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PubMed1996

[Myocardial metastasis in the right ventricle from uterine cervical carcinoma with high 67Ga-citrate accumulation: a case report].

We report a case of high 67Ga-citrate accumulation with myocardial metastasis in the right ventricle from uterine cervical carcinoma. A 41-year-old woman was admitted to our hospital because of acute abdomen after operation and radiotherapy for uterine cervical carcinoma. On performing 67Ga-scintigraphy for differentiation from fever of unknown origin, we found significant 67Ga-citrate accumulation in the right ventricle. To the best of our knowledge, this is a rare case.

Adult↗
PubMed2002

Maternal stress and T-cell differentiation of the developing immune system: possible implications for the development of asthma and atopy.

The constant increase in asthma and atopy prevalences--despite improved treatment and knowledge of many aspects of the diseases--has raised growing concern. Accumulating evidence suggests that these increases in atopic diseases are largely attributable to environmental and lifestyle factors, and the lack of systemic childhood infections has in many studies emerged as a major factor. In addition to current high standards of hygiene and the lack or scarcity of such infections, another factor characteristic of our present-day lives could be involved. This review briefly outlines the possibility that prolonged maternal stress associated with sustained excessive cortisol secretion could affect the developing immune system--especially T(H)1/T(H)2 cell differentiation--and further increase the susceptibility to asthma and atopy in genetically predisposed individuals. This hypothesis is critically evaluated in the light of current knowledge.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2007

RNA interference technologies and their use in cancer research.

PURPOSE OF REVIEW: Recently, RNA interference has evolved into a powerful research tool to functionally characterize genes. Genome-wide RNA interference reagents can study the loss-of-function phenotypes of candidate genes in the context of various disease model systems. In this review, we discuss the data from the most recent studies using RNA interference reagents with a focus on RNA interference-based genomic screening as a tool to expand our knowledge about the molecular basis of cancer. RECENT FINDINGS: Tumorigenesis is the result of the progressive accumulation of mutations in genes controlling cell proliferation and death. Various genes carrying these alterations are known to be directly linked to tumor growth; however, how to translate this knowledge into effective chemotherapeutics, nontoxic to normal cells, is still a subject of intensive research. SUMMARY: Loss-of-function studies offer a potential for validation of known and unrecognized tumor-associated targets. RNA interference-mediated gene knockdown can be exploited to study the reprogrammed circuitry of genes, discover gene interactions restricted to cancer cells and identify mechanisms of chemoresistance in cancer cells. In addition, the simultaneous use of cancer drugs and RNA interference also provides a paradigm to develop strategies to inactivate essential genes promoting neoplastic growth.

Humans↗
PubMed2004

[Families at risk of colon cancer I. Familial adenomatous polyposis].

Familial adenomatous polyposis (FAP) is a well-defined autosomal dominant inherited disease characterised by a diffuse polyposis of the colon and rectum leading to inevitable colorectal cancer by 50 years. The purpose of this review is to summarize the current knowledge regarding this entity with the focus on recent knowledge on genetic testing, surveillance guidelines and therapy of FAP. Available medical databases were searched from 1998 to May 2003 using keywords "familial adenomatous polyposis", followed by further search for particular issues. Additional articles were identified through the reference sections of retrieved articles and from personal archives of authors. Approximately 300 papers on FAP are published yearly. There has been a large progress in our understanding of the genetics of FAP leading to the development of genetic counselling, reliable genetic tests and screening strategies. There is accumulating evidence about genotype-phenotype associations with direct clinical implications. Our knowledge about the extracolonic manifestations is also expanding resulting in new surveillance and treatment strategies for FAP patients after proctocolectomy. Although still representing a serious burden for affected patients and their families, the research of last decades together with national registers improved the life expectancy and the quality of life of FAP patients dramatically. Further research in the area of molecular genetics, genetic testing and emerging gene therapy for FAP patients is to be expected in the near future.

Adenomatous Polyposis Coli↗
PubMed2000

Metabolism of oxidized LDL by macrophages.

Oxidation products of lipids and proteins are found in atherosclerotic plaque and in macrophage foam cells. Macrophages avidly endocytose in-vitro oxidized LDL and accumulate sterols. What is the evidence that such a process is involved in in-vivo foam cell formation? The present review surveys current knowledge on the metabolism of oxidized LDL by macrophages, and the types, amounts and location of oxidation products that accumulate in these cells. Comparable studies of lesion lipoproteins and foam cells indicate that limited extracellular lipoprotein oxidation, perhaps followed by more extensive intracellular oxidation subsequent to uptake by macrophages, is a more likely scenario in vivo.

Animals↗
PubMed2002

Cellular and clinical pharmacology of fludarabine.

In the past decade, fludarabine has had a major impact in increasing the effectiveness of treatment of patients with indolent B-cell malignancies. This has come about in a variety of clinical circumstances, including use of fludarabine alone as well as in combinations with DNA-damaging agents or membrane-targeted antibodies. Other strategies have used fludarabine to reduce immunological function, thus facilitating non-myeloablative stem cell transplants. Fludarabine is a prodrug that is converted to the free nucleoside 9-beta-D-arabinosyl-2-fluoroadenine (F-ara-A) which enters cells and accumulates mainly as the 5'-triphosphate, F-ara-ATP. The rate-limiting step in the formation of triphosphate is conversion of F-ara-A to its monophosphate, which is catalyzed by deoxycytidine kinase. Although F-ara-A is not a good substrate for this enzyme, the high specific activity of this protein results in efficient phosphorylation of F-ara-A in certain tissues. F-ara-ATP has multiple mechanisms of action, which are mostly directed toward DNA. These include inhibition of ribonucleotide reductase, incorporation into DNA resulting in repression of further DNA polymerisation, and inhibition of DNA ligase and DNA primase. Collectively these actions affect DNA synthesis, which is the major mechanism of F-ara-A-induced cytotoxicity. Secondarily, incorporation into RNA and inhibition of transcription has been shown in cell lines. With the standard dose of fludarabine (25 to 30 mg/m(2)/day given over 30 minutes for 5 days), plasma concentrations of about 3 micromol/L F-ara-A are achieved at the end of each infusion. Serial sampling of leukaemia cells from patients receiving these standard doses of fludarabine has demonstrated that the peak concentrations of F-ara-ATP are achieved 4 hours after start of fludarabine infusion. Although there is heterogeneity among individuals with respect to rate of F-ara-ATP accumulation, the peak concentrations are generally proportional to the dose of the drug. Knowledge of the plasma pharmacokinetics of its principal nucleoside metabolite F-ara-A, and the cellular pharmacology of the proximal active metabolite, F-ara-ATP, has provided some understanding of the activity of fludarabine when used as a single agent. Preclinical studies directed toward learning the mechanisms of action of this agent have formed the basis for several mechanism-based strategies for its combination and scheduling with other agents. As a single agent fludarabine has been effective for the indolent leukaemias. Biochemical modulation strategies resulted in enhanced accumulation of cytarabine triphosphate and led to the use of fludarabine for the treatment of acute leukaemias. Combination of fludarabine with DNA damaging agents to inhibit DNA repair processes has been highly effective for indolent leukaemias and lymphomas. The current review brings together knowledge of the mechanisms of fludarabine, the state of understanding of the plasma pharmacokinetics, and cellular pharmacodynamics of fludarabine nucleotides. This may be useful in the design of future therapeutic approaches.

Antineoplastic Agents↗
PubMedDate not supplied

Iron in neurodegenerative disorders.

Increasing evidence implicates a role of iron in the pathogenesis of numerous neurodegenerative diseases due to its capacity to enhance production of toxic reactive radicals and to induce protein aggregation. The underlying mechanism of iron accumulation in areas of the brain specific for the respective disease, however, is still unknown. Recent molecular and biochemical studies provide new insights into the consequences of impairment of brain iron metabolism. This review summarizes our understanding of the regulation of iron in the brain and defines the current knowledge on the involvement of iron metabolism in neurodegenerative diseases with genetically determined iron accumulation in the brain.

Journal Article↗
PubMed1999

Olfactory bulb dysplasia: a novel subtype of neuronal migration disorder.

We present a novel subtype of neuronal migration disorder found in a case of Pena-Shokeir phenotype, in which the deformation sequence originated from neurogenic fetal akinesia. The autopsied brain showed dysplastic features of dentate and olivary nuclei as well as a bilaterally enlarged olfactory bulb with abnormal laminar structures. The laminar structures comprised four layers: (1) a superficial layer without glomeruli, (2) a neuronal cell layer containing neurons simulating mitral cells, (3) a sparse cell layer enriched with tangential neuronal fibers, and (4) a reticular layer showing a mottled appearance with the accumulation of fine reticular neurites intermingled with granule cells. To our knowledge, these malformed laminar changes have never been reported, and we propose the term olfactory bulb dysplasia.

Autopsy↗
PubMed2002

Aggregation of actin and cofilin in identical twins with juvenile-onset dystonia.

The neuropathology of the primary dystonias is not well understood. We examined brains from identical twins with DYT1-negative, dopa-unresponsive dystonia. The twins exhibited mild developmental delays until age 12 years when they began developing rapidly progressive generalized dystonia. Genetic, metabolic, and imaging studies ruled out known causes of dystonia. Cognition was subnormal but stable until the last few years. Death occurred at ages 21 and 22 years. The brains were macroscopically unremarkable. Microscopic examination showed unusual glial fibrillary acidic protein-immunoreactive astrocytes in multiple regions and iron accumulation in pallidal and nigral neurons. However, the most striking findings were 1) eosinophilic, rod-like cytoplasmic inclusions in neocortical and thalamic neurons that were actin depolymerizing factor/cofilin-immunoreactive but only rarely actin-positive; and 2) abundant eosinophilic spherical structures in the striatum that were strongly actin- and actin depolymerizing factor/cofilin-positive. Electron microscopy suggested that these structures represent degenerating neurons and processes; the accumulating filaments had the same dimensions as actin microfilaments. To our knowledge, aggregation of actin has not been reported previously as the predominant feature in any neurodegenerative disease. Thus, our findings may shed light on a novel neuropathological change associated with dystonia that may represent a new degenerative mechanism involving actin, a ubiquitous constituent of the cytoskeletal system.

Actin Depolymerizing Factors↗
PubMed2004

Multiseptate gallbladder with acute acalculous cholecystitis.

Multiseptate gallbladder is a rare congenital malformation of the gallbladder. In some cases, right upper quadrant pain, recurrent abdominal pain, and gallstones were present. We present the sonographic findings in a case of multiseptate gallbladder with acute cholecystitis, which (to our knowledge) has not been reported before. We hypothesize that bile sludge accumulated and subsequent cholecystitis developed as a result of bile stasis in our case because the classic predisposing factors that have been described were absent.

Adult↗
PubMed2005

The origin of tubular aggregates in human myopathies.

Tubular aggregates are morphological abnormalities characterized by the accumulation of densely packed tubules in skeletal muscle fibres. To improve knowledge of tubular aggregates, the formation and role of which are still unclear, the present study reports the electron microscopic analysis and protein characterization of tubular aggregates in six patients with 'tubular aggregate myopathy'. Three of the six patients also presented with myasthenic features. A large panel of immunochemical markers located in the sarcoplasmic reticulum, T-tubules, mitochondria, and nucleus was used. Despite differences in clinical phenotype, the composition of tubular aggregates, which contained proteins normally segregated differently along the sarcoplasmic reticulum architecture, was similar in all patients. All of these proteins, calsequestrin, RyR, triadin, SERCAs, and sarcalumenin, are involved in calcium uptake, storage, and release. The dihydropyridine receptor, DHPR, specifically located in the T-tubule, was also present in tubular aggregates in all patients. COX-2 and COX-7 mitochondrial proteins were not found in tubular aggregates, despite being observed close to them in the muscle fibre. The nuclear membrane protein emerin was found in only one case. Electron microscopy revealed vesicular budding from nuclei, and the presence of SAR-1 GTPase protein in tubular aggregates shown by immunochemistry, in all patients, suggests that tubular aggregates could arise from endoplasmic reticulum exit sites. Taken together, these results cast new light on the composition and significance of tubular aggregates.

Adult↗
PubMed1990

Physiology of monoclonal antibody accretion by tumors.

During the past 8 years numerous patients have been injected with radiolabeled monoclonal antibodies for both the diagnosis and treatment of cancer. In general the results, while somewhat promising, have failed to fulfill initial expectations. It is now clear that there are many physiologic barriers that antibodies face in their trek toward their tumor-binding site. Use of terms such as antibody-guided delivery or antibody-guided targeting do not take into account the fact that the antibodies are subject to the same physiologic rules as drugs and hormones. Antibodies are no more 'guided' than any drug or hormone. They reach their binding site via the same delivery mechanisms and accumulate in proportion to their 'receptor's' (antigen's) density. Our knowledge and understanding of the physiologic barriers to the uptake of tumor-associated monoclonal antibodies is limited. To date very few studies have been reported that shed light on this problem. For radiolabeled monoclonal antibodies to fulfill their promise, a greater understanding of these physiologic barriers is needed in order to devise ways in which they may be overcome.

Antibodies, Monoclonal↗
PubMed1997

Reference frames in saccadic targeting.

We attempt to determine the egocentric reference frame used in directing saccades to remembered targets when landmark-based (exocentric) cues are not available. Specifically, we tested whether memory-guided saccades rely on a retina-centered frame, which must account for eye movements that intervene during the memory period (thereby accumulating error) or on a head-centered representation that requires knowledge of the position of the eyes in the head. We also examined the role of an exocentric reference frame in saccadic targeting since it would not need to account for intervening movements. We measured the precision of eye movements made by human observers to target locations held in memory for a few seconds. A variable number of saccades intervened between the visual presentation of a target and a later eye movement to its remembered location. A visual landmark that allowed for exocentric encoding of the memory target appeared in half the trials. Variable error increased slightly with a greater number of intervening saccades. The landmark aided targeting precision, but did not eliminate the increase in variable error with additional intervening saccades. We interpret these results as evidence for a representation that relies on knowledge of eye position with respect to the head and not one that relies solely on updating in a retina-centered frame. Our results allow us to set an upper bound on the standard deviation of an eye position signal available to the saccadic system during short memory periods at 1.4 degrees for saccades of about 10 degrees.

Adult↗
PubMed2006

MRI myocardial motion and fiber tracking: a confirmation of knowledge from different imaging modalities.

OBJECTIVE: A helical configuration underlies the anatomy of cardiac structure, and a structure/function relationship is needed to determine if the ventricular myocardial band model defines this spatial relationship. This report explores how studies of velocity-encoded phase contrast magnetic resonance imaging (MRI) for myocardial motion and fiber tracking algorithms that imply fiber orientations can (a) quantify regional myocardial wall motion of the entire heart, (b) determine if these motion of implied fiber orientation link with the helical heart model, and (c) reveal if this new knowledge correlates with imaging information from other different imaging modalities. METHODS: Accumulated left ventricular motion patterns that accurately differentiate radial (i.e. contraction and expansion), rotational (i.e. twisting and untwisting), and longitudinal (i.e. lengthening and shortening) motion components are correlated with structure/function data achieved by sonomicrometer crystals, echocardiography, corrosion casts, and MUGA recordings. RESULTS: Acceleration fiber tracking to determine fiber orientation and cardiac motion during the ejection and rapid filling phases of the cardiac cycle corresponded to maximal force displayed by ultrasonic crystals placed into the angulation of the presumed functional units of the descending and ascending segments of the apical loop of the helical ventricular myocardial band, and motion by echocardiographic recordings. These integrated findings imply a favourable interaction of MRI with the myocyte orientation of the helical ventricular myocardial band. CONCLUSIONS: These composite findings indicate that phase contrast MRI techniques for high temporal resolution velocity mapping during cardiac motion and myocardial fiber tracking confirm other technologies, and centralize the capacity of MRI to link other imaging methods together relative to a single helical structural model. The close agreement amongst a spectrum of imaging studies provide a very powerful integration that transcends a single look; the same thing is observed by each component of global technology, thereby implying that the helical ventricular band is the structural basis for these functional changes.

Echocardiography↗
PubMed2006

PTMs on H3 variants before chromatin assembly potentiate their final epigenetic state.

Histone posttranslational modifications (PTMs) and sequence variants regulate genome function. Although accumulating evidence links particular PTM patterns with specific genomic loci, our knowledge concerning where and when these PTMs are imposed remains limited. Here, we find that lysine methylation is absent prior to histone incorporation into chromatin, except at H3K9. Nonnucleosomal H3.1 and H3.3 show distinct enrichments in H3K9me, such that H3.1 contains more K9me1 than H3.3. In addition, H3.3 presents other modifications, including K9/K14 diacetylated and K9me2. Importantly, H3K9me3 was undetectable in both nonnucleosomal variants. Notably, initial modifications on H3 variants can potentiate the action of enzymes as exemplified with Suv39HMTase to produce H3K9me3 as found in pericentric heterochromatin. Although the set of initial modifications present on H3.1 is permissive for further modifications, in H3.3 a subset cannot be K9me3. Thus, initial modifications impact final PTMs within chromatin.

Amino Acid Sequence↗
PubMed1996

Regulation of phosphatase synthesis in Saccharomyces cerevisiae--a review.

Transcription of the genes encoding acid and alkaline phosphatases and the inorganic phosphate (Pi) transporter of Saccharomyces cerevisiae are coordinately repressed and derepressed depending on the Pi concentration in the culture medium. This phosphatase system is particularly suited for the study of regulatory mechanisms, because the acid phosphatase activity of each colony on a plate is easily detected by specific staining methods and there is a 500-fold difference between the repressed and derepressed levels of acid phosphatase activity. With these advantages, considerable amounts of genetic and molecular evidence have been accumulated in the past two decades. This article summarizes our current knowledge on this subject.

Acid Phosphatase↗
PubMedDate not supplied

Prevention of HIV among drug users.

The relationship between injection drug use and HIV was established early in the HIV epidemic, and injection drug use has continued to be an important risk factor for HIV throughout the world. This panel included 4 papers related to HIV prevention among drug users, focusing on effective prevention strategies, the importance of organizing the AIDS-affected community, the impact of knowledge of serostatus on risk behaviors, and developing interventions for drug-using homosexual and bisexual men. These papers, addressing various aspects of the epidemic and methods to enhance prevention efforts, all indicate that although extensive knowledge regarding how to reduce HIV risks among drug users has accumulated, many areas for further research and intervention development remain.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Localization and synthesis of zona pellucida proteins in the marmoset monkey (Callithrix jacchus) ovary.

In most species, the zona pellucida (ZP), an extracellular matrix surrounding the mammalian oocyte, is composed of three glycoproteins: ZPA, ZPB and ZPC. Based mainly on results with mice, the site of zona pellucida biosynthesis has been suggested to be exclusively in the oocyte cytoplasm. However, evidence is accumulating that among various species cumulus/granulosa cells may be involved. Because knowledge of ZP biosynthesis in primates is lacking, we used the common marmoset (Callithrix jacchus) to acquire information about the localization and the site of synthesis of ZP proteins in this species. Using antibodies against synthetic ZPA and ZPC peptides, immunoreactivity was found in the marmoset ZP and in surrounding cumulus cells. Interestingly, the amounts of ZPA and ZPC proteins expressed appeared to differ depending on the stage of folliculogenesis. RT-PCR analysis of mRNA from marmoset oocytes and from oocyte-free follicle cells revealed expression of ZPA, ZPB and ZPC in oocytes and in follicle cells of different stages of marmoset monkey folliculogenesis. Our data suggest that the biosynthesis of marmoset ZPA, ZPB and ZPC proteins takes place both in oocytes and in follicle cells of different follicle stages, although the abundance of ZP glycoproteins may differ depending on the individual ZP protein.

Animals↗