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Biomedical subjects

D Srivastava

Publications and source records attributed to D Srivastava.

At least 55 records · Page 3Linked to original sources
PubMed1996

Molecular pathways controlling heart development.

Heart formation requires complex interactions among cells from multiple embryonic origins. Recent studies have begun to reveal the genetic pathways that control cardiac morphogenesis. Many of the genes within these pathways are conserved across vast phylogenetic distances, which has allowed cardiac development to be dissected in organisms ranging from flies to mammals. Studies of cardiac development have also revealed the molecular defects underlying several congenital cardiac malformations in humans and may ultimately provide opportunities for genetic testing and intervention.

Animals↗
PubMed1995

A subclass of bHLH proteins required for cardiac morphogenesis.

Skeletal muscle development is controlled by a family of muscle-specific basic helix-loop-helix (bHLH) transcription factors. Two bHLH genes, dHAND and eHAND, have now been isolated that are expressed in the bilateral heart primordia and subsequently throughout the primitive tubular heart and its derivatives during chick and mouse embryogenesis. Incubation of stage 8 chick embryos with dHAND and eHAND antisense oligonucleotides revealed that either oligonucleotide alone had no effect on embryonic development, whereas together they arrested development at the looping heart tube stage. Thus, dHAND and eHAND may play redundant roles in the regulation of the morphogenetic events of vertebrate heart development.

Actins↗
PubMed1995

Hepatic venous blood and the development of pulmonary arteriovenous malformations in congenital heart disease.

BACKGROUND: Pulmonary arteriovenous malformations (PAVMs) are a known complication after some types of cavopulmonary anastomoses (CVPAs). Their cause is unknown, but they may be related to the absence of pulsatile flow or the presence or absence of circulating factors. These PAVMs are diffuse and are presumed to be progressive and irreversible. METHODS AND RESULTS: All patients with congenital heart disease (CHD) seen at Children's Hospital, Boston, Mass, between 1970 and 1993 were reviewed. We report on the 10 patients with CHD who were found to have developed PAVMs, as diagnosed by cardiac catheterization. Diagnoses included heterotaxy syndrome/polysplenia, with interrupted inferior vena cava and hepatic veins draining to the right atrium (n = 6); heterotaxy/asplenia (n = 1); corrected transposition with pulmonary stenosis (n = 1); and biliary atresia and associated CHD (n = 2). PAVMs were diagnosed 0.1 to 7.0 years (median, 3.5 years) after creation of a CVPA that resulted in exclusion of hepatic venous flow from one or both lungs in 8 of the 10 patients; the remaining 2 patients had normal drainage of hepatic veins to the lungs but had biliary atresia. In all, the common anatomic feature was the exclusion of normal hepatic venous return from the affected pulmonary arterial circulation. All patients with interrupted inferior vena cava, azygous continuation to the superior vena cava, and hepatic veins draining to the right atrium (polysplenia syndrome) were reviewed to determine the incidence of PAVMs in those with CVPA (ie, hepatic venous flow excluded from the pulmonary arteries) and without CVPA. Six of 28 (21%) of those with versus 1 of 56 (1.8%) of those without CVPA developed PAVMs (P = .004). The 1 patient without CVPA who had PAVMs also had biliary atresia. Among patients with CVPA, the probability of developing PAVMs was 15% and 28% at 3 and 5 years, respectively, after CVPA. The histological and angiographic appearances of PAVMs after CVPA are similar to those seen in PAVMs associated with hepatic cirrhosis. CONCLUSIONS: We postulate that PAVMs after CVPA are related to the diversion of normal hepatic venous flow from the pulmonary circulation. In this sense, these PAVMs may be analogous to those associated with liver disease, which have been found to resolve after liver transplantation. Redirection of hepatic flow to the pulmonary bed in some patients with CHD and PAVMs may lead to reversibility of the PAVMs.

Adult↗
PubMed1995

Effects of magnesium on cyclic GMP hydrolysis by the bovine retinal rod cyclic GMP phosphodiesterase.

Knowledge of the kinetics of the rod cyclic GMP phosphodiesterase is essential for understanding the kinetics and gain of the light response. Therefore, the interactions between Mg2+, cyclic GMP, and purified, trypsin-activated bovine rod cyclic GMP phosphodiesterase (EC 3.1.4.17) were examined. The effects of Mg2+ and of cyclic GMP on the rod phosphodiesterase activity were mutually concentration-dependent. Formation of a free Mg-cyclic GMP complex is unlikely due to its high dissociation constant (Kd = 19 mM). Plots of 1/velocity versus 1/[cyclic GMP] as a function of [Mg2+] and 1/velocity versus 1/[Mg2+] as a function of [cyclic GMP] intersected to the left of the 1/velocity axis. This is consistent with the formation of a ternary complex between the phosphodiesterase, Mg2+, and cyclic GMP. A competitive inhibitor of the phosphodiesterase relative to cyclic GMP, 3-isobutyl-1-methylxanthine, non-competitively inhibited the enzyme relative to Mg2+, Pb2+, a competitive inhibitor of the phosphodiesterase relative to Mg2+ [D. Srivastava, R.L. Hurwitz and D. A. Fox (1995) Toxicol. Appl. Pharmacol, in the press] non-competitively inhibited the enzyme relative to cyclic GMP. Collectively these results are suggestive of a rapid equilibrium random binding order of Mg2+ and cyclic GMP to the rod phosphodiesterase.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1995

Lead- and calcium-mediated inhibition of bovine rod cGMP phosphodiesterase: interactions with magnesium.

Previously we showed that cGMP hydrolysis in rat whole retinal homogenates exhibited a dose-dependent inhibition following developmental lead exposure and a concentration-dependent inhibition with direct Pb2+ exposure. Additionally, developmental lead exposure resulted in a dose-dependent increase in retinal cGMP and rod Ca2+ levels. To determine whether Pb2+ or Ca2+ directly inhibited the rod-specific cGMP phosphodiesterase (PDE) and to examine the kinetic mechanism of this inhibition, purified bovine rod cGMP PDE was assayed in the presence of varying concentrations of cGMP, and Mg2+, Pb2+, and/or Ca2+. Increasing concentrations of the substrate, cGMP, resulted in a shift of the Pb2+ and Ca2+ concentration-response curves to the left, indicating a decrease in the half-maximal inhibitory concentrations of Pb2+ from nanomolar to picomolar levels. Increasing concentrations of the cofactor, Mg2+, resulted in a shift of the Pb2+ and Ca2+ concentration-response curves to the right, indicating a decrease in the inhibition of PDE activity by Pb2+ or Ca2+. A plot of 1/velocity vs 1/Mg2+ as a function of Pb2+ revealed that picomolar concentrations of Pb2+ competitively inhibited PDE relative to millimolar concentrations of Mg2+. Consistent with this finding, Mg2+ reversed the Pb(2+)-induced inhibition of PDE. Our recent kinetic analysis showed that Mg2+ and cGMP bind at interacting sites on the PDE in a random order. The present results reveal that Pb2+ may bind at the same site but with 4-6 log units higher affinity than Mg2+, thus preventing the hydrolysis of cGMP. These findings provide a novel mechanism for understanding the Pb(2+)-induced inhibition of cGMP PDE. These results may have implications for other enzymes using Mg2+ as a cofactor and suggest that Mg2+ may be useful in these situations for reversing the inhibition by Pb2+.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1995

Molecular mechanism of the lead-induced inhibition of rod cGMP phosphodiesterase.

Retinal cGMP hydrolysis is inhibited following developmental and in vitro lead exposure. To determine whether Pb2+ directly inhibits the rod-specific cGMP phosphodiesterase (PDE) and to examine the kinetic mechanism of this inhibition, purified bovine rod cGMP PDE was assayed at varying [cGMP], [Mg2+] and [Pb2+]. Increasing [cGMP] or [Mg2+] shifted the Pb2+ curves leftward or rightward revealing increased or decreased potency of Pb2+ (nM to pM range), respectively. A 1/velocity vs. 1/mg2+ plot revealed that picomolar [Pb2+] competitively inhibited PDE relative to millimolar [Mg2+]. These novel findings reveal that Pb2+ binds at the Mg2+ site but with 4-6 log units higher affinity, thus preventing cGMP hydrolysis. These results may have implications for other enzymes using Mg2+ as a co-factor and suggest that Mg2+ may be useful for reversing the PDE inhibition by Pb2+.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1994

The Dautrey procedure in recurrent dislocation: a review of 12 cases.

The Dautrey procedure was used to treat 12 patients with chronic recurrent dislocation of the temporomandibular joint. There was no recurrent dislocation in 11 patients during a follow-up period of up to 5 years and 2 months, and joint function appeared to be undisturbed. The surgical procedure and evaluation of the results are presented.

Adult↗
PubMed1994

Lead-induced alterations in rod-mediated visual functions and cGMP metabolism: new insights.

Long-term scotopic (rod-mediated) visual deficits following developmental lead exposure occur in monkeys and hooded rats. This report describes and summarizes previous ERG and biochemical findings, presents new biochemical data aimed at determining the mechanism of inhibition of lead on rod cGMP-PDE, presents an integratory framework for understanding the ERG and cGMP results and speculates on the implications of the present data. A- and b-wave voltage-log intensity and latency-log intensity functions, generated from single-flash ERGs in fully dark-adapted rats, revealed that low and moderate level lead exposure caused decreases in absolute sensitivity and amplitude, and increases in latency. Rod- and cone-mediated flicker fusion frequency measures revealed selective rod deficits in temporal resolution. In addition, the slope of the increment threshold function was decreased, but only at scotopic adapting backgrounds, and dark adaptation was delayed. Prior exposure to lead produced a dose-response inhibition of retinal cGMP-phosphodiesterase (PDE) resulting in an increase in cGMP in dark-adapted and light-adapted states and an increase in the calcium content of rods. In vitro experiments with adult rat retinas incubated with 10(-9) to 10(-4) M Pb2+ revealed a concentration-dependent inhibition of cGMP-PDE which suggested that Pb2+ directly inhibited the rod cGMP-PDE. This was confirmed in experiments conducted with isolated, purified, trypsin-activated bovine rod cGMP-specific PDE exposed to 5 x 10(-8) to 10(-4) M Pb2+. The cGMP data are entirely consistent with the observed ERG changes. The ERG data is relevant to low level pediatric lead poisoning since rat rods are similar to human rods. Finally, since a lesion in the gene that codes for a cAMP-PDE leads to defective learning and memory in the Drosophila dunce flies, it is possible that lead-induced alterations in cyclic nucleotide phosphodiesterases contribute to the long-term CNS deficits produced by developmental lead exposure.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1990

Two glucocorticoid binding sites on the human glucocorticoid receptor.

Glucocorticoids are known to have a lytic effect in leukemic cells via interactions with the glucocorticoid receptor (GR). Cortisol and various synthetic glucocorticoids bind to the GR with one-site kinetics. Cortivazol (CVZ) is a unique, high potency synthetic glucocorticoid, which has a phenylpyrazol fused to the A-ring of the steroid nucleus and displays binding consistent with two or more sites in the cytosol from CEM C7 cells (a human acute lymphoblastic T-cell line). It has previously been shown that the lower affinity class of sites are similar in affinity and site molarity to those recognized by dexamethasone. The higher affinity sites bind CVZ with 20- to 50-fold greater affinity, consistent with CVZ's enhanced biological effects. In mutant leukemic cells resistant to the lytic effects of dexamethasone, CVZ both lyses the cells and recognizes a single class of sites similar to the high affinity site in CEM C7 cells. We have carried out experiments to define the nature of the higher affinity CVZ binding site. We now show that: 1) CVZ has more than one binding site in a second, independent, B-cell line, IM-9; 2) the antiglucocorticoid RU 38486 is able to block both CVZ's higher and lower affinity sites; 3) all of CVZ's binding sites are on a protein immunologically indistinguishable from the human GR; and 4) freshly isolated clones of CVZ-resistant cells have lost all binding sites for CVZ. These data indicate that CVZ is recognizing two glucocorticoid binding sites on the human GR or a protein very similar to it.

B-Lymphocytes↗
PubMed1990

Cross-sectional study to evaluate variations in attached gingiva and gingival sulcus in the three periods of dentition.

The dimensional differences of the attached gingiva and gingival sulcus in the primary, mixed and permanent dentition were studied clinically in normal gingivae of 382 children, aged 4-15 years. The depth of the gingival sulcus and the width of keratinized gingiva were also measured. Shallow gingival sulcus was observed in the primary dentition as compared to that in permanent dentition. However, in the mixed dentition deeper sulcus was observed around the newly erupted teeth. This was attributed to deeper penetration of the instrument, at the time of eruption. The widest zone of attached gingiva was observed in maxillary and mandibular incisors, decreasing gradually over the cuspids and first premolars (first primary molars), and again attached gingiva increased in second premolars (second primary molars) and first and second permanent molars. The width of attached gingiva in case of newly erupted permanent teeth (mixed dentition) was narrower in the corresponding primary teeth. This was due to an increase in the gingival sulcus depth. The attached gingiva increased in width with age. This was related to a concomitant reduction in sulcus depth.

Adolescent↗
PubMed1989

Interactions of the phenylpyrazolo steroid cortivazol with glucocorticoid receptors in steroid-sensitive and -resistant human leukemic cells.

The interactions of glucocorticoids with their receptors somehow determine the cellular responses seen. The high potency glucocorticoid cortivazol differs from the usual glucocorticoids in two ways, structurally and in binding to receptors. Cortivazol contains a phenylpyrazol fused at carbon atoms 2 and 3 to the A ring of the cyclophenathrene, replacing the supposedly essential 3-keto,4,5-double bond pattern of glucocorticoids. Cortivazol binds to the glucocorticoid receptor in the cytosol from CEM C7 cells (a human acute lymphoblastic leukemia line) in a fashion consistent with interaction with at least two sites. Standard glucocorticoids show only one-site binding. In mutant leukemia cells derived from CEM C7, resistant to kill by 10(-6) M dexamethasone and deficient in standard glucocorticoid binding sites, cortivazol still finds a binding site and kills the cells. In wild-type leukemia cells, the binding sites of cortivazol, those with both higher (Kd approximately 5 x 10(-10) M) and lower (Kd approximately 1 x 10(-8] affinity appear to be on forms of the glucocorticoid receptor itself, and not on two different classes of molecules.

Alleles↗