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PubMedDate not supplied

Correlation of serum levels of adenosine deaminase activity and its isoenzymes with disease activity in rheumatoid arthritis.

OBJECTIVE: Adenosine deaminase (ADA) is involved in purine metabolism and plays a significant role in the mechanisms of the immune system. The aim of this study was to investigate the correlation between the activity of total ADA (tADA) and isoenzymes ADA1 and ADA2 and clinical activity in patients with rheumatoid arthritis (RA). METHODS: The study comprised 37 patients with rheumatoid arthritis and 30 healthy controls. Total serum ADA activity was measured spectrophotometrically. The isoenzyme pattern of ADA was analyzed using erytro-9-(2-hydroxy-3-nonyl) adenine (EHNA). Disease activity was assessed using DAS criterion. RESULTS: The means of tADA, ADA1 and ADA2 levels were found to be 22.7 +/- 5.9, 3.9 +/- 2.0 and 18.8 +/- 4.9 IU/L in patients with RA, and 15.1 +/- 4.4, 4.1 +/- 1.2 and 11.0 +/- 3.7 IU/L in healthy control subjects. When compared to the healthy controls, serum tADA and ADA2 levels were significantly higher (p < 0.001) in patients with RA, but the decrease of ADA1 level was not statistically significant (p > 0.05). There was a strong correlation (r = 0.527, p < 0.001) between serum tADA level and disease activity by DAS (Pearson's rank correlation), and no correlation between tADA and CRP or ESR in the patient groups (p > 0.05). CONCLUSION: Serum tADA and ADA2 activity is closely associated with RA and these non-invasive investigations can be used as biochemical markers for inflammation. These may provide additional information regarding disease activity along with the traditional indices such as ESR and CRP.

Adenosine Deaminase↗
PubMed2003

Pyranophane transannular diels-alder approach to (+)-chatancin: a biomimetic asymmetric total synthesis.

An asymmetric total synthesis of (+)-chatancin was achieved via a transannular Diels-Alder (TADA) reaction of an in situ generated macrocyclic pyranophane pseudobase. The presented route constitutes the second of two proposed biosynthetic pathways that involves a TADA reaction. It links this diterpene biogenetically to the cembranoids. A set of TADA selection rules that rationalize the formation of (+)-chatancin from a dynamic equilibrium of four 2-hydroxy-2H-pyrane bicycles and their 16 potential TADA transition states are also outlined. Beyond the TADA reaction, highlights of the synthetic work include the assembly of a chiral acyclic macrocyclization substrate from (S)-citronellol and an efficient macrocyclization via a beta-ketosulfoxyde/enone Michael addition.

Biomimetics↗
PubMed2025

A streamlined base editor engineering strategy to reduce bystander editing.

Base editing (BE) can permanently correct over half of known human pathogenic genetic variants without requiring a repair template, thus serving as a promising therapeutic tool to treat a broad spectrum of genetic diseases. However, the broad activity windows of current base editors pose a major challenge to their therapeutic application. Here, we show that integrating a naturally occurring oligonucleotide binding module into the deaminase active center of TadA-8e, a highly active deoxyadenosine deaminase, enhances its editing specificity. When conjugated with a Cas9 nickase or alternative PAM Cas9 variants, the engineered TadA variant-TadA-NW1-consistently achieves robust A-to-G editing efficiencies within an editing window consisting of four nucleotides, substantially narrower than the 10-bp editing window of the TadA-8e-derived ABEs. Moreover, compared to ABE8e, ABE-NW1 shows significantly decreased Cas9-dependent and -independent off-target activity while maintaining similar on-target editing efficiency. Further, TadA-NW1 can be reprogrammed to perform desired cytidine deamination and adenine transversion within a restricted editing window. Finally, in a cystic fibrosis (CF) cell model, ABE-NW1 outperforms existing ABEs in accurately and efficiently correcting the CFTR W1282X variant, one of the most common CF-causing mutations. In all, we engineered a suite of base editors with refined activity windows, enabling more precise base editing. Importantly, this study presents a streamlined genome editor re-engineering strategy to accelerate the development of therapeutic base editing.

Gene Editing↗
PubMedDate not supplied

Metabotropic glutamate receptors in spatial and nonspatial learning in rats studied by means of agonist and antagonist application.

We examined the effects of both the metabotropic glutamate receptor (mGluR) antagonist MCPG and the agonist tADA in two behavioral paradigms in rats: (1) brightness discrimination and (2) spatial alternation. Compounds were applied intracerebroventricularly at different times, either 30 min prior to training or immediately after training, and rats were tested for retention 24 hr later in the same paradigms. Both MCPG and tADA caused amnesia in the spatial alternation test, when applied pretraining, but no effect was obtained in the brightness discrimination paradigm. Drug-induced amnesia was shown not to be attributable to state-dependent effects of MCPG or tADA. Moreover, the memory inhibiting effect of MCPG was dose dependent, with a low dose (20 mM/5 ml) having no effect on learning and memory and a 10 times higher concentration (200 mM/5 ml) causing complete amnesia. Application of both saline and MCPG immediately post-training prevented memory formation, which may be attributable to an interference by the injection procedure with the process of memory formation. The mGluR agonist tADA, however, facilitated memory formation in the spatial alternation task, when injected immediately after training. Post-training application of the compounds had no effect on retention in the brightness discrimination task. On the basis of these data we conclude that (1) mGluRs are of particular importance for spatial learning and play no role in visual discrimination; (2) both the block and the activation of mGluRs inhibit spatial learning, suggesting that saturated activation prevents further modulation of mGluRs, which may be required during learning or memory formation; and (3) mGluR agonist tADA may be memory facilitating when applied after training, thus enhancing the establishment of the memory trace.

Animals↗
PubMed2004

Adenosine deaminase activity and its isoenzyme pattern in women with recurrent spontaneous abortions.

Normal pregnancy is characterized by suppressed cell-mediated immunity. Adenosine deaminase (ADA) is a purine metabolic enzyme enriched in trophoblast cells of the placenta. It is an early marker of trophoblast cell differentiation. Also, the activation of ADA gene expression in the placenta is crucial and essential for proper fetal development. The activity of ADA shows changes in diseases characterized by the alteration of cell-mediated immunity. The purpose of this study was to assess the possible role of the alteration of cell-mediated immunity in women with recurrent spontaneous abortions (RSA) as a cause of changes in tADA activity, and also to evaluate the extent of the contribution of ADA1 and ADA2 to changes of tADA activity in serum and peripheral blood lymphocytes (PBLs). We measured in serum and in PBLs activities of tADA, ADA1 and ADA2 of 25 married women with RSA (group A) and of 28 healthy non-pregnant women (group B). According to our results in women with RSA, mean serum tADA, ADA1 and ADA2 activities were significantly higher than those of non-pregnant women (p < 0.001, p < 0.05 and p < 0.05 respectively). In women with RSA, mean PBLs tADA, ADA1 and ADA2 activities were significantly higher than those of non-pregnant women (p < 0.001, p < 0.05 and p < 0.05 respectively). The findings of this study show a marked increase of serum and PBLs ADA activities, which is derived from an increase of ADA2 and ADA1 activity in women with RSA. These changes reflect cell-mediated immunological changes.

Abortion, Habitual↗
PubMed1995

Open field behaviour in rats: role of metabotropic glutamate receptors.

Previous studies have shown that spatial memory retention is affected by the metabotropic glutamate receptor (mGluR) influencing agents (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG) and trans-azetidine-2,4-dicarboxylic acid (tADA). In the present investigation we examined whether the mGluR antagonist MCPG (20 mM and 200 mM/5 microliters, respectively) and the agonist tADA (20 mM/5 microliters) have other behavioural effects using the open field test on two successive days. Only minor effects of MCPG (decrease of crossings during the 1st min on day 1) and tADA (increase of rearings on both days) were found. These results suggest that memory influencing doses of MCPG and tADA have no or only little behavioural effects in the open field situation.

Animals↗
PubMedDate not supplied

Serum procalcitonin, adenosine deaminase and its isoenzymes in the aetiological diagnosis of pneumonia in children.

A prospective study was undertaken to assess the usefulness of leukocyte count, serum C-reactive protein (CRP), procalcitonin (PCT), and the activities of total adenosine deaminase (tADA) and its isoenzymes ADA1 and ADA2, in the aetiological diagnosis of pneumonia in children. The study included three groups. Group A consisted of 23 children with bacterial pneumonia, group B of 50 children with viral and mycoplasmal pneumonia and group C of 46 healthy children. On the first day of admission in the clinic, blood samples were collected before the start of antimicrobial treatment, for culture, serological tests, leukocyte count and for the determination of CRP and PCT levels as well as tADA activity and its isoenzymes ADA1 and ADA2. According to our results, the mean leukocyte count and the mean concentrations of PCT and CRP were significantly higher in the children of group A than those in groups B and C. The admission serum PCT concentration has a higher sensitivity, specificity and positive predictive value for bacterial pneumonia than either CRP or the leukocyte count. The mean serum tADA, ADA1 and ADA2 activity in children of group A was not significantly different from those in group C, while the difference between groups B and C was statistically significant. In conclusion, we found that CRP is a good marker for screening various infectious diseases, but it cannot be used to distinguish between bacterial and viral infections. Serum PCT measurement might be a useful tool for the physician for the aetiological diagnosis of pneumonia in children. Measurements of serum tADA and ADA2 activity may provide useful additional diagnostic information on the aetiology of pneumonia so that appropriate antibiotic therapy can be given promptly. Further studies with larger patients groups are required to confirm our results.

Journal Article↗
PubMedDate not supplied

Response of ADA and its isoenzymes in mice infected by Trichinella spiralis and treated with mimosine.

Infections caused by the nematode Trichinella spiralis (T. spiralis) are characterized by an inflammatory response in the host. The aim of this study was to identify and evaluate markers for monitoring mice infected with T. spiralis and treated with or without mimosine. The markers that have been used were total and differential white blood cell counts, subpopulations of lymphocytes, serum tADA and its isoenzymes ADA1 and ADA2 activity. The study included 3 groups of BALB/c mice. Group A consisted of 16 healthy mice, Group B of 16 mice infected with T. spiralis and treated with saline, and Group C of 16 mice infected with T. spiralis and treated with mimosine. The measurements were made once per week for the first six weeks continuously following the infection. According to our results, leukocytosis, lymphocytosis and increased percentages of adhesion molecules and CD4 lymphocytes were present in groups B and C one week post-infection. Total ADA activity as well as ADA1 and ADA2 was higher in groups B and C versus group A from the first week post-infection. The levels of tADA activity, ADA1 and ADA2 were higher in group B compared to those of group C and the difference was statistically significant (p<0.05) during the 4th week post-infection. The majority of tADA activity, essential for an efficient immune response, was derived from ADA1 which may have been produced by infected tissues. The elevated activities of tADA and ADA1 may be sensitive markers for infection of T. spiralis and for monitoring the course of the infection.

Adenosine Deaminase↗
PubMed2006

Thumb polydactyly: clinical outcome after reconstruction.

PURPOSE: To evaluate clinical and cosmetic outcomes of reconstruction in thumb polydactyly and prognostic value of the Wassel classification. METHODS: Between 1993 and 2000 inclusive, out of the patients with thumb polydactyly (involving 80 thumbs) operated on, 34 patients (36 thumbs) were available for review and underwent clinical and radiological assessment. Outcomes in terms of the Tada score and complications were recorded. RESULTS: The mean age of patients at the time of operation was 2.8 (range, 0.6-47) years. The mean follow-up period was 5 (range, 2.4-10) years. According to the Wassel classification, 12 were type-II thumb polydactyly, 3 type-III, 11 type-IV, 6 type-V, one type-VI, and 3 type-VII. There was no perioperative mortality or wound infection. More than 88% of the patients were satisfied or very satisfied with functional and cosmetic outcomes. Postoperative complications such as scar hypertrophy, pulp atrophy, joint deformity, and instability were common but minor. Ridge nail deformity after the Bilhaut Cloquet procedure was amenable to secondary corrective procedures. All types of operated thumb polydactyly achieved similar mean Tada scores (14.7- 16.6 out of 20). The Wassel classification category, age, and surgical procedures were found to have no prognostic value with regard to the Tada score and presence of complications. CONCLUSION: Surgery on thumb polydactyly is rewarding. The Wassel classification category can be used as a guide for treatment, although it fails to predict the occurrence of postoperative complications or Tada scores. Our patients' results can serve as guidelines of expected outcomes after reconstructive procedures in different sub-types of thumb polydactyly.

Adolescent↗
PubMed1998

Novel, sensitive and low-cost diagnostic tests for 'river blindness'--detection of specific antigens in tears, urine and dermal fluid.

Sensitive, specific and low-cost diagnostic tests for onchocerciasis are indispensable for monitoring the efficacy of control programs, as well as for preventing blindness (when the tests are combined with efficacious chemotherapy. Three new tests to detect Onchocerca-specific antigens in tears, dermal fluid and urine employ antibodies to O. volvulus-specific recombinant proteins, Oncho-C27 and OvD3B, encoded by genes within the immunodominant Onchocerca OV 33-3 gene family, and expressed in yeast and in E. coli, respectively. In these assays, Onchocerca-specific antigens in test samples are bound onto a solid surface and revealed using appropriate enzyme-labelled antibodies. Proteins in the samples are first transferred to Hybond-N + membrane disks or nitrocellulose paper using either a transblot or a dotblot machine, and then reacted with specific O. volvulus antibodies. Bound antibodies are revealed with species-specific peroxidase-labelled antibodies and peroxidase substrate. Positive tests give a brown colour. In one of the two assays developed to detect Onchocerca antigens in tears, the sensitivity was enhanced by first adsorbing the specific antibodies onto the membrane surface in order to immobilize and concentrate the Onchocerca-specific antigen molecules on the membrane. The specificity of the recombinant proteins for Onchocerca volvulus had been verified by ELISA, classical Western blot and modified DSIA. The tests are a dipstick immunobinding assay for ocular microfilariae (DSIA), a transblot immunobinding assay for the detection of skin microfilariae (TADA) and a dot-blot immunobinding assay for detecting urinary microfilariae and their antigens (DIA). Their specificity and sensitivity were evaluated in the field on 110 subjects with proven ocular microfilariae, 130 subjects with clinical and parasitological evidence of onchocerciasis, 25 subjects infected with other helminths and 120 normal controls. The minimal detection limits of Oncho-C27 protein by DSIA, TADA and DIA were 500 ng/ml, 154 ng/ml and 508 ng/ml, respectively By contrast, their sensitivities were: 100% for DSIA and 82.5% for TADA employed on samples of tears; 97% for TADA skin test and 96% for DIA used on urine samples.

Amino Acid Sequence↗
PubMed2006

Disconnect between inflammation and joint destruction after treatment with etanercept plus methotrexate: results from the trial of etanercept and methotrexate with radiographic and patient outcomes.

OBJECTIVE: To determine the relationship between disease activity and radiographic progression of joint destruction in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX), those treated with etanercept, and those treated with the combination of MTX plus etanercept. METHODS: Baseline, 12-month, and 24-month data from the Trial of Etanercept and Methotrexate with Radiographic and Patient Outcomes database were analyzed. The dependent variable was the 1-year change in the modified Sharp/van der Heijde score (Sharp score); therefore, 2 interval changes per patient were available. Interval change in the Sharp score was modeled by time (years), treatment, disease activity, and the interaction (disease activity x treatment). Disease activity was reflected by the time-averaged Disease Activity Score (taDAS) and the time-averaged C-reactive protein (taCRP) level, which were calculated per 1-year interval. Generalized mixed linear modeling (GMLM) was used to adjust for within-patient correlation. RESULTS: GMLM confirmed a significant interaction between treatment and the taCRP level and taDAS with respect to the change in Sharp score (P = 0.012 and P = 0.03, respectively). In patients treated with MTX alone, radiographic progression increased with an increasing taCRP level or taDAS, although progression rates were low in patients whose disease was in remission and in those with low-to-moderate disease activity. This relationship was less clear in patients treated with etanercept and was absent in those who received combination therapy. CONCLUSION: Combination therapy with MTX plus etanercept uncouples the classic relationship between disease activity and radiographic progression in patients with RA.

Antirheumatic Agents↗
PubMed1985

I-J as a restriction element in the suppressor T cell system.

This review attempts to sort out the differences between macrophage and T cell I-J determinants. We propose that suppressor T cells have receptors for self-I-J determinants which are expressed on macrophage-like accessory cells. The I-J determinants associated with accessory cells are responsible for the selection of the Ts receptors. Although the major histocompatibility complex is involved in the selection of Ts receptors, the receptors themselves need not be encoded by genes which reside within the MHC. In fact, the molecular genetic evidence presently available has established that suppressor T cell factors do not express gene products associated with the postulated I-J region of the H-2 complex. In spite of the failures of biochemists and molecular geneticists to identify I-J genes and gene products, there is extensive biological data demonstrating the existence of I-J. The activity of anti-I-J reagents has been verified by numerous laboratories. Sera containing anti-I-J activity have been prepared in many strain combinations. Immunization between a variety of strains differing at the purported I-J region produce active anti-I-J antibodies (Murphy et al. 1976, Tada et al. 1976, Pierres et al. 1977, Tada et al. 1978). Furthermore, in many suppressor cell systems the interactions of Ts cells and factors are restricted by I-J (Tada & Okumara 1980, Sorensen & Pierce 1982, Green et al. 1983, Dorf & Benacerraf 1984). Most investigators who have attempted to detect I-J have analyzed T cells. Since we propose that T cells express a complementary anti-I-J receptor, subsequent efforts at identifying I-J should include analysis of macrophage I-J determinants. In spite of extensive biological data, we still do not know if I-J is a protein, carbohydrate or lipid. In addition, the role of H-2 in determining I-J structure is unknown. Nevertheless, the overwhelming biological data demonstrate that I-J is an important structure for suppressor T cell interactions. Much remains to be accomplished, including the characterization of I-J products and locating the I-J genes.

Animals↗
PubMed1984

The staining properties of thiazolylazoalkylaminophenol derivatives in histochemical staining of cadmium.

In the continuous research for a more sensitive chelator for cadmium, thiazolylazoalkylaminophenol derivatives were synthesized. The staining sensitivity for cadmium and molar absorptivity of their cadmium chelates were examined. Though the molar absorptivity of bromothiazolylazodiethylaminophenol(Br-TADA)-cadmium chelate demonstrated an order of 10(5), the staining sensitivity of Br-TADA was unexpectedly low. The lowering of the sensitivity of Br-TADA may be attributed to alkaline hydrolysis and a decrease in the stability constant of the cadmium chelate.

Azo Compounds↗
PubMed1975

Phosphorylation of a 22,000-dalton component of the cardiac sarcoplasmic reticulum by adenosine 3':5'-monophosphate-dependent protein kinase.

Cardiac microsomes were incubated with [gamma-32P]ATP and a cardiac adenosine 3':5'-monophosphate (cyclic AMP)-dependent protein kinase in the presence of ethylene glycol bis(bets-aminoethyl ether)-N,N'-tetraacetic acid. After solubilization in sodium dodecyl sulfate and fractionation by polyacrylamide gel electrophoresis, a single microsomal protein component of approximately 22,000 daltons was found to bind most of the 32P label. The 32P labeling of this component increased several fold when NaF was included in the incubation medium. No other component of cardiac microsomes, including sarcoplasmic reticulum ATPase protein, contained significant amounts of 32P label. This 22,000-dalton phosphoprotein formed by cyclic AMP-dependent protein kinase had stability characteristics of a phosphoester rather than an acyl phosphate. Washing of microsomes with buffered KCl did not decrease the amount of 32P labeling to the 22,000-dalton protein, suggesting that this protein is associated with the membranes of sarcoplasmic reticulum rather than being a contaminant from other soluble proteins. The 22,000-dalton protein was susceptible to trypsin. Brief digestion with trypsin in the presence of 1 M sucrose did not significantly affect microsomal calcium transport activity, but prevented both subsequent phosphorylation of the 22,000-dalton protein and stimulation of calcium uptake by cyclic AMP-dependent protein kinase, suggesting that this protein is a modulator of the calcium pump. These results are consistent with previous findings (Kirchberger, M.A., Tada, M., and Katz, A.M. (1974) J. Biol. Chem. 249, 6166-6173; Tada, M., Kirchberger, M.A., Repke, D.I., and Katz, A.M. (1974) J. Biol. Chem. 249, 6174-6180) that cyclic AMP-dependent protein kinase-catalyzed phosphorylation is associated with stimulation of calcium transport in the cardiac sarcoplasmic reticulum, and further indicate that this phosphorylation occurs at a component of low mass (22,000 daltons) of the cardiac sarcoplasmic reticulum which, while separable from the calcium transport ATPase protein (100,000 daltons) by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, has the ability to regulate calcium transport by the cardiac sarcoplasmic reticulum.

Animals↗
PubMed1995

Metabotropic glutamate receptor agonist trans-azetidine-2,4-dicarboxylic acid facilitates maintenance of LTP in the dentate gyrus in vivo.

We examined the role of metabotropic glutamate receptors by studying the effect of intracerebroventricular infusion of the putative mGluR agonist trans-azetidine-2,4-dicarboxylic acid (tADA) on long-term potentiation (LTP) in the dentate gyrus of freely moving rats. Weak tetanization caused a decremental potentiation which returned to baseline levels within 2 hr. Injections of tADA (20 mM/5 microliters) 30 min prior to weak tetanization prolonged LTP of the field EPSP for at least 24 hr.

Animals↗
PubMed2001

Theoretical and experimental determination of the effects governing the transannular Diels-Alder reaction of trans-trans-cis systems with or without activation of the dienophile.

A thorough study of the transannular Diels-Alder (TADA) reaction of trans-trans-cis macrocyclic trienes was carried out. It led to a better understanding of various parameters that govern the TADA reaction in particular and the Diels-Alder reaction in general. Thus, carbonyl activation of the dienophile and substitution of the diene are discussed, as well as the presence of substituents on the macrocycle and their respective effects at the transition-state level.

Journal Article↗
PubMed2003

First experimental and theoretical evidence of a deactivating enone dienophile in the transannular Diels-Alder reaction.

A thorough study of the transannular Diels-Alder (TADA) reaction of trans-trans-trans macrocyclic trienes was carried out. It led to a better understanding of various parameters that govern the TADA reaction in particular and the Diels-Alder reaction in general. Thus, carbonyl activation of the dienophile is thoroughly discussed in light of new experimental and theoretical data. An enone dienophile is found to deactivate the reaction, although it remains planar at the transition state. This unusual result was discussed in terms of tether substituents that provoke destabilization of the transition state.

Journal Article↗
PubMed2003

Furanophane transannular Diels-Alder approach to (+)-chatancin: an asymmetric total synthesis of (+)-anhydrochatancin.

(+)-anhydrochatancin was synthesized while attempting an enantioselective total synthesis of (+)-chatancin. The presented route constitutes the furanophane approach, one of the two ways of proposed biosynthesis which may involve transannular Diels-Alder (TADA) reaction to link this diterpene biogenetically to the furanocembranoids. Highlights of the synthetic work include the assembly of chiral, acyclic, trisubstituted furan 28 via a coupling of aldehyde 10 and dilithiofuroic acid 11, a macrocyclization to furanophane 29E via ring-closing metathesis, a TADA reaction to reach tetracyclic intermediate 4, and a hydride shift mediated oxygen transposition as a final rearrangement to the target. Unfortunately, the strongly acidic condition required for the last step allows only the isolation of anhydrochatancin 30 due to the acid sensitivity of chatancin 1.

Aldehydes↗