The Stent report, one year on. Christchurch Hospital's Medical Specialists Association.
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Hospital Administration↗
Biomedical subjects
P George
Publications and source records attributed to P George.
Structural elements of the gamma-aminobutyric acid type A receptor conferring subtype selectivity for benzodiazepine site ligands.
gamma-aminobutyric acid type A (GABAA) receptors comprise a subfamily of ligand-gated ion channels whose activity can be modulated by ligands acting at the benzodiazepine binding site on the receptor. The benzodiazepine binding site was characterized using a site-directed mutagenesis strategy in which amino acids of the alpha5 subunit were substituted by their corresponding alpha1 residues. Given the high affinity and selectivity of alpha1-containing compared with alpha5-containing GABAA receptors for zolpidem, mutated alpha5 subunits were co-expressed with beta2 and gamma2 subunits, and the affinity of recombinant receptors for zolpidem was measured. One alpha5 mutant (bearing P162T, E200G, and T204S) exhibited properties similar to that of the alpha1 subunit, notably high affinity zolpidem binding and potentiation by zolpidem of GABA-induced chloride current. Two of these mutations, alpha5P162T and alpha5E200G, might alter binding pocket conformation, whereas alpha5T204S probably permits formation of a hydrogen bond with a proton acceptor in zolpidem. These three amino acid substitutions also influenced receptor affinity for CL218872. Our data thus suggest that corresponding amino acids of the alpha1 subunit, particularly alpha1-Ser204, are the crucial residues influencing ligand selectivity at the binding pocket of alpha1-containing receptors, and a model of this binding pocket is presented.
Allosteric Site↗
Progesterone-regulated determinants of stromal cell survival and death in uterine decidua are linked to protein kinase C activity.
This study examined the role of protein kinase C enzymatic activity as a physiologic determinant of stromal cell death in decidua basalis (DB) during pregnancy. The expression of epidermal growth factor receptor (EGF-R) and Bcl2 was used as an indicator of stromal cell proliferation/survival, whereas Bax and the occurrence of apoptosis provided an index of cell death. Stromal cell cycle progression during pregnancy and after in vivo administration of phorbol esters was analyzed by flow cytometry. DB were isolated from pregnant rats between Days 8 and 21 of pregnancy and prepared for immunohistochemistry, Western blotting procedures, or flow cytometry. The results showed that stromal cells were actively proliferating on Days 8 and 10, whereas the frequency of cell death by apoptosis increased progressively between Days 14 and 21 (Day 22 is term). The proliferative stage was characterized by low PKC activity and high levels of EGF-R and Bcl2 expression. On the other hand, DB regression (Days 14-21) was marked by an elevation in endogenous PKC activity and Bax expression; EGF-R and Bcl2 were suppressed. Administration of phorbol 12-myristate, 13-acetate (0.4 micromole/kg) induced apoptosis on Day 10. Additionally, antiprogestin (RU-486) given on Day 9 induced PKC activity and Bax expression within 6 h and suppressed Bcl2 and EGF-R. By 12 h, RU-486 enhanced percent apoptotic cells. Thus, enhanced levels of PKC activity were closely linked to stromal cell apoptosis.
Animals↗
Spermidine-induced glycoprotein fucosylation in immature rat intestine.
In rat small intestine, during postnatal development, the glycoprotein fucosylation is markedly increased at weaning. At the same time, a rise in the intestinal spermidine level was observed, partly due to the increase in the spermidine content of solid food given to animals at this period as compared to the spermidine content of milk. In order to mimic the spermidine increase observed in weanling rat intestines, we had treated suckling rats with spermidine by oral ingestion to study its role as maturation factor of the small intestine. In spermidine-treated suckling rats, the spermidine and N-acetyl-spermidine contents were highly increased. Spermidine treatment induced the rise in alpha-1,2-fucosyltransferase activity and the precocious appearance in the brush-border membrane of some alpha-1,2-fucoproteins in weaned rats. Such results indicate that spermidine could be a maturation factor implicated in the appearance of alpha-1,2-fucoproteins naturally observed at weaning time.
Administration, Oral↗
Synthesis and benzodiazepine receptor (omega receptor) affinities of 3-substituted derivatives of pyrrolo[2,3-c]pyridine-5-carboxylate, a novel class of omega1 selective ligands.
Based on the structure of ZK91296 (4d), a high affinity partial agonist of the central benzodiazepine (omega) receptor, a series of pyrrolo[2,3-c]pyridine-5-carboxylate derivatives having mainly aralkyl and aralkyloxy substituents at C-3 was synthesized. The in vitro binding affinities of these compounds for three subclasses of the omega receptor (omega1, omega2, omega5) were determined using rat brain tissue. Practically all of these compounds (except the diethyl ester derivative 22c) showed an approximately twofold selectivity for omega1 (IC50's in the 200-500 nM range) compared to omega2 receptors and practically no affinity for omega5 receptors. Compound 22c showed the highest affinity of all the compounds synthesized (IC50 = 70 nM for omega1 receptors) as well as a fivefold selectivity for omega1 versus omega2 receptors but also displayed significant binding to omega5 receptors (IC50 = 250 nM). The absence of appreciable binding of 4-methyl and 4-methoxymethyl derivatives to omega receptors, in contrast to beta-carbolines having these similarly located substituents, suggests that the pyrrolo[2,3-c]pyridine-5-carboxylates may be considered an entirely novel class of selective omega receptor ligands.
Animals↗
A reversible monoamine oxidase A inhibitor, befloxatone: structural approach of its mechanism of action.
Experimental and theoretical physico-chemical methods were used to investigate the interaction between several reversible monoamine oxidase A inhibitors in the oxazolidinone series and the active site of the enzyme. Phenyloxazolidinones include toloxatone and analogues, among which befloxatone was selected as drug candidate for the treatment of depression. Identification of the forces responsible for the crystal cohesion of befloxatone reveals functional groups that could interact with monoamine oxidase. Calculation of electronic properties of those compounds using ab initio molecular orbital methods lead to a description of the mode of interaction between befloxatone and the cofactor of the enzyme. Electronic absorption spectroscopy measurements confirm the hypothesis of a privileged interaction of phenyloxazolidinone-type inhibitors with the flavin cofactor of MAO. Additional sites of interaction with the protein core of MAO A are also examined with regard to the primary structure of the enzyme. As a result of this work, a model is proposed for the reversible inhibition of MAO A by befloxatone via long distance, reversible interactions with the flavin adenine dinucleotide (FAD) cofactor of the enzyme and with specific amino acids of the active site. This model is partially corroborated by experimental evidence and should be helpful in designing new potent inhibitors of monoamine oxidase.
Animals↗
A pilot controlled family study of DSM-III-R and DSM-IV ADHD in African-American children.
BACKGROUND: Very little is known about attention-deficit hyperactivity disorder (ADHD) in African-American children, and although the familial transmission of ADHD has been well established in white samples, prior work has not evaluated this feature of ADHD in African-American families. METHOD: Subjects were 37 first-degree relatives of children with DSM-III-R-defined ADHD and 52 first-degree relatives of non-ADHD comparison children matched for ethnicity, age, and gender. DSM-III-R-based structured interviews (modified to include DSM-IV diagnoses) provided the basis for psychiatric diagnoses in relatives. RESULTS: The risks for both DSM-III-R and DSM-IV ADHD were significantly greater in first-degree relatives of ADHD probands than in relatives of controls. In addition, the relatives of ADHD probands also were at higher risk for oppositional defiant disorder, antisocial personality disorder, major depression, generalized anxiety, and substance use disorders. CONCLUSIONS: These results suggest that ADHD and related disorders are familial in African-Americans. Further work is needed to confirm the familial transmission of ADHD in African-American children and to explore the role of genetics as well as environmental factors in the transmission of the disorder.
Adolescent↗
Agreement in pathologic interpretation of liver biopsy specimens in posttransplant hepatitis C infection.
Hepatitis C virus-related disease is rapidly becoming the most common indication for orthotopic liver transplant (OLT) in the United States. Although post-OLT hepatitis C viremia is universal, 40% to 60% of patients develop recurrent chronic hepatitis C. Distinguishing recurrent chronic hepatitis C infection from acute rejection may be difficult because of overlapping histopathologic features. To improve our diagnostic accuracy we undertook a study to determine interobserver and intraobserver agreement between pathologists examining post-OLT liver biopsy specimens in patients from our transplant database. Clinical data and microscopic sections from 26 patients with hepatitis C virus-related OLT were reviewed. Biopsy specimens were obtained because of abnormal liver enzymes (21/26) or routine post-OLT follow-up (5/26), representing both early (18+/-11 days) and late (252+/-206 days) post-OLT periods. Unidentified sections were examined by an experienced pathologist in a randomly assigned order and reexamined 6 weeks later in the same fashion by the initial reviewer and a second experienced pathologist. Interobserver and intraobserver agreement was calculated using K statistic. The intraobserver agreement was 81 % with a kappa coefficient of 0.67 (P = .001). The interobserver agreement was 78% with a kappa coefficient of 0.60 (P < .001). The early post-OLT biopsy specimens (18+/-11 days) were the most difficult to interpret.
Adult↗
[Successful PMA. Review of the activities of the Center for Medically Assisted Procreation of University of Liege, 1985-1997].
Assisted reproductive treatments (ART) hold an increasing place in the field of female infertility but also of male infertility with the development of new micromanipulative technologies. From January 1985 to December 1997, more than 3,000 ovarian punctures were achieved at the CPMA of the University of Liege and more than 40,000 oocytes were recovered. Global results show a take home baby rate of 23% per ovum pick-up and 27% per embryo transfer. Embryo cryopreservation offers an efficient solution to the problem of supernumerary embryos and opens the way for IVF-derived procedures such as oocyte or embryo donation, surrogate mother. The transfer of frozen-thawed embryos increases the total ongoing pregnancy rate per cycle of 31%. One of the aims of our Centre in the near future is the development of new technologies such as control of chromosomal abnormalities or genetic defect in preimplantation embryos and clinical applications of oocyte or ovarian tissue freezing.
Belgium↗
Molecular lipophilicity potential by CLIP, a reliable tool for the description of the 3D distribution of lipophilicity: application to 3-phenyloxazolidin-2-one, a prototype series of reversible MAOA inhibitors.
The capacity factor of eleven derivatives belonging to a prototype series of 3-phenyloxazolidin-2-one, reversible MAO inhibitors, was measured and compared to the calculated log Pcalc using the CLIP package. We demonstrate that this Molecular Lipophilicity Potential (MLP) approach is a valuable tool to estimate log Pcalc of such compounds.
Chromatography, High Pressure Liquid↗
A possible involvement of endogenous polyamines in the TNF-alpha cellular sensitivity.
A critical step in the cytotoxic action mechanism of tumor necrosis factor-alpha (TNF-alpha) involves, among mitochondrial dysfunctions, an early change of the inner membrane permeability displaying the characteristics of permeability transition. Cytosolic polyamines, especially spermine, are known to inhibit it. Our results show that spermine is only detectable in the TNF-alpha resistant C6 cells while N1-acetylspermidine is present in the TNF-alpha sensitive WEHI-164 cells, and putrescine and spermidine are found in both. TNF-alpha treatment does not change this distribution but only induces a quantitative alteration in TNF-alpha sensitive cells. Omission of glutamine (energetic substrate) from the culture media alters neither the TNF-alpha responsiveness of both cell lines nor their polyamine distributions, only their quantitative polyamine contents.
Animals↗
The albumins of Chinook salmon (Oncorhynchus tshawytscha) and brown trout (Salmo trutta) appear to lack a propeptide.
Plasma samples from two members of the Salmonidae family, the chinook salmon (Oncorhynchus tshawytscha) and brown trout (Salmo trutta), were examined. Albumin, initially identified as the predominant anionic palmitate-binding band on agarose gel electrophoresis of plasma, was purified from both species by DEAE-ion exchange chromatography. Albumin has a plasma concentration of approximately 15 mg/ml in both species. Like other fish species, neither trout nor salmon albumin binds nickel; a characteristic of many mammalian albumins. Salmon and trout albumins have molecular masses of 65 and 67 kDa, respectively, indicating some sequence differences. However, N-terminal sequencing of the first 15 residues of both these proteins indicated identical sequences of 1QNQICTIFTEAKEDG15-. This showed that the mature N-terminal sequence (SQAQNQICTIFTEAKEDG-) predicted from the cDNA of Atlantic salmon albumin is in fact incorrect, with the actual N-terminus for salmonids starting three amino acids later than that predicted. Examination of the Atlantic salmon cDNA sequence suggested that salmonid albumin is unique, in lacking a propeptide. No proalbumin convertase site (RXYR/XYRR) is present and it appears that the salmonid albumin precursor is cleaved only by the signal peptidase, between -1 Ala and +1 Gln, to produce mature albumin. This site has a preferrred motif for the signal peptidase of -1 Ala and -3 Ser, as well as -2 Gln. Thus, salmonid albumin possesses a 21-residue prepeptide, but no propeptide.
Amino Acid Sequence↗
Molecular structure and stereoelectronic properties of sarmazenil--a weak inverse agonist at the omega modulatory sites (benzodiazepine receptors): comparison with bretazenil and flumazenil.
X-ray diffraction and ab initio MO theoretical calculations were used in order to investigate the structural and electronic properties of sarmazenil, a weak inverse agonist at the omega modulatory sites (benzodiazepine receptors). This compound was compared to bretazenil, a partial agonist, and to the antagonist flumazenil on the basis of structural and electronic data. The conformational and theoretical properties (interatomic pi overlap populations, molecular electrostatic potential (MEP), the topology of frontier orbitals, and proton affinity) of these three imidazobenzodiazepinones were determined in order to analyse the stereoelectronic properties in relation with their distinct intrinsic efficacies at the omega modulatory sites.
Benzodiazepines↗
Regulation of the progesterone receptor and estrogen receptor in decidua basalis by progesterone and estradiol during pregnancy.
In this study we examined the roles of progesterone (P4) and estradiol-17beta (E2) in regulation of the P4 receptor (PR) and estrogen receptor (ER) in the decidua basalis (DB) during stromal cell proliferation and regression (Days 10 and 14 of pregnancy, respectively). Pregnant rats were ovariectomized (Ovx) on Day 8 or 12 and killed on Day 10 or 14, respectively, following treatment with P4, E2, or both. In some experiments, rats received pellets of the anti-progestin RU-486 on Day 9 and were killed 3, 6, 12, and 24 h later. Immunolocalization of PR and ER showed that both receptors decreased from Day 10 to Day 14. Histologic integrity of the placenta and DB were maintained only when P4 was present. Control and hormone-treated groups expressed established isoforms of PR and ER: PR-B, 110 kDa; PR-A, 80-90 kDa; PR-C, 64-60 kDa; ER-66, 66 kDa; and ER-49, 49 kDa. On Day 10, expression of PR-A, PR-B, and ER-66 decreased 50-99% (p < 0.05) after Ovx or RU-486 treatment but was restored to control levels after Ovx by exogenous P4. On Day 14, PR-B and ER-66 declined 66-75% (p < 0.05) after Ovx and could not be restored by P4 treatment. Estrogen could not substitute for P4, and co-administration of E2 with P4 did not enhance the response over P4 alone. In contrast, PR-C was abundantly expressed on Days 10 and 14 in all treatment groups after Ovx and RU-486. P4 maintained PR mRNA and ER mRNA after Ovx. Thus, regression of the DB may be initiated via changes in relative expression of PR isoforms, which result in impaired stromal cell response to P4 action.
Animals↗
Progesterone and estrogen regulation of rat decidual cell expression of proliferating cell nuclear antigen.
This study was an examination of the role of progesterone (P4) and estradiol-17beta (E2) as stromal cell mitogens in the decidua basalis (DB) of the rat during pregnancy. Pregnant rats were ovariectomized (Ovx) on Days 8 and 12 of pregnancy, treated with P4, E2, or both, and killed on Days 10 and 14, which correspond to times of stromal cell proliferation and regression, respectively. In some experiments, rats received pellets of the anti-progestin RU-486 on Day 9 and were killed 6, 12, and 24 h later. The mitotic index (MI) and in situ image analysis of expression of proliferating cell nuclear antigen (PCNA) were used to assess cell cycle progression. Highest expression of PCNA occurred on Days 8-12 of pregnancy, and MI was maximum; MI became zero and PCNA expression decreased dramatically thereafter (i.e., Days 14, 17, 21). Percentage of cells expressing intense PCNA on Day 10 (40%) declined to 5% after Ovx and Ovx + E2 (p < 0.05), whereas Ovx + P4 maintained PCNA. By Day 14, only 1% of stromal cells expressed intense PCNA, which was not significantly altered by Ovx, Ovx + E2, or Ovx + P4 but increased after Ovx + P4 and E2 (p < 0.05). By 6 h of RU-486, MI declined 3-fold, and intense PCNA expression was essentially lost. These changes preceded loss of histological integrity of the DB. Cells with undetectable PCNA steadily increased from 8% at 6 h to 28% by 24 h (p < 0.05). Thus RU-486 appeared to block cell cycle progression and enhanced PCNA turnover. P4 was essential for stromal cell proliferation during early pregnancy (Days 8-10), but this action was lost by Day 14.
Animals↗
Clinical characteristics of attention deficit hyperactivity disorder in African American children.
OBJECTIVE: The authors' goal was to explore the nature of attention deficit hyperactivity disorder (ADHD) in African American children, which has received scant attention by psychiatric researchers. METHOD: Subjects were 19 African American children with DSM-III-R ADHD and 24 African American children without ADHD. Ethnically sensitive methods were used to evaluate the children comprehensively. The findings were compared with those from an earlier study of Caucasian children with ADHD. RESULTS: African American children with ADHD had higher levels of psychiatric disorders other than ADHD than did African American children who did not have ADHD. CONCLUSIONS: Among African American children, ADHD may be characterized by a narrower pattern of psychiatric comorbidity and dysfunction than has been observed in Caucasians. Given the small number of subjects studied, these findings are preliminary and must be replicated to confirm their validity.
Adolescent↗
Vertebral haemangioma causing acute spinal cord compression--a report of two cases.
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Adult↗
The role of p53 tumor suppressor gene and bcl-2 protooncogene in rat corpus luteum death.
OBJECTIVE: The purpose of this study was to find out whether the mammalian corpus luteum undergoes genetically programmed cell death as evidenced by the positive or negative expression of specific biochemical markers of apoptosis (p53 and bcl-2). STUDY DESIGN: Twenty-six immature 28-day-old female Sprague-Dawley rats were given 10 IU of pregnant mare's serum gonadotropin to induce ovulation and corpus luteum formation. Corpora lutea were collected on postovulatory days 8, 10, 12, and 14 and snap-frozen immediately. Determinations of apoptotic fragmentation of deoxyribonucleic acid were performed with use of samples radiolabeled at 3'-ends with deoxynucleotide alpha-phosphorus 32-deoxycytidine triphosphate (3000 Ci/mmol). Transcription of p53 and bcl-2 was determined by Northern blot analysis of total ribonucleic acid. Protein expression of p53 and bcl-2 was determined by Western blot analysis with a monoclonal rat antibody for p53 and a polyclonal rabbit antibody for bcl-2. RESULTS: The nuclear fragmentation assay revealed formation of oligonucleosomes resulting in typical laddering of the deoxyribonucleic acid (corpus luteum) consistent with programmed cell death. Northern blot analysis of total ribonucleic acid prepared from immature (28-day-old) rat corpus luteum revealed the presence of a single p53 messenger ribonucleic acid transcript (2.1 kb) in all ages of corpus luteum studied from day 8 to day 14. Western blot analysis for p53 revealed a gradual reduction in p53 protein in corpus luteum from day 8 to day 12 until it became undetectable on day 14. Western blotting revealed expression of specific protein for bcl-2. CONCLUSIONS: It appears that programmed cell death, as evidenced by formation of oligonucleosomes, occurs during mammalian luteal regression. The patterns of p53 ribonucleic acid expression in the corpus luteum suggest that the protein products of p53 and bcl-2 do not act in a diametric manner to regulate programmed cell death in the corpus luteum. The current results suggest that the mechanisms leading to programmed cell death in the mammalian corpus luteum may differ considerably from those in other organ systems.
Animals↗