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Biomedical subjects

T M Nguyen

Publications and source records attributed to T M Nguyen.

At least 19 recordsLinked to original sources
PubMed2002

Tryptophan missense mutation in the ligand-binding domain of the vitamin D receptor causes severe resistance to 1,25-dihydroxyvitamin D.

In this study, two related young children, brother and sister, exhibited severe vitamin D-resistant rickets without alopecia. Sequence analysis of the total vitamin D receptor (VDR) cDNA from skin fibroblasts revealed a substitution of the unique tryptophan of the VDR by arginine at amino acid 286 (W286R). Cultured skin fibroblasts of the two patients expressed normal-size VDR protein (immunocytochemistry and Western blotting) and normal length VDR mRNA (Northern blotting). But, these fibroblasts, as well as COS-7 cells transfected with the W286R mutant, failed to bind 3H 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The tryptophan substitution did not affect VDR trafficking toward the nucleus but abolished the 24-hydroxylase gene response to 1,25(OH)2D3, even at 10(-6) M concentrations. In conclusion, this case report of a new family with hereditary vitamin D-resistant rickets (HVDRR) emphasizes the crucial role of the VDR tryptophan for ligand binding and for transactivation of 1,25(OH)2D3 target genes. It clearly shows the clinical significance of this VDR amino acid for calcium homeostasis and bone mineralization. This observation suggests further that the presence of a stable VDR-bound ligand may not be obligatory for normal hair follicle development.

Amino Acid Sequence↗
PubMed2001

A novel reactivity of SeO(2) with 1,3-dienes: formation of syn 1,2- and 1,4-diols via a facile C-Se bond oxidation.

[reaction: see text] A novel reaction between 1,3-dienes and selenium dioxide to give syn 1,2- and 1,4-diol cyclic selenites was studied in detail. This study indicates that an initial concerted [4 + 2] cycloaddition followed by a stereospecific carbon-selenium bond oxidation is involved in this unprecedented syn dihydroxy addition reaction mediated by selenium dioxide.

Alcohols↗
PubMed2001

[2',6'-Dimethyltyrosine]dynorphin A(1-11)-NH2 analogues lacking an N-terminal amino group: potent and selective kappa opioid antagonists.

Recent studies showed that dermorphin and enkephalin analogues containing two methyl groups at the 2',6'-positions of the Tyr(1) aromatic ring and lacking an N-terminal amino group were moderately potent delta and mu opioid antagonists. These results indicate that a positively charged N-terminal amino group may be essential for signal transduction but not for receptor binding and suggested that its deletion in agonist opioid peptides containing an N-terminal 2',6'-dimethyltyrosine (Dmt) residue may represent a general way to convert them into antagonists. In an attempt to develop dynorphin A (Dyn A)-derived kappa opioid antagonists, we prepared analogues of [Dmt(1)]Dyn A(1-11)-NH2 (1), in which the N-terminal amino group was either omitted or replaced with a methyl group. This was achieved by replacement of Tyr(1) with 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) or (2S)-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(2S)-Mdp]. Compounds were tested in the guinea pig ileum and mouse vas deferens bioassays and in rat and guinea pig brain membrane receptor binding assays. All analogues turned out to be potent kappa antagonists against Dyn A(1-13) and the non-peptide agonist U50,488 and showed only weak mu and delta antagonist activity. The most potent and most selective kappa antagonist of the series was [(2S)-Mdp(1)]Dyn A(1-11)-NH2 (5, dynantin), which showed subnanomolar kappa antagonist potency against Dyn A(1-13) and very high kappa selectivity both in terms of its K(e) values determined against kappa, mu, and delta agonists and in terms of its ratios of kappa, mu, and delta receptor binding affinity constants. Dynantin is the first potent and selective Dyn A-derived kappa antagonist known and may complement the non-peptide kappa antagonists norbinaltorphimine and GNTI as a pharmacological tool in opioid research.

Animals↗
PubMed2001

Solution structure of the squash trypsin inhibitor MCoTI-II. A new family for cyclic knottins.

The "knottin" fold is a stable cysteine-rich scaffold, in which one disulfide crosses the macrocycle made by two other disulfides and the connecting backbone segments. This scaffold is found in several protein families with no evolutionary relationships. In the past few years, several homologous peptides from the Rubiaceae and Violaceae families were shown to define a new structural family based on macrocyclic knottin fold. We recently isolated from Momordica cochinchinensis seeds the first known macrocyclic squash trypsin inhibitors. These compounds are the first members of a new family of cyclic knottins. In this paper, we present NMR structural studies of one of them, MCoTI-II, and of a beta-Asp rearranged form, MCoTI-IIb. Both compounds display similar and well-defined conformations. These cyclic squash inhibitors share a similar conformation with noncyclic squash inhibitors such as CPTI-II, and it is postulated that the main effect of the cyclization is a reduced sensitivity to exo-proteases. On the contrary, clear differences were detected with the three-dimensional structures of other known cyclic knottins, i.e., kalata B1 or circulin A. The two-disulfide cystine-stabilized beta-sheet motif [Heitz et al. (1999) Biochemistry 38, 10615-10625] is conserved in the two families, whereas in the C-to-N linker, one disulfide bridge and one loop are differently located. The molecular surface of MCoTI-II is almost entirely charged in contrast to circulin A that displays a well-marked amphiphilic character. These differences might explain why the isolated macrocyclic squash inhibitors from M. cochinchinensis display no significant antibacterial activity, whereas circulins and kalata B1 do.

Amino Acid Sequence↗
PubMed2001

Pharmacological characterization of the dermorphin analog [Dmt(1)]DALDA, a highly potent and selective mu-opioid peptide.

The dermorphin-derived peptide [Dmt(1)]DALDA (H-Dmt-D-Arg-Phe-Lys-NH(2)), labels mu-opioid receptors with high affinity and selectivity in receptor binding assays. In mouse, radiant heat tail-flick assay [Dmt(1)]DALDA produced profound spinal and supraspinal analgesia, being approximately 5000- and 100-fold more potent than morphine on a molar basis, respectively. When administered systemically, [Dmt(1)]DALDA was over 200-fold more potent than morphine. Pharmacologically, [Dmt(1)]DALDA was distinct from morphine. [Dmt(1)]DALDA displayed no cross-tolerance to morphine in the model used and it retained supraspinal analgesic activity in morphine-insensitive CXBK mice. Supraspinally, it also differed from morphine in its lack of sensitivity towards naloxonazine. Finally, in antisense mapping studies, [Dmt(1)]DALDA was insensitive to MOR-1 exon probes that reduced morphine analgesia, implying a distinct receptor mechanism of action. Thus, [Dmt(1)]DALDA is an interesting and extraordinarily potent, systemically active peptide analgesic, raising the possibility of novel approaches in the design of clinically useful drugs.

Analgesics↗
PubMed2001

Nuclear gems and Cajal (coiled) bodies in fetal tissues: nucleolar distribution of the spinal muscular atrophy protein, SMN.

SMN, the affected protein in spinal muscular atrophy (SMA), is a cytoplasmic protein that also occurs in nuclear structures called "gems" and is involved in snRNP maturation. Coilin-p80 is a marker protein for nuclear Cajal bodies (coiled bodies; CBs) which are also involved in snRNP maturation, storage or transport. We now show that gems and CBs are present in all fetal tissues, even those that lack gems/CBs in the adult. Most gems and CBs occur as separate nuclear structures in fetal tissues, but their colocalization increases with fetal age and is almost complete in the adult. In adult tissues, up to half of all gems/CBs are inside the nucleolus, whereas in cultured cells they are almost exclusively nucleoplasmic. The nucleolar SMN is often more diffusely distributed, compared with nucleoplasmic gems. Up to 30% of cells in fetal tissues have SMN distributed throughout the nucleolus, instead of forming gems in the nucleoplasm. The results suggest a function for gems distinct from Cajal bodies in fetal nuclei and a nucleolar function for SMN. Spinal cord, the affected tissue in SMA, behaves differently in several respects. In both fetal and adult motor neurons, many gems/CBs occur as larger bodies closely associated with the nucleolar perimeter. Uniquely in motor neurons, gems/CBs are more numerous in adult than in fetal stages and colocalization of gems and CBs occurs earlier in development. These unusual features of motor neurons may relate to their special sensitivity to reduced SMN levels in SMA patients.

Adult↗
PubMed2001

Sequential use of Prepidil and extra-amniotic saline infusion for the induction of labor in nulliparous women with very low Bishop scores.

OBJECTIVE: To evaluate the efficacy of sequential use of Prepidil (prostaglandin E2 gel) and extra-amniotic saline infusion for the induction of labor in nulliparous women with very low Bishop scores. STUDY DESIGN: Nulliparous women with singleton gestations, intact membranes and a cervical Bishop score of < or = 2 who received Prepidil gel and extra-amniotic saline infusion sequentially for the induction of labor between July 1996 and July 1998 were studied. RESULTS: Thirty-one women met the inclusion criteria. Indications for induction included post-dates (six of 31), pre-eclampsia (ten of 31), diabetes (three of 31), oligohydramnios (three of 31), intrauterine growth restriction (two of 31) and non-reactive non-stress test (NST) (seven of 31). The average time from onset of induction to delivery was 38.1 +/- 13.5 h. Vaginal delivery was achieved in 80.6%. Women requiring > 2 doses of Prepidil had a higher risk of delivering abdominally (OR = 3.5). Three of seven (42.9%) women with labor induced for non-reactive NST but only three of 24 (12.5%) with labor induced for other indications had a Cesarean section delivery (p < 0.001). CONCLUSIONS: Nulliparous women with very unfavorable cervices can be counselled that they have an 80% chance of vaginal delivery using sequential Prepidil and extra-amniotic saline infusion as an induction method, with 90% delivering within the first 48 h.

Administration, Intravaginal↗
PubMed2001

In vitro comparison of peak polymerization temperatures of 5 provisional restoration resins.

BACKGROUND: The heat produced by provisional restoration materials may injure the dental pulp. This study measured and compared peak temperatures during polymerization of 5 materials used in the fabrication of provisional restorations. METHODS: The tested materials were 2 self-curing resins (Integrity and Protemp) and 3 dual-cure resins (Iso-Temp, TCB Dual Cure and Provipont DC). A mould the size of a maxillary molar tooth was fabricated to contain 0.5 cc of resin. The temperature rise of the different materials was recorded every 10 seconds over a 10-minute period. RESULTS: The rise in temperature of Integrity (peak temperature of 33.8 degrees C) and Protemp Garant (35.6 degrees C) was significantly higher than the rise in temperature of Iso-Temp (29.5 degrees C), TCB Dual Cure (28.4 degrees C) and Provipont DC (29.5 degrees C). CONCLUSION: Use of the dual-cure resins in provisional restorations may reduce the risk of pulp injury.

Acrylic Resins↗
PubMed2001

Relationship between normal amniotic fluid index and birth weight in term patients presenting for labor.

OBJECTIVE: To investigate whether a relationship between birth weight (BW) and amniotic fluid index (AFI) existed for term patients with intact membranes and, if so, whether it could predict macrosomia and intrauterine growth retardation. STUDY DESIGN: Two hundred thirty-one eligible women at term (37-42 weeks' gestation) had an AFI between 5.0 and 24.0 cm at the time of admission. Demographic information was collected, including BW. Statistical comparisons were made, with significance set at P < .05. RESULTS: The mean gestational age was 39.5 weeks, and the mean AFI was 11.3. There were 28 infants with BWs > 4,000 g (macrosomia). The cesarean section rate was 16.9%. Macrosomia was associated with a higher cesarean section rate (39.2% vs. 13.8%, P < .002). The mean AFI was higher for those with macrosomia (13.5 vs. 11.0, P < .001). Patients with an AFI > 15.0 had over twice the incidence of macrosomia (RR 2.72, 1.1-6.6, 32.1% vs. 14.8%, P < .027). The risk was even greater for them with an AFI > 18.0 (RR 6.4, 2.2-18.7, P < .002). A linear relationship was observed between AFI and BW (r2 .061, P < .0001). BW increased with increasing AFI. No relationship between AFI of 5-8 and BW < 2,500 g was found. CONCLUSION: Increasing AFI correlates linearly with increasing BW, and macrosomia is associated with an increased incidence of cesarean delivery. AFI > 15 carries over double the risk of birth of a macrosomic infant, while AFI > 18 has a risk of over six times. No association between low normal AFI and a growth-restricted infant was found.

Amniotic Fluid↗
PubMed2000

Characterization of a monoclonal antibody panel shows that the myotonic dystrophy protein kinase, DMPK, is expressed almost exclusively in muscle and heart.

Myotonic dystrophy (DM) is a multisystemic disorder caused by an inherited CTG repeat expansion which affects three genes encoding the DM protein kinase (DMPK), a homeobox protein Six5 and a protein containing WD repeats. Using a panel of 16 monoclonal antibodies against several different DMPK epitopes we detected DMPK, as a single protein of approximately 80 kDa, only in skeletal muscle, cardiac muscle and, to a lesser extent, smooth muscle. Many earlier reports of DMPK with different sizes and tissue distributions appear to be due to antibody cross-reactions with more abundant proteins. One such antibody, MANDM1, was used to isolate two related protein kinases, MRCK alpha and beta, from a human brain cDNA library and the shared epitope was located at the catalytic site of DMPK using a phage-displayed random peptide library. The peptide library also identified an epitope shared between DMPK and a 55 kDa muscle-specific protein. The results suggest that effects of the repeat expansion on the DMPK gene may be responsible for muscle and heart features of DM, whereas clinical changes in other tissues may be due to effects on the other two genes.

Amino Acid Sequence↗
PubMed2000

Squash trypsin inhibitors from Momordica cochinchinensis exhibit an atypical macrocyclic structure.

Three trypsin inhibitors (TIs), from the seeds of the squash Momordica cochinchinensis (MCo), have been isolated and purified using gel filtration, ion exchange chromatography, and reverse-phase HPLC. Their sequences could be determined only after proteolytic cleavages. In the case of MCoTI-I and -II, it was shown that their polypeptide backbones are cyclic, a structure that has never been described in squash TIs. They contain 34 amino acid residues with 3 disulfide bridges and measured molecular masses of 3453.0 and 3480.7, respectively. They are the largest known macrocyclic peptides containing disulfide bridges. Their sequences show strong homology to other squash TIs, suggesting a similar three-dimensional structure and an analogous mechanism of action. A model of MCoTI-II was constructed by analogy to the crystal structure of the complex between bovine trypsin and CMTI-I, indicating that the linker connecting the two termini is flexible and does not impose significant geometrical constraints. This flexibility allows an Asp-Gly peptide bond rearrangement to occur in this region, giving rise to two isoforms of MCoTI-II. Although the importance of cyclization is not clear, it might confer increased stability and resistance to proteolysis. A minor species, MCoTI-III, was also characterized as containing 30 amino acid residues with a molecular mass of 3379.6. This component possesses a linear backbone with a blocked N-terminus. MCoTIs represent interesting candidates for drug design, either by changing their specificity of inhibition or by using their structure as natural scaffolds bearing new binding activities.

Amino Acid Sequence↗
PubMed2000

Novel ligands lacking a positive charge for the delta- and mu-opioid receptors.

Recently we reported using minilibraries to replace Lys(9) [somatostatin (SRIF) numbering] of the potent somatostatin agonist L-363,301 (c[-Pro-Phe-D-Trp-Lys-Thr-Phe-]) to generate the potent neurokinin receptor (NK-1) antagonist c[-Pro-Phe-D-Trp-p-F-Phe-Thr-Phe-]. This novel cyclic hexapeptide did not bind the SRIF receptor. Thus, a single mutation converted L-363,301, a SRIF agonist with potency ca. 2-8 times the potency of SRIF in laboratory animals,(24) into a selective NK-1 receptor antagonist with an IC(50) of 2 nM in vitro. During the screening of the same libraries for ligands of the delta-opioid receptor, we identified four compounds (1-4) which represent a new class of delta-opioid antagonists, some of which were also NK-1 receptor antagonists. The most potent delta-opioid antagonist, c[-Pro-1-Nal-D-Trp-Tyr-Thr-Phe-] (2), showed a K(e) value of 128 nM in the mouse vas deferens assay and a delta-receptor binding affinity constant of 152 nM in the rat brain membrane binding assay. These results are of interest because they represent a novel class of delta-opioid antagonists and, like two previously reported delta-opioid antagonists, they lack a positive charge. To examine further the requirement for a positive charge in the delta-opioid ligands, we prepared two analogues of the beta-casomorphin-derived mixed mu-agonist/delta-antagonist, H-Dmt-c[-D-Orn-2-Nal-D-Pro-Gly-] (7), in which we eliminated the positive charge either through formylation of the primary amino group (5) or by the deletion of this N-terminal amino group (6). These latter compounds proved to be delta-opioid antagonists with K(e) values in the 16-120 nM range, as well as fairly potent mu-opioid antagonists (K(e) approximately 200 nM). These six compounds provide the most convincing evidence to date that there is no requirement for a positive charge in mu- and delta-opioid receptor antagonists. In addition, cyclic hexapeptide 4 lacks a phenolic hydroxyl group. Taken together, these data suggest that the prevailing assumptions about delta- and mu-opioid receptor binding need revision and that the receptors for these opioid ligands have much in common with the NK-1 and somatostatin receptors.

Animals↗
PubMed2000

Matrix-assisted laser desorption/ionization mass spectrometric quantification of the mu opioid receptor agonist DAMGO in ovine plasma.

The synthetic opioid peptide analog Tyr-D-Ala-Gly-N-methyl-Phe-Gly-ol (DAMGO), which is a mu opioid receptor-selective agonist, was quantified in ovine plasma samples with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS), using delayed extraction and a reflectron. The internal standard was pentadeuterated DAMGO. Timed-ion selection was used to select the precursor ion. The analysis of the post-source decay fragments improved the detection sensitivity, and the use of the precursor-product ion relationship optimized the specificity. For plasma samples, the inter-assay variability of this method was 6.4% (n = 79) and the intra-assay variability was 6.0% (n = 10). The variability for controls was 3.4% (n = 43). The profile of DAMGO amount versus time was determined in sheep plasma, and the corresponding pharmacokinetic data were calculated.

Analysis of Variance↗
PubMed2000

Synthesis and in vitro opioid activity profiles of DALDA analogues.

The tetrapeptide DALDA (H-Tyr-D-Arg-Phe-Lys-NH2) is a polar and selective mu agonist showing poor penetration of the placental and blood-brain barriers. In an effort to enhance the potency of DALDA, analogues containing 2',6'-dimethyltyrosine (Dmt), N,2',6'-trimethyltyrosine (Tmt), 2'-methyltyrosine (Mmt) or 2'-hydroxy,6'-methyltyrosine (Hmt) in place of Tyr1, or Orn or alpha,gamma-diaminobutyric acid (A2bu) in place of Lys4, were synthesized. All compounds displayed high mu receptor selectivity in the rat and guinea pig brain membrane binding assays and most of them were more potent mu agonists than DALDA in the mu receptor-representative guinea pig ileum assay, with [Dmt1]DALDA showing the highest potency. Because of its extraordinary mu agonist potency, high mu selectivity, polar character (charge of 3 + ) and metabolic stability, [Dmt1]DALDA has potential for use in obstetrical or peripheral analgesia.

Analgesics↗
PubMed2000

Digital overlay technique for documenting toric intraocular lens axis orientation.

PURPOSE: To describe a digital overlay technique for documenting toric intraocular lens (IOL) axis alignment. SETTING: Jules Stein Eye Institute and the Department of Ophthalmology, University of California at Los Angeles School of Medicine, Los Angeles, California, USA. METHODS: Digital overlay imaging was used to evaluate the alignment of Staar toric IOLs in 4 eyes of 3 patients who had regular corneal astigmatism at the time of cataract surgery. Lens axes were determined by computerized analysis of digitally scanned retroillumination photographs. A stock digital image of a Staar AA4203TF toric IOL was superimposed on corneal topography images to document IOL alignment with the steep corneal meridian. RESULTS: Digital overlay images demonstrated that 3 IOLs in the sample group were within 5 degrees and 1 was within 20 degrees of the intended axis at the time of the final postoperative examination. Slitlamp lens axis estimations were 3 to 18 degrees different from that determined by this technique. CONCLUSION: Digital overlay imaging of correctly oriented toric IOLs on computerized corneal topography maps represents an intuitive, accurate, and visually appealing method of documenting toric IOL axis alignment.

Aged↗
PubMed2000

Imaging the sphenoid sinus: pictorial essay.

This paper focuses on the spectrum of sphenoid sinus lesions that may be seen radiologically and the mapping of disease extent. Imaging plays a central role in the assessment of sphenoid sinus disease. Although primary sphenoid sinus disease is uncommon, this sinus is nevertheless affected secondarily by a variety of pathological processes.

Humans↗
PubMed2000

Expectant management of severe preterm preeclampsia: is intrauterine growth restriction an indication for immediate delivery?

OBJECTIVE: Expectant management of severe preterm preeclampsia is gaining widespread acceptance in clinical practice. The objective of our study was 2-fold-to determine the frequency of fetal deterioration with expectant management of severe preterm preeclampsia and to evaluate whether the presence of intrauterine growth restriction on admission is associated with a shorter admission-to-delivery interval or more deliveries resulting from nonreassuring fetal status in comparison with pregnancies with preeclampsia but without intrauterine growth restriction. STUDY DESIGN: This was an observational study of women with singleton pregnancies at <34 completed weeks' gestation who were admitted to the hospital with the diagnosis of severe preeclampsia and managed expectantly. Fetal status on admission, admission-to-delivery interval, indication for delivery, and neonatal outcome were examined. RESULTS: Forty-seven women were studied during a 3-year period (1996-1999). Gestational age at admission was 29.8 +/- 2.6 weeks. The mean admission-to-delivery interval for the entire group was 6.0 +/- 5.1 days; in 42.5% delivery was for fetal indications. In comparison with the absence of intrauterine growth restriction, the presence of intrauterine growth restriction at admission resulted in a significantly shorter admission-to-delivery interval (3.1 +/- 2.1 vs 6.6 +/- 6.1 days; P <.05). Most fetuses with intrauterine growth restriction (85.7%) were delivered before 1 week. Although 57% of fetuses with intrauterine growth restriction were delivered for fetal indications, versus 39% of fetuses without intrauterine growth restriction, these rates were not found to be significantly different. Neonatal outcomes, as reflected by Apgar scores, number of admissions to and duration of stay in the neonatal intensive care unit, and neonatal mortality rates, were similar. CONCLUSION: Pregnancies complicated by severe preterm preeclampsia and the presence of intrauterine growth restriction at admission may not benefit from expectant management beyond the 48 hours needed for betamethasone to act. Furthermore, all patients may benefit from close fetal monitoring before delivery because of the high rate of intervention for deteriorating fetal status.

Adolescent↗