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PubMed1999

Identification of the Hb Lepore phenotype by HPLC.

BACKGROUND AND OBJECTIVE: Hb Lepore is a structurally abnormal hemoglobin in which the abnormal globin chain is a hybrid or fused globin chain (db). Three different Lepore hemoglobins have been identified, differing from each other in the point at which the db fusion occurs; Hb Lepore Hollandia (d22/b50), Hb Lepore Baltimore (d59/b86) and Hb Lepore Boston (d87/b116). In Spain only Hb Lepore Boston and Hb Lepore Baltimore have been identified. Hb Lepore is easily detected by electrophoretic and chromatographic studies, whereas the type of Hb Lepore is distinguished by chromatography of tryptic peptides of abnormal db chain. In this work, we show an easier chromatography technique for identifying the Hb Lepore phenotype. DESIGN AND METHODS: Thirteen different unrelated families (23 patients) from different parts of Spain were studied. The existence of Hb Lepore was diagnosed by standard methodology and quantified by ionic exchange HPLC. The globin chains were studied by reversed phase HPLC, which showed us the phenotype of Hb Lepore; this phenotype was corroborated by a gold standard test using molecular biology techniques. The statistical analysis was designed to determine the behavior of the quantitative (hematologic) variables using the independent variable (Hb Lepore Baltimore or Hb Lepore Boston) categorized by Student's t-test for independent groups. The distribution of the variable was established using theoretical models and the variance homogeneity hypothesis was tested. The validity of the hematologic data was estimated by creating a receiver operating characteristic (ROC) curve. RESULTS: In the study of globin chains by reversed phase HPLC, in 14 patients (8 families) three peaks were eluted; they corresponded to a, b and db globin chains. In these cases when DNA was studied by PCR followed by digestion with the restriction enzyme Pvu II, the phenotype of Hb Lepore was identified as being the Boston variant, whereas in the rest of patients (9 in total), the peak identified with hybrid chain globin (db) was not present and the molecular study showed that these patients were heterozygotes for Hb Lepore Baltimore. INTERPRETATION AND CONCLUSIONS: The study of globin chains by reversed phase HPLC is sufficient to know the phenotype of Hb Lepore and thus tedious techniques such as chromatography of tryptic digestion product of db abnormal chains are not essential, a particularly important consideration in those laboratories that do not have the possibility of carrying out molecular biology studies. Neverteheless, we should continue to use a gold standard molecular biology test in cases of prenatal diagnosis because this technique is the most exact and reproducible that we have.

Chromatography, High Pressure Liquid↗

PubMed1977

A discrepancy in XC and oncogenicity assays for murine leukemia virus in AKR mice.

Studies of murine leukemia virus expression in AKR mice are presented. Material from in vivo and in vitro sources of normal tissues and lymphomas was assayed for in vitro infectivity, using the XC plaque assay, and for oncogenicity, by assessing lymphoma-accelerating capacity after inoculation into newborn animals. Normal tissues from healthy young AKR mice up to 7 months of age were found to have XC but not oncogenic activity. XC activity persisted, and weak oncogenic activity appeared in older mice. Cocultivation of normal young cells with NIH Swiss mouse embryo cells did not result in the appearance of oncogenic activity, although XC virus increased in titer. A cell-free filtrate of a virus-accelerated lymphoma was studied for host range. Virus as measured by polymerase and gs antigen was found to be propagated on NIH Swiss mouse embryo and wild mouse embryo cells, but not on human rhabdomyosarcoma, normal rat kidney, rabbit corneal, and BALB/c embryo cells. Virus as measured by the XC assay grew better on NIH Swiss mouse than on BALB/c embryo cells. Both of these cell lines propagated virus as measured by the oncogenicity assay. Supernatants from an in vitro cell line from a virus-accelerated lymphoma did not produce XC plaques but were oncogenic. Those from two cell lines of spontaneous lymphomas were negative with both assays. Cultivation of supernatants from these cultured lymphoma cells with NIH Swiss mouse embryo cells resulted in material which produced small plaques on the XC assay. These findings are interpreted as showing the presence of two viruses in AKR mice. One is XC positive and present throughout life. The other is oncogenic, appears later in life, and could be a separate virus or a variant of the first one.

AKR murine leukemia virus↗

PubMed1990

Accumulation of the insoluble PiZ variant of human alpha 1-antitrypsin within the hepatic endoplasmic reticulum does not elevate the steady-state level of grp78/BiP.

Greater than 85% of the transport-impaired PiZ variant of human alpha 1-antitrypsin is retained within cells and subsequently degraded within a pre-Golgi nonlysosomal compartment that is apparently separate from the endoplasmic reticulum (ER) (Le, A., Graham, K. S., and Sifers, R. N. (1990) J. Biol. Chem. 265, 14001-14007). Despite this phenomenon, human patients and PiZ-bearing transgenic mice exhibit an accumulation of the undegraded protein as insoluble aggregates within distended cisternae of the hepatic ER (Carlson, J. A., Rogers, B. B., Sifers, R. N., Finegold, M. J., Clift, S. M., DeMayo, F. J., Bullock, D. W., and Woo, S. L. C. (1989) J. Clin. Invest. 83, 1183-1190). Immunoprecipitation of the PiZ variant from pulse-radiolabeled hepatocytes from the transgenic animals has demonstrated that a minute quantity of the newly synthesized mutant protein is apparently resistant to degradation and accumulates gradually within the particulate fraction of the cell. Although the steady-state level of the resident ER protein grp78/BiP is elevated in response to the accumulation of malfolded proteins within that subcellular compartment, this phenomenon is not elicited by the accumulation of the insoluble PiZ variant. These results indicate that neither the accumulation of this malfolded protein within the ER nor even the distention of that subcellular compartment is sufficient to cause the up-regulation of grp78/BiP levels. The interpretation of these results with regard to the factors that regulate the levels of grp78/BiP in the ER is discussed.

Animals↗

PubMed1979

[Coronary vessel abnormalities of aortal origin].

Anomalies of aortal origin of the coronary vascular system are found in approximately one percent of the population and can be exactly documented by coronary angiography. Although such variants of origin and in the coronary vascular course are not associated with an increased incidence in coronary sclerosis, it is important that they be known for several reasons: 1. in order to avoid false interpretations of the coronarogram that can be of grave consequence, 2. for the selection of the correct incision at heart surgery, 3. a very rare anomaly, the origin of the trunk of the left coronary artery in the right Valsalva's sinus, is clearly related to sudden cardiac death in children and youths. A correct diagnosis can be life-saving.

Coronary Angiography↗

PubMed1992

Sequence variation of cytotoxic T cell epitopes in different isolates of Epstein-Barr virus.

Previous results have identified two distinct cytotoxic T lymphocyte (CTL) epitopes encoded by Epstein-Barr virus (EBV), TETA (ORF BLRF3/BERF1 residues 329-353) and EENL (ORF BERF3/BERF4 residues 290-309). Measurement of the specificities of CTL clones (TETA-specific clone 13 and EENL-specific clone 7) directed against these epitopes indicated that the EENL epitope is conserved in all strains of EBV tested while the TETA epitope varied between individual virus strains. Sequencing of the DNA regions encoding these two CTL epitopes in different EBV isolates confirmed these interpretations and demonstrated that different TETA epitope sequences were encoded by B-type EBV strains and by the B95-8 isolate of EBV compared to the other A-type EBV strains. Titration of synthetic variants of the TETA epitope revealed that the epitope encoded by B95-8 was 15-fold less efficient as a T cell epitope than the sequence encoded by other A-type viral strains while the TETA variant encoded by the B-type strains displayed essentially no activity as a T cell epitope.

Amino Acid Sequence↗

PubMed1986

Electron and X-ray diffraction studies of influenza neuraminidase complexed with monoclonal antibodies.

Complexes of influenza virus neuraminidase both with antigen-binding (Fab) fragments and with whole monoclonal antibody molecules have been crystallized. Uniformly thin platelet microcrystals suitable for structure analysis by electron diffraction, yielding reflections to approximately 4.3 A resolution, have been grown from one neuraminidase-Fab complex, that of N9 neuraminidase with 32/3 Fab, and thicker crystals of a second neuraminidase-Fab complex (N9 neuraminidase-NC35 Fab) diffract X-rays to approximately 4.0 A resolution. Electron microscope lattice images of microcrystals both of Fab and of immunoglobulin G complexed with neuraminidase have been interpreted in terms of negatively stained images of the respective individual complex protomers. The sites of binding of the antibodies to the antigen are consistent with the notion that single amino acid changes observed in monoclonal variants of neuraminidase occur in binding epitopes for the antibody used for their selection.

Antibodies, Monoclonal↗

PubMed1993

Intraspecific variation in serum proteins of brown hare (Lepus europaeus Pallas, 1778).

1. Serum proteins of brown hare (Lepus europaeus Pallas, 1778) were studied by the use of 1D PAGE, 2D agarose-PAGE, immunoblotting, inhibitions of trypsin and chymotrypsin, and specific staining for esterase. 2. Some serum proteins were identified, and easily interpretable polymorphisms were found in transferrin alpha 1B glycoprotein, protease inhibitors ATC2, ATC3 and AT1, esterase ES1 and in an unidentified postalbumin PO. 3. On the basis of family studies the evidence was obtained that the variants observed in these polymorphic proteins are under genetic control by codominant alleles of autosomal loci.

Animals↗

PubMed2004

A glycogen synthase kinase 3-beta promoter gene single nucleotide polymorphism is associated with age at onset and response to total sleep deprivation in bipolar depression.

The molecular mechanisms driving the biological clock in the suprachiasmatic nucleus of the hypothalamus may play a role in mood disorders. A single nucleotide polymorphism (SNP) (-50T/C) falling into the effective promoter region (nt -171 to +29) of the gene coding for glycogen synthase kinase 3-beta (GSK3-beta) has been linked with different age at onset of bipolar illness. GSK3-beta codes for an enzyme which is a target for the action of lithium and valproic acid, and the inhibition of which causes antidepressant-like behaviors in a preclinical model. We studied the effect of this polymorphism on the acute response to total sleep deprivation of 60 depressed bipolar type I inpatients. Homozygotes for the mutant allele of GSK3-beta promoter (-50T/C) SNP showed a later onset of bipolar illness, and better acute effects of TSD treatment on perceived mood (as rated on VAS). Overall, these observations suggest a protective role for this genotype in respect to bipolar illness. Results warrant interest for the variants of genes pertaining to the molecular clock as possible endophenotypes of bipolar disorder, and for GSK3-beta as a target of a new class of antidepressant drugs, but caution ought to be taken in interpreting these preliminary results and future replication studies must be awaited because of the low frequency of the GSK3-beta*C/C genotype in the studied populations.

Adult↗

PubMed2006

Exploring the energy landscape of a small RNA hairpin.

The energy landscape of a small RNA tetraloop hairpin is explored by temperature jump kinetics and base-substitution. The folding kinetics are single-exponential near the folding transition midpoint T(m). An additional fast phase appears below the midpoint, and an additional slow phase appears above the midpoint. Stem mutation affects the high-temperature phase, while loop mutation affects the low-temperature phase. An adjusted 2-D lattice model reproduces the temperature-dependent phases, although it oversimplifies the structural interpretation. A four-state free energy landscape model is generated based on the lattice model. This model explains the thermodynamics and multiphase kinetics over the full temperature range of the experiments. An analysis of three variants shows that one of the intermediate RNA structures is a stacking-related trap affected by stem but not loop modification, while the other is an early intermediate that forms some stem and loop structure. Even a very fast-folding 8-mer RNA with an ideal tetraloop sequence has a rugged energy landscape, ideal for testing analytical and computational models.

Kinetics↗

PubMed2006

Simulation of infrared spectra for beta-hairpin peptides stabilized by an Aib-Gly turn sequence: correlation between conformational fluctuation and vibrational coupling.

Vibrational spectra of a 12-residue beta-hairpin peptide, RYVEVBGKKILQ (HBG), stabilized by an Aib-Gly turn sequence (B = Aib) were investigated theoretically using a combination of molecular dynamics (MD) and density functional theory (DFT) calculations. Selected conformations of HBG were extracted from a classical MD trajectory and used for spectral simulations. DFT calculations, based on the Cartesian coordinate spectral property transfer protocol, were carried out for peptide structures in which all residues are replaced with Ala, except for the Aib and Gly residues, but the backbone (phi, psi, omega) structure of the original configuration is retained. The simulations provide a basis for interpretation of the HBG amide I infrared spectra in terms of structural variables such as detailed secondary structure and thermal conformational fluctuation as well as vibrational coupling as indicated by spectra of 13C isotope-labeled variants. The characteristic amide I band shape of such small beta-hairpin peptides appears to arise from the structure of the short antiparallel beta-sheet strands. The role of structural parameter fluctuation in vibrational coupling is evaluated by comparison of DFT-derived amide coupling constants for selected configurations and from transition dipole coupling calculations of coupling parameters between (13)C isotopically labeled residues for a MD-derived ensemble of configurations. Calculated results were compared with the experimentally obtained spectra for several (13)C isotope-labeled peptides of this sequence.

Journal Article↗

PubMed1997

Genetic history of cystic fibrosis mutations in Italy. I. Regional distribution.

Earlier analysis of the Italian population showed patterns of genetic differentiation that were interpreted as being the result of population settlements going back to pre-Roman times. DNA disease mutations may be a powerful tool in further testing this hypothesis since the analysis of diseased individuals can detect variants too rare to be resolved in normal individuals. We present data on the relative frequencies of 60 cystic fibrosis (CF) mutations in Italy and the geographical distribution of the 12 most frequent CF mutations screened in 3492 CF chromosomes originating in 13 Italian regions. The 12 most frequent mutations characterize about 73% of the Italian CF chromosomes. The most common mutation, delta F508, has an average frequency of 51%, followed by N1303K and G542X, both with average frequencies around 5%. Multivariate analyses show that the relative frequencies of CF mutations are heterogeneous among Italian regions, and that this heterogeneity is weakly correlated with the geographical pattern of non-DNA 'classical' genetic markers. The northern regions are well differentiated from the central-southern regions and within the former group the western and eastern regions are remarkably distinct. Moreover, Sardinia shows the presence of mutation T338I, which seems absent in any other European CF chromosome. The north-western regions of Italy, characterized by the mutation 1717-1G-->A, were under Celtic influence, while the north-east regions, characterized by the mutations R1162X, 2183AA-->G and 711 + 5G-->A, were under the influence of the Venetic culture.

Cystic Fibrosis↗

PubMed1977

Prospects of cure in lymphocyte-predominant Hodgkin's disease.

This report concerns a particular benign histologic variant of Hodgkin's disease, the lymphocyte-predominant category of the Rye classification. The group of 24 cases, all involving localized disease, was first reported in 1960, and is now reappraised, incorporating subsequent data. The interpretations of the original findings are confirmed and elaborated. A characteristic feature had been the long relapse-free and symptom-free survival period, which gave a false impression of security but was followed in some instances by disseminated disease, usually after 5-15 years. The proportion of such cases is now shown to be greater, and the possible quiescent period extended. Cure was suspected in some instances, and can now be considered likely in about half of the cases. The present results include a substantial number of patients who have survived for very long periods and who must be regarded as cured, though careful confirmatory autopsies are still unavailable.

Adolescent↗

PubMed2006

Imaging of cerebral venous thrombosis: current techniques, spectrum of findings, and diagnostic pitfalls.

Cerebral venous thrombosis is a relatively uncommon but serious neurologic disorder that is potentially reversible with prompt diagnosis and appropriate medical care. Because the possible causal factors and clinical manifestations of this disorder are many and varied, imaging plays a primary role in the diagnosis. Magnetic resonance (MR) imaging, un-enhanced computed tomography (CT), unenhanced time-of-flight MR venography, and contrast material-enhanced MR venography and CT venography are particularly useful techniques for detecting cerebral venous and brain parenchymal changes that may be related to thrombosis. To achieve an accurate diagnosis, it is important to have a detailed knowledge of the normal venous anatomy and variants, the spectrum of findings (venous sinus thrombi and recanalization, parenchymal diffusion or perfusion changes or hemorrhage), other potentially relevant conditions (deep venous occlusion, isolated cortical venous thrombosis, idiopathic intracranial hypertension), and potential pitfalls in image interpretation.

Cerebral Angiography↗

PubMed1992

[Approaches for identifying the functional application of Greek-Roman medical instruments].

Various approaches may be used in attempting to identify ancient medical instruments in cases where documentary or archaeological evidence fails to provide adequate information about their appearance or application, viz.: 1) the etymological approach, which is appropriate when only the instrument's name is known and when this indicates something about its form or function. 2) the philological approach, involving a Constitutio textus, the etymological analysis of the instrument's name and an examination of parallel references. This method is suitable in the case of instruments described in an ancient medical text whose meaning is not completely clear. 3) the philological-technical approach, which attempts an interpretation using the above philological approach supplemented by a consideration of the present-day function of a particular instrument or procedure. 4) the technical approach, which may be useful either when the existence of specific variants of an instrument has already been reliably established by means of appropriate technical terms or archaeological evidence and when the instrument is designated in the next in question only by some generic term, or alternatively when terminological specifications are lacking but the available archaeological evidence points to the existence of variants of an ancient instrument adapted for specific ends. For the purpose of illustration, the approaches described here will be applied to problem cases.

Greece, Ancient↗

PubMed1989

An ultrastructural evaluation of cell heterogeneity in invasive ductal carcinomas of the human breast. I. An in vivo study.

The present ultrastructural study has been undertaken in order to contribute to the problem of morphological heterogeneity in the ductal infiltrating carcinoma of the human breast. In spite of the well known topographical variability of scirrhous breast cancers, the comparative analysis of 12 primary tumours has brought to light some basic phenotypical expressions of the neoplastic cell population. The major observation is the occurrence of two main categories of cells, which are interpretable as the transformed counterparts of the dark and light lumenal cells of the normal mammary epithelium. The phenotypical identity of the two categories has been assessed by in vitro cultivation (parallel paper). Many aberrant morphological variants, attributable to the two cell types, were observed at the tumour-stroma interface. We have therefore suggested that the high level of morphological heterogeneity may, at least in part, be the result of stromal influences on the gene expression of the transformed cells.

Aged↗

PubMed1996

Kinetics of rod outer segment phagocytosis by cultured retinal pigment epithelial cells. Relationship to cell morphology.

PURPOSE: To study phenotypic variation in primary cultures of rat retinal pigment epithelium (RPE) and to correlate cell morphology with rates of binding and ingestion of rod outer segments (ROS). METHOD: Replicate cultures were prepared using RPE cell sheets isolated with Dispase from Royal College of Surgeons normal (RCS rdy+ p+) and dystrophic (RCS p+) rats. Retinal pigment epithelial morphology was analyzed, and phagocytosis was assessed by fluorescence microscopy in cultures fixed at 2-hour intervals from 3 to 19 hours after continuous incubations with fluorescein isothiocyanate (FITC)-stained ROS. RESULTS: A wide range of RPE cell size, shape, and pigmentation was present at confluence; however, distinct morphologic subtypes were recognized, defined as types 1 to 3, and studied separately. In both normal and dystrophic cultures, the extent and rate of ROS binding varied with RPE phenotype. In normal cultures, highly spread pigmented binucleate cells (type 3) bound and rapidly ingested multiple ROS per cell starting at 3 hours and reached a peak at 9 hours. Lightly pigmented daughter cells (type 2) bound and ingested far fewer ROS per cell than did type 3 RPE, which had not divided. Patches of hexagonally packed cells with in vivo morphology (type 1) bound large numbers of ROS per cell only after prolonged (9- to 11-hour) incubations and ingested them synchronously. Comparison of normal versus dystrophic RPE subtypes 1 to 3 revealed the known ingestion defect in all three mutant phenotypes but indicated delayed ROS binding in type 2 and type 3 cells as well. CONCLUSIONS: Kinetics of ROS binding and ingestion differ markedly among phenotypic variants of RPE cells typically found in primary cultures at confluence. Thus, accurate quantitation requires comparison of equivalent microscopic fields or like RPE subtypes, and the heterogeneous responses of various RPE subtypes should be considered when interpreting phagocytic data obtained from entire cultures at a particular time.

Animals↗

PubMed1998

A genetic propensity to high factor VII is not associated with the risk of myocardial infarction in men.

Several studies have examined the relation between factor VII and coronary artery disease by measuring factor VII levels in plasma and some found an association between high levels and disease. This suffers problems of interpretation concerning the causality of high factor VII levels, because factor VII levels may be affected by atherogenic risk factors and may become elevated as a consequence of atherosclerosis. We investigated the association between a genetic variant (353Arg-->Gln), shown to be related to factor VII levels, and myocardial infarction in a large case-control study, including 560 cases and 644 controls. Individuals carrying the 353Arg-Arg genotype seemed to have a lower risk of myocardial infarction (odds ratio 0.80 [95% confidence interval 0.60-1.061). In this study, we confirmed higher factor VII antigen and activity level in 529 men homozygous for the 353Arg allele compared with 115 men carriers of the 353Gln allele (around 20% higher). Our results indicate that a genetic propensity to high factor VII levels is not associated with the risk of myocardial infarction. Since we confirmed the association of the 353Arg-Arg genotype with higher factor VII levels, we conclude that high levels of factor VII are not a causal determinant of myocardial infarction.

Adult↗

PubMed1987

Bleomycin-induced pulmonary nodules: a variant of bleomycin pulmonary toxicity.

Bleomycin has been associated with pulmonary toxicity which is typically manifested as an interstitial pneumonitis resulting in fine, diffuse reticular or reticulomicronodular infiltrates. Attention is drawn to an additional radiologic appearance where discrete pulmonary nodules are seen and representative of bleomycin-induced change. The pitfalls of interpreting such changes as toxic effects versus metastatic disease and proposed mechanisms of bleomycin pulmonary toxicity are discussed.

Adolescent↗