Kaposi's sarcoma in pregnant women.
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Animals↗
Biomedical subjects
P Berger
Publications and source records attributed to P Berger.
Changing the reaction specificity of a pyridoxal-5'-phosphate-dependent enzyme.
The electron distribution in the coenzyme-substrate adduct of aspartate aminotransferase was changed by replacing active-site Arg386 with alanine and introducing a new arginine residue nearby. [Y225R, R386A]Aspartate aminotransferase decarboxylates L-aspartate to L-alanine (kcat = 0.04 s-1), while its transaminase activity towards dicarboxylic amino acids is decreased by three orders of magnitude (kcat = 0.19 s-1). Molecular-dynamics simulations based on the crystal structure of the mutant enzyme suggest that a new hydrogen bond to the imine N atom of the pyridoxal-5'-phosphate- aspartate adduct and an altered electrostatic potential around its beta-carboxylate group underlie the 650,000-fold increase in the ratio of beta-decarboxylase/transaminase activity.
Aspartate Aminotransferases↗
Human beta-actin retropseudogenes interfere with RT-PCR.
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Actins↗
Immunoreactive human chorionic gonadotropin beta core fragment in human pituitary.
The human pituitary has been shown to produce small amounts of immunoreactive human chorionic gonadotropin (hCG) and its alpha- and beta- subunit (hCG alpha, hCG beta). The aim of the present studies was to further examine the various hCG-related materials in the human pituitary, particularly to search for the existence of pituitary hCG beta core fragment (hCG beta cf)--like material. HCG beta cf has been found in the urine of pregnant women, patients with trophoblastic tumors and also in postmenopausal women. Gel chromatography of pituitary extract on Superdex 200 showed three distinct peaks of hCG-related immunoreactivities, i.e. hCG, hCG beta and hCG beta cf, which were distinguishable from hLH and hLH beta peaks. HCG beta cf was recognized by a specific immunometric assay (crossreactivities with hCG beta 0.016%, hLH beta 0.04%), but unreactive in an hLH + hLH beta assay. It was purified and displayed physical properties similar to those of hCG beta cf derived from pregnancy urine. Apart from immunological differences between the small molecular weight forms or fragments of hCG and LH origin, reversed phase HPLC was able to physically discriminate between hCG beta cf and hLH beta fragment. The latter was much more abundant than the former in the pituitary extract. HCG beta cf showed microheterogeneity related to its sialic acid content. In conclusion, the present data indicate that immunoreactive hCG beta cf is present in human pituitary extracts. The physical and immunological properties of pituitary hCG beta cf are distinguishable from those of the more abundant hLH beta and its fragment, and compare favorably with those of urinary hCG beta cf of trophoblastic origin.
Aged↗
Measurement of human chorionic gonadotropin-related immunoreactivity in serum, ascites and tumour cysts of patients with gynaecologic malignancies.
Human chorionic gonadotropin (hCG)-like molecules have been reported to be elevated in a substantial fraction of serum samples from patients with various gynaecologic tumours and have been discussed as possible markers in these malignancies. Employing highly sensitive and specific immunoradiometric assays, we determined total hCG-related immunoreactivity (hCG/hCG beta), as well as free alpha-subunit (alpha-SU), common to all glycoprotein hormones, in serum (n = 106) and malignant effusions (n = 26) of women with gynaecologic malignancies. For comparison, we also measured hCG/hCG beta in nonmalignant ascitic fluids (n = 21). HCG/hCG beta serum levels were elevated (> 5 IU L-1) in 39 of 106 patients (37%) with gynaecologic malignancies, whereas free alpha-SU was above normal range only in seven (6.6%). Frequencies of hCG/hCG beta elevations were similar in women with endometrial, (n = 39), cervical (n = 40) and ovarian (n = 27) cancer, being 30%, 35% and 41%, respectively. In malignant ascites (n = 15) and tumour cyst fluids (n = 11) of patients with ovarian cancer, hCG/hCG beta concentrations were significantly higher than in the corresponding serum samples and benign ascitic samples. Free alpha-SU, on the other hand, was increased in only one of 26 malignant effusions. In conclusion, hCG/hCG beta is frequently elevated in serum of patients with endometrial, cervical and ovarian cancer and may serve as a tumour marker in these malignancies, particularly in patients where other markers are negative. In this respect, analysis of ascitic or tumour cyst fluids may be of higher diagnostic value as serum measurements.
Adult↗
Is there a pathophysiological and therapeutic link between panic disorder and epilepsy?
Relations between panic disorder (PD) and epilepsy (E) have repeatedly been discussed. Three patients with juvenile E who had been free of seizures under anticonvulsant medication for many years and developed PD are presented. Increasing anticonvulsant medication resulted in complete and stable remission of PD. It is hypothesized that, in a subgroup of patients with PD, there is a pathophysiological relation to E. Further research into the usefulness of anticonvulsants in the treatment of PD, especially in therapy-refractory cases, is suggested.
Adult↗
Vaccination for birth control.
The global population is currently expanding at the unprecedented rate of nearly 1 billion per decade, with 94% of the increase occurring in the developing world. New methods of fertility regulation are urgently needed, and the development of birth control vaccines by active immunization against antigens specific for reproduction has made substantial progress during the last two decades. These vaccines are meant to have an outstanding impact on future control of worldwide population growth by providing safe, effective, long-lasting and reversible contraception. The most advanced of these vaccines are based on the placental pregnancy hormone human chorionic gonadotropin (hCG), and have already entered clinical trials. However, immunological cross-reactivity and lack of efficacy of anti-hCG antibodies seriously challenge this strategy. Conversely, efforts to understand the molecular events involved in the fusion of sperm and egg have led to the identification of new target structures for the development of fertility-regulating vaccines. Herein, we summarize the current state of birth control vaccines and discuss the risks and drawbacks of this approach to fertility regulation.
Antigens↗
[Modification of chorionic carcinoma cells by immunomodulators. Cytokines and chorionic carcinoma cells].
OBJECTIVES: The role of inflammatory cytokines on regulation of hCG biosynthesis was studied. METHODS: JAR choriocarcinoma cells were cultured and treated with interleukin-1 (IL-1), IL-3. IL-4, stem cell factor (SCF), tumor necrosis factor (TNF), and granulocyte or granulocyte-macrophage-colony stimulating factor. hCG concentration was determined by immunoradiometric methods and cell number was enumerated by means of an electronic particle counter. RESULTS: Il-1 and TNF increased biosynthesis of holo-hCG as well as the free alpha- and free beta-subunit and the beta-core protein. Proliferation was not affected by any cytokine tested. CONCLUSION: Inflammatory cytokines are able to increase the biosynthesis of hCG.
Cell Division↗
The "VGF" protein in rat adenohypophysis: sex differences and changes during the estrous cycle and after gonadectomy.
Gene expression and cell localization of the neuroendocrine protein VGF were studied in the rat anterior pituitary. In females, four antisera against nonoverlapping regions of VGF immunostained a small number of lactotropes and many gonadotropes. In the latter cells, VGF immunoreactivity was localized to a subpopulation of secretory granules. Distinct changes were seen after estrus, with a significant increase in VGF messenger RNA (whole pituitary), whereas VGF immunostaining was strikingly reduced in gonadotropes and somewhat more abundant in lactotropes. In male rats, gene expression was low, and immunoreactivity was restricted to a few lactotropes. After castration or ovariectomy, VGF messenger RNA was high, and VGF immunoreactivity was abundant in gonadotropes. Selective localization and cyclic modulation suggest involvement of the VGF gene product(s) in pituitary gonadotrope and/or lactotrope function.
Animals↗
[Presumed transudative pleural effusion?].
We report a case of recurrent transudative pleural effusion. The initial cardiovascular investigations failed to determine its cause. The catheterization showed a "dip-plateau" suggesting a restrictive cardiomyopathy. Endomyocardial biopsy finally proved a cardiac amyloidosis.
Aged↗
[Fragments of human chorionic gonadotropin (hCG): diagnosis of pregnancy and tumors].
The pregnancy and tumor marker human chorionic gonadotropin (hCG) belongs to the family of the glycoprotein hormones. Information on epitope forming sequences of hCG and its subunits hCG alpha and hcg beta has significant impact on the examination of intra- and extracellular metabolism and the standardization of diagnostic assay systems. Variants of hCG appear in biological fluids with variable modifications on different parts of the molecule. These changes may influence the binding patterns of monoclonal antibodies (MCA), thereby causing erroneous results in hCG immunoassays. The aim of the present work was to investigate the influence of peptide bond cleavages and the loss of certain segments of the molecule, which were induced by proteases on the expression of the seven hCG alpha-(alpha 1-alpha 7), nine hCG beta- (beta 1-beta 9) and four hCG beta-core-fragment-epitopes (beta 10-beta 13), previously identified by us [1-10]. To this end, we digested hCG alpha and hCG beta with chymotrypsin. Hormone fragments were separated by high performance liquid chromatography (HPLC) and subsequently immunochemically examined by direct binding radioimmunoassay (DB-RIA), competitive RIA and immunoenzymometric assays (IEMA). Fractions containing hCG-like immunoreactivity were sequenced by Edman and carboxypeptidase-Y degradation. It appeared that: (I) Amino acids (AA) alpha 41-47 and the peptide bonds between AA alpha 40/41, alpha 47/48 and alpha 29/30 do not influence the expression of the 7 alpha-epitopes, (II) The absence of the hCG beta N-terminus plays a crucial role for the formation of epitopes beta 10 and beta 13. (III) Neither the presence nor the absence of the C-terminal peptide of hCG beta (hCG beta CTP, AA beta 114-145) has any importance for the expression of epitopes beta 1-beta 7 and beta 10-beta 13 (IV).(ABSTRACT TRUNCATED AT 250 WORDS)
Biomarkers, Tumor↗
Human chorionic gonadotropin (hCG) and its free subunits in hydrocele fluids and neoplastic tissue of testicular cancer patients: insights into the in vivo hCG-secretion pattern.
To obtain insight into the secretion pattern of human chorionic gonadotropin (hCG) and its free subunits, hCG alpha and hCG beta, in vivo, we analyzed hydrocele fluids of 13 patients with testicular cancer and correlated the respective values to those of cubital vein and testicular vein serum. As a control population, patients with nonmalignant hydroceles (n = 11) were studied. Analyses were performed with a set of highly sensitive and specific time-resolved fluoroimmunoassays based on our own panel of monoclonal antibodies. In the collective of testicular cancer patients, increased hydrocele levels of either hCG or free hCG alpha or free hCG beta were observed in 77, 54, and 92% of cases; the corresponding percentages for cubital vein serum were 62, 23, and 31%. The cubital vein ratio of hCG:hCG alpha (546:1) and hCG:hCG beta (51:1) decreased to 64:1 and to 7:1 in the hydrocele fluids. Surprisingly, hydrocele fluids of five patients with pure seminoma, who were negative for the three markers in the periphery, revealed an elevation of free hCG beta in all cases, while hCG alpha and holo-hCG were elevated twice. Final proof that hCG beta and hCG alpha are indeed produced by these previously termed "marker negative" seminomas has been achieved by reverse transcriptase-polymerase chain reaction with primers specific for the alpha-subunit and the four most abundantly transcribed hCG beta genes 3, 5, 7, and 8. From these data, we conclude that: (alpha) seminomatous and nonseminomatous testicular cancers, irrespective of histology, secrete hCG and its free subunits; (b) the amount of free subunits being secreted in vivo by these tumors has been underestimated; and (c) the classification in marker-positive and marker-negative testicular cancer should be reconsidered.
Adult↗
Eutopic production of human chorionic gonadotropin beta (hCG beta) and luteinizing hormone beta (hLH beta) in the human testis.
The classical pregnancy and tumor marker hCG has long been considered to be only accidentally expressed ectopically, e.g. by tumors. The biological functions of low levels of hCG beta, hCG alpha and holo-hCG in the sera of nonpregnant healthy individuals remained unclear. Immunological analyses by our ultrasensitive time-resolved fluoroimmunoassays revealed a concentration gradient from < 5 pg hCG beta/ml in cubital vein serum versus up to 480 pg hCG beta/ml in the corresponding benign testicular hydrocele fluids. Moreover, hCG beta and its cognate molecule luteinizing hormone beta (LH beta) were present in cytosolic extracts of normal human testes. Both hCG beta and hLH beta are eutopically produced as proven by RT-PCR and subsequent Southern and dot blot analyses. Thus, the view of a purely systemic hormonal function of hLH, and of hCG during pregnancy needs a reassessement as hCG beta and hLH beta are synthesized in the human testis and autocrine/paracrine actions seem to be likely.
Base Sequence↗
Drugs acting at the strychnine-insensitive glycine receptor do not induce HSP-70 protein in the cingulate cortex.
The potential for compounds acting at the strychnine-insensitive glycine receptor to injure neurons was examined using induction of a 70 kDa heat shock protein (HSP-70) as a marker. HSP-70 was consistently detected in retrosplenial and cingulate cortices after MK-801 but not glycine drug treatment. Elsewhere in the cortex, mild diffuse HSP-70 immunoreactivity was detected following 7-chlorokynurenic acid. Following HA-966, intense hippocampal HSP-70 immunoreactivity was observed. These findings indicate that even after very high doses, drugs acting at the strychnine-insensitive glycine receptor are less likely to injure cingulate cortical neurons than other classes of NMDA antagonists.
Amino Acids↗
The International Personality Disorder Examination. The World Health Organization/Alcohol, Drug Abuse, and Mental Health Administration international pilot study of personality disorders.
BACKGROUND: One of the aims of the World Health Organization/Alcohol, Drug Abuse, and Mental Health Administration joint program on psychiatric diagnosis and classification is the development and standardization of diagnostic assessment instruments for use in clinical research worldwide. The International Personality Disorder Examination (IPDE) is a semistructured clinical interview compatible with the International Classification of Diseases, Tenth Revision, and the DMS-III-R classification systems. This is the first report of the results of a field trial to investigate the feasibility of using the IPDE to assess personality disorders worldwide. METHODS: The IPDE was administered by 58 psychiatrists and clinical psychologists to 716 patients enrolled in clinical facilities at 14 participating centers in 11 countries in North America, Europe, Africa, and Asia. To determine interrater reliability, 141 of the IPDEs (20%) were independently rated by a silent observer. To determine temporal stability, 243 patients (34%) were reexamined after an average interval of 6 months. RESULTS: The IPDE proved acceptable to clinicians and demonstrated an interrater reliability and temporal stability roughly similar to instruments used to diagnose the psychoses, mood, anxiety, and substance use disorders. CONCLUSION: It is possible to assess personality disorders with reasonably good reliability in different nations, languages, and cultures using a semistructured clinical interview that experienced clinicians find relevant, meaningful, and user-friendly.
Adult↗
The suitability of human chorionic gonadotropin (hCG)-based birth-control vaccines.
It has been widely hoped that immunological methods of fertility regulation by active immunization against specific antigens of the oocyte, sperm, zygote and early embryo, and the placental pregnancy hormone human chorionic gonadotropin (hCG), will provide a means to control the problem of worldwide population growth. The most advanced candidate vaccines are based on hCG immunogens and have entered clinical trials. However, during the past few years, increasing evidence has emerged that the current approaches using hCG as the target molecule may have some major drawbacks. On the basis of their recent findings, Stephan Dirnhofer and colleagues raise doubts on the suitability, safety and efficacy of gonadotropin-based immunological contraceptive vaccines.
Chorionic Gonadotropin↗
Alpha-subunit and human chorionic gonadotropin-beta immunoreactivity in patients with malignant endocrine gastroenteropancreatic tumours.
In the serum of patients with malignant endocrine gastroenteropancreatic (GEP) tumours, both alpha-subunit (alpha-SU), common to all glycoprotein hormones, as well as free beta-subunit of human chorionic gonadotropin (hCG-beta) have been reported to be elevated in a substantial fraction. Both have been discussed as markers of malignancy in these neoplasms. In the present study we evaluated the diagnostic significance of alpha-SU and hCG-beta as serum markers in patients with malignant endocrine gastroenteropancreatic tumours. The study group consisted of 52 patients with endocrine GEP-malignancies (24 nonfunctioning, 23 carcinoid syndromes, four gastrinoma, one glucagonoma), located in the small intestine (n = 29), pancreas (n = 17), colon or rectum (n = 3), retroperitoneum (n = 2) and stomach (n = 1). alpha-SU and hCG-beta immunoreactivity was also assessed in the serum of patients with benign GEP-tumors (five insulinoma, and three gastrinoma). Concentrations of alpha-SU and hCG-beta were determined using two highly sensitive and specific immunoradiometric assays employing two monoclonal antibodies each. In 19 of 52 patients (37%), either alpha-SU (n = 9), hCG-beta (n = 7) or both subunits (n = 3) were elevated. In the subgroup of 24 patients with nonfunctioning GEP-tumours, increased concentrations of either alpha-SU (n = 6) or hCG-beta(n = 3) or both subunits (n = 1) were found in 10 of 24 patients (42%). In four of 23 patients with carcinoid syndrome (17%), either alpha-SU (n = 2), hCG-beta(n = 1) or both subunits (n = 1) were above the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Free alpha subunit of human chorionic gonadotrophin: molecular basis of immunologically and biologically active domains.
Immunochemical studies were undertaken to identify surface-orientated epitopes of the free alpha subunit of human chorionic gonadotrophin (hCG-alpha) at the amino acid sequence level. We investigated the molecular organization of these epitopes, resolved the immunological topography in terms of spatial arrangement of antigenic domains and related structures to functions such as subunit association or receptor binding. Overlapping synthetic peptides covering the entire amino acid sequence of hCG-alpha, an enzymatically digested hCG-alpha subunit, and a reduced and alkylated hCG-alpha preparation were assayed in a solid-phase one-site enzyme-linked immunoassay, and in a solution-phase competitive radioimmunoassay (RIA). The antigenic topography was mapped by monoclonal antibodies (MCAs) in two-site binding assays (sandwich RIA). On the surface of hCG-alpha, seven different epitopes (alpha 1-alpha 7), arranged in four spatially distinct domains, could be distinguished: A, alpha 1,2,4; B, alpha 3,5; C, alpha 6; D, alpha 7. The peptides spanning hCG-alpha(13-18), hCG-alpha(17-22) and hCG-alpha(33-42) appeared to contribute to the formation of epitopes alpha 2, alpha 4 and alpha 6 respectively. Since epitope alpha 6 is present only on the free non-assembled subunit of different species, we concluded that the region hCG-alpha(33-42), which is evolutionarily highly conserved, represents a subunit assembly site. All but one epitope (alpha 7) are destroyed by reducing and alkylating hCG-alpha. In contrast, chymotryptic digestion of hCG-alpha, leading to release of the heptapeptide hCG-alpha(41-47), did not affect epitope expression, indicating that this sequence is not involved in the formation of antigenic determinants. Addressing the biological properties of hCG-alpha epitopes by radioreceptor assay revealed that the three hCG-alpha peptides corresponding to epitopes alpha 2, alpha 4 and alpha 6 did not displace radiolabelled hCG from its receptor, whereas any of the MCAs directed against determinants (alpha 1-alpha 5), shared by hCG and hCG-alpha, totally inhibited binding. Consistent with this, the antibodies neutralized the biological activity of hCG in terms of testosterone production in a mouse Leydig cell in vitro bioassay. We therefore concluded that hormone antibody-binding sites differ from those of hormone receptor binding, revealing no essential congruence of immunologically and biologically active domains.
Amino Acid Sequence↗