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PubMed1986

[Volatile anesthetics and tricyclic antidepressives. A case study].

Tricyclic antidepressants (TAD) are administered for therapy of nearly all types of depression. Interactions with anaesthetics are well known and are reported frequently in the literature. A case report about incidental findings from a series of experimental anaesthesias in healthy volunteers using different inhalation anaesthetics is presented enabling discussion of the problem of a possibly increased risk of anaesthesia in the presence of chronic TAD medication. 16 unpremedicated healthy subjects (mean age 27 +/- 4 y) received, at intervals of four weeks, inhalation anaesthesia by breathing spontaneously one of the volatile anaesthetics halothane, enflurane, or isoflurane in oxygen. The aim of the study was to investigate the influence of volatile anaesthetics on the human electroencephalogram. When evaluating the results an atypical increase of heart rate during anaesthesia was noticed in one subject. This tachycardia appeared during all three types of anaesthesia, all other observed parameters being normal. With the knowledge of these facts the volunteer was interviewed more thoroughly. He then admitted to have taken daily 125-175 mg of the TAD amitriptyline during the whole period of experiments (self-medication from lover's grief). We supposed therefore that the tachycardia during anaesthesia could be interpreted as an interaction between the TAD amitriptyline and the volatile anaesthetics halothane, enflurane, and isoflurane. After having discontinued TAD medication for some months, the volunteer, a medical student, repeated the experimental isoflurane anaesthesia with all other conditions identical. This time his heart rate did not differ from that of the other subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

[Grover disease: a disease remotely related to malignant tumors of internal organs].

On the basis of their own findings and literature the authors attempt to give a survey of transient acantholytic dermatosis (TAD) described by Grover. The occurrence, etiology, histological types and other features of TAD are discussed with special attention paid interest to its relation to malignant tumors of internal organs. 18 cases of TAD with concomitant internal malignancy have been reported up to now. According to the authors TAD is loosely associated with neoplasm of internal organs. It is suggested that all patients suffering from TAD should be investigated for underlying primary condition (i.e.tumors) and direct immunofluorescence studies may be helpful to clear the etiology.

Acantholysis↗

PubMed1996

Nutrient intake of patients with rheumatoid arthritis is deficient in pyridoxine, zinc, copper, and magnesium.

OBJECTIVE: To determine nutrient intake of patients with active rheumatoid arthritis and compare it with the typical American diet (TAD) and the recommended dietary allowance (RDA). METHODS: 41 patients with active RA recorded a detailed dietary history. Information collected was analyzed for nutrient intake of energy, fats, protein, carbohydrate, vitamins and minerals, which were then statistically compared with the TAD and the RDA. RESULTS: Both men and women ingested significantly less energy from carbohydrates [women 47.4% (6.4) vs 55% RDA. p = 0.0001: men = 48.9% (7.4). p = 0.025] and more energy from fat [women = 36.8% (4.5) vs 30% RDA. p = 0.001 and men = 35.2% (5.9) p = 0.02]. Women ingested significantly more saturated and mono-unsaturated fat than the RDA (p = 0.02 and p = 0.04 respectively) while men ingested significantly less polyunsaturated fat (PUFA) (p = 0.0001). Both groups took in less fiber (p = 0.0001). Deficient dietary intake of pyridoxine was observed vs the RDA for both sexes (men and women p = 0.0001). Deficient folate intake was seen vs the TAD for men (p = 0.02) with a deficient trend in women (p = 0.06). Zinc and magnesium intake was deficient vs the RDA in both sexes (p values < or = 0.001) and copper was deficient vs the TAD in both sexes (p = 0.004 women and p = 0.02 men). CONCLUSION: Patients with RA ingest too much total fat and too little PUFA and fiber. Their diets are deficient in pyridoxine, zinc and magnesium vs the RDA and copper and folate vs the TAD. These observations, also documented in previous studies, suggest that routine dietary supplementation with multivitamins and trace elements is appropriate in this population.

Arthritis, Rheumatoid↗

PubMed1996

Dominant-negative mutants of cJun inhibit AP-1 activity through multiple mechanisms and with different potencies.

We have previously described a dominant-negative mutant of cJun that lacks the transactivation domain (TAD) of cJun and prevents AP-1-mediated transcriptional activation by quenching endogenous Jun or Fos proteins. We now report the development of a panel of cJun mutants that have inactivating mutations in the TAD, DNA-binding domain (DBD), or leucine zipper domain. These mutants are all unable to activate transcription, but only TAD and DBD mutants function in a dominant-negative fashion by inhibiting both cJun-induced transcriptional activation and transformation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate in ras-transfected rat embryo cells. Although the TAD and DBD mutants both function as transdominant inhibitors, they work through different mechanisms and with different inhibitory potencies. The DBD mutants, which function by inhibiting DNA binding, are relatively weak inhibitors, whereas the TAD mutants inhibit by quenching and are much more potent. Dimerization assays demonstrate that mutations in the DBD decrease the dimerization affinity of these mutants with cJun. These results demonstrate that the most potent dominant-negative mutants of cJun are proteins that have intact DBDs and quench the activity of the endogenous transcription factors.

Animals↗

PubMed1982

Treatment of acute myelogenous leukemia: influence of three induction regimens and maintenance with chemotherapy or BCG immunotherapy.

The effect of a synchronizing-recruiting drug schedule vs. myelotoxic therapy on remission rate and of Bacillus Calmette-Guerin on remission duration and survival of adults with acute myelogenous leukemia were studied in a prospective cooperative trial. After randomized remission induction with Arabinosyl Cytosine + vincristine + methotrexate + leucovorin (AVML), thioguanine + Ara-C + Daunorubin (TAD), or Daunorubicin + Ara-C (DA), complete remissions (CR) were consolidated with TAD or AVML. CRs were maintained with BCG vaccination (Tice strain) by the tine technique, or BCNU plus Ara-C (B/A), or no further therapy (NFT). Of 209 evaluable TAD patients, 105 (50%) achieved CR; of 187 DA, 97 (52%) achieved CR. AVML yielded only 15 CR among 59 patients (25%). The time to remission was significantly shorter with DA compared with TAD. Ninety-seven patients were randomized to maintenance therapy (35 B/A, 30 BCG, 32 NFT). There were no differences in remission duration (7, 8, 6 months) or survival (16, 22, 16 months, respectively). Manipulation of the cell cycle, as employed in this study, was not helpful. There may be a marginal effect of BCG, but our data fail to show a statistically significant benefit.

Adolescent↗

PubMed1977

Tricyclic antidepressant plasma levels and adverse effects after overdose.

Forty patients ingesting tricyclic antidepressant (TAD) overdoses were studied as a pharmacologic model to determine whether total tricyclic antidepressant plasma levels correlated with major adverse effects and electrocardiographic findings. Maximum TAD plasma levels were higher in patients who died (p less than 0.025) or had cardiac arrest (p less than 0.02), needed respiratory support (p less than 0.005), were unconscious (p less than 0.02), had grand mal seizures (p less than 0.001), ventricular rate larger than or equal to 120/min (p less than 0.01), cardiac arrhythmia (p less than 0.05), QRS duration larger than or equal to 100 msec (p less than 0.001), or bundle branch block (p less than 0.05). TAD plasma levels correlated with the dose ingested by history (N = 29, r = 0.58, p less than 0.001). Measurement of total TAD (free and protein-bound) appears to correlate well with biologic response.

Antidepressive Agents, Tricyclic↗

PubMed1997

High-performance liquid chromatographic separation of microcystins derivatized with a highly fluorescent dienophile.

Microcystins are potent hepatotoxins produced by cyanobacteria, and are also tumor promoters as well as potent inhibitors of the catalytic subunits of protein phosphatases 1 and 2A. In order to establish a physicochemical method for individual detection and determination of trace amounts of microcystins, we developed a derivatization method for fluorescence (FL) and chemiluminescence (CL) detection, in which a highly fluorescent dienophile, DMEQ-TAD (4-[2-(6,7-dimethoxy-4-methyl-3-oxo-3,4-dihydroquinoxalinyl) ethyl]-1,2,4-triazoline-3,5-dione), was used as the labeling reagent. DMEQ-TAD reacted smoothly with the conjugated diene of the Adda moiety to give 2 stereoisomers of the adducts. As a result of the extensive experiments, the following reaction conditions were optimized for the labeling: sample amount, 10 micrograms; reaction solvent, DMF:acetonitrile (1:1); reaction time, 15 minutes; reaction temperature, 70 degrees C; amount of DMEQ-TAD used relative to that of microcystin, 80 equivalent. The resulting 6 adducts from microcystins-LR, -YR, and -RR can be separated from one another using the following reversed phase HPLC conditions in combination with a clean-up using ODS silica gel: column, Cosmosil 5C18-AR (150 x 4.6 I.D. mm); mobile phase, methanol:0.05M phosphate buffer (pH 3) (1:1); flow rate, 1.0 ml/min; detection, FL lambda ex 370 nm, lambda em 440 nm. The detection limits of the DMEQ-TAD derivatives were estimated to be 100 and 500 pg for LR, and 65 and 2,500 pg for RR using FL and CL detections, respectively; and the detection behavior was different from that of the Dns-Cys derivatives, which were more sensitive to CL than FL.

Bacterial Toxins↗

PubMed1996

Genetic analysis of the bovine papillomavirus E2 transcriptional activation domain.

The bovine papillomavirus type 1 E2 transactivator has a large amino-terminal 215-residue transcriptional activation domain (TAD) that is active in Saccharomyces cerevisiae and higher eukaryotic cells. Comparison to other transcriptional activators suggests that its functions may be mediated in part through two acidic regions, A1 and A2, in this domain. We have characterized the functional elements within the E2 TAD using LexA-E2 fusions and by screening randomly generated libraries of E2 mutations for transcriptional activation in yeast. The A1 region was highly sensitive to substitutions that reduce negative charge, although there was not a perfect correlation between overall charge and transcriptional activity. Mutations were isolated within a hydrophobic amino acid motif that overlaps the A2 region and resembles elements described in other viral and cellular transactivation domains. When fused to the LexA DNA binding domain, this hydrophobic motif within the acidic A2 region was unable to activate transcription in S. cerevisiae. Multiple highly defective mutations primarily altering hydrophobic amino acids were identified in the distal third of the E2 TAD. The transcription phenotype of many of these E2 TAD mutations was similar in yeast and COS cells.

Amino Acid Sequence↗

PubMed1994

Tad1-1, an active LINE-like element of Neurospora crassa.

Tad is a LINE-like retrotransposon of Neurospora crassa. The element was originally detected and cloned using the am gene as a transposon trap in hybrid strains derived from a cross of Adiopodoume (a wild collected strain) and a laboratory strain devoid of Tad elements. We report the cloning and sequencing of an active Tad element, Tad1-1, which is capable of independent transposition. Transposition was demonstrated by screening for transfer of the element from a donor nucleus that contained the Tad1-1 element as the only active Tad, into a naive nucleus within a forced heterokaryon. We also report here the sequence analysis of Tad1-1, and its comparison with the sequence of another active element, Tad3-2. These elements are approximately 7 kb in length. They contain two long open reading frames (ORFs) encoded on the strand of the same polarity as the full-length transcript. ORF1 encodes a putative protein of 486 amino acids. Homology to the first ORF of other LINE elements is confined to three cysteine-rich motifs, located near the carboxy-terminus, that are thought to be involved in binding nucleic acids. The second ORF is 1156 amino acids in length and shows homology to the reverse transcriptase domains of various retroviruses and retrotransposons. Tad1-1 and Tad3-2 differ in only ten positions over their whole length.

Base Sequence↗

PubMed1997

[Transitory acantholytic dermatosis (Grover's disease) in sarcoptic scabies infection].

An eighty-two year old patient had scabies and transient acantholytic dermatosis (TAD, Grover's disease) at the same time. Persistent itching papules after lindane therapy finally led us to the microscopic diagnosis of TAD. Different trigger mechanisms can apparently induce the typical acantholysis. In addition to solar radiation, tumors and tumor therapy-dependent conditions, cutaneous infections have been implicated reports (Demodex folliculorum, Malassezia furfur) as causes of TAD. This may be the first report about a relationship between TAD and mite infection with Sarcoptes scabiei.

Acantholysis↗

PubMed1990

IMP dehydrogenase and action of antimetabolites in human cultured blast cells.

Tiazofurin was demonstrated to be an effective inhibitor of the growth of human cultured blast cells, and the high specific activities of IMP dehydrogenase (EC 1.1.1.205) were observed in all the cell extracts tested. IMP dehydrogenase has been purified to homogeneity from MOLT 4F human T-lymphoblast, and the Km values for IMP and NAD were 29 and 54 microM, respectively. The inhibitory mechanisms of thiazole-4-carboxamide adenine dinucleotide (TAD) and ribavirin 5'-monophosphate (RMP), the active forms of the antimetabolites tiazofurin and ribavirin, were investigated on the purified enzyme. RMP inhibits competitively with respect to IMP as well as XMP, and the inhibition by TAD was similar to that by NADH, which was uncompetitive with NAD. However, the Ki values of RMP (0.58 microM) and TAD (0.075 microM) were several orders of magnitude lower than those of XMP (85 microM) and NADH (94 microM). Thus, the drugs interact with the two distinct sites of IMP dehydrogenase with much higher affinities than the natural substrates and products. Preincubation of the purified enzyme with RMP enhanced its inhibitory effect in a time-dependent manner, and the enhancement was further increased by the addition of TAD. The combination of tiazofurin and ribavirin exerted a synergistic effect on the growth inhibition in MOLT 4F cells.

Adenine Nucleotides↗

PubMed2026

Metadomain and metaloop genome interactions in mammalian T cells.

Recent studies have advanced understanding of chromosomal organization and its role in gene regulation, yet most analyses focus on short-range interactions (<2 Mb), limiting insight into broader architecture. The relationships between topologically associating domains (TADs), sub-TAD loops, cross-TAD interactions, and chromosomal compartmentalization remain poorly understood. Here, using high-resolution Hi-C analysis, we identify extensive multi-megabase and interchromosomal interactions (metaloops) in T lymphocytes that organize into meta-TAD associations (metadomains). These metaloops connect distal promoters and regulatory elements of genes functionally important in T cells, including Ctla4, Ikzf2, Il2ra, Ets1, and Foxo1. Reanalysis of mouse and human datasets confirms their reproducibility and dependence on superenhancers. Genome-wide clustering reveals three distinct interchromosomal hubs, including a superenhancer-enriched hub linked to T cell-specific gene activation. Integrative analysis of regulatory genomics data identifies factors associated with short- versus long-range interactions. This study introduces a broadly applicable computational framework and reveals features of T cell genome organization.

Animals↗

PubMed2004

N and C-terminal sub-regions in the c-Myc transactivation region and their joint role in creating versatility in folding and binding.

The proto-oncogene c-myc governs the expression of a number of genes targeting cell growth and apoptosis, and its expression levels are distorted in many cancer forms. The current investigation presents an analysis by proteolysis, circular dichroism, fluorescence and Biacore of the folding and ligand-binding properties of the N-terminal transactivation domain (TAD) in the c-Myc protein. A c-Myc sub-region comprising residues 1-167 (Myc1-167) has been investigated that includes the unstructured c-Myc transactivation domain (TAD, residues 1-143) together with a C-terminal segment, which appears to promote increased folding. Myc1-167 is partly helical, binds both to the target proteins Myc modulator-1 (MM-1) and TATA box-binding protein (TBP), and displays the characteristics of a molten globule. Limited proteolysis divides Myc1-167 in two halves, by cleaving in a predicted linker region between two hotspot mutation regions: Myc box I (MBI) and Myc box II (MBII). The N-terminal half (Myc1-88) is unfolded and does not alone bind to target proteins, whereas the C-terminal half (Myc92-167) has a partly helical fold and specifically binds both MM-1 and TBP. Although this might suggest a bipartite organization in the c-Myc TAD, none of the N and C-terminal fragments bind target protein with as high affinity as the entire Myc1-167, or display molten globule properties. Furthermore, merely linking the MBI with the C-terminal region, in Myc38-167, is not sufficient to achieve binding and folding properties as in Myc1-167. Thus, the entire N and C-terminal regions of c-Myc TAD act in concert to achieve high specificity and affinity to two structurally and functionally orthogonal target proteins, TBP and MM-1, possibly through a mechanism involving molten globule formation. This hints towards understanding how binding of a range of targets can be accomplished to a single transactivation domain.

Amino Acid Sequence↗

PubMed1986

Late right ventricular reconstruction following valvotomy in pulmonary atresia with intact ventricular septum.

Experience over two decades in the surgical management of pulmonary atresia with intact ventricular septum demonstrates that eventual right ventricular (RV) reconstruction is possible in the majority of patients surviving valvotomy in infancy. Ten of 17 operative survivors of early valvotomy have eventually received a patch graft to the RV outflow tract, with no reoperative deaths (mean follow-up, 7.4 years). RV systolic pressures, suprasystemic prior to reoperation, are near normal after outflow patch reconstruction. Serial cineangiograms show evidence of RV growth by measurement of tricuspid annulus diameter (TAD), and demonstrate a rate of growth [d(TAD)/d(body length)] greater than a normal rate derived from autopsy data. The mean TAD growth rate is significantly greater than that of patients with less favorable ventricle types treated with a systemic-pulmonary shunt alone. Measurement of TAD is a useful method for following RV growth, and may aid in selecting patients for RV reconstruction.

Adolescent↗

PubMedDate not supplied

Novel nicotinamide adenine dinucleotide analogues as potential anticancer agents: quest for specific inhibition of inosine monophosphate dehydrogenase.

Synthetic nicotinamide adenine dinucleotide (NAD) analogues containing 5-beta-D-ribofuranosylnicotinamide (C-NAD), 6-beta-D-ribofuranosylpicolinamide (C-PAD), 3-beta-D-ribofuranosylbenzamide (BAD), and 2-beta-D-ribofuranosylthiazole-4-carboxamide (TAD) in place of the nicotinamide riboside moiety are described and evaluated as potential inhibitors of inosine monophosphate dehydrogenase (IMPDH). TAD and BAD showed potent inhibitory activity against the enzyme in the form of pyrophosphates, as well as metabolically stable methylene- and difluoromethylenebis(phosphonate)s. Fluorination at the C2' (ribo and arabino configuration) and C3' (ribo) of the adenosine moiety of TAD afforded analogues highly potent against IMPDH, but weakly active against alcohol dehydrogenase. With the exception of the methylenebis(phosphonate) analogue of TAD compounds containing a methylene bridge were poor inhibitors of growth of K562 cells. On the other hand, NAD analogues containing difluoromethylene linkage were highly effective in inhibition of K562 cell growth, as well as potent inducers of K562 cell differentiation. Such compounds, therefore, may be of potential therapeutic interest.

Animals↗

PubMed2002

Enhancement of proteolytic enzyme activity excreted from Bacillus stearothermophilus for a thermophilic aerobic digestion process.

Proteolysis is one of the main enzymatic reactions involved in waste activated sludge (WAS) digestion. In this study, proteases excreted from Bacillus stearothermophilus (ATCC 31197) were classified, and an enhancement of protease activity was achieved using economical chemical additives for WAS digestion. Proteases excreted from B. stearothermophilus were classified into two families: serine and metallo-proteases. Various metal ions were investigated as additives which could potentially enhance protease activity. It was observed that Ca2+ and Fe2+ could markedly activate these enzymes. These results were applied to thermophilic aerobic digestion (TAD) of industrial WAS using B. stearothermophilus. The addition of these divalent ions enhanced the degradation performance of the TAD process in terms of reducing the total suspended solids (TSSs), the dissolved organic carbon (DOC) content, and the intracellular and extracellular protein concentrations. The best result, with respect to protein reduction in a digestion experiment, was obtained by the addition of 2 mM Ca2+. Therefore, a proposed TAD process activated by calcium addition can be successfully used for industrial and municipal WAS digestion to the upgrading of TAD process performance.

Biotechnology↗

PubMed2001

Genes for tight adherence of Actinobacillus actinomycetemcomitans: from plaque to plague to pond scum.

The Gram-negative periodontal pathogen Actinobacillus actinomycetemcomitans forms an extremely tenacious biofilm on solid surfaces such as glass, plastic and hydroxyapatite. This characteristic is likely to be important for colonization of the oral cavity and initiation of a potentially devastating form of periodontal disease. Genetic analysis has revealed a cluster of tad genes responsible for tight adherence to surfaces. Evidence indicates that the tad genes are part of a locus encoding a novel secretion system for the assembly and release of long, bundled Flp pili. Remarkably similar tad loci appear in the genomes of a wide variety of Gram-negative and Gram-positive bacteria, including many significant pathogens, and in Archaea. We propose that the tad loci are important for microbial colonization in a variety of environmental niches.

Aggregatibacter actinomycetemcomitans↗

PubMed2001

Synthesis and antimicrobial activity of the symmetric dimeric form of Temporin A based on 3-N,N-di(3-aminopropyl)amino propanoic acid as the branching unit.

Dimeric derivative of antimicrobial peptide amide Temporin A (TA) was synthesized by using a new branching unit 3-N,N-di(3-aminopropyl)amino propanoic acid (DAPPA), which allows building of the parallelly symmetric alpha-helical structures. Antimicrobial effect of the original peptide amide, its monomeric carboxy (TAc) and novel dimeric (TAd) analogues were tested against Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative). Both TA and TAd completely inhibited the growth of S. aureus at the concentrations of 5 and 10 microM, respectively, whereas TAc did not show any inhibitory activity. The activities of TAc, TA and TAd correlate directly with the net charges of the molecules, +1, +2 and +4, respectively. Interestingly, TAd displayed antibacterial effect against E. coli at a concentration of 10 microM, where as monomeric TA did not show any activity at concentration as high as 20 microM. The results indicate that the novel structural modification improves the antibacterial properties of Temporin A especially towards Gram-negative bacteria.

Anti-Bacterial Agents↗