[Acute adrenal cortex insufficiency and spondylodiscitis caused by reactivated pulmonary tuberculosis].
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Adrenal Cortex Diseases↗
Biomedical subjects
J Roth
Publications and source records attributed to J Roth.
A human STX cDNA confers polysialic acid expression in mammalian cells.
Polysialic acid, or PSA, is a term used to refer to linear homopolymers of alpha(2,8)-sialic acid residues displayed at the surface of some mammalian cells. PSA is typically linked to the neural cell adhesion molecule N-CAM, where it can modulate the homotypic adhesive properties of this polypeptide. PSA expression is developmentally regulated, presumably through mechanisms involving regulated expression of sialyltransferases involved in PSA biosynthesis. Several different sialytransferase sequences have been implicated in PSA expression, although the precise roles of these enzymes in this context remain unclear. One such sequence, termed STX, maintains approximately 59% amino acid sequence identity with another sialyltransferase (PST-1, from hamster; PST, human) that is known to participate in PSA expression. While a murine STX fusion protein can catalyze the synthesis of a single alpha(2,8)-sialic acid linkage in vitro, the ability of STX to participate in PSA expression in vivo has not been demonstrated. We show here that STX transcripts are present in a PSA-positive, N-CAM-positive human small cell carcinoma line (NCI-H69/F3), but are absent in a variant of this line (NCI-H69/E2) selected to be PSA-negative and N-CAM-positive. To functionally confirm this correlation, we have cloned a human cDNA encoding the human STX sequence, and show, by transfection studies, that human STX can restore PSA expression when expressed in the PSA-negative, N-CAM-positive small cell carcinoma variant. We furthermore show that STX can confer PSA expression when expressed in a PSA-negative, N-CAM-positive murine cell line (NIH-3T3 cells), or when expressed in PSA-negative, N-CAM-negative COS-7 cells. These observations imply that STX, like PST-1/PST, can determine PSA expression in vivo. When considered together with the correlation between STX expression and PSA expression in vivo in the brain, these results suggest a regulatory role for STX in PSA expression in the developing central nervous system and small cell lung carcinoma.
3T3 Cells↗
Activation of nuclear factor-kappa B and gene expression in human endothelial cells by the common haptens nickel and cobalt.
Nickel chloride (NiCl2) and cobalt chloride (CoCl2), two haptens frequently leading to contact hypersensitivity in industrialized countries, induce gene transcription of adhesion molecules ICAM-1, VCAM-1, and E-selectin in endothelial cells. In search of transcriptional mechanisms underlying their gene-inductive effects, we studied the capacity of both haptens to activate nuclear factor (NF)-kappa B, a transcription factor involved in inducible expression of adhesion molecules. Using electrophoretic mobility shift assays, a strong increase of NF-kappa B DNA binding was detected after stimulation of HUVEC with NiCl2 or CoCl2. Supershift analysis using antisera against p50 and p65 confirmed the authenticity of the induced NF-kappa B complex. Neutralizing Abs against TNF-alpha and IL-1 did not inhibit metal hapten-induced activation of NF-kappa B, thus ruling out action via an indirect autocrine pathway. In addition, NiCl2-induced activation of NF-kappa B and adhesion molecule expression was inhibited by the antioxidant pyrrolidine dithiocarbamate, indicating the involvement of redox-dependent mechanisms. Furthermore, NiCl2 was found to induce dose-dependency mRNA production and protein secretion of the NF-kappa B-controlled proinflammatory cytokine IL-6. Our data suggest that distinct allergens represent a new class of so far unknown agents that induce NH-kappa B binding activity that subsequently modulates transcription of cytokine and adhesion molecule genes. Thus, pathomechanisms leading to contact hypersensitivity to NiCl2 and CoCl2 appear to involve not only Ag-specific Langerhans- and T cell-dependent events but also include direct effects on other immunocompetent cells such as the endothelium.
Antioxidants↗
Analysis of RET protooncogene point mutations distinguishes heritable from nonheritable medullary thyroid carcinomas.
BACKGROUND: The distinction of sporadic from inherited medullary thyroid carcinomas (MTCs) is of clinical importance because of the differences in prognosis, and the need for family screening for genetic counseling required in the latter. Germline mutations in the RET protooncogene are associated with multiple endocrine neoplasia (MEN) type 2A, familial medullary thyroid carcinoma (FMTC), and MEN type 2B. Somatic point mutations in the same gene have been identified in a subset of sporadically occurring medullary thyroid carcinomas. METHODS: A nonisotopic polymerase chain reaction-(PCR) based single strand conformation polymorphism (SSCP) analysis and heteroduplex gel electrophoresis method was used to screen DNA extracted from 32 formaldehyde fixed and paraffin embedded MTC specimens and normal tissue or blood of the same patient for point mutations in RET exons 10, 11, and 16. Point mutations were identified by nonisotopic cycle sequencing of PCR-products using an automated DNA-sequencer. Results were compared with the disease phenotype, clinical findings, and follow-up. RESULTS: Six different missense germline mutations were identified at cysteine residues 618, 630, and 634 of the cysteine-rich extracellular RET domain encoded by exons 10 and 11 in all patients with FMTC and MEN 2A. The frequency of mutations at codon 634 was higher in patients with MEN 2A than with FMTC and a 634 Cys-->Arg mutation was associated with parathyroid disease in three patients. A germline Met-->Thr point mutation at codon 918 of the RET tyrosine kinase domain was identified in all three patients with MEN 2B. Two patients with clinically sporadic MTCs and negative family history exhibited a RET germline mutation at codon 634, indicating the presence of an nonpredicted inherited MTC. Furthermore, one patient had a 618 Cys-->Ser mutation in the tumor and nontumorous thyroid DNA but not in blood DNA, indicating a mosaic mutation affecting thyroid tissue but not blood cells. Tumor specific (somatic) Met-->Thr point mutations at codon 918 were identified in 5 of 13 sporadic MTCs. The remaining eight sporadic MTCs lacked mutations in all three RET exons tested. CONCLUSIONS: This study demonstrates that (1) the molecular methods are not only suitable to identify asymptomatic individuals at risk for MEN 2A, FMTC, and MEN 2B but also to distinguish heritable from nonheritable MTCs using archival tissue specimens, and (2) that more MTCs than clinically expected are heritable, indicating the need for genetic analysis of all patients with MTC.
Adult↗
Increase of calcium levels in epithelial cells induces translocation of calcium-binding proteins migration inhibitory factor-related protein 8 (MRP8) and MRP14 to keratin intermediate filaments.
Migration inhibitory factor-related protein 8 (MRP8) and MRP14, two S-100-like Ca(2+)-binding proteins, have been described in cells of the epithelial lineage where they are either expressed constitutively (e.g. by mucosal squamous epithelium) or induced during disease (e.g. in keratinocytes during the course of psoriasis). Their biological function, however, is not yet clear. Recent studies have provided evidence that S-100-like proteins may interact with cytoskeletal components; we have therefore studied the biochemical properties and subcellular distribution of MRP8 and MRP14 in epithelial cells. TR146 human squamous carcinoma cells, which were found to express MRP8 and MRP14 in Northern and Western blot studies, were chosen for analysis. Cross-linking experiments using bis(sulphosuccinimidyl)suberate followed by SDS/PAGE and Western blot analysis revealed formation of heteromeric MRP8-MRP14 complexes. On subjecting TR146 cell lysates to two-dimensional gel electrophoresis and Western blotting, four distinct MRP14 isoforms could be identified resembling those described earlier in macrophages. A differential centrifugation technique revealed a Ca(2+)-dependent translocation of MRP8-MRP14 from the cytoplasm to the membrane and the Nonidet P40-insoluble cytoskeletal fraction. Double-label immunofluorescence microscopy of Ca2+ ionophore A23187-stimulated TR146 cells and cytochalasin B and demecolcine cytoskeleton disruption studies identified these structures as keratin intermediate filaments. Ca(2+)-dependent binding of MRP8-MRP14 to keratin filaments was additionally confirmed by an in vitro binding assay. In conclusion, our data suggest that MRP8 and MRP14 may be involved in Ca(2+)-dependent reorganization of cytoskeletal filaments in epithelial cells, which could be of importance for events associated with differentiation and inflammatory activation.
Antigens, Differentiation↗
The consequences of the discovery by W. C. Röntgen for present-day medical physics and radiation protection.
When the German physicist W. C. Röntgen discovered X-rays, which were named after him, he introduced a new development in medicine and biology: together with the discoveries of A. H. Becquerel and M. Curie, radiology with its diagnostic and therapeutic methods was made possible. The medical physicist has an important task to fulfill in modern radiotherapy, nuclear medicine and radiodiagnostics. The longtime interdisciplinary collaboration has won the international recognition of medical physics as a scientific discipline, a health care profession and a university subject. Several incidents, including contemporary ones, show that the efforts made towards radiation protection must remain an important domain of the specialist.
Health Physics↗
[Selegiline in the treatment of Alzheimer's disease].
Alzheimer's disease accounts for 60-70% of all dementias. Although its etiology has not been elucidated so far, its multiple transmitter effect has been proved reliably. Treatment with selegiline, 10 mg per day, which blocks irreversibly monoaminooxidase type B, when administered on a long-term basis, revealed improvement of cognitive functions and of general functional fitness during objective examinations by means of a battery of psychometric tests. The danger of a hypertensive crisis due to excessive supplies of exogenous monoamines ("cheese effect") can be ruled out when this dose is used. Selegiline has moreover a detoxicating potential and the ability to block the transformation of some protoxins into an effective toxin. The reduced formation of free radicals is of particular importance. The latter participate in a significant way in the destruction of cellular membranes, proteins and nucleic acids. In experiments on rats selegiline improves sexual functions, learning and its use significantly prolongs survival. As a symptomatic drug selegiline is the drug of choice in AD. Only future studies will show the justification of extensive preventive medication in advanced age groups.
Alzheimer Disease↗
Hodgkin and Reed-Sternberg cells do not carry T-cell receptor gamma gene rearrangements: evidence from single-cell polymerase chain reaction examination.
Hodgkin and Reed-Sternberg (H&RS) cells are generally accepted to be the neoplastic cells of Hodgkin's disease (HD), even though they represent only a minority of the cellular infiltrate in affected tissues. Recent immunologic studies and Southern blot analyses of DNA extracted from whole lymph node tissue favored, but did not convincingly prove a lymphoid origin of H&RS cells. To detect rearrangements of the T-cell receptor gamma chain (TCR gamma) genes at the single-cell level as an indication of early T-cell lymphoid differentiation, we isolated H&RS cells by micromanipulation from cytospin preparations of fresh biopsy material. TCR gamma chain rearrangement was detected by polymerase chain reaction using four "forward primers" that were constructed corresponding to all four V families and two "reverse primers" corresponding to consensus sequences of J segments. Rearrangements of all V families in combination with the different J segments were detected in human peripheral blood and tonsillar T cells. Although rearrangements of TCR gamma chain genes were shown in single cells of 10 of 10 T-cell leukemias, no rearrangement of these genes was found in single H&RS cells from 13 consecutive patients with HD. Our results indicate that H&RS cells from the vast majority of cases are not derived from T cells. This finding may have implications for the pathogenesis of HD and the development of more effective treatment regimens.
Base Sequence↗
Changes in survival patterns of very low-birth-weight infants from 1980 to 1993.
OBJECTIVE: To determine changes in survival patterns among very low-birth-weight ( < 1500 g) infants between 1980 and 1993. METHODS: The records of 12,960 infants treated in nine perinatal intensive care centers in Florida were analyzed on the basis of survival (discharged alive from hospital) according to four independent variables: birth weight, race, sex, and transport status. Survival curves were generated using log linear regression techniques for each race by sex by transport status group. RESULTS: Race, sex, and transport status correlated significantly with survival: survival percentages were higher among black infants, female infants, and infants transported to the perinatal intensive care centers than among white infants, male infants, and those admitted initially to the tertiary care centers. After 1985, 95% of neonates with birth weights between 1200 and 1500 g survived. In addition, survival of 500- to 500-g transported black male infants increased from zero to near 80% during the 13-year period; that of 500- to 550-g inborn white female infants rose from 35% to 70%. CONCLUSIONS: These results illustrate the value of taking into account race, sex, and transport status in efforts to understand the contribution that neonatal intensive care of extremely low-birth-weight infants makes to the lowering of infant mortality, and of using multivariable statistical procedures to generate predicted survival probabilities for different subpopulations. These probabilities can be applied to (1) predicting survival for specific subgroups of extremely low-birth-weight infants, and (2) helping physicians develop clinical guidelines for extending care to infants at the threshold of viability.
Birth Weight↗
Subcellular distribution of terminal alpha-D- and beta-D-galactosyl residues in Ehrlich tumour cells studied by lectin-gold techniques.
We have studied by high resolution in situ light and electron microscopic lectin-gold techniques the subcellular distribution of alpha-D-Gal residues using the Griffonia simplicifolia I-B4 isolectin and compared it with that of beta-D-Gal residues as detected with the Datura stramonium lectin in Ehrlich tumour cells grown as ascites or monolayer. The microvillar but not the smooth plasma membrane regions were labelled with the Griffonia simplicifolia I-B4 isolectin whereas both plasma membrane regions were equally well labelled with the Datura stramonium lectin. Elements of the endocytotic/lysosomal system such as coated membrane invaginations and vesicles, early and late endosomes and secondary lysosomes were positive for both alpha-D-Gal and beta-D-Gal residues. A particular feature of Ehrlich tumour cells is an elaborate tubular membrane system located in the pericentriolar region which is labelled throughout by both lectins and represents part of the endosomal system. In the Golgi apparatus labelling with both lectins was observed to commence in trans cisternae which is indirect evidence for a joint distribution of the sequentially acting beta 1,4 and alpha 1,3-galactosyl-transferases.
Animals↗
The ability to re-express polysialylated NCAM in soleus muscle after denervation is reduced in aged rats compared to young adult rats.
The neural cell-adhesion molecule, NCAM, contains an unusual homopolymer of sialic acid units, polysialic acid. This carbohydrate seems to be involved in neurite outgrowth, bundling and branching, processes which are important during reinnervation. In aged rats, reinnervation of denervated muscle fibres is incomplete. In this study, age-related changes in the degree of polysialylation of NCAM re-expressed after denervation were examined using a monoclonal antibody recognizing polysialic acid and a polyclonal antibody recognizing NCAM. The results show that, after denervation, the degree of polysialylation on NCAM was clearly reduced in rat soleus muscle of aged, compared to young, adult rats. This age-related change in expression of polysialic acid probably influences the reinnervation process in aged muscle.
Animals↗
[A comparative study of the imaging quality and picture dosage of a new conventional film-screen system for skeletal x-ray diagnosis].
PURPOSE: This paper compares a new film-screen system (FSS) called INSIGHT Skeletal Imaging System with the previously used Lanex/T-MAT G FSS. MATERIAL AND METHODS: Using a Bronder phantom, measurements were made of dose, resolution and contrast. 135 skeletal phantom images were assessed in order of quality by six observers. RESULTS: Comparable high resolution film-screen combinations (FSC) showed similar geometric resolution. Comparing high intensifying screens, the new INSIGHT Skeletal Regular FSS showed better resolution than the Lanex medium FSC. Dose reduction for the INSIGHT Skeletal Imaging FSS was 29-56%. The new FSS showed image quality similar to high resolution screens but was significantly better when using high intensifying screens. CONCLUSION: The new INSIGHT Skeletal Imaging System can replace the Lanex/T-MAT G FFS by retaining quality but reducing radiation dose by 29-56%. Using the new high intensifying FSC, images showed in addition improved film quality.
Bone and Bones↗
[Fatal soccer injury as an unfortunate sequela of collision].
The tragic death of a 26-year old hobby soccer player is described, who had a collision with the opposing goalie and suffered from a fracture of the left lateral process of the atlas, an extensive subarachnoid haemorrhage, tamponade of the third and fourth cerebral ventricles, bleeding into both lateral cerebral ventricles, infratentorial and supratentorial cerebral oedema. Furthermore, a survey of the literature concerning acute death in soccer is presented.
Adult↗
Uterine vascularity during stimulation and its correlation with implantation in in-vitro fertilization.
The changes in uterine artery blood flow in women undergoing in-vitro fertilization cycles were studied throughout stimulation after gonadotrophin-releasing hormone (GnRH) desensitization. The data obtained showed that the uterine vascularity was related to hormonal changes. The GnRH agonist effect was seen only after the third week of administration, and the uterine perfusion was significantly (P = 0.002) improved by the oestradiol secretion. Human chorionic gonadotrophins increased the resistance index (RI) significantly (P = 0.0001) for a period of 48 h. Then the progesterone secretion modified the curve with a significant improvement in the uterine blood flow (P = 0.03). Comparison of the RI value 2 days before human menopausal gonadotrophin (HMG) commencement, in patients with and without pregnancy, showed a higher RI in patients who did not conceive but no difference was observed on the day of embryo transfer. The pregnancy rates were similar whatever the range of the RI observed. The data available so far suggest that haemodynamic parameters alone, detected by Doppler sonography, do not provide full information on endometrial receptivity on the day of embryo transfer. A resistance index > 0.79 before HMG commencement seems to indicate poor uterine vascularity and may necessitate an increase in the HMG doses to prevent endometrial immaturity.
Adult↗
Five promoters integrate control of the cob/pdu regulon in Salmonella typhimurium.
Propanediol is degraded by a B12-dependent pathway in Salmonella typhimurium. The enzymes for this pathway are encoded in a small region (minute 41) that includes the pdu operon (controlling B12-dependent degradation of propanediol) and the divergent cob operon (controlling synthesis of cobalamin, B12). Expression of both operons is induced by propanediol and globally controlled by the ArcA and Crp systems. The region between the two operons encodes two proteins, PduF, a transporter of propanediol, and PocR, which mediates the induction of the regulon by propanediol. Insertion mutations between the pdu and cob operons have been characterized, and their exact positions have been correlated with mutant phenotypes. The region includes five promoters, four of which are controlled by the PocR protein and induced by propanediol. The cob and pdu operons each have one regulated promoter; the pduF gene is expressed from two regulated promoters (P1 and P2). The P1 and P2 transcripts extend beyond pduF to include the pocR gene; thus the PocR protein autoregulates its expression from these promoters. The fifth promoter, PPoc, is adjacent to the pocR gene and associated with a Crp binding site. We suggest that all global control of the regulon is exerted by regulating the level of PocR protein at the P1, P2, and PPoc promoters. A putative binding site for the PocR protein has been identified by computer analysis. Eight close matches to this proposed site were found in regions near the four promoters known to be regulated by PocR protein: PPdu, P1, P2, and PCob. A three-state model is proposed in which the regulon uses all five of its promoters to control expression.
Bacterial Outer Membrane Proteins↗
Isolation of NAD cycle mutants defective in nicotinamide mononucleotide deamidase in Salmonella typhimurium.
The NAD or pyridine nucleotide cycle is the sequence of reactions involved in the breakdown of NAD to nicotinamide mononucleotide (NMN) and regeneration of NAD. This cycle is fivefold more active during aerobic growth of Salmonella typhimurium and under this condition breaks down half of the NAD pool every 90 min. DNA ligase is known to convert NAD to NMN but is only a minor contributor to the NAD cycle during aerobic growth. The dominant aerobic route of NMN formation is otherwise uncharacterized. Accumulated NMN generated by either of these routes is potentially dangerous in that it can inhibit the essential enzyme DNA ligase. The reactions which recycle NMN to NAD may serve to minimize the inhibition of ligase and other enzymes by accumulated NMN. The predominant recycling reaction in S. typhimurium appears to be NMN deamidase, which converts NMN directly to the biosynthetic intermediate nicotinic acid mononucleotide. Mutants defective in this recycling step were isolated and characterized. By starting with a ligase-deficient (lig mutant) parent strain that requires deamidase to assimilate exogenous NMN, two classes of mutants that are unable to grow on minimal NMN media were isolated. One class (pncC) maps at 83.7 min and shows only 2% of the wild-type levels of NMN deamidase. Under aerobic conditions, a lig+ allele allows a pncC mutant to grow on NMN and restores some deamidase activity. This growth ability and enzyme activity are not found in lig+ strains grown without oxygen. This suggests that the existence of a second NMN deamidase (pncL) dependent on ligase and stimulated during aerobic growth. The second class of mutants (pncD) gains a requirement for isoleucine plus valine with growth in the presence of exogenous NMN. We propose that pncD mutations reduce the activity of an ilv biosynthetic enzyme that is naturally sensitive to inhibition by NMN.
Amidohydrolases↗
The end of the cob operon: evidence that the last gene (cobT) catalyzes synthesis of the lower ligand of vitamin B12, dimethylbenzimidazole.
The cob operon of Salmonella typhimurium includes 20 genes devoted to the synthesis of adenosyl-cobalamin (coenzyme B12). Mutants with lesions in the promoter-distal end of the operon synthesize vitamin B12 only if provided with 5,6-dimethylbenzimidazole (DMB), the lower ligand of vitamin B12. In the hope of identifying a gene(s) involved in synthesis of DMB, the DNA base sequence of the end of the operon has been determined; this completes the sequence of the cob operon. The cobT gene is the last gene in the operon. Four CobII (DMB-) mutations mapping to different deletion intervals of the CobII region were sequenced; all affect the cobT open reading frame. Both the CobT protein of S. typhimurium and its Pseudomonas homolog have been shown in vitro to catalyze the transfer of ribose phosphate from nicotinate mononucleotide to DMB. This reaction does not contribute to DMB synthesis but rather is the first step in joining DMB to the corrin ring compound cobinamide. Thus, the phenotype of Salmonella cobT mutants conflicts with the reported activity of the affected enzyme, while Pseudomonas mutants have the expected phenotype. J. R. Trzebiatowski, G. A. O'Toole, and J. C. Escalante Semerena have suggested (J. Bacteriol. 176:3568-3575, 1994) that S. typhimurium possesses a second phosphoribosyltransferase activity (CobB) that requires a high concentration of DMB for its activity. We support that suggestion and, in addition, provide evidence that the CobT protein catalyzes both the synthesis of DMB and transfer of ribose phosphate. Some cobT mutants appear defective only in DMB synthesis, since they grow on low levels of DMB and retain their CobII phenotype in the presence of a cobB mutation. Other mutants including those with deletions, appear defective in transferase, since they require a high level of DMB (to activate CobB) and, in combination with a cobB mutation, they eliminate the ability to join DMB and cobinamide. Immediately downstream of the cob operon is a gene (called ORF in this study) of unknown function whose mutants have no detected phenotype. Just counterclockwise of ORF is an asparagine tRNA gene (probably asnU). Farther counterclockwise, a serine tRNA gene (serU or supD) is weakly cotransducible with the cobT gene.
Amino Acid Sequence↗
Endotoxin tolerance alters thermal response of guinea pigs to systemic infusions of tumor necrosis factor-alpha.
In guinea pigs, intra-arterial infusions of 5 micrograms/kg tumor necrosis factor-alpha (TNF; specific activity 20,000 U/micrograms; duration of infusion 45-50 min) evoked a biphasic elevation of abdominal temperature lasting approximately 6 h. One week after systemic infusion of TNF, the animals started to receive either five intramuscular injections of bacterial lipopolysaccharide (LPS from Escherichia coli; 20 micrograms/kg) or equivalent volumes of solvent (0.9% NaCl) in intervals of 3 days. Fever in response to repeated injections of LPS was progressively attenuated; the animals developed endotoxin tolerance. Repeated injections with solvent did not cause any measurable changes in abdominal temperature. Three days after the fifth injection of LPS or solvent, all animals again received an intra-arterial infusion of 5 micrograms/kg TNF. In guinea pigs injected five times with solvent, the biphasic elevation of abdominal temperature could again be observed in response to systemic infusions of TNF. In endotoxin-tolerant animals, however, only the first peak of the biphasic thermal response lasting approximately 60 min could be monitored after infusions with TNF. The second phase of the thermal response to administration of TNF, which normally lasts > 5 h, was abrogated almost completely. The significant suppression of the febrile response to TNF infusions did not seem to be caused by a more rapid elimination of TNF from the circulation of endotoxin-tolerant guinea pigs. Circulating levels of TNF, measured 60 and 180 min after the start of TNF infusions, were not different before and after development of endotoxin tolerance. In conclusion, the development of endotoxin tolerance in guinea pigs is accompanied by a reduced responsiveness to TNF administered exogenously.
Animals↗