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Tracing the origins of "fetal origins" of adult diseases: programming by oxidative stress?

Too small size at birth (due to poor fetal growth and/or preterm delivery) has been associated with substantially elevated risks of the metabolic syndrome (dislipidemia, insulin resistance, hypertension), type 2 diabetes and cardiovascular disease in adulthood. The mechanisms of such "fetal origins" or "programming" of disease phenomenon remain unresolved. Too large size at birth seems also associated with an increased risk. Many known or suspected causes of or conditions associated with adverse (poor or excessive) fetal growth or preterm birth have been associated with oxidative stress. Plausibly, oxidative stress may be a common link underlying the superficial "programming" associations between adverse fetal growth or preterm birth and elevated risks of certain chronic diseases. The mechanisms of oxidative stress programming may be through directly modulating gene expression or indirectly through the effects of certain oxidized molecules. Experimental investigations have well demonstrated the role of redox balance in modulating gene expression, and recent studies indicate that both the insulin functional axis and blood pressure could be sensitive targets to oxidative stress programming. Adverse programming may occur without affecting fetal growth, but more frequently among low birth weight infants merely because they more frequently experienced known or unknown conditions with oxidative insults. As oxidative stress levels are easily modifiable during pregnancy and early postnatal periods (which are plausible critical windows), the hypothesis, if proved valid, will suggest new measures that could be very helpful on fighting the increasing epidemic of the metabolic syndrome, type 2 diabetes and cardiovascular disease. Currently, there are several ongoing large randomized trials of antioxidant supplementation to counter oxidative stress during pregnancy for the prevention of preeclampsia. It would be invaluable if long-term follow-ups of infants born to women in such trials could be realized to test the oxidative stress programming hypothesis in such experimental trial settings.

Birth Weight↗

Wolffian adnexal tumor, so-called female adnexal tumor of probable Wolffian origin (FATWO): immunohistochemical evidence in support of a Wolffian origin.

Wolffian adnexal tumor (WAT) is a rare neoplasm believed to originate from wolffian remnants on the basis of its location in areas where these remnants are abundant. To study its histogenesis, the immunoprofile of 25 WATs was compared with that of 10 cervical and vaginal mesonephric remnants and 12 rete ovarii. WATs were unilaterally located in the broad ligament (n = 10), mesosalpinx (n = 9), ovarian hilus (n = 5), and pelvis, not otherwise specified (n = 1). They showed varying morphologies with solid (spindle cells), tubular (lined by columnar cells), retiform and multicystic (spaces lined by cuboidal and attenuated cells) patterns. WATs were immunoreactive for pan-cytokeratin (AE1/3, CK1) (100%), CAM 5.2 (100%), cytokeratin 7 (CK7) (88%, focal staining), keratin 903 (17%), epithelial membrane antigen (EMA) (12%), estrogen receptor (28%), progesterone receptor (24%), androgen receptor (78%), inhibin (68%), calretinin (91%), and vimentin (100%). No immunostaining was detected with monoclonal carcinoembryonic antigen and cytokeratin 20. The pattern of staining was nearly identical to that of the rete ovarii and differed somewhat from mesonephric remnants, which were diffusely immunoreactive for CK7, immunopositive for EMA (apical staining), and nonreactive for inhibin. Our findings provide immunohistochemical support for the derivation of WATs from wolffian remnants, in particular from the rete ovarii. Because of immunoreactivity for inhibin and calretinin in a significant number of WATs, our results further show that these immunostains alone do not allow absolute distinction of WATs from sex cord-stromal tumors and adenomatoid tumors, respectively, with which they may be confused.

Adnexal Diseases↗

Determination of geographical origin of olive oils using 13C nuclear magnetic resonance spectroscopy. I - Classification of olive oils of the Puglia region with denomination of protected origin.

13C nuclear magnetic resonance spectroscopy was used to classify olive oils from the three production areas of the Puglia region labeled with the "denomination of protected origin" (DPO) Terra di Bari, Colline di Brindisi, and Dauno. High resolution (13)C spectra of 173 olive oil samples were measured, and the intensity data of triacylglycerol resonances were processed by using linear discriminant analysis, which was carried out stepwise for variable selection. The olive oil samples from the DPOs Colline di Brindisi and Terra di Bari were 90% correctly classified, whereas only 74% of "Dauno" DPO oils were classified in the true group. The performance of the discriminant model was verified by applying the cross-validation procedure based on the "leave one out" formalism. The discriminant model was evaluated against a blind test set of olive oils from the three DPO areas. All the oils used for the purpose were correctly assigned to their respective groups, with the exception of the Dauno oil samples based on the Coratina cv. They were misclassified as Terra di Bari oils because of a common monovarietal composition.

Discriminant Analysis↗

Biphasic expression of CD4 in acute myelocytic leukemia (AML) cells: AML of monocyte origin and hematopoietic precursor cell origin.

In 227 of 495 (45.9%) Japanese adult patients with acute myelocytic leukemia (AML), leukemic cells expressed CD4. Incidence of CD4 expression in each FAB subtype was as follows: M1 37.4%, M2 33.7%, M3 35.4%, M4 65.0%, and M5 78.3%. The typical expression pattern of myelomonocytic differentiation antigens and cytokine receptors in CD4+ AML was CD34lowCD33high CD11bhighGM-CSFRhigh. AML cases with 11q23 abnormalities and with inv(16) were frequently CD4-positive. These data collectively indicate that CD4 expression in AML cells is associated with monocytic characteristics. However, CD4+CD34high AML cases appear to have unique immature characteristics including low expression of myelomonocytic differentiation antigens (ie CD33 and CD11b), and accumulation of chromosome abnormalities (ie t(8;21) in CD4lowCD34high AML and chromosome 7 abnormalities in CD4highCD34high AML). We speculate that these leukemia subsets originate from CD4+ hematopoietic precursor cells, therefore then should be considered separately from most of the CD4+ AML as represented by CD34lowCD33high CD11bhighGM-CSFRhigh. Overall survival of patients with CD4+ AML in our series was worse than that of those with CD4 AML (P = 0.0202).

Adult↗

CA125 and thyroglobulin staining in papillary carcinomas of thyroid and ovarian origin is not completely specific for site of origin.

AIMS: A 70-year-old woman presented with metastatic psammoma body-rich papillary carcinoma in a supraclavicular lymph node. No primary site was evident. The tumour showed strong staining for CA125 and weak staining for thyroglobulin. Prompted by this case we aimed to assess the reliability of immunostaining for CA125 and thyroglobulin in making the distinction between thyroid and ovarian papillary carcinoma. METHODS AND RESULTS: Nine papillary carcinomas of the thyroid and 17 serous papillary carcinomas of the ovary were stained for CA125 and thyroglobulin, as well as CAM 5.2, LP 34, carcinoembryonic antigen (CEA), S100 and diastase/periodic acid-Schiff. Nine of nine thyroid carcinomas stained for thyroglobulin; in addition CA125 was positive in four of nine. Normal surrounding thyroid also showed some reaction. Seventeen of 17 ovarian serous carcinomas were positive for CA125; in addition one case showed moderately strong staining for thyroglobulin. Mucin stains were positive in 14/17 ovarian serous carcinomas, but negative in all thyroid carcinomas. The other antibodies assessed showed no useful differences in staining frequency. CONCLUSION: Many cases of papillary carcinoma of the thyroid show CA125 staining, and this feature therefore has little positive predictive value for an ovarian origin. Occasional cases of ovarian papillary carcinoma may show staining for thyroglobulin, and this result should therefore be interpreted cautiously.

Aged↗

[Documents on the origins of myopia. 2. The genetic factor in the origin of myopia (author's transl)].

The study reported confirms that the inheritance of myopia may be autosomal-dominant as well as autosomal recessive. The recessive type starts earlier and is more serious in its course. The genes which determine myopia were found to be of low expressivity and penetrance, with some modifying factors which influence its origin. The length of the ocular axis, refractive power of the cornea, general refraction and refractive power of the lens are, in the order stated, consecutively less heritable. No genetically determined parameters of dynbamic refraction were found. The genetic factor is much more active in hypermetropia than in myopia.

Adolescent↗

Cells derived from omental fat tissue and used for seeding vascular prostheses are not endothelial in origin. A study on the origin of epitheloid cells derived from omentum.

The use of microvascular endothelial cells derived from omental tissue has been advocated to seed vascular grafts with autologous endothelial cells in high density. The purpose of our study was to evaluate the precise origin of these cells. Therefore we have compared cellular characteristics of these cells with those of endothelial cells isolated by collagenase treatment of human umbilical veins. The omental cells were isolated from from omental tissue from four different patients by incubation in a collagenase-dispase solution. Part of the material was processed by Percoll density gradient centrifugation in an attempt to purify the isolates. Cellular characteristics of both types of cells were determined by studying the morphologic features of the cells and by determining the presence of von Willebrand factor, antigens EN-4 and PAL-E specific for endothelial cells, cytokeratins 8 and 18, vimentin and desmin, and uptake of diI-acetylated low-density lipoprotein. Epitheloid cells from omental tissue, isolated after collagenase treatment and either purified or nonpurified by Percoll density gradient centrifugation, differed from human umbilical vein endothelial cells with respect to the presence of surface microvilli, the expression of von Willebrand factor, EN-4 and PAL-E, and the presence of cytokeratins 8 and 18 and desmin. von Willebrand factor (in a granular staining pattern) and the presence of EN-4 and PAL-E were only detected in human umbilical vein endothelial cells. Vimentin was present in both cell types, whereas cytokeratins 8 and 18 and desmin were only present in cells derived from omentum. From these data we conclude that the so called microvascular endothelial cells from omentum are not endothelial but mesothelial in nature.

Adipose Tissue↗

Human macromolecular insoluble cold globulin (MICG). I. T-cell origin of T-MICG and null cell origin of N-MICG.

Although surface immunoglobulin characterizes B cells in man, there are few surface markers that distinguish T cells. We have described a new protein synthesized in human T cells, termed T-MICG. This protein is a macromolecule of 225,000 daltons, is insoluble in the cold, and migrates as a beta-globulin on electrophoresis. Separation of human peripheral blood lymphocytes into T and B-cell populations by rosette sedimentation and anti-human-Fab columns clearly demonstrated the T-cell origin of the 225,000 dalton component. Furthermore, null cells were shown to synthesize a protein of 185,000 daltons, termed N-MICG, with physical properties similar to T-MICG, T-MICG and N-MICG were shown to be antigenically dissimilar, employing antiserum to each of these proteins. The present studies demonstrate two novel cell surface markers, T-MICG and N-MICG, which characterize T cells and null cells, respectively.

Antigens, Surface↗

On the origin of mitochondrial mutants: evidence for intracellular selection of mitochondria in the origin of antibiotic-resistant cells in yeast.

In wild-type Saccharomyces cerevisiae, erythromycin and certain other antibacterial antibiotics inhibit the formation of respiratory enzymes in mitochondria by inhibiting translation on mitochondrial ribosomes. This paper is concerned with the origin of mutant cells, resistant to erythromycin by virtue of having a homogeneous population of mutant mitochondrial DNA molecules. Such mutant cells are obtained by plating wild-type (sensitive) cells on a nonfermentable substrate plus the antibiotic. Colonies of mutant cells appear first about four days after the time of appearance of established mutant cells; new colonies continue to appear, often at a constant rate, for many days. Application of the Newcombe respreading experiment demonstrates that most or all of the mutant cells which form the resistant colonies on selective medium arise only after exposure of the population to erythromycin. It is suggested that this result is most probably due to intracellular selection for mitochondrial genomes. Resistant mitochondria arising from spontaneous mutation are postulated to be at a selective disadvantage in the absence of erythromycin; reproducing more slowly than wild-type sensitive mitochondria, they cannot easily accumulate in sufficient numbers in a cell to render it resistant as a whole. In the presence of erythromycin, resistant mitochondria can continue to reproduce while sensitive mitochondria cannot, until there is a sufficient number to make the cell resistant, i.e. to permit normal cell growth. The same phenomenon is seen with respect to chloramphenicol resistance. Intracellular selection is considered more likely than direct induction of mutation by the antibiotic, since mutant cells do not accumulate in the presence of erythromycin if the mitochondrial genome is rendered non-essential by growth on glucose or nontranslatable by chloramphenicol. Intra-cellular selection provides a mechanism for direct adaptation at the cell level, compatible with currently acceptable ideas of spontaneous mutation and selection at the organelle level.

Cell Count↗

Detection of phosphonoacetate degradation and phnA genes in soil bacteria from distinct geographical origins suggest its possible biogenic origin.

Phosphonoacetate is regarded as an antiviral xenobiotic whose mineralization can be catalysed by an enzyme, phosphonoacetate hydrolase, encoded by the phnA gene. To date the enzyme's activity has been detected in only a limited number of bacteria. Its expression has been shown to occur in a manner independent of the phosphate status of the cell, in direct contrast to the general rule of organophosphonate metabolism being under the control of the pho regulon. In this study the environmental occurrence of the phnA gene was evaluated by polymerase chain reaction amplification of DNA extracts obtained directly from various soil environments. Sensitivity of this method was improved such that a positive result was routinely obtained with soil spiked with as few as 6 colony-forming units (cfu) per gram of soil of Pseudomonas fluorescens 23F (phnA(+)). When total DNA from a variety of Northern Irish, Greek and Bolivian soils was tested, all were positive for phnA. Bacteria capable of utilizing phosphonoacetate as sole carbon, energy and phosphorus source, with the release of essentially equimolar concentrations of phosphate to the culture supernatant, were isolated from all soil samples tested. Analysis of three such isolates revealed all to be species of Pseudomonas sensu stricto, possessing phosphonoacetate hydrolase activity in cell-free extracts. Sequence determination of the phnA gene revealed a similarity of the putative protein sequences at levels of 98.3-99.3% between the Pseudomonas strains. This is the first study to use molecular methods to investigate the distribution of a gene encoding organophosphonate metabolism, and indicates that the phnA gene is ubiquitous within soils from geographically distinct regions. Such an observation supports the proposition that phosphonoacetate is a compound that may also have a biogenic origin.

Alkaline Phosphatase↗

AIDS as a zoonosis? Confusion over the origin of the virus and the origin of the epidemics.

Based on findings demonstrating the simian ancestry of HIV, AIDS has been reported to be a zoonosis. However, this theory has never been proved and must seriously be questioned. Several arguments show that HIV-AIDS is not a zoonosis. (i) If AIDS were a zoonosis, there must be evidence of AIDS being directly acquired from an animal species, as is rabies, a disease that is directly acquired from animals. (ii) Despite long-term and frequent human exposure to SIV-infected monkeys in Africa, only 11 cross-species transmission events are known, and only four of these have resulted in significant human-to-human transmission, generating HIV-1 groups M and O and HIV-2 groups A and B. The closest relatives of SIVcpz (HIV-1 group N) and of SIVsm (HIV-2 groups C-H) are extremely rare, with only six HIV-1 group N-infected patients and only single individuals known to be infected by HIV-2 groups C-H. SIV, while capable of cross-species transmission, is thus poorly adapted for disease and epidemic spread. If AIDS were a zoonosis that is capable of significant human-to-human spread, there would be a plethora of founder subtypes and groups. (iii) Human exposure to SIV is thousands of years old, but AIDS emerged only in the 20th century. If AIDS were a zoonosis that spread into the human population, it would have spread to the West during slave trade. (iv) Experimental transmission of SIVs to different species of monkeys is often well controlled by the new host, showing that the virus and not the disease is transmitted. Therefore, we conclude that cross-species transmission of SIV does not in itself constitute the basis for a zoonosis. Transmission per se is not the major requirement for the generation of the AIDS epidemic. All HIVs do derive from simian species, but AIDS does not qualify as a zoonosis and this explanation cannot in itself account for the origin of AIDS epidemic. It is important to distinguish AIDS from true zoonoses (e.g. rabies) because research is needed to understand the processes by which animal viruses cause sustained human-to-human transmission, epidemics and even pandemics. Much is known about emerging viruses, but almost nothing is known about emerging viral diseases.

Acquired Immunodeficiency Syndrome↗

Cloning of deoxyribonucleic acid regions encoding a heat-labile and heat-stable enterotoxin originating from an enterotoxigenic Escherichia coli strain of human origin.

A heat-labile and heat-stable enterotoxin (LT+ ST+) plasmic (62.7 kilobases in size) was isolated from an enterotoxigenic Escherichia coli human strain, H10407, and used for analysis of the LT+ and ST+ deoxyribonucleic acid (DNA) regions. A DNA segment containing the LT+ and ST+ DNA regions, which consisted of two restriction endonuclease EcoRI fragments (E1 and E2), was inserted into the cloning vehicle ColE1::Tn5 by EcoRI digestion and subsequent ligation. Further cloning experiments localized the LT+ DNA region on a 5.1-kilobase restriction endonuclease PstI fragment present over the junction between the E1 and E2 fragments, as seen in the original LT+ ST+ plasmid, and the ST+ DNA region on a 1.5-kilobase PstI fragment present in either the E1 or E2 fragment. A change in the relative orientation of the E1 and E2 fragments resulted in altered levels of LT production. The relative orientation of the ColE1::Tn5 fragment to the E1 and E2 fragments also markedly influenced both LT and ST production levels. The LT+ ST+ E1-E2 region contained two unique DNA sequences consisting of a DNA segment flanked by inverted repeats which were readily distinguished from each other by size. The cloned ST+ PstI fragment was structurally very similar to one of these unique DNA sequences present in the LT+ ST+ E1-E2 region.

Bacterial Toxins↗

Formation of a cruciform structure at the simian virus 40 replication origin abolishes T-antigen binding to the origin in vitro.

Heteroduplex DNA molecules were formed by annealing an intact simian virus replication origin-containing fragment to a mutant derivative lacking the indigenous wild-type 27-base-pair (bp) inverted repeat within this structure and containing a nonhomologous 26-bp inverted repeat sequence in its place. Results of restriction enzyme and S1 endonuclease cleavage analyses strongly suggested that a 13-bp stem-loop structure formed at the site of nonhomology between these two DNAs. This structure lies within the boundary of simian virus 40 T-antigen-binding site 2, and its presence inhibited T-antigen binding to that sequence but not to an adjacent higher-affinity binding site (site 1). Therefore, the conformation of sequences within an otherwise intact T-antigen-binding site can have major effects upon T-antigen binding there.

Antigens, Viral, Tumor↗

Inhibition of structural changes in the simian virus 40 core origin of replication by mutation of essential origin sequences.

Mutation of the simian virus 40 (SV40) origin of replication (ori) has revealed the presence of three critical domains needed for DNA replication. The outer two domains, the AT tract and early palindrome element (EP), colocalize with DNA regions that become structurally altered in the presence of the SV40 large tumor antigen (T antigen) and ATP. Mutations within each domain were examined for their effect on the distortion of ori DNA by T antigen, as assayed by the sensitivity of DNA to KMnO4 oxidation. We have found that mutations in the AT tract that inhibit SV40 DNA replication also inhibit the distortion of the AT tract. Similarly, mutations in the EP inhibited the generation of structural changes in this element by T antigen. Although AT-tract mutations or mutations on the late side of ori affected structural changes only in the AT tract, certain EP mutations or mutations on the early side of ori also inhibited AT-tract distortion. Mutation of the flanking regions did not significantly affect either the affinity of T antigen for ori or the rate of binding to ori. We conclude from these results that the primary function of the flanking ori domains is to undergo structural changes required during the initiation of SV40 DNA replication. Moreover, our results suggest that the efficiency of replication initiation is significantly affected by the degree to which the flanking elements undergo a structural transition.

Antigens, Polyomavirus Transforming↗

Features and genomic origins of matrix cell adhesion molecules-1 and -2 expressed by fibroblasts of human aortic adventitial origin.

Precursor mRNAs for proteins that we have called matrix cell adhesion molecules-1 and -2 (Mat-CAM-1 and Mat-CAM-2) were cloned from fibroblasts cultured from a specimen of human abdominal aorta. Both protein sequences have the unusual feature that there is an immunoglobulin kappa (Igkappa)-like domain at the N terminus and they are glycine/proline rich in the C-terminal domain. Antibodies were raised in rabbit against peptides synthesized for a specific unique sequence of Mat-CAM-1 and Mat-CAM-2, respectively (not detected in any other proteins referenced in GenBank). Both antibodies were immunoreactive with adventitial microfibrils of the aorta and some additional arteries. Mat-CAM-1 was detected in the common/internal iliac arteries, but it was not detected in the external iliac artery. Conversely, Mat-CAM-2 was conspicuous in the external iliac artery, but not the common/internal iliac arteries. Thus, these proteins show features of site-specific expression within the arterial tree. Computerized searches show that the genomic origins of Mat-CAM-1 and -2 are in the so-called nasopharnygocarcinoma (NPC) gene on chromosome 2, which is a putative oncogene. Expression of the two different gene products from the same genomic sequence requires shifts of reading frame. Further studies will be required to determine whether these proteins are prototypes for a larger family of tissue-specific matrix proteins arising from alternative transcriptions of the same genomic sequence.

Amino Acid Sequence↗

The origin of the pseudoglandular spaces in metastatic smooth muscle neoplasm of uterine origin. Report of a case with ultrastructure and review of previous cases studied by electron microscopy.

The entity known as "leiomyomatous hamartoma," a term that has been used in reference to metastatic smooth muscle neoplasms of uterine origin (MSMNUO), is uncommon. Several articles have dealt with clinical and light microscopic aspects of this lesion. Four reports on the ultrastructure of this type of neoplasm have been published, but they have been primarily concerned with its smooth muscle component. Much controversy exists as to whether the glandular elements are part of the neoplastic process or preexisting pulmonary elements. This ultrastructural study confirms that the gland-like spaces represent entrapped alveoli and terminal respiratory bronchioles.

Female↗

[Neck lymph node metastases of unknown origin: nasopharyngeal origin and EBV (Epstein-Barr virus)].

We present a retrospective series of 16 cases of undifferentiated squamous carcinoma in cervical metastatic nodes of unknown primary. We review their clinical and radiological evaluation in search of a possible primary tumor, their response to treatment and the eventual development of a primary tumor. Furthermore, we study the presence of Epstein-Barr virus in the metastases as a predictor of their nasopharyngeal origin, in relation to the finding of primary lesions in the nasopharynx during further follow-up of the cases.

Adult↗

[New thoughts on the hypothesis of the origin of the balm of Commander of Pernes: it originated from the balm of Jerusalem].

The Baume du commandeur appears in France in 1694 in the Histoire générale des drogues... written by Pomet. It is a drug for healing wounds which also has numerous internal uses. Still present in formularies and occasionally used, its invention is attributed to Gaspard de Pernes, commander of the Order of Malta in Toul, in France, at this period. However, some observations have induced me to think that the drug originated in the Ottoman Empire at the end of the XVIlth century, and was derived from the Jerusalem Balsam of the Franciscans of St. Savior Monastery's pharmacy, in Jerusalem.

France↗