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At least 1,405 records · Page 78Linked to original sources
PubMed2001

Finding drug targets in microbial genomes.

In this era of genomic science, knowledge about biological function is integrated increasingly with DNA sequence data. One area that has been significantly impacted by this accumulation of information is the discovery of drugs to treat microbial infections. Genome sequencing and bioinformatics is driving the discovery and development of novel classes of broad-spectrum antimicrobial compounds, and could enable medical science to keep pace with the increasing resistance of bacteria, fungi and parasites to current antimicrobials. This review discusses the use of genomic information in the rapid identification of target genes for antimicrobial drug discovery.

Journal Article↗
PubMed2002

[Mechanisms of antibiotic resistance].

Antibiotics interfere with structural and regulatory elements of bacterial cells leading to growth arrest or cell death. Bacteria have evolved a variety of strategies to overcome the effects of antibiotics. Examples are enzymatic destruction, alteration of the target, efflux and permeability changes. Resistance towards the same substance can be mediated by several mechanisms. Efflux pumps can probably act as mediators of higher resistance development. Alteration of common targets can lead to cross-resistance against several classes of antibiotics. Genetic events, such as point mutations, transfer of plasmids and gen regulation, can mediate a rapid emergence of resistance. Therefore, substances like rifampicin should be only used in combination with other drugs. Accumulation of resistance genes under common regulatory control in integrons induces co-resistance against substances of different specificity. Detailed knowledge of resistance mechanisms, their evolution and dynamics is important for a rational use of antibiotics and other strategies against antibiotic resistance.

Anti-Bacterial Agents↗
PubMed2004

Hepatitis with special reference to dogs. A review on the pathogenesis and infectious etiologies, including unpublished results of recent own studies.

The causes of hepatitis in dogs are mostly unknown. Known causes of canine hepatitis are infectious (CAV-1), toxic (e.g. aflatoxin), and metabolic (copper accumulation). In order to understand the unknown causes, research in this field is necessary. Despite the marked progress in the knowledge on viral causes for human hepatitis, the involvement of infectious agents in the pathogenesis of hepatitis in the dog is still largely unknown. It is, like in human hepatitis, very likely that more than one causative infectious agent may cause hepatitis in the dog. This review presents the various forms of hepatitis in the dog, the known infectious and non-infectious causes of canine hepatitis, the infectious causes of hepatitis in man and other animals, and finally our recent infection and molecular studies to investigate possible infectious causes of canine hepatitis.

Acute Disease↗
PubMed1996

Nature of deleterious mutation load in Drosophila.

Much population genetics and evolution theory depends on knowledge of genomic mutation rates and distributions of mutation effects for fitness, but most information comes from a few mutation accumulation experiments in Drosophila in which replicated chromosomes are sheltered from natural selection by a balancer chromosome. I show here that data from these experiments imply the existence of a large class of minor viability mutations with approximately equivalent effects. However, analysis of the distribution of viabilities of chromosomes exposed to EMS mutagenesis reveals a qualitatively different distribution of effects lacking such a minor effects class. A possible explanation for this difference is that transposable element insertions, a common class of spontaneous mutation event in Drosophila frequently generate minor viability effects. This explanation would imply that current estimates of deleterious mutation rates are not generally applicable in evolutionary models, as transposition rates vary widely. Alternatively, much of the apparent decline in viability under spontaneous mutation accumulation could have been nonmutational, perhaps due to selective improvement of balancer chromosomes. This explanation accords well with the data and implies a spontaneous mutation rate for viability two orders of magnitude lower than previously assumed, with most mutation load attributable to major effects.

Animals↗
PubMed1984

The relative merits and drawbacks of new nucleoside analogues with clinical potential.

A large number of nucleoside analogues have been found to have antiviral activity, mainly against herpesviruses. The involvement of cellular as well as viral enzymes in the mode of action of several nucleoside analogues makes a prediction of clinical efficacy difficult. The possibility and consequences of incorporation into cellular DNA are other important aspects of nucleoside analogues as antiviral drugs. It seems likely that in the next few years enough knowledge about mechanism of action, consequences of incorporation into DNA, efficacy in different test systems and in clinical trials will accumulate to allow an understanding of how to design even better antiviral drugs.

Acyclovir↗
PubMed1997

Characterization and functional expression of a ubiquitously expressed tomato pectin methylesterase.

Pectin methylesterase (PME), a ubiquitous enzyme in plants, de-esterifies the methoxylated pectin in the plant cell wall. We have characterized a PME gene (designated as pmeu1) from tomato (Lycopersicon esculentum) with an expression that is higher in younger root, leaf, and fruit tissues than in older tissues. Hypocotyls and epicotyls show higher accumulation of pmeu1 transcripts compared with cotyledons. pmeu1 represents a single-copy gene in the tomato genome. Comparison of the deduced amino acid sequence of pmeu1 with other PME homologs showed that the N-terminal halves are highly variable, and the C-terminal halves are relatively conserved in plant PMEs. Constitutive expression of a fruit-specific PME antisense gene does not affect the level of pmeu1 transcripts in vegetative tissues but does lower the level of PMEU1 mRNA in developing tomato fruits. These results suggest that there exists developmentally regulated silencing of pmeu1 by a heterologous PME antisense gene. Expression of pmeu1 in tobacco (Nicotiana tabacum) under the control of the cauliflower mosaic virus 35S promoter caused up to a 4-fold increase in PME specific activity that was correlated with the accumulation of PMEU1 mRNA. In vitro transcription-translation analyses show that pmeu1 encodes a 64-kD polypeptide, whereas transgenic tobacco plants expressing pmeu1 accumulate a new 37-kD polypeptide, suggesting extensive posttranslational processing of PMEU1. These results are the first evidence, to our knowledge, of the functional characterization of a PME gene and the extensive modification of the encoded polypeptide.

Amino Acid Sequence↗
PubMed1995

AGL15, a MADS domain protein expressed in developing embryos.

To extend our knowledge of genes expressed during early embryogenesis, the differential display technique was used to identify and isolate mRNA sequences that accumulate preferentially in young Brassica napus embryos. One of these genes encodes a new member of the MADS domain family of regulatory proteins; it has been designated AGL15 (for AGAMOUS-like). AGL15 shows a novel pattern of expression that is distinct from those of previously characterized family members. RNA gel blot analyses and in situ hybridization techniques were used to demonstrate that AGL15 mRNA accumulated primarily in the embryo and was present in all embryonic tissues, beginning at least as early as late globular stage in B. napus. Genomic and cDNA clones corresponding to two AGL15 genes from B. napus and the homologous single-copy gene from Arabidopsis, which is located on chromosome 5, were isolated and analyzed. Antibodies prepared against overexpressed Brassica AGL15 lacking the conserved MADS domain were used to probe immunoblots, and AGL15-related proteins were found in embryos of a variety of angiosperms, including plants as distantly related as maize. Based on these data, we suggest that AGL15 is likely to be an important component of the regulatory circuitry directing seed-specific processes in the developing embryo.

Amino Acid Sequence↗
PubMed2006

Transgenic Medicago truncatula plants that accumulate proline display nitrogen-fixing activity with enhanced tolerance to osmotic stress.

Legume root nodule nitrogen-fixing activity is severely affected by osmotic stress. Proline accumulation has been shown to induce tolerance to salt stress, and transgenic plants over-expressing Delta(1)-pyrroline-5-carboxylate synthetase (P5CS), which accumulates high levels of proline, display enhanced osmotolerance. Here, we transformed the model legume Medicago truncatula with the P5CS gene from Vigna aconitifolia, and nodule activity was evaluated under osmotic stress in transgenic plants that showed high proline accumulation levels. Nitrogen fixation was significantly less affected by salt treatment compared to wild-type (WT) plants. To our knowledge, this is the first time that transgenic legumes have been produced that display nitrogen-fixing activity with enhanced tolerance to osmotic stress. We studied the expression of M. truncatula proline-related endogenous genes M. truncatulaDelta(1)-pyrroline-5-carboxylate synthetase 1 (MtP5CS1), M. truncatulaDelta(1)-pyrroline-5-carboxylate synthetase 2 (MtP5CS2), M. truncatula ornithine delta-aminotransferase (MtOAT), M. truncatula proline dehydrogenase (MtProDH) and a proline transporter gene in both WT and transgenic plants. Our results indicate that proline metabolism is finely regulated in response to osmotic stress in an organ-specific manner. The transgenic model allowed us to analyse some of the biochemical and molecular mechanisms that are activated in the nodule in response to high salt conditions, and to ascertain the essential role of proline in the maintenance of nitrogen-fixing activity under osmotic stress.

Adaptation, Physiological↗
PubMed2004

Pretreatment with dexamethasone increases antitumor activity of carboplatin and gemcitabine in mice bearing human cancer xenografts: in vivo activity, pharmacokinetics, and clinical implications for cancer chemotherapy.

PURPOSE: The present study was undertaken to determine the effects of dexamethasone (DEX) pretreatment on antitumor activity and pharmacokinetics of the cancer chemotherapeutic agents carboplatin and gemcitabine. EXPERIMENTAL DESIGN: Antitumor activities of carboplatin and gemcitabine with or without DEX pretreatment were determined in six murine-human cancer xenograft models, including cancers of colon (LS174T), lung (A549 and H1299), and breast (MCF-7 and MDA-MB-468) and glioma (U87-MG). Effects of DEX on plasma and tissue pharmacokinetics of carboplatin and gemcitabine were also determined by using the LS174T, A549, and H1299 models. RESULTS: Although DEX alone showed minimal antitumor activity, DEX pretreatment significantly increased the efficacy of carboplatin, gemcitabine, or a combination of both drugs by 2-4-fold in all xenograft models tested. Without DEX treatment, the tumor exposure to carboplatin, measured by the area under the curve, was markedly lower than normal tissues. However, DEX pretreatment significantly increased tumor carboplatin levels, including 200% increase in area under the curve, 100% increase in maximum concentration, and 160% decrease in clearance. DEX pretreatment similarly increased gemcitabine uptake in tumors. CONCLUSIONS: To our knowledge, this is the first report that DEX significantly enhances the antitumor activity of carboplatin and gemcitabine and increases their accumulation in tumors. These results provide a basis for further evaluation of DEX as a chemosensitizer in patients.

Animals↗
PubMed2002

Induction of puberty in the hypogonadal girl--practices and attitudes of pediatric endocrinologists in Europe.

The management of children and adolescents with hypogonadism and in particular the induction of puberty in the hypogonadal girl is subject to controversy. Therefore, under the auspices and through organization of the Drugs and Therapeutics Committee of the European Society of Paediatric Endocrinology (ESPE), an interactive voting session and workshop was held at the 39th ESPE Annual Meeting in Brussels to discuss these topics. Common practice in Europe and attitudes of pediatric endocrinologists in Europe were questioned and recorded in the 1.5-hour program. We now report on some of the results of the questionnaires and discussions of that session to further the discussion on and knowledge of current concepts of induction of puberty in the hypogonadal girl in Europe. It became clear from the data accumulated here that the start of treatment, the aims of therapy and the modalities of how to treat the hypogonadal girl vary amongst pediatric endocrinologists in Europe. For example, a chronological age > or =11 years was considered appropriate for the start of estrogen therapy by 40.4% (out of 188 answers), while 47.8 and 7.5% felt that a chronological age > or =13 and > or =15 years respectively was appropriate. In respect to the form and route of estrogen administration, the audience was asked for their common estrogen replacement practice: 31.9% used oral 17beta-estradiol treatment, while 10% would prescribe 17beta-estradiol transdermal patches. Another 12.2% would recommend conjugated estrogens (e.g. Premarin) orally, 4.8% use oral estradiol valerate and 39.3% ethinylestradiol orally. Only 1.8% out of 229 physicians answering were undecided. In addition, counseling of patients and their families is quite variable and perceptions for example regarding potential pregnancies in affected women are also not uniform. In this report the authors do not want to provide their own personal views but rather reflect current practice in Europe. It is hoped that a more uniform picture will emerge once European and international guidelines on how to treat the girl with hypogonadism will be available and even more discussions amongst doctors from different countries have been led.

Adolescent↗
PubMed1997

A new type of hazardous chemical: the chemosensitizers of multixenobiotic resistance.

The purpose of this overview is to introduce the property of a new class of hazardous chemicals-the inhibitors of multixenobiotic resistance (MXR) in aquatic organisms, referred to as chemosensitizers. Aquatic organisms possess MXR, a mechanism similar to the well-known P-glycoprotein extrusion pump in multidrug resistant (MDR) tumor cells. MXR in aquatic organism moves from cells and organisms both endogenous chemicals and xenobiotics, including also some man-made chemicals. MXR in aquatic organisms represents a general biological first-line defense mechanism for protection against environmental toxins. Many chemical agents, the chemosensitizers, may after the function of this fragile mechanism. It is this new, MXR-inhibiting property, unrecognized as yet, that classifies these chemicals among top-rank hazardous water pollutants. The knowledge that the presence of one xenobiotic may block the pumping out of other xenobiotic(s), and hence accelerate their accumulation, may have important implications on environmental parameters like exposure, uptake, bioaccumulation, and toxicity. In this overview we present the evidence for the expression of MXR-phenotype in aquatic organisms, the demonstration of toxic consequences caused by MXR inhibitors, and the description of methods for measurement of concentration of MXR inhibitors in environmental samples.

Animals↗
PubMed1998

Secrecy, anonymity, and deception in donor insemination: a genetic, psycho-social and ethical critique.

The number of medically assisted conceptions involving donors is increasing. At the same time, due to advances in medicine, greater emphasis has been placed on an individual's genetic origins. This trend places individuals who have no access to information on their genetic origins in a vulnerable position. Because of the secrecy and anonymity that has surrounded donor inseminations, many individuals who were so conceived are irreversibly cut off from any possible contact with or even knowledge about their genetic fathers, who will also never have the opportunity to meet their offspring. In view of the accumulated evidence concerning the detrimental effect of secrecy, anonymity and deception in donor insemination, this paper argues that these practices are not only psychologically and socially harmful but also ethically unacceptable.

Choice Behavior↗
PubMed2004

Iron and brain disorders.

Iron is the most important element in the body, essential for almost all types of cells, including brain cells. The role of iron in the brain has been known for years. Iron deficiency and iron excess have been associated with pathophysiology of different brain disorders. Iron deficiency has been reported to have a role in brain development and the pathophysiology of restless legs syndrome. Iron accumulation has been related to some neurologic disorders such as Alzheimer disease, Parkinson disease, type I neurodegeneration with brain iron accumulation, and other disorders. Despite years of investigation, the reason for iron imbalance in the brain is not known. It also is not known whether the accumulation of iron in the brain is primary or secondary to development of neurodegenerative disorders. This review summarizes the present knowledge on the role of iron in human brain disorders.

Animals↗
PubMed2004

Efalizumab: Advancing psoriasis management with a novel, targeted T-cell modulator.

Recent research has demonstrated that psoriasis is not the result of a keratinocyte disorder, as previously believed. Although the exact etiology has not been clearly defined, much data has accumulated to elucidate the role of the immune system, particularly T lymphocytes, in the pathogenesis of the disease. With this knowledge, a number of biologic therapies that specifically target key pathogenic events have been developed. Efalizumab, a recombinant humanized monoclonal IgG1 antibody, is a T-cell modulator approved for patients with moderate to severe chronic plaque psoriasis. This article reviews the role of T lymphocytes in psoriasis pathogenesis, the mechanism of efalizumab action, and the efficacy and safety data observed during the efalizumab clinical trials.

Animals↗
PubMedDate not supplied

Regulatory effects of the mitochondrial energetic status on mitochondrial p66Shc.

p66(Shc) promotes apoptosis and controls the intracellular redox balance. A fraction of p66(Shc) exists within mitochondria, where it oxidizes cytochrome c to form hydrogen peroxide, which in turn induces mitochondrial permeability and apoptosis. However, cells tolerate p66(Shc) expression and accumulate oxidative damage under normal conditions, implying that the p66(Shc) functions must be tightly regulated. Here we review available knowledge on the regulation of p66(Shc) transcription, protein stabilization and post-translational modifications. In addition, we report novel investigations into the role of the mitochondrial import machinery on p66(Shc) activation, which highlight the energetic status of mitochondria as a crucial determinant of p66(Shc) function.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Carisoprodol withdrawal syndrome.

A 43-year-old man with chronic back and shoulder pain was treated with hydrocodone. He began taking excessive amounts of the drug, so his physicians stopped prescribing it. The patient then obtained the muscle relaxant carisoprodol on his own from several sources. He was consuming up to 30 or more tablets/day (> or =10,500 mg/day) for several weeks, then abruptly stopped taking the drug. Within 48 hours he developed anxiety, tremors, muscle twitching, insomnia, auditory and visual hallucinations, and bizarre behavior. The symptoms intensified and peaked on the fourth day after carisoprodol cessation. The patient required brief treatment with olanzapine and tapering dosages of lorazepam while the symptoms gradually resolved. To our knowledge, this is the first documented case of a withdrawal syndrome with carisoprodol. The symptoms most likely resulted because of accumulation of meprobamate, the active metabolite of carisoprodol in humans. Clinicians prescribing carisoprodol should be aware of the possibility for abuse or addiction. Further, we recommend that carisoprodol be designated a controlled substance at the federal level.

Adult↗
PubMed1995

Genetic changes in ovarian cancer.

The development of cancer is a multistep process involving accumulation of genetic changes which progressively transform normal cells to neoplastic cells. During the last few years, our understanding and knowledge of the genetic changes involved in ovarian carcinogenesis have increased dramatically. In this review I will focus on karyotypic abnormalities in ovarian cancer and will also refer to molecular studies involving alterations in oncogenes and tumour suppressor genes in ovarian tumorigenesis. Cytogenetic analyses have identified two distinct subgroups. Simple karyotypic changes, trisomy 12 being the most common aberration in this group, are recurrently found in well differentiated ovarian carcinomas. Complex karyotypic abnormalities, including predominantly chromosome losses, deletions and unbalanced translocations, are found in moderately and poorly differentiated carcinomas. The bands and regions most commonly involved in structural rearrangements have been, in decreasing order of frequency, 19p13, 1p36, 1q21, 1q23-25, 3p11-13, 6q21, 19q13, 11p13-15, 11q13, 11q23, 12q24, 12p11-13, and 7p13-22. The finding of identical karyotypic and other genetic changes in tumour samples taken from different sites, such as tumours from both ovaries and omental metastases, indicate that ovarian cancer is of unicentric origin with subsequent metastatic spread giving rise to multiple implants. Molecular genetic changes important in ovarian cancer involve both classes of tumor-associated genes: RAS activation is generally not observed in ovarian cancer. Alterations of MYC1, ERBB2, AKT2, TP53 has been described in some ovarian carcinomas. The temporal relationship of these mutations, i.e. early or late events in ovarian carcinogenesis, remains to be determined.

Female↗
PubMed2001

Increased metabolic activity in the thymus gland studied with 18F-FDG PET: age dependency and frequency after chemotherapy.

UNLABELLED: This study was designed to evaluate the age dependency of 18F-FDG uptake in the thymus and the frequency of PET confirmation of thymus hyperplasia after chemotherapy in cancer patients. METHODS: Whole-body FDG PET recordings of 168 patients were retrospectively examined for a retrosternal lesion in the anterior mediastinum that was attributable to the thymus. The patients were assigned to the following four groups: children with malignant lesions before the first therapy (group Ia; n = 15; mean age +/- SD, 11.9 +/- 3.7 y), children with malignant disease after chemotherapy (group Ib; n = 12; mean age, 10.3 +/- 5.0 y), adults with histologically confirmed malignant lymphoma before the first therapy (group IIa; n = 37; mean age, 43.9 +/- 16.7 y), and adult lymphoma patients 3 wk to 4 mo after chemotherapy (group IIb; n = 104; mean age, 40.9 +/- 14.6 y). RESULTS: Increased FDG accumulation in the thymus was seen in 11 patients (73%) of group Ia and 9 patients (75%) of group Ib. Thymus hyperplasia was found in 5 patients (5%) of group IIb. The eldest of these 5 patients was 25 y old. No increased FDG accumulation in the thymus was observed in any of the group IIa patients. In cases of visible FDG uptake in the thymus, standardized uptake values did not exceed 4. CONCLUSION: FDG accumulation in the thymus is a common finding in children and can occasionally be observed in young adults after chemotherapy. Knowledge of the characteristics of a typical retrosternal lesion in conjunction with the clinical history allows avoidance of diagnostic uncertainty and unnecessary procedures.

Adolescent↗