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PubMed1991

European approach to the Human Gene Project.

In the history of gene mapping, which extends through most of the present century, Europe has played an important role. This has continued during the evolution of the 10 International Human Gene Mapping Workshops that have been held in seven different countries since 1973. Nationally coordinated programs have been a recent development, and several European countries, including the United Kingdom and Italy, have followed the lead of the United States in investing substantial sums of money in research on the human genome. In addition, the European Community has launched a multinational program of research on Human Genome Analysis to complement the various national initiatives. The particular approach in Europe has been to support those in the field by establishing resource centers for distributing biomaterials and accessing databases, by assisting in the training of scientists, and by funding programs of research directed at present needs in both physical and genetic mapping.

Chromosome Mapping↗

PubMed1981

Design of glycolysis.

The design of the glycolytic pathway resulting from the continuous refinement of evolution is discussed with regard to three aspects. 1. Functional and structural properties of individual enzymes. The catalytic constants of the glycolytic enzymes are remarkably optimized; the turnover numbers are within one order of magnitude. The same is true for the molarities of catalytic centres in the cytosol, as is noted for yeast. Functional properties of the enzymes are reflected in their tertiary and quaternary structures. 2. Regulatory mechanisms of single enzymes. A classification of the various types of enzymic control mechanisms operating in the glycolytic pathway is given. In addition to the usual Michaelis-Menten saturation kinetics and the various types of inhibition there is control by positive and negative effectors based on oligomeric structures (fast acting, fine control) as well as regulation by chemical interconversion structures (fast acting, fine control) as well as regulation by chemical based on enzymes cascades (slow acting, very effective). 3. Functional and regulatory mechanisms of the whole glycolytic reaction pathway. A prominent feature is the high enzyme:substrate ratio, which guarantees fast response times. However, a quantitative treatment of the overall kinetics is limited by an incomplete knowledge of the enzymes' dynamic and chemical compartmentation as well as some of their control properties. From an analysis of the oscillatory state, certain control points in the glycolytic chain can be located that coincide with major branching points to other metabolic pathways. These points are controlled by fast-acting cooperative enzymes that operate in a flip-flop mechanism together with the respective antagonistic enzymes, preventing futile cycles. The gating enzymes leading to the glycogen store and the citric acid cycle are of the slow-acting but very effective interconvertible type. The combination of all the complex and intricate features of design yields a glycolytic network that enables the cell to respond to its various metabolic needs quickly, effectively and economically.

Animals↗

PubMed2026

Bayesian inference of lineage trees by joint analysis of single-cell multimodal lineage-tracing data with BiLinT.

The advent of single-cell lineage-tracing technologies has enabled the simultaneous profiling of gene expression and lineage barcodes. However, accurate, high-resolution reconstruction of cell lineage trees remains challenging because most existing approaches treat these modalities separately and therefore fail to fully exploit their complementary information. Here we present BiLinT, a Bayesian framework that jointly models multimodal single-cell lineage-tracing data for lineage tree reconstruction. BiLinT integrates barcode evolution (a continuous-time Markov chain) with gene expression dynamics (an Ornstein-Uhlenbeck process) within a unified probabilistic model. Across synthetic and real data sets, BiLinT provides accurate lineage-tree reconstruction and reveals differentiation-associated clonal structure and developmental fate biases.

Journal Article↗

PubMed1976

Stepwise generation of the natural oxidant in a reconstituted chloroplast system.

Isolated chloroplasts which have lost their envelopes and, in consequence, the soluble components which constitute the stroma, will nevertheless evolve O(2) when supplied with an artificial oxidant (the Hill reaction). They will also evolve O(2) with NADP as the Hill oxidant if supplemented with ferredoxin. With catalytic NADP, continuing O(2) evolution can be maintained by the inclusion of a suitable reaction or reaction sequence which reoxidizes NADPH.In the Benson-Calvin cycle the terminal oxidant is glycerate 1,3-bisphosphate which is generated by phosphorylation of 3-phosphoglycerate, its immediate precursor. Experiments with a reconstituted chloroplast system are described in which this reaction sequence is catalyzed by stromal protein and supported by photophosphorylation of catalytic ADP. In the presence of CO(2), 3-phosphoglycerate can be progressively replaced by ribulose 1,5-bisphosphate, ribose 5-phosphate, fructose 6-phosphate, fructose 1,6-bisphosphate, and finally by glyceraldehyde 3-phosphate. In this last instance the natural oxidant is regenerated from its own reduction product (via the carboxylation step) and the reaction sequence therefore involves the entire photosynthetic carbon cycle.

Journal Article↗

PubMed1989

Effects of gradual increases in o(2) concentration on nodule activity in soybean.

The objectives of this study were to determine whether attached nodules of soybean (Glycine max L. Merr.) could adjust to gradual increases in rhizosphere pO(2) without nitrogenase inhibition and to determine whether the nitrogenase activity of the nodules is limited by pO(2) under ambient conditions. A computer-controlled gas blending apparatus was used to produce linear increases (ramps) in pO(2) around attached nodulated roots of soybean plants in an open gas exchange system. Nitrogenase activity (H(2) production in N(2):O(2) and Ar:O(2)) and respiration (CO(2) evolution) were monitored continuously as pO(2) was ramped from 20 to 30 kilopascals over periods of 0, 5, 10, 15, and 30 minutes. The 0, 5, and 10 minute ramps caused inhibitions of nitrogenase and respiration rates followed by recoveries of these rates to their initial values within 30 minutes. Distinct oscillations in nitrogenase activity and respiration were observed during the recovery period, and the possible basis for these oscillations is discussed. The 15 and 30 minute ramps did not inhibit nitrogenase activity, suggesting that such inhibition is not a factor in the regulation of nodule diffusion resistance. During the 30 minute ramp, a stimulation of nitrogenase activity was observed, indicating that an O(2)-based limitation to nitrogenase activity occurs in soybean nodules under ambient conditions.

Journal Article↗

PubMed1996

Linking of isozyme and class variability patterns in the emergence of novel alcohol dehydrogenase functions. Characterization of isozymes in Uromastix hardwickii.

The nature of the isozyme differences in the class-I alcohol dehydrogenase structure from the lizard, Uromastix hardwickii, was determined and related to those in the human and horse enzymes, for which isozyme structures have also been established. The Uromastix isozymes differ much (at a total of 72 positions, 19%) but, in spite of this, have similar properties and were not obtained resolved. Their structures were analyzed in mixture, and the two sub-sets of peptides obtained could be distinguished by evaluation of the recovery ratios within the peptide pairs. The isozymes have class-I activities, with an ethanol dehydrogenase activity of 0.6 U/mg and no formaldehyde dehydrogenase activity, have typical class-I structures, and are composed of N-terminally acetylated 375-residue subunits (a and b). Importantly, variability patterns between the isozymes are reminiscent of those both in the other two lines with isozymes (primates and horse) and in the class distinctions of the enzyme. Hence, the variability pattern since the distant stage of class-I emergence is also visible within the more recent isozyme divergence, illustrating a continuity in the evolution of isozymes to classes (and then to enzymes). The pattern also links the different levels of multiplicity and may suggest an acceptability in common to duplications and mutations, compatible with the emergence of novel functions.

Alcohol Dehydrogenase↗

PubMed1981

Long-term prognosis after infantile spasms: a statistical study of prognostic factors in 200 cases.

A follow-up study was made on 200 children (115 boys, 85 girls) who had had infantile spasms, in order to compare their present condition over the age of six years with various prognostic factors. 48 of the children (30 males and 18 females) had died, and all the rest were aged six years or older at the time of final follow-up. 139 of the children had received ACTH therapy: at final follow-up, spasms had ceased in 43.5 per cent, and about the same proportion showed normal physical development; 23 per cent had normal mental development and 15.4 per cent were attending ordinary schools. Complete recovery (normal mental and physical development and attending ordinary schools) was achieved in only 19 cases (9.5 per cent). Of the cryptogenic cases, 44.4 per cent had made a full recovery. The poor prognostic factors for continuing seizures were evolution into other types of fits, relapse of seizures after ACTH therapy, seizures concomitant with spasms, and convulsions before the onset of spasms. Poor prognostic factors for physical development were delayed development before the onset of spasms, neurological abnormalities, PEG abnormality, symptomatic aetiology, neonatal convulsions, low birthweight, perinatal asphyxia and being female. Poor prognostic factors for mental development were delayed development before the onset of spasms, neurological abnormalities, PEG abnormality, prenatal and perinatal aetiology, relapse after initial ACTH therapy, laughing attacks, and evolution into other types of fits. Only in the cryptogenic cases was there significant correlation between the delay in treatment and the long-term prognosis for mental development. Poor prognostic factors for educability were very similar to those for mental development. In spite of conflicting views as to the long-term effects of ACTH, prompt treatment seems to be mandatory, at least in cryptogenic cases of infantile spasms.

Achievement↗

PubMed1996

Magnetic Resonance Imaging of the Thoracic Aorta.

Magnetic resonance imaging (MRI) is well-suited for imaging the vascular system and is of particular value in assessing the anatomy and pathologies of the thoracic aorta. The intrinsic contrast between the blood pool and the vascular structures allows excellent depiction of intra- and extravascular anatomy and eliminates the need for intravenous contrast agents. A large field of view provides a complete evaluation of the mediastinum and chest. Both qualitative and quantitative techniques are available, which can yield physiological data in addition to anatomical information. The multiplanar capability offers images in any plane, allowing an accurate assessment of the longitudinal extent of disease and providing images perpendicular to vessels, even when tortuous. MRI currently represents an essential component of the imaging strategies available to assess the thoracic aorta and may come to function as a gold standard for certain conditions. As the technology continues its rapid evolution, MRI will most likely be able to serve as an effective noninvasive evaluation to provide all of the anatomical, pathological, and physiological information required of a comprehensive examination of the thoracic aorta. (ECHOCARDIOGRAPHY, Volume 13, March 1996)

Journal Article↗

PubMed2000

Editorial.

The cosmopolitan nature of current travel practices, as well as significant immigration from endemic areas, has led to increases in the incidence of leprosy. The classic presentation of leprosy usually appears as the indeterminate form, demonstrates hypopigmented macules with a loss of sensation. However, the manifestations can sometimes be quite protean. Sadeghi et al. review the rheumatic manifestations of leprosy with an illustrating case presenting with arthritis. Rheumatic symptoms are common in leprosy patients and may be the presenting manifestations and should be considered in patients with persistent rash and unusual arthritis who have a history of exposure to endemic areas. Significant interest has developed over the past decade in inhibiting cutaneous carcinogenesis with retinoic acid. This has been used as an effective therapy in certain genetically predisposed individuals, including individuals with a DNA repair defect in xeroderma pigmentosa. The molecular mechanisms of retinoids ability to inhibit ultraviolet light induced carcinogenesis have not been determined. Li and co-workers have examined the effect of retinoic acid on ultraviolet light induced programmed cell death (apotosis) as well as expression of the tumour suppressor gene P53. Their studies suggest that retinoic acid does not work on the initiation stages of the cancer development, but may work in the promotion and progression stage. Of more immediate clinical importance, in the Point-Counterpoint section, we have two insightful articles on how physician reimbursement affects patient care. As North American health care continues to evolve, there is constant debate on what model system works best for the ultimate benefit of our patients. Physicians, politicians, and administrators are constantly comparing the United States health care delivery to that of Canada. While no one can accurately predict the future developments in these areas, I think Dr. McElgunn sums the concerns that indeed are applicable on both sides of the border: ".socialized medical system has been of great benefit to patients but the ability of its physicians to continue to carry the system is at or near the breaking point. The ramifications of the issues of access and quality of care are harbingers of a system in turmoil." While these concerns must be dealt with, strong physician input is vital to continuing the effective evolution of our health care system. A vital part of our health care delivery is the increasing use of diagnostic tests. Key treatment decisions and interventions are based on the interpretation of these tests. However, most tests are "imperfect instruments." The article by Binder and Dreiseitl concisely reviews sensitivity, specificity, prevalence, predictive values, and likelihood ratios in a highly informative manner with significant examples. This paper provides a reference with which all physicians should be familiar. Traditionally, Western medicine has focused on a model of disease whereby pathology was regarded as well defined alteration in normal physiology that should respond to appropriate pharmaceutical or surgical interventions. However, in recent years patient focused medicine has become an important aspect of our practices. The concept of health related quality of life has represented an important advance in dealing with these concerns in our treatment of disease. Drs. Price and Harding examine the concept of health related quality of life using the example of a diabetic foot ulcer complications. These types of measures are important to understand, not only in the context of this disease but in the context of any chronic dermatologic condition.

Journal Article↗

PubMed2003

Natural patterns of neural activity: how physiological mechanisms are orchestrated to cope with real life.

Physiological mechanisms of neuronal information processing have been shaped during evolution by a continual interplay between organisms and their sensory surroundings. Thus, when asking for the functional significance of such mechanisms, the natural conditions under which they operate must be considered. This has been done successfully in several studies that employ sensory stimulation under in vivo conditions. These studies address the question of how physiological mechanisms within neurons are properly adjusted to the characteristics of natural stimuli and to the demands imposed on the system being studied. Results from diverse animal models show how neurons exploit natural stimulus statistics efficiently by utilizing specific filtering capacities. Mechanisms that allow neurons to adapt to the currently relevant range from an often immense stimulus spectrum are outlined, and examples are provided that suggest that information transfer between neurons is shaped by the system-specific computational tasks in the behavioral context.

Action Potentials↗

PubMed2005

A history of microarrays in biomedicine.

The fundamental strategy of the current postgenomic era or the era of functional genomics is to expand the scale of biologic research from studying single genes or proteins to studying all genes or proteins simultaneously using a systematic approach. As recently developed methods for obtaining genome-wide mRNA expression data, oligonucleotide and DNA microarrays are particularly powerful in the context of knowing the entire genome sequence and can provide a global view of changes in gene expression patterns in response to physiologic alterations or manipulation of transcriptional regulators. In biomedical research, such an approach will ultimately determine biologic behavior of both normal and diseased tissues, which may provide insights into disease mechanisms and identify novel markers and candidates for diagnostic, prognostic and therapeutic intervention. However, microarray technology is still in a continuous state of evolution and development, and it may take time to implement microarrays as a routine medical device. Many limitations exist and many challenges remain to be achieved to help inclusion of microarrays in clinical medicine. In this review, a brief history of microarrays in biomedical research is provided, including experimental overview, limitations, challenges and future developments.

Animals↗

PubMedDate not supplied

[Instrument for the evaluation of the adult patients' ability for self-care--CADEM].

This study develops a tool to facilitate the determination of adult patients selfcare ability aiming at promoting clear and objective communication. The tool developed, called CADEM, establishes levels to determine patient's categorization according to their need of nursing care. It has been-considered that CADEM is a valid tool and can help in planning nursing care, and also to register the patients' evolution through its continued and systematic use, therefore helping to justify necessary changes in Nursing care planning.

Activities of Daily Living↗

PubMed2004

Trends in the development of new antidepressants. Is there a light at the end of the tunnel?

Since the introduction of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) in mid-1950's, treatment of depression has been dominated by monoamine hypotheses. The well-established clinical efficacy of TCAs and MAOIs is due, at least in part, to the enhancement of noradrenergic or serotonergic mechanisms, or to both. Unfortunately, their very broad mechanisms of action also include many unwanted effects related to their potent activity on cholinergic, adrenergic and histaminergic receptors. The introduction of selective serotonin reuptake inhibitors (SSRIs) over twenty years ago had been the next major step in the evolution of antidepressants to develop drugs as effective as the TCAs but of higher safety and tolerability profile. During the past two decades SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) gained incredible popularity and have become the most widely prescribed medication in the psychiatric practice. The evolution of antidepressants continued resulting in introduction of selective and reversible monoamine oxidase inhibitors (eg. moclobemid), selective noradrenaline (eg. reboxetine), dual noradrenaline and serotonin reuptake inhibitors (milnacipram, venlafaxin, duloxetin) and drugs with distinct neurochemical profiles such as mirtazapine, nefazadone and tianeptine. Different novel serotonin receptor ligands have also been intensively investigated. In spite of the remarkable structural diversity, most currently introduced antidepressants are 'monoamine based'. Furthermore, these newer agents are neither more efficacious nor rapid acting than their predecessors and approximately 30% of the population do not respond to current therapies. By the turn of the new millennium, we are all witnessing a result of innovative developmental strategies based on the better understanding of pathophysiology of depressive disorder. Several truly novel concepts have emerged suggesting that the modulation of neuropeptide (substance P, corticotrophin-releasing factor, neuropeptide Y, vasopressin V1b, melanin-concentrating hormone-1), N-methyl-D-aspartate, nicotinic acetylcholine, dopaminergic, glucocorticoid, delta-opioid, cannabinoid and cytokine receptors, gamma-amino butyric acid (GABA) and intracellular messenger systems, transcription, neuroprotective and neurogenic factors, may provide an entirely new set of potential therapeutic targets, giving hope that further major advances might be anticipated in the treatment of depressive disorder soon. The goal of this review is to give a brief overview of the major advances from monoamine-based treatment strategies, and particularly focus on the new emerging approaches in the treatment of depression.

Antidepressive Agents↗

PubMed2005

Chemotherapy and novel therapeutic approaches in malignant glioma.

Glial neoplasms represent 0.5-1% of all cancers in most Western countries. Malignant gliomas are among the most devastating cancers, leading to death in most cases. They present unique challenges due to their location, aggressive biological behavior and diffuse infiltrative growth. Notwithstanding the development of new surgical and radiation techniques in the last thirty years, a cure for malignant gliomas remains elusive. In this article, we will review the standard and new therapies used for malignant gliomas. As standard therapies, surgery, radiation therapy and systemic chemotherapy, are in a continuous process of evolution. Multiple chemotherapies have been used in malignant gliomas, as single agents, in combination, or with different modes of administration, including high-dose chemotherapy with stem cell rescue and intra-arterial chemotherapy. The last decade has been noticeable for the advent of a better understanding of the biology of malignant gliomas. This has stimulated active research in multiples areas and the advent of new treatment strategies. Techniques to circumvent the resistance mechanisms to chemotherapy have been evaluated, tyrosine kinase inhibitors have shown activity in malignant primary brain tumors and radioimmunotherapy remains an area of active research. In this article, we review the past, present and future treatments of malignant gliomas with a special interest on chemotherapy, resistance mechanisms and tyrosine kinase inhibitors.

Antineoplastic Agents↗

PubMed1998

Breast cancer advocacy in clinical care.

Although still in a continual state of evolution, breast cancer advocacy has come of age in the last few years. Advocacy is a very broad term that can be defined as the viewpoint of a breast cancer patient or survivor, or a viewpoint that is fully patient centered. In the area of clinical care and research, a cooperative atmosphere has developed that has required a close working relationship and understanding of cultures between advocates and those in the professional medical care and research communities. Interaction with patients and decision makers, which reflects individual values and preferences, requires a firm knowledge of medical outcomes; in this way, the advantages and disadvantages of a screening, diagnostic, or treatment plan can be analyzed. Moreover, a clear communication strategy needs to be in place to convey these concepts to patients and to elicit their individual choices and concerns. The development of optimal, shared decision making will require ongoing innovations in all these areas, and some are now being piloted and tested in the areas of screening, prevention, and treatment. The role of advocacy in research has likewise involved a sharp learning curve from both sides. Multiple models of mutual education, exchange of ideas, and the conversion of this interaction into research strategies are now in place in many settings. The intent of such interaction is to move forward with discovery and clinical application in a way that forces a rethinking and innovation of approaches but emphasizes proper scientific methodology. Patient-focused themes of relevance to patients with breast cancer, timely translation to the clinic, and a broader scope of research and ideas are all being integrated into the scientific review process. An emphasis on advocacy issues, along with stepwise scientific progress, will be essential in the new era of rapid technology development, clinical testing, and adoption into the standard of patient care.

Journal Article↗

PubMed1995

Accelerating momentum for change!

As we develop strategies to compete globally, we are challenged with integrating our resources to execute these strategies effectively. Many companies are in the midst of dramatic shifts in corporate cultures, giving more responsibility to employees while raising expectations for their performance. The extent of these changes is far reaching and brings significant challenges to both employees and corporations. This article is a continuation of the evolution (over five years) of a corrective action/continuous improvement process implemented at Exide Electronics. It discusses organizational structures, including steering committees, corrective action teams, task teams, and work cells. Specific expectations, goals, and results of the teams are presented, along with ground rules for functioning within the organization. After structuring the organization and coordinating the resources effectively, the next challenge is accelerating momentum for change. The presentation also discusses the evolutionary process required to make a culture focused on change, including ongoing communication and feedback, constant evaluation and direction of the process, and measuring and paying for performance.

Communication↗

PubMed2001

Treatment of stage I lung cancer.

This article reviews changes in the roles of surgeons, medical oncologists, and radiation oncologists that have occurred over the past 20 years. A gradual evolution will certainly continue over the next several decades in the multidisciplinary quest to improve the dismal survival results.

Carcinoma, Non-Small-Cell Lung↗

PubMed2005

Osteodistraction in the craniofacial region.

In the specific field of maxillofacial surgery, the use of osseous distraction is always more and more helpful not only in the rehabilitation of malformation pathologies, but also in the clinical situations that require bone deficit correction resulting from traumatic events and postsurgical effects, for example oncologic surgery. The reason for this versatility in the distraction protocols is, undoubtedly, due to the fact that, at present, they are valid surgical methods in alternative to or supporting maxillofacial surgery, since they are feasible from a very early age and they obtain a level of distraction that is often higher than with orthopedic devices or conventional surgery. There are multiple indications for osteodistraction and they range from cases of hyper- or hypodevelopment of the maxilla and mandible, of both their anteroposterior and transverse components, to complex syndromes such as cleft lip and palate. Even the clinical distraction of the upper and middle thirds of the cranium, through a coronal craniotomy, has been shown to be a safe surgical procedure and it allows, for example, the successful rehabilitation of adult patients suffering from hemifacial microsomia or craniosynostosis. With the continuous and constant evolution of the integration of osteodistraction principles in the rehabilitation of the craniofacial region, an ever-more effective interdisciplinary relationship between orthodontics and osteodistraction has been seen with growing interest. More often treatment plans are programmed in which the orthodontic and osteodistractive phases are integrated and complete each other, each supporting the other. Scientific and clinical progress achieved in this field in recent years, allows more and more refined therapeutic solutions to be programmed, permitting craniofacial operations and to repair an ankylotic dental arch or reposition osteointegrated implants to the most convenient bone sites.

Craniofacial Abnormalities↗