypertrophied myocytes of CSQ-overexpressing mice compared to their age-matched controls. Sporadic Ca2+ sparks seen in CSQ-overexpressing myocytes had intensities and durations similar to those of controls although quantitative analysis showed a trend towards more diffuse focal releases. 3. Activation of Ca2+ current (ICa) failed to produce the typical sarcomeric Ca2+ striping pattern consistently seen in control myocytes. Instead, focal Ca2+ releases appeared as a disorganized patchwork of diffuse or 'woolly' fluorescence signals, resulting in slowly developing and reduced global Ca2+ transients. 4. Although the density of ICa in CSQ-overexpressing myocytes was only slightly smaller than that of controls, the inactivation kinetics of the current were greatly reduced, consistent with the much smaller rate of rise of cytosolic Ca2+. 5. Enhancement of ICa by elevation of [Ca2+]o from 2 to 10 mM or addition of 3 microM isoproterenol (isoprenaline) failed to normalize the frequency of spontaneous Ca2+ sparks at rest or the pattern and the magnitude of ICa-gated Ca2+ transients. Isoproterenol was somewhat more effective than elevation of [Ca2+]o. 6. In sharp contrast, low (0.5 mM) caffeine concentrations that produced no measurable effects on ICa or Ca2+ transients in control myocytes, re-established spontaneous focal Ca2+ releases in CSQ-overexpressing cells, triggered large ICa-gated cellular Ca2+ transients, and strongly enhanced the kinetics of inactivation of ICa. 7. Our data suggest that impaired Ca2+ signalling in CSQ-overexpressing myocytes results from reduced co-ordination and decreased frequency of Ca2+ sparks. The impaired Ca2+ signalling could not be restored by procedures that increased ICa, but was mostly restored in the presence of caffeine, which may alter the Ca2+ sensitivity of the ryanodine receptor.

Adrenergic beta-Agonists↗
PubMed2000

Redox regulation of cardiac muscle calcium signaling.

Signal transduction for cardiac muscle contraction is regulated by the Ca2+-induced Ca2+-release mechanism. Redox reactions by biological oxidants and antioxidants have been shown to alter the kinetics of Ca2+-induced Ca2+ release. We postulate that altered kinetics of Ca2+-induced Ca2+ release may divert the contractile pool of Ca2+ to elicit excitation-transcription coupling. We provide evidence that redox reactions regulate excitation-transcription coupling by showing that membrane depolarization may activate the GATA4 transcription factor only when the cells are pretreated with hydrogen peroxide. Therefore, redox regulation of the ryanodine receptor may serve as a mechanism to determine whether the contractile pool of Ca2+ should signal gene transcription during excitation-contraction coupling.

Action Potentials↗
PubMed2000

Universal health care? The views of Negev Bedouin Arabs on health services.

BACKGROUND: This study examines health and health care attitudes, practices and utilization patterns among the Bedouin Arab minority in the south of Israel. Particular attention is given to the effects of the new National Insurance Law that provides universal coverage for the first time, and to the identification of critical issues for further research. METHODS: Focus groups, adapted to Bedouin culture, were the primary method of data collection. Twelve groups (158 participants) from throughout the Negev met for 3-7 sessions each, using specially trained local moderators and observers. Issues discussed and analyzed included experience and satisfaction with the current health system (both modern and traditional), health service availability/barriers, health care needs, influences of social change, and the National Insurance Law. RESULTS: Participants voice dissatisfaction with modern health services in the Bedouin sector and the state of health of Negev Bedouin. They place great emphasis on the connection between health and the rapid social and economic changes, which this traditionally nomadic group is undergoing. Traditional health care is felt to still exist, but its importance is waning. The National Insurance law is having a major impact on the Bedouin, particularly because it provides universal health insurance coverage where only partial coverage had been in effect. CONCLUSIONS: This study, one of the first of its kind in the Bedouin sector, showed that the focus group method, if properly modified to cultural norms, can be a valuable research tool in traditional communities and in health service research. The findings from this research can be used to direct efforts to improve health policy and health services for this group, as well as preparing the way for further qualitative or quantitative studies.

Arabs↗
PubMed2000

Kaitiakitanga: protecting New Zealand's native biodiversity.

Kaitiakanga is a Maori word meaning guardianship. It is a word that has become central to New Zealand's efforts to conserve native biodiversity as well as encapsulating the new emphasis on inclusion of Maori cultural values and land concerns.

Animals↗
PubMed1999

Modulation of Ca2+ channel-gated Ca2+ release by W-7 in cardiac myocytes.

Cardiac muscle excitation-contraction coupling is controlled by the Ca(2+)-induced Ca2+ release mechanism. The present study examines the effects of a calmodulin antagonist W-7 on Ca2+ current (ICa)-induced Ca2+ release in whole cell-clamped rat ventricular myocytes. Exposure of cells to W-7 suppressed ICa, but the intracellular Ca(2+)-transients showed a lesser degree of reduction, suggesting possible enhancement of Ca(2+)-induced Ca2+ release. The effects of W-7 on the efficacy of Ca2+ release were most prominent at negative potentials. At test potentials of -30 mV, 20 microM W-7 almost completely blocked ICa, but significant Ca(2+)-transients remained, thus causing a four to six-fold increase in the efficacy of Ca(2+)-induced Ca2+ release. The depolarization-dependent Ca(2+)-transients were eliminated in absence of extracellular Ca2+, blocked by Cd2+, and were absent when the sarcoplasmic reticulum was depleted of Ca2+, implicating dependency on Ca(2+)-signaling between the L-type channel and the ryanodine receptor. W-7 mediated increase in the efficacy of Ca(2+)-induced Ca2+ release was eliminated when myocytes were dialyzed with the internal solution containing gluathione (5 mM), suggesting the possible role of cellular redox state in the regulation of Ca2+ release by the calmodulin antagonist.

Animals↗
PubMed1999

Regulation of GATA-4 and AP-1 in transgenic mice overexpressing cardiac calsequestrin.

Transgenic mouse hearts overexpressing the Ca(2+)-binding protein calsequestrin (CSQ) have an accompanying 10-fold increase in the sarcoplasmic reticulum (SR) Ca2+ load, however, exhibits slow and small Ca(2+)-induced Ca2+ release. Such slow kinetics of Ca2+ release may have activated excitation-transcription coupling as CSQ overexpressing hearts have induced levels of NFAT and GATA-4 activities and higher levels of c-fos mRNA and cFos protein compared to those of non-transgenic littermates. Adaptive responses, however, appear to downregulate transcriptional regulators controlling c-fos gene including serum response factor and Ca2+/cAMP response element-binding protein. CSQ-overexpressing hearts also had decreased levels of cJun protein, resulting in downregulated AP-1 activity. The mRNA levels of angiotensin II type1a receptor which requires AP-1 and GATA-4 for gene transcription was suppressed in CSQ overexpressing hearts. These results demonstrate that CSQ can regulate GATA-4- and AP-1-dependent transcriptional events, indicating the existence of SR-nuclear circuits of signal transduction in adult cardiac muscle.

Animals↗
PubMed1999

Activation and Ca2+ permeation of stably transfected alpha3/beta4 neuronal nicotinic acetylcholine receptor.

The alpha3/beta4 rat neuronal nicotinic acetylcholine receptor, stably transfected in human embryonic kidney cells, was examined using the whole-cell-clamp technique and 2-dimensional confocal imaging. Application of agonists (nicotine, cytisine, epibatidine) activated a large (100-200 pA/pF) inwardly rectifying monovalent current, with little current at voltages between 0 and +40 mV. Rapid application of nicotine and cytisine indicated EC50 values of congruent with22 and congruent with64 microM, respectively, and suggested second order binding kinetics (Hill coefficient approximately 2). The time constant of desensitization (decay) of nicotine-activated current was concentration-dependent (typically approximately 10 s at 30 microM versus approximately 1.0 s at 100-1000 microM), but not voltage-dependent and was significantly smaller than the approximately 200 s reported for the alpha3/beta4 receptor expressed in Xenopus oocytes. Nicotine-activated current was rapidly and reversibly blocked by coapplication of mecamylamine and d-tubocurarine. At -80 mV holding potentials, the current was also suppressed by approximately 25% either upon complete removal or elevation of Ca2+ to 10 mM. Total replacement of Na+ by Ca2+ also completely blocked the current. On the other hand, evidence for permeation of Ca2+ was indicated by increased inward current at -40 mV upon elevation of Ca2+ from 2 to 10 mM, as well as a rise in the cytosolic Ca2+ proportional to the current carried by the receptor. These findings are consistent with the idea that Ca2+, in addition to its channel-permeating properties, may also regulate the receptor from an extracellular site. Our results suggest that the alpha3/beta4 neuronal nicotinic acetylcholine receptor, when stably expressed in human embryonic kidney 293 cells, has desensitization kinetics and Ca2+ regulatory mechanisms somewhat different from those described for the receptor expressed in Xenopus oocytes.

Animals↗
PubMed1999

BAY K 8644 modifies Ca2+ cross signaling between DHP and ryanodine receptors in rat ventricular myocytes.

The amplification factor of dihydropyridine (DHP)/ryanodine receptors was defined as the amount of Ca2+ released from the sarcoplasmic reticulum (SR) relative to the influx of Ca2+ through L-type Ca2+ channels in rat ventricular myocytes. The amplification factor showed steep voltage dependence at potentials negative to -10 mV but was less dependent on voltage at potentials positive to this value. In cells dialyzed with 0.2 mM cAMP in addition to 2 mM fura 2, the Ca2+-channel agonist (-)-BAY K 8644 enhanced Ca2+-channel current (ICa), shifted the activation curve by -10 mV, and significantly delayed its inactivation. Surprisingly, BAY K 8644 reduced the amplification factor by 50% at all potentials, even though the caffeine-releasable Ca2+ stores were mostly intact at holding potentials of -90 mV. In contrast, brief elevation of extracellular Ca2+ activity from 2 to 10 mM enhanced both ICa and intracellular Ca2+ transients in the absence or presence of BAY K 8644 but had no significant effect on the amplification factor. BAY K 8644 abolished the direct dependence of the rate of inactivation of ICa on the release of Ca2+ from the SR. These findings suggest that the gain of the Ca2+-induced Ca2+ release in cardiac myocytes is regulated by the gating kinetics of cardiac L-type Ca2+ channels via local exchange of Ca2+ signals between DHP and ryanodine receptors and that BAY K 8644 suppresses the amplification factor through attenuation of the Ca2+-dependent inactivation of Ca2+ channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗