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At least 631 records · Page 35Linked to original sources
PubMed2006

Progress and prospects: cell based regenerative therapy for cardiovascular disease.

Experimental and clinical studies are progressing simultaneously to investigate the mechanisms and efficacy of progenitor cell treatment after an acute myocardial infarction and in chronic congestive heart failure. Multipotent progenitor cells appear to be capable of improving cardiac perfusion and/or function; however, the mechanisms still are unclear, and the issue of whether or not trans-differentiation occurs remains unsettled. Both experimentally and clinically, cells originating from different tissues have been shown capable of restoring cardiac function, but more recently multiple groups have identified resident cardiac progenitor cells that seem to participate in regenerating the heart after injury. Clinically, cells originating from blood or bone marrow have been proven to be safe whereas injection of skeletal myoblasts has been associated with the occurrence of ventricular arrhythmias. Myoblasts can transform into rapidly beating myotubes; however, thus far convincing evidence for electro-mechanical coupling between myoblasts and cardiomyocytes is lacking. Moving forward, mechanistic studies will benefit from the use of genetic markers and Cre/lox reporter systems that are less prone to misinterpretation than fluorescent antibodies, and a more convincing answer regarding therapeutic efficacy will come from adequately powered randomized placebo controlled trials.

Animals↗
PubMed1999

Mapping disease genes using the Malecot model for allelic association and the beta model for linkage.

Although there are a number of alternative methods for mapping oligogenes the beta model implemented in the program BETA has been shown to be amongst the more powerful. The model has been applied to a sample of 240 asthma and atopy families typed for markers on chromosome 12 and the results suggest at least one asthma determinant may be present. The Malecot model implemented in the program ALLASS has yet to be applied to oligogenes but has been effective in the localization of major genes by exploiting the relationship between linkage disequilibrium and distance from the gene. Extension to oligogenes would seem to be a profitable way forward.

Alleles↗
PubMed2005

Neurochemistry in the pathophysiology of autism.

Significant progress has been made in the search for underlying pathophysiologic mechanisms in autism over the past 50 years. The cause of the disorder, however, remains largely unknown. This article reviews neurochemical contributions to the pathophysiology of autism with a focus on monoamines, glutamate/gamma-aminobutyric acid systems, and neuropeptides. As these efforts move forward, it will be important to begin to integrate genetic studies with those involving neuroimaging and postmortem research in each of these 3 areas, as well as with pharmacologic treatment approaches.

Adolescent↗
PubMedDate not supplied

[Human hemoglobin: polymorphism, neutrality of variants, evolutionary aspect].

Integrated analysis of the polymorphism of human hemoglobin has been made using populational genetics, hematological, physiological, protein chemistry and molecular biology data. The known variants of human hemoglobin are conventionally classified as "widely common", "less common" and "rare", depending on their contribution to polymorphism. The importance of homeostasis and compensatory reactions for maintaining the resistance of the human body against mutant hemoglobins is emphasized. Hb D Punjab and Hb O Arab being relatively neutral, the genetic structure of populations may restrict their distribution. A hypothesis is put forward concerning the possible role of an increased local conformational mobility of protein in creating neutral protein variants. It is proposed to discriminate between truly neutral and pseudoneutral protein variants. In case of possible changes in the genetic and environmental factors, the former are not subject to selection, while the latter may be. Contribution to neutral evolution can be made only by truly neutral variants. In a compensated heterozygotic state the truly neutral and pseudoneutral variants may give rise to new functions and adaptively valuable properties in protein. The evolution of proteins is believed to proceed from a stage which is consistent with M. Kimura's concept of neutrality of protein polymorphism toward a stage which is consistent with the concept of selectionism. It is concluded, that the currently observed degree of polymorphism of human hemoglobin corresponds to the present stage of molecular evolution of the protein.

Biological Evolution↗
PubMed1992

Historical perspective: a forward look, a backward look.

This paper summarizes how the problems of fallout, genetics, radioactive waste, and regulatory control of radiation were perceived by Dunning, Straub, Taylor, and others in 1955 at the inaugural meeting of the Health Physics Society. It was stated that health physicists had a great opportunity to resolve these problems and to avoid past mistakes. Throughout the 1950s, health physicists made major contributions to elucidating the fallout problem and contributed to its resolution, and it can be considered a success story. Waste disposal is not considered to be a success to date. A major difference has been the lack of political will to grapple with a perceived "no win" situation. The evolution of radiation limits is briefly traced over the past 37 y from voluntary standards to rigorously enforced regulations demanded by society. This paper speculates that the changing international scene makes the United States the pre-eminent nuclear power which will challenge future health physicists to maintain a balance between the control of radioactive material and its peaceful applications.

Health Physics↗
PubMed2000

Design and testing of a genetic algorithm neural network in the assessment of gait patterns.

It is important to be able to quantify changes in gait pattern accurately in order to understand the clinical implications of surgery or rehabilitation. Although supervised feed-forward backpropagation neural networks are very efficient in many pattern-recognition tasks, the genetic algorithm neural network (GANN), which can search in some appropriate space, has not been used previously for gait-pattern recognition. This study discusses how to use the GANN approach in gait-pattern recognition, and evaluates the complexity and training strategy of the particular classification problem. Both the GANN and a traditional artificial neural network (ANN) were used to classify the gait patterns of patients with ankle arthrodesis and normal subjects. The GANN model was able to classify subjects with recognition rates of up to 98.7%. In contrast, the ANN trained by using all possible predictor variables was only able to classify the subjects with recognition rates of 89.7%. It is suggested that the GANN model is more suitable to exploit the patient's gait pattern. The value of the neuron output can be used as an index of the difference from normal. By this means, all pathological gait patterns may be presented quantitatively.

Algorithms↗
PubMed2001

Pharmacologic and genetic therapy for childhood muscular dystrophies.

The outstanding advances in the molecular characterization of muscle diseases, including muscular dystrophies, inflammatory myopathies, and ion channel disorders, have resulted in the identification of potential targets for pharmacologic and genetic therapy in the best characterized of these diseases. The most common myopathy in children, Duchenne muscular dystrophy (DMD), is the focus of active pharmacologic clinical trials. Genetic transfer therapy research for this and other dystrophies is rapidly moving forward. However, as new approaches for treatment are being actively investigated, the current modality of treatment for all myopathies is still in the realm of physical medicine and rehabilitation. The focus of this review is on the advances in pharmacologic and genetic therapy research in DMD and limb girdle muscular dystrophies.

Animals↗
PubMed1982

A model for the development of genetic translation.

Several models have been advanced, both in this journal and others, for the development of the genetic code and translation apparatus. Eigen in particular has put forward a detailed model based on the hypercycle. This paper uses some of these previous ideas to develop a new model of the code and translation in which the pairs AU and GC play complementary roles, and in which tRNAs develop from a molecule with two loops which stacks in repetitive patterns without the need for a messenger RNA. Thus a bridge is provided between random, (or autocatalytic) polymerization, and coded translation. In addition, alternative postulates to several of Eigen's ideas are tested by computer simulation.

Base Composition↗
PubMed1998

Genotoxic effects of inhaled ethylene oxide, propylene oxide and butylene oxide on germ cells: sensitivity of genetic endpoints in relation to dose and repair status.

We report here results on forward mutation induction (recessive lethal mutations, RL) in Drosophila spermatozoa and spermatids by the three 1,2-alkyl-epoxides ethylene oxide (EO), propylene oxide (PO) and butylene oxide (BO), at doses ranging from 47 to 24,000 ppm h for EO, 375 to 48,000 ppm h for PO, and 24,000 to 91,200 ppm h for BO. The results indicate for EO mutation induction at doses 500-fold below the LD50. In crosses of mutagenized NER+ males with NER+ females, the 500-fold increase in EO dose from 47 ppm h to 24,000 ppm h resulted in no more than a 17-fold enhanced mutant frequency in spermatozoa. This flat dose-response relationship is primarily the result of efficient repair of EO-induced DNA adducts in the fertilized egg, as was evident from the up to 40-fold or 240-fold increased mutant frequencies above NER- or NER+ background levels, respectively, in crosses with NER- females. With decreasing dose, MNER-/MNER+ ratios decreased from 9 to 14 at high doses down to approximately 1 at the two lowest doses, indicating that a small fraction of premutagenic lesions induced by EO cannot be repaired by the NER system of Drosophila. Linear extrapolation from high to low EO exposure led to an underestimation of the mutation frequency actually observed at low doses. The pattern of EO-induced ring chromosome loss (CL) differed in two respects from that observed for forward mutations: (a) an increase in CL frequencies was observed only at the two highest EO exposure levels, and (b) inactivation of the NER pathway by the mus201 mutant had no measurable effect on the occurrence of CL. The absence of a potentiating effect of mus201 on EO-induced clastogenicity suggests the formation of clastogenic DNA lesions not causing point mutations, and which are not repaired by NER. Consistent with an inversed correlation of reactivities towards N7-guanine and chain length of 1,2-alkyl-epoxides, the relative mutagenic efficiencies of EO:PO:BO are 100:7.2:1.8 for the NER+ groups, and 100:20:0.7 in the absence of NER. Although in Drosophila germ cells EO is also more effective as a clastogen than PO, the difference (EO:PO=100:58) is much smaller than for recessive mutations. These results provide another argument that DNA lesions generating base substitutions as opposed to those causing clastogenic damage may not be the same for these agents.

Administration, Inhalation↗
PubMed2005

Familial cortical myoclonic tremor with epilepsy: a single syndromic classification for a group of pedigrees bearing common features.

Fifty Japanese and European families with cortical myoclonic tremor and epilepsy have been reported under various names. Unfamiliarity with the syndrome often leads to an initial misdiagnosis of essential tremor or progressive myoclonus epilepsy. A detailed overview of the literature is lacking and is the scope of this study. Disease characteristics are adult onset, distal action tremor and myoclonus, epileptic seizures, autosomal dominant inheritance, benign course, effectiveness of antiepileptic drugs, and possibly cognitive decline. A channelopathy is hypothesized to be the basis of the disease. Despite phenotypic and genetic differences between the Japanese and European pedigrees, the clinical and electrophysiological data point toward one syndrome. To avoid confusion in literature and possible misdiagnosis of patients, we propose to use one description and suggest "familial cortical myoclonic tremor with epilepsy" (FCMTE). In addition, we put forward diagnostic criteria to give a starting point from which to conduct genetic studies.

Adolescent↗
PubMed2002

Introducing genetic psychophysiology.

Genetic psychophysiology examines interindividual variation in psychophysiological traits using behavioral genetic and molecular genetic techniques. It aims to delineate the pathways that lead from genomic variation to individual differences in cognitive abilities, affect regulation, and mental and physical health. This editorial provides an introduction to the twin design and gene finding strategies using psychophysiological endophenotypes. It also gives a brief outline of the papers presented in this special issue on genetic psychophysiology. Its main objective, and the objective of the entire special issue, is to interest psychophysiologists in the enormous potential of research in this area and to foster the development of collaborative relationships between psychophysiologists and molecular and behavioral geneticists that are necessary to move research in this area forward.

Animals↗
PubMed2005

Establishing genetic transformation for comparative developmental studies in the crustacean Parhyale hawaiensis.

The amphipod crustacean Parhyale hawaiensis has been put forward as an attractive organism for evolutionary developmental comparisons, and considerable effort is being invested in isolating developmental genes and studying their expression patterns in this species. The scope of these studies could be significantly expanded by establishing means for genetic manipulation that would enable direct studies of gene functions to be carried out in this species. Here, we report the use of the Minos transposable element for the genetic transformation of P. hawaiensis. Transformed amphipods can be obtained from approximately 30% of surviving individuals injected with both a Minos element carrying the 3xP3-DsRed fluorescent marker and with mRNA encoding the Minos transposase. Integral copies of the transposon are inserted into the host genome and are stably inherited through successive generations. We have used reporter constructs to identify a muscle-specific regulatory element from Parhyale, demonstrating that this transformation vector can be used to test the activity of cis-regulatory elements in this species. The relatively high efficiency of this transgenic methodology opens new opportunities for the direct study of cis-regulatory elements and gene functions in Parhyale, allowing functional studies to be carried out beyond previously established model systems in insects.

Amphipoda↗
PubMed2004

Selenium and selenoproteins in mammals: extraordinary, essential, enigmatic.

Selenium (Se), once known only for its potential toxicity, is now well established as an essential trace element for mammals. Insufficient Se intake predisposes to and manifests in a variety of diseases. Recent studies have proven that it is the synthesis of selenocysteine (Sec)-containing proteins, designated selenoproteins, which represents an essential prerequisite for regular development and a long and healthy life. New transgenic mouse models analysing those selenoproteins with proven enzymatic functions displayed particular phenotypes and highlighted essential Se-dependent processes in development, growth or against specific challenges. While there is a growing molecular understanding of and general agreement on the importance of sufficiently high Se intake and undisturbed selenoprotein biosynthesis, many of the recently identified selenoproteins are still uncharacterised, and the effects and consequences of supra-physiological Se dosages are not biochemically understood. With the recent definition of the human and mouse selenoproteomes and a growing number of available tools, the Se field is now geared for a great leap forward. Se biology has already broadened our knowledge about the genetic code and about protein translation. It now holds great promises also for a better understanding of some key aspects of cancer, inflammation, fertility and prevention of age-associated diseases.

Animals↗
PubMed2006

Bridging the gap between anatomy and molecular genetics for an improved understanding of congenital heart disease.

Birth defects are the leading cause of infant mortality and malformations in congenital heart disease (CHD) are among the most prevalent and fatal of all birth defects. Yet the molecular mechanisms leading to CHD are complex and the causes of the cardiac malformations observed in humans are still unclear. In recent years, the pivotal role of certain transcription factors in heart development has been demonstrated, and gene targeting of cardiac-specific transcription factor genes in animal models has provided valuable insights into heart anomalies. Nonetheless results in these models can be species specific, and in humans, germline mutations in transcription factor genes can only account for some cases of CHD. Furthermore, most patients do not have family history of CHD. There is, therefore, a need for a better understanding of the mechanisms in both normal cardiac development and the formation of malformations. The combining of expertise in cardiac anatomy, pathology, and molecular genetics is essential to adequately comprehend developmental abnormalities associated with CHD. To help elucidate genetic alterations in affected tissues of malformed hearts, we carried out genetic analysis of cardiac-specific transcription factor genes from the Leipzig collection of formalin-fixed malformed hearts. Working with this morphologically well-characterized archival material not only provided valuable genetic information associated with disease, but enabled us to put forward a hypothesis of somatic mutations as a novel molecular cause of CHD. Knowledge of cause and disease mechanism may allow for intervention that could modify the degree of cardiac malformations or development of new approaches for prevention of CHD.

Germ-Line Mutation↗
PubMed2006

New insights into prostate cancer biology.

Prostate cancer is common, biologically heterogeneous, and protean in its clinical manifestations. Through the use and analysis of isogenic cell lines, xeno-grafts, transgenic mice, and human tumors, one begins to deconvolute the precise biologic mechanisms that combine to create the native complexity and heterogeneity of this disease. In this article, the authors have underscored compelling recent discoveries in prostate cancer so as to provide the reader with molecular paradigms with which to interpret future insights into its biology. Although it was inevitably necessary to omit a significant amount of important research in prostate cancer, the work discussed here is exemplary of current prostate cancer research. Looking forward, it is hoped that the collective work of mapping genetic and biologic interactions among key regulators of prostate epithelial cells, epithelial-stromal interactions, host immune system, and host genetics will eventually result in a comprehensive understanding of prostate cancer. Although it is likely that the molecular characteristics of an individual's prostate cancer will be analyzed using limited molecular tools in the near future, eventual application of genomic technologies and nanotechnology offers the promise of robust future characterization. Such a characterization is likely to be required to maximize our ability to optimize and individualize preventive and treatment strategies.

Genomics↗