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Kinetics of osteoclasts and their nuclei in evolving secondary Haversian systems.

A study of osteoclast and osteoclast nuclear population kinetics within evolving secondary osteons was undertaken in young adult Beagle dogs. Autoradiographs of serial longitudinal rib biopsy sections taken from 1 hour to 15 days after tritiated thymidine injection were analysed as to the time and the rate of appearance of the labelled nuclei within the osteoclasts and their nuclei. Such systems contained an average of nine osteoclasts, each containing an average of nine nuclei. Labelled osteoclast nuclei first appeared within 24 hours, peaked at 10% at 4 days, and declined to 1% or less after 11.5 days more. Thus, the entry rate of new nuclei into (and their exit from) the population of osteoclast nuclei under steady state conditions approximates 8% per day. Therefore, the total mononuclear osteoclast population may be viewed as divided into functional units, i.e. osteoclasts. From the ratio of the osteoclast nuclei in the cutting cone to the number of osteoblasts in the closing cone (as well as from their rates of resorption and formation), it was deduced that the osteoclast per nucleus is approximately 20-40 times more efficient than the osteoblast. Because of the intrinsically different efficiencies and life spans of these two cell types, the rates of resorption and formation within evolving Haversian systems and the amounts of bone ultimately resorbed and formed by the system, are determined by the rate and duration of the respective precursor cell proliferation. It is at this level that factors which control the bone remodelling and balance must operate.

Animals↗

Study of cell kinetics within evolving secondary Haversian systems.

A study of the origin, proliferation rate and migration of cells within the secondary evolving Haversian systems was undertaken in young adult Beagle dogs. Autoradiographs of serial longitudinal sections prepared from rib biopsies taken from one hour to eleven days after the injection of tritiated thymidine were subjected to semiquantitative analysis as to the time of appearance, number, location and transformation of various labelled cells. Numerous labelled osteoblasts appeared early (at 14-24 hours) in the most proximal closing cone. With time, this zone was seen to have been left behind the advancing cutting cone and the successive generations of osteoblasts. The first labelled osteocytes were seen at nine days after injection, in the distal closing cone. Labelled nuclei within the osteoclasts were few and appeared late (none before 24 hours). It is apparent that each self renewing cell population within these systems (i.e. osteoclasts, osteoblasts and endothelial cells) derives from its own immediate precursor and evolves at its own speed. The mononuclear osteoclasts' precursors divide locally and infrequently and the turnover of osteoclastic nuclei appears to be slow; consequently their life span and that of the osteoclasts appears to be longer than the time of the observation, i.e. 11 days. The proliferation of osteoblasts' precursors and osteoblasts recruitment is rapid. The life span of osteoblasts was found to be indeterminate; some osteoblasts may become osteocytes within a few days while others may continue to deposit bone for several weeks. Since the recruitment of osteoclastic nuclei is slow while that of the osteoblasts is fast, it is unlikely that the osteoclasts in the sites of lamellar bone remodelling modulate into osteoblasts.

Animals↗

Temperature-induced functional and structural transformations of the photosystem II oxygen-evolving complex in spinach subchloroplast preparations.

Heat inactivation of the process of O2 evolution, temperature-induced Mn2+ release and structural transitions revealed by differential scanning calorimetry (DSC) were studied in photosystem II (PSII) enriched subchloroplast fragments, granal thylakoids and the isolated oxygen-evolving pigment-lipoprotein complexes (OEC). It was found that the temperature of semi-inactivation of O2 evolution, which coincided with Mn2+ release, declined from 45 degrees C to 40 degrees C and 34 degrees C in this series of preparations, in accordance with the decreased structural stability of OEC. This was paralleled by a decrease in the content of light harvesting complex (LHC) and by an increase in the accessibility of OEC to hydrophilic electron acceptors. Thermoinactivation processes were accompanied by a two-fold decrease in PSII particle size on the EFs surface of membrane fragments. A "bi-core" oxygen-evolving complex model is proposed to account for these findings.

Calorimetry, Differential Scanning↗

Detection of evolving immunoglobulin heavy-chain gene rearrangements in acute lymphoblastic leukemia: a PCR-based assay employing overlapping DJH primers.

The use of the polymerase chain reaction (PCR) to amplify clonal immunoglobulin heavy-chain (IgH) gene rearrangements appears to be a particularly promising technique for detecting minimal residual disease (MRD). However, a major obstacle to successful implementation of this technique involves the problem of clonal evolution, in which instability of the VHDJH region leads to the generation of further rearrangements of the IgH gene over time. Such clonal evolution results in a high likelihood of false negative results when detecting MRD using clone-specific primers based on the rearrangement present at diagnosis. Since in acute lymphoblastic leukemia (ALL), clonal evolution commonly involves alterations of the VHD joining but not the DJH joining, we have devised a novel PCR strategy to circumvent the problem of false negativity in these evolved leukemias. The strategy, which involves construction of overlapping clone-specific DJH primers for use with a consensus VH segment primer, can be used to amplify both evolved and nonevolved ALL populations with high sensitivity and specificity. The method does not require radioactivity and should prove valuable for improving the effectiveness of PCR-based detection of residual leukemia.

Base Sequence↗

[Rapidly evolving pulmonary bullous degeneration in HIV-infected patients. Description of 4 cases and review of the literature].

Cavitary lung lesions are common in intravenous drug-addicts (IVDA) and in AIDS patients. Four cases are reported of IVDA patients with HIV positive serology who developed an initially thick-walled lesion, which grew rapidly and evolved into bullous lesions. The negative results in microbiological investigations for Pneumocystis carinii, Nocardia spp., staphylococci; the topographic superposition on a previous tuberculous lesion; a prolonged asymptomatic period; and a particularly rapid evolution in all cases led us to consider the rapidly evolving bullous degeneration to be more than a casual finding. Previous infection with M. tuberculosis in AIDS patients might somehow influence on the later development of a rapidly growing, fatal, bullous degenerative lesion. The elucidation of the pathogenic mechanisms of these lesions was hampered by the lack of pathological studies.

Adult↗

[Thrombolysis for evolving myocardial infarction in a rural primary care clinic].

Early thrombolytic therapy gives maximum benefit in acute myocardial infarction. In remote rural areas with no mobile intensive care service there is a significant delay between onset of symptoms and administration of thrombolytic therapy which has a critical impact on revascularization. Thrombolytic therapy with streptokinase 1,500,000 U was given in a primary care rural clinic to 2 patients with evolving myocardial infarction 45-50 minutes from onset of symptoms. In both patients, who were transported to hospital after the therapy, there were clinical signs of reperfusion. There were no complications during treatment or transportation. We conclude that thrombolytic therapy given for evolving myocardial infarction in a rural primary care clinic is possible and safe.

Aged↗

Influx of leukocytes and platelets in an evolving brain infarct (Wistar rat).

The results of several experimental studies of focal ischemia and anecdotal observations suggest that leukocytes may contribute to the injury initiated by an arterial occlusion. The timing and the nature of leukocyte responses in evolving brain infarcts (either human or experimental) are incompletely characterized. This is a study of experimental brain lesions in 96 Wistar rats that underwent occlusion of a large intracranial artery for variable intervals ranging between 30 minutes and 7 days. The experimental model, based on the occlusion of a middle cerebral artery ostium via the insertion of a nylon monofilament through the external carotid artery, does not require opening the skull; therefore, the inflammatory response is not influenced by the effects of craniotomy and changes in intracranial pressure are only those induced by the ischemic lesion. All 96 animals having the same type of arterial occlusion developed an ischemic brain lesion (limited to the territory of the corresponding artery) that evolved into an area of extensive neuronal necrosis over a period of 6 to 12 hours followed by pan-necrosis (infarct) approximately 60 hours later. In this study, leukocytes (in particular polymorphonuclear cells) were detected in the microvessels (capillaries and venules) of the ischemic hemisphere as early as 30 minutes after the arterial occlusion. Numbers of intravascular neutrophils peaked at 12 hours, whereas intraparenchymal granulocytes were most numerous at 24 hours; a few granulocytes were visible in the brain infarct as late as day 7. Circulating monocytes were first detected within the capillaries/venules of the ischemic area after 4 to 6 hours. Platelet aggregates were more abundant in the arterial than the venous side of the circulation, and luminal obstruction of arteries by platelet aggregates became noticeable only 48 hours after the arterial occlusion. Fibrin thrombi were conspicuous for their absence. These observations provide the background for studies that will attempt to unravel the relationship between the biological responses of leukocytes and neuronal necrosis secondary to focal ischemia.

Animals↗

Homoharringtonine in patients with myelodysplastic syndrome (MDS) and MDS evolving to acute myeloid leukemia.

Current anti-leukemic chemotherapy in patients with myelodysplastic syndromes (MDS) and MDS evolving to acute myeloid leukemia (AML) is associated with low response rates and high treatment-related toxicity. Homoharringtonine (HHT) is a novel cephalotaxime alkaloid with reported efficacy in relapsed and de novo AML and more recently, chronic myeloid leukemia. Although its mechanism(s) of action is not completely understood, in vitro studies have demonstrated both cytotoxic and differentiating activity in leukemic cells, as well as intra-cellular changes suggestive of apoptotic cell death. In a phase II trial, HHT was administered at a dose od 5 mg/m2 by 24-h continuous infusion daily for 9 days to patients with MDS and MDS evolving to AML (MDS/AML). Twenty-eight patients (MDS 16, MDS/AML 12) with a median age of 67 years (range 23-83) were entered. A complete remission was achieved in seven patients, a partial remission was achieved in one patient for an overall response rate of 28% (8/28). There were four of 13 responders in MDS/AML patients and four of 15 in patients with MDS. The median duration of complete response was 7 months (range 2-10). Significant myelosuppression was universal and resulted in a high incidence of induction deaths (13/28) due to neutropenic-related infections. Extramedullary toxicity was mild and consisted of hypo-tension, fluid retention, hypoglycemia, diarrhea, nausea and vomiting. HHT given in this dose and schedule demonstrated limited activity in MDS and MDS/AML and was associated with prolonged pancytopenia and marrow hypoplasia in many patients. Administration of HHT at a lower dose or in combination with hematopoietic growth factors may lead to better results, but treatment with HHT as single agent at this dose and schedule is not currently recommended for these patients.

Adult↗

[Mast cell leukemia evolved from RAEB-T (5q-syndrome) in a 12 year-old girl].

A 12-year-old, female 5q- syndrome case of refractory anemia with excess of blasts in transformation (RAEB-T) evolving to mast cell leukemia is described. This case was admitted because of general fatigue, when her peripheral blood count revealed anemia and leukocytosis with basophil-like cells. RAEB-T was diagnosed based on the laboratory findings of her peripheral blood and bone marrow aspiration, which revealed over 10% peripheral blast cells and dysmyelopoietic changes in all three lineages. Chromosomal analysis of the bone marrow cells showed 46, XX, 5q-. Six months later, the RAEB-T phase evolved to acute leukemia, despite prednisolone, vitamin D3, oxymetholone and low-dose cytosine arabinoside treatment. She had remarkable pancytopenia, hemorrhage, and hepatosplenomegaly, which were not responsive to daunomycin, enocitabine, etoposide, and 6-mercaptopurine, and eventually died. This case was unique in that her karyotype changed to normal; 46, XX, and her blast cells were mast cell lineage during the overt leukemic phase. Interestingly, some blasts were intermediate cells possessing the ultrastructural features typical of both basophils and mast cells.

Anemia, Refractory, with Excess of Blasts↗

Avian tumor viruses: persistent and evolving pathogens.

Most neoplasias of lymphoid and other hematopoietic cells in commercial poultry are caused by viruses which belong to one of four distinct groups. Marek's disease virus (MDV) is an oncogenic herpesvirus. Avian leukosis virus (ALV), reticuloendotheliosis virus (REV) and lymphoproliferative disease virus (LPDV) are oncogenic retroviruses. Each group is distinguished by nucleic acid type, molecular structure, antigenicity, epidemiology, host range and other characteristics. However, most of these viruses have in common a unique ability to persist, both in the host and in the ecosystem. In addition, both the viruses and the virus-host relationships for several members of the group have demonstrated a propensity to evolve with time, creating new dilemmas for diagnosis and control. A focus on the persistence and evolution of avian tumor viruses will be used to address a number of current issues with individual viruses of economic importance. Issues of primary concern include (1) the evolution of MDV towards greater virulence with concomitant reduction of vaccine efficacy and expansion of host range, (2) the emergence of subgroup J ALV as a major pathogen in meat-type breeder stocks, and (3) the increasing prevalence of REV and its evolving role as a pathogen in chickens and turkeys.

Animals↗

Critical issues in the evolving management of rectal cancer.

Evolving trends in the management of rectal cancer have focused on organ preservation, improved quality of life, and survival of patients. A significant shift is underway in our thinking about what constitutes the true rectum and defining the "proximal" and "distal" segments of the rectum. Tumor mobility remains a dominant prognostic factor in patient selection and choice of surgery. A clinical staging with tumor location in the rectum provides a logical algorithm for treatment decision making with either chemoradiation therapy or surgery as initial treatment of choice. Current rectal cancer management has largely focused on postoperative adjuvant radiation strategies with improvement reported for T3 and N+ cases. Recent data from Europe suggests that preoperative radiation has a significant advantage over surgery alone or postoperative treatment. This appears to be borne out by institutional studies of high-dose preoperative radiation (>45 Gy) in the United States. Aggressive preoperative combined chemoradiation has also led to significant downstaging of cancer with pathological complete response rates of 20% to 30%. This offers new options for surgical management of residual disease with endocavitary radiation or local excision. The development of new agents Gemcitabine, paclitaxel, and CPT-11 may also prove beneficial. New treatment strategies need to be coordinated with evolving knowledge of the biological behavior of the tumor based on its genetic fingerprints. c-Ki-ras and C-myc mutations have been implicated in tumor initiation and progression. A number of other tumor suppressor genes, APC gene, p53, and DCC have also been implicated in colorectal tumor carcigenesis. The modification of biological behavior by mutations in these genes is currently under study. This may guide new treatment strategies significantly reducing the death rates from rectal cancer and improving functional results of treatment.

Combined Modality Therapy↗

How some attitudes, beliefs and motivations of Spanish blood donors evolve over time.

OBJECTIVES: To determine whether the attitudes, beliefs and motivations of blood donors evolve over time. MATERIALS AND METHODS: Using questionnaires a 7-year longitudinal study of a cohort of 126 donors was performed to gather their sociodemographic characteristics and their attitudes, beliefs and motivations relating to blood donation. RESULTS: Changes were observed in a large number of beliefs and attitudes, with a reduction in fear about donation and in the need for rewards and recognition, and an increase in comfort during donation and in attitudes of duty and solidarity. However, the motivations of 65% of the sample did not change. CONCLUSION: With the passage of time, donors' attitudes and beliefs evolve in a way that is favourable to blood donation and their motivations remain stable.

Adult↗

Evolving lipoprotein risk factors: lipoprotein(a) and oxidized low-density lipoprotein.

Cardiovascular disease is the leading cause of morbidity and mortality in Westernized populations. Evolving lipoprotein risk factors include LDL oxidation and lipoprotein(a) [lp(a)]. Several lines of evidence support a role for oxidatively modified LDL in atherogenesis and its in vivo existence. There are both direct and indirect measures of oxidative stress. The most relevant direct measure of lipid peroxidation is urinary F2 isoprostanes. The most common indirect measure of LDL oxidation is quantifying the lag phase of copper-catalyzed LDL oxidation by assaying conjugated diene formation. Lp(a) is increased in patients with cardiovascular and cerebrovascular disease. However, not all prospective studies have confirmed a positive relationship between Lp(a) and cardiovascular events. Lp(a) appears to present three major problems: standardization of the assay, establishing its role in atherogenesis, and the lack of an effective therapy that can substantially lower Lp(a) concentrations. Thus, at the present time, Lp(a) concentrations should not be recommended for the general population but be reserved for patients with coronary artery disease without established risk factors, young patients with coronary artery disease or cerebrovascular disease, or a family history of premature atherosclerosis and family members of an index patient with increased concentrations of Lp(a). Although both LDL oxidation and Lp(a) are evolving risk factors for cardiovascular disease, more data are needed before they become part of the established lipoprotein repertoire.

Animals↗

Hologenomic interactions promote the higher-order evolvability of phenotypic complexity.

Current models for evolvability and complexity generally focus on mutational and regulatory processes in the host genome alone, limiting their ability to explain the origin, inheritance, and dynamics of many phenotypes. We describe a framework treating multigenome interactions in the holobiont as a central process that impacts the genotype-phenotype map, expanding the dimensionality of mechanisms producing heritable variation, generating novel traits, and exploring adaptive trajectories. These mechanisms can promote both complex phenotypic innovation and evolutionary systems drift. Many evolutionary pathways and novelties cannot be fully understood from host data alone but require consideration of hologenomic targets of selection. We outline hypotheses and methods to quantify and evaluate their impacts as a fundamental macroevolutionary process.

cellular innovation↗

Laser therapy for lymphatic malformations of the upper aerodigestive tract. An evolving experience.

Lymphatic malformations of the upper aerodigestive tract can present therapeutic challenges. Symptoms associated with these lesions include bleeding, dysphagia, changes in speech, and dyspnea. Surgical therapy is recommended, which often leads to functional interference and cosmetic deformities. Laser photocoagulation of these malformations can control symptoms and may be repeated as necessary, preserving tissue and function. The results in four patients treated with the carbon dioxide laser and in five patients treated with the neodymium-YAG laser were reviewed. Reduction of bulk and improvement of symptoms were achieved in all patients, most of whom required multiple treatments. The average duration of each procedure was 30 minutes. All patients were discharged from the hospital on the same day or 1 day after laser therapy with minimal morbidity. The indications, evolving technique, and results of laser therapy are discussed.

Adolescent↗

Pancreatic transection. A concept of evolving injury.

We describe the difficulties in diagnosing a pancreatic injury in two patients with multiple injuries who did not have an obvious need for a celiotomy. Multiple diagnostic tests were employed, but in each patient, there was a delay in the diagnosis of the injury. A pancreatic injury may evolve over time so that repetitive clinical diagnostic studies may be required to evaluate the condition of these patients.

Adult↗

DXplain. An evolving diagnostic decision-support system.

DXplain is an evolving computer-based diagnostic decision-support system designed for use by the physician who has no computer expertise. DXplain accepts a list of clinical manifestations and then proposes diagnostic hypotheses. The program explains and justifies its interpretations and provides access to a knowledge base concerning the differential diagnosis of the signs and symptoms. DXplain was developed with the support and cooperation of the American Medical Association. The system is distributed to the medical community through AMA/NET--a nationwide computer communications network sponsored by the American Medical Association--and through the Massachusetts General Hospital Continuing Education Network. A key element in the distribution of DXplain is the planned collaboration with its physician-users whose comments, criticisms, and suggestions will play an important role in modifying and enhancing the knowledge base.

Artificial Intelligence↗

Acute myeloid leukemia evolving from essential thrombocythemia in two patients treated with hydroxyurea.

Essential thrombocythemia (ET) is an uncommon myeloproliferative disorder, which is thought to develop from a multipotent stem cell. Like other myeloproliferative diseases, ET is associated with an increased risk of development of acute leukemia (AL). However, the large majority of cases of leukemic transformation in ET are thought to be related to prior therapy, usually radioactive phosphorous or alkylating chemotherapy, and the development of AL in ET is extremely rare in the untreated patient. In this report, two cases of ET which evolved into AL without prior exposure to radiation or alkylating agents, and which were treated with long-term hydroxyurea therapy, are described. The first case had cytogenetic changes in the bone marrow suggestive of therapy-associated leukemia, and the second developed myelodysplastic syndrome on therapy which was likely chemotherapy-induced and led to acute leukemia. Prolonged used of hydroxyurea in patients with ET may lead to therapy-associated acute leukemia.

Acute Disease↗