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PubMed2006

Correlation of brain magnetic resonance imaging changes with pallidal manganese concentrations in rhesus monkeys following subchronic manganese inhalation.

High-dose manganese exposure is associated with parkinsonism. Because manganese is paramagnetic, its relative distribution within the brain can be examined using magnetic resonance imaging (MRI). Herein, we present the first comprehensive study to use MRI, pallidal index (PI), and T(1) relaxation rate (R1) in concert with chemical analysis to establish a direct association between MRI changes and pallidal manganese concentration in rhesus monkeys following subchronic inhalation of manganese sulfate (MnSO(4)). Monkeys exposed to MnSO(4) at > or = 0.06 mg Mn/m(3) developed increased manganese concentrations in the globus pallidus, putamen, olfactory epithelium, olfactory bulb, and cerebellum. Manganese concentrations within the olfactory system of the MnSO(4)-exposed monkeys demonstrated a decreasing rostral-caudal concentration gradient, a finding consistent with olfactory transport of inhaled manganese. Marked MRI signal hyperintensities were seen within the olfactory bulb and the globus pallidus; however, comparable changes could not be discerned in the intervening tissue. The R1 and PI were correlated with the pallidal manganese concentration. However, increases in white matter manganese concentrations in MnSO(4)-exposed monkeys confounded the PI measurement and may lead to underestimation of pallidal manganese accumulation. Our results indicate that the R1 can be used to estimate regional brain manganese concentrations and may be a reliable biomarker of occupational manganese exposure. To our knowledge, this study is the first to provide evidence of direct olfactory transport of an inhaled metal in a nonhuman primate. Pallidal delivery of manganese, however, likely arises primarily from systemic delivery and not directly from olfactory transport.

Animals↗

PubMed2004

Regulation of ubiquitin-proteasome pathway on pig oocyte meiotic maturation and fertilization.

Degradation of proteins mediated by the ubiquitin-proteasome pathway (UPP) plays essential roles in the eukaryotic cell cycle. The main aim of the present study was to analyze the functional roles and regulatory mechanisms of the UPP in pig oocyte meiotic maturation, activation, and early embryo mitosis by drug treatment, Western blot analysis, and confocal microscopy. By using the hypoxanthine-maintained meiotic arrest model, we showed that the meiotic resumption of both cumulus-enclosed oocytes and denuded oocytes was stimulated in a dose- and time-dependent manner by two potent and cell-permeable proteasome inhibitors. Both the mitogen-activated protein kinase (MAPK) kinase inhibitor U0126 and the maturation-promoting factor inhibitor roscovitine overcame the stimulation of germinal vesicle breakdown induced by proteasome inhibitors. The phosphorylation of MAPK and p90rsk and the expression of cyclin B1 increased in a dose- and time-dependent manner when treated with proteasome inhibitors during oocyte in vitro-maturation culture. Both U0126 and roscovitine inhibited the phosphorylation of MAPK and p90rsk, and the synthesis of cyclin B1 stimulated by proteasome inhibitors. When matured oocytes were pretreated with proteasome inhibitors and then fertilized or artificially activated, the second polar body emission and the pronuclear formation were inhibited, and the dephosphorylation of MAPK and p90rsk as well as the degradation of cyclin B1 that should occur after oocyte activation were also inhibited. We also investigated, to our knowledge for the first time, the subcellular localization of 20S proteasome alpha subunits at different stages of oocyte and early embryo development. The 20S proteasome alpha subunits were accumulated in the germinal vesicle, around the condensed chromosomes at prometaphase, with spindle at metaphase I and II, the region between the separating chromosomes, and especially the midbody at anaphase I and telophase I, the pronucleus, and the nucleus in early embryonic cells. In conclusion, our results suggest that the UPP is important at multiple steps of pig oocyte meiosis, fertilization, and early embryonic mitosis and that it may play its roles by regulating cyclin B1 degradation and MAPK/p90rsk phosphorylation.

Animals↗

PubMed2002

Probing green algal hydrogen production.

The recently developed two-stage photosynthesis and H(2)-production protocol with green algae is further investigated in this work. The method employs S deprivation as a tool for the metabolic regulation of photosynthesis. In the presence of S, green algae perform normal photosynthesis, carbohydrate accumulation and oxygen production. In the absence of S, normal photosynthesis stops and the algae slip into the H(2)-production mode. For the first time, to our knowledge, significant amounts of H(2) gas were generated, essentially from sunlight and water. Rates of H(2) production could be sustained continuously for ca. 80 h in the light, but gradually declined thereafter. This work examines biochemical and physiological aspects of this process in the absence or presence of limiting amounts of S nutrients. Moreover, the effects of salinity and of uncouplers of phosphorylation are investigated. It is shown that limiting levels of S can sustain intermediate levels of oxygenic photosynthesis, in essence raising the prospect of a calibration of the rate of photosynthesis by the S content in the growth medium of the algae. It is concluded that careful titration of the supply of S nutrients in the green alga medium might permit the development of a continuous H(2)-production process.

Algal Proteins↗

PubMed2006

Decoding the fine-scale structure of a breast cancer genome and transcriptome.

A comprehensive understanding of cancer is predicated upon knowledge of the structure of malignant genomes underlying its many variant forms and the molecular mechanisms giving rise to them. It is well established that solid tumor genomes accumulate a large number of genome rearrangements during tumorigenesis. End Sequence Profiling (ESP) maps and clones genome breakpoints associated with all types of genome rearrangements elucidating the structural organization of tumor genomes. Here we extend the ESP methodology in several directions using the breast cancer cell line MCF-7. First, targeted ESP is applied to multiple amplified loci, revealing a complex process of rearrangement and co-amplification in these regions reminiscent of breakage/fusion/bridge cycles. Second, genome breakpoints identified by ESP are confirmed using a combination of DNA sequencing and PCR. Third, in vitro functional studies assign biological function to a rearranged tumor BAC clone, demonstrating that it encodes anti-apoptotic activity. Finally, ESP is extended to the transcriptome identifying four novel fusion transcripts and providing evidence that expression of fusion genes may be common in tumors. These results demonstrate the distinct advantages of ESP including: (1) the ability to detect all types of rearrangements and copy number changes; (2) straightforward integration of ESP data with the annotated genome sequence; (3) immortalization of the genome; (4) ability to generate tumor-specific reagents for in vitro and in vivo functional studies. Given these properties, ESP could play an important role in a tumor genome project.

Breast Neoplasms↗

PubMed2005

Antimicrobial peptides in human skin.

Human skin is permanently exposed to a wide variety of potential harmful microorganisms. Despite these microbial threats, skin is surprisingly highly resistant against infections. Various studies in the last decade discovered a chemical cutaneous defense system based on the production of antimicrobial proteins. These antimicrobial proteins act as a first defense line through their broad spectrum of potent antimicrobial activity. In addition to constitutively expressed antimicrobial proteins, production of various antimicrobial proteins in keratinocytes is induced by bacterial compounds as well as proinflammatory cytokines. The resulting local accumulation of antimicrobial proteins offers a fast and very efficient way to prevent microbes from establishing an infection. In this review we summarize the current status of our knowledge of expression of antimicrobial proteins in human skin.

Acute-Phase Proteins↗

PubMed2006

Prenatal exclusion/confirmation of Fanconi anemia via flow cytometry: a pilot study.

OBJECTIVE: To explore the potential of flow cytometry in the prenatal exclusion or confirmation of Fanconi anemia (FA). METHODS: Indications for prenatal diagnosis were (1) FA-negative family history, but suspicious ultrasound findings such as radial ray aplasia, (2) FA-positive family history, but without knowledge of the affected gene and/or mutation. Amniotic fluid (AF) cell cultures and umbilical cord (UC) blood cultures were assayed for typical cell cycle changes (G2-phase accumulations) without and with mitomycin C (MMC) treatments using single- and dual-parameter (BrdU-Hoechst) flow cytometry. RESULTS: Single-parameter flow cytometry correctly identified 2 positive and 9 negative cases on the basis of MMC sensitivity of cultivated AF cells. Likewise, 8 negative and 2 positive cases were correctly predicted using bivariate flow cytometry of 72-hour UC blood cultures. In contrast, bivariate flow cytometry applied to AF cells grown in the presence of bromodeoxyuridine (BrdU) yielded false-positive and false-negative results. CONCLUSIONS: Single-parameter flow cytometry of AF cell cultures and bivariate flow cytometry of UC cell cultures have the potential to correctly predict the affected status in cases at risk for FA, whereas bivariate flow cytometry proved unreliable when applied to BrdU-substituted AF cell cultures. Cases with a low a priori risk (e.g. sonographic finding of radial ray abnormalities and negative family history) would benefit most from flow cytometry as a rapid and economical prenatal screening procedure.

Amniocentesis↗

PubMed2004

Unusual uptake of radioiodine in the chest in a patient with thyroid carcinoma.

A wide spectrum of potentially misleading artefacts can arise in 131I whole body scans from various anatomical variants and physiological processes as well as several unrelated non-thyroidal disease processes. A proper understanding of the causes of false positive 131I scans is essential for accurate interpretation of the images and to obviate diagnostic errors which may lead to administration of unnecessary therapy doses. The authors, in this article, present a case which had 131I uptake in the mediastinum persisting after surgical excision of mediastinal nodes, which was subsequently found to be due to accumulation of radioiodine in a hugely dilated oesophagus in secondary to achalasia. A comprehensive and rational classification of the various false positive 131I scintigraphic patterns based on the knowledge of the existing literature is reviewed.

Artifacts↗

PubMed2006

Cellular functions of vaults and their involvement in multidrug resistance.

Vaults are evolutionary highly conserved ribonucleoprotein (RNP) particles with a hollow barrel-like structure. They are 41 x 73 nm in size and are composed of multiple copies of three proteins and small untranslated RNA (vRNA). The main component of vaults represents the 110 kDa major vault protein (MVP), whereas the two minor vault proteins comprise the 193 kDa vault poly(ADP-ribose) polymerase (VPARP) and the 240 kDa telomerase-associated protein-1 (TEP1). Vaults are abundantly present in the cytoplasm of eukaryotic cells and they were found to be associated with cytoskeletal elements as well as occasionally with the nuclear envelope. Vaults and MVP have been associated with several cellular processes which are also involved in cancer development like cell motility and differentiation. Due to the over-expression of MVP (also termed lung resistance-related protein or LRP) in several P-glycoprotein (P-gp)-negative chemoresistant cancer cell lines, vaults have been linked to multidrug resistance (MDR). Accordingly, high levels of MVP were found in tissues chronically exposed to xenobiotics. In addition, the expression of MVP correlated with the degree of malignancy in certain cancer types, suggesting a direct involvement in tumor development and/or progression. Based on the finding that MVP binds several phosphatases and kinases including PTEN, SHP-2 as well as Erk, evidence is accumulating that MVP might be involved in the regulation of important cell signalling pathways including the PI3K/Akt and the MAPK pathways. In this review we summarize the current knowledge concerning the vault particle and discuss its possible cellular functions, focusing on the role of vaults in chemotherapy resistance.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed1999

Current trends in cognitive rehabilitation for memory disorders.

Progress in the neuropsychology of memory disorders has provided a foundation for development of cognitive rehabilitation for amnesic patients. Accumulating evidence in the past two decades suggested that certain training techniques could be beneficial to many amnesic patients, such as teaching and acquisition of domain-specific knowledge, motor coding, reality orientation, and meta-cognition improvement. In this article we review and discuss the current trends in cognitive rehabilitation of memory disorders and provide a future direction in this emerging field. In addition, our experience in the successful rehabilitation of Korsakoff syndrome patients is also introduced.

Alcohol Amnestic Disorder↗

PubMed2002

[Human mycobacterial infections: impact of host genetic factors].

Humans are exposed worldwide to a variety of environmental mycobacteria (EM) and most children are inoculated with live Bacille Calmette-Guérin (BCG) vaccine. Although rarely pathogenic, poorly virulent mycobacteria, including BCG and most EM, may cause a variety of clinical diseases. M. tuberculosis and M. leprae are more virulent, causing tuberculosis, and leprosy, respectively. Remarkably, only a minority of individuals develop clinical disease, even if infected with virulent mycobacteria. There is now accumulating evidence that the large interindividual variability of clinical outcome results in part from variability in the human genes that control host defense. We review here in current knowledge about genetic predisposition to common (leprosy and tuberculosis) and rare (BCG and EM infections) mycobacterial infections.

Genetic Predisposition to Disease↗

PubMed1992

[Physiopathology of venous stasis at the microcirculation level].

The division of the venous circulation in to two sectors, one constituted by the superficial and deep venous trunks (macrocirculation) and the other by the capillaries and precapillary venules (microcirculation), is surely schematical but aids the comprehension of many hemodynamic effects connected to hampered venous return and to the incompetence of the valvular devices. In fact many of the effects of stasis and venous hypertension (oedema, red cell diapedesis, skin dystrophies) cannot be explained merely by hydraulic mechanisms but require a primary alteration of the microvascular wall associated with structural changes of the perivascular connective tissue. The alterations that occur in microcirculation are of the utmost importance in the formation of the venules ulcerations. The passage of fibrinogen through large pores in the venules of the patients affected by venous hypertension derived from venous insufficiency creates a pericapillary fibrin deposition that cannot be removed because of inadequate blood and tissue fibrinolysis. This accumulation acts as a barrier to the diffusion of oxygen and other nutrients, determining a stasis dermatitis that may lead to tissue necrosis and ulceration. The more precise knowledge of the phenomena connected with the venous stasis at the level of microcirculation (pericapillary fibrin deposition, endothelial ischemia, blocked lymphatic drainage) will not only allow a deeper comprehension of the clinical signs but hopefully will lead to a more effective treatment of the postphlebitic syndrome.

Humans↗

PubMed2005

[Mechanisms and medical implications of replicative senescence].

Normal somatic cells divide in vitro only for a limited number of times, and then enter a state of replicative senescence. In most human cells replicative senescence is triggered by critical shortening and uncapping of telomeres, which leads to the up-regulation of p53 and/or p16 suppressor proteins that inhibit cell divisions. Because both reconstruction of telomeres and inactivation of suppressor proteins enables the cells to grow further or even immortalize, it has been hypothesized that replicative senescence acts as a natural barrier against neoplastic transformation. On the other hand, however, recent reports suggest that the accumulation of senescent cells may jeopardize tissue integrity and create a specific microenvironment that promotes tumorogenesis in elderly people. In this review we describe recent advances in our knowledge on the mechanisms of replicative senescence and discuss its medical implications.

Aging↗

PubMed1989

Giant colonic mucocele after diversion colostomy for ulcerative colitis.

We report an unusual complication occurring after diversion transverse loop colostomy in a patient with long-standing ulcerative colitis. The formation of a giant colonic mucocele resulted from distal stomal and rectal stenosis, with subsequent accumulation of mucus in the obstructed segment over many years. The pathophysiologic features of this case, which are similar to mucocele of the appendix, are discussed. To our knowledge, this is the first report in the literature of a giant colonic mucocele after diversion colostomy.

Aged↗

PubMed1994

The calcium ion and cell death.

There is now convincing evidence that the calcium ion can play a critical role in cell killing in the central nervous system and other tissues. Recent research has established some of the biochemical mechanisms by which intracellular Ca2+ overload can trigger either necrotic or apoptotic cell death, and a number of studies have shown that prevention of Ca2+ overload by pretreatment with either Ca2+ chelators, receptor antagonists or channel blockers can rescue cells that would otherwise die. Similarly, cells which express high levels of certain Ca(2+)-binding proteins (e.g. calbindin-D28K) seem to be more resistant to killing. Thus, it appears that the development of improved strategies to prevent Ca2+ overload will be of importance for neuroprotection. The role of the calcium ion as intracellular regulator of many physiological processes is now well established. Thus, the effects of a variety of hormones and growth factors have been found to be mediated by transient increases in the level of cytosolic Ca2+, which frequently assume oscillatory patterns (see Carafoli, 1989 and Berridge, 1991 for reviews). Most often, the Ca2+ increase is initiated by the release of Ca2+ from intracellular stores followed by the stimulation of influx of extracellular Ca2+. Most regulatory effects of Ca2+ are mediated by Ca(2+)-binding proteins (e.g. calmodulin) and achieved by alterations of the phosphorylation state of target proteins. Along with this knowledge has come the understanding that Ca2+ can also play a determinant role in a variety of pathological and toxicological processes. It has long been recognized that Ca2+ accumulates in necrotic tissue, and more recent work has revealed that a disruption of intracellular Ca2+ homeostasis is frequently associated with the early development of cell injury (Schanne et al., 1979; Jewell et al., 1982; Fleckenstein et al., 1983). This led to the formulation of the calcium hypothesis of cell injury, proposing that perturbation of intracellular Ca2+ homeostasis may be a common step in the development of cytotoxicity. Support for this hypothesis has come from a large number of studies demonstrating that the calcium ion plays a critical role in cytotoxicity and cell killing in many tissues, notably the central nervous system and the immune system (see Nicotera et al., 1992 for review).

Animals↗

PubMed2004

Nuclear accumulation of epidermal growth factor receptor and acceleration of G1/S stage by Epstein-Barr-encoded oncoprotein latent membrane protein 1.

Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is considered to be the major oncogenic protein of EBV-encoded proteins and has always been the core of the oncogenic mechanism of EBV. Advanced studies on nuclear translocation of the epidermal growth factor receptor (EGFR) family have greatly improved our knowledge of the biological function of cell surface receptors. In this study, we used the Tet-on LMP1 HNE2 cell line as a cell model, which is a dual-stable LMP1-integrated nasopharyngeal carcinoma (NPC) cell line and the expression of LMP1 which could be regulated by the Tet system. We found that LMP1 could regulate the nuclear accumulation of EGFR in a dose-dependent manner quantitatively and qualitatively. We also demonstrated that the nuclear localization sequence of EGFR played some roles in the location of the protein within the nucleus under LMP1 regulation and EGFR in the nucleus could bind to the promoters of cyclinD1 and cyclinE, respectively. We further demonstrated that EGFR is involved in the acceleration of the G1/S phase transition by LMP1 through binding to cyclinD1 and cyclinE directly. These findings provided a novel view that the acceleration of LMP1 on the G1/S transition via the nuclear accumulation of EGFR was critical in the process of nasopharyngeal carcinoma.

Base Sequence↗

PubMed2001

[Molecular mechanisms controlling the cell cycle: fundamental aspects and implications for oncology].

INTRODUCTION: Comprehension of cell cycle regulation mechanisms has progressed very quickly these past few years and regulators of the cell cycle have gained widespread importance in cancer. This review first summarizes major advances in the understanding of the control of cell cycle mechanisms. Examples of how this control is altered in tumoral cells are then described. CURRENT KNOWLEDGE AND KEY POINTS: The typical mammalian cell cycle consists of four distinct phases occurring in a well-defined order, each of which should be completed successfully before the next begins. Progression of eukaryotic cells through major cell cycle transitions is mediated by sequential assembly and activation of a family of serine-threonine protein kinases, the cyclin dependent kinases (CDK). The timing of their activation is determined by their post-translational modifications (phosphorylations/dephosphorylations), and by the association of a protein called cyclin, which is the regulatory subunit of the kinase complex. The cyclin family is divided into two main classes. The 'G1 cyclins' include cyclins C, D1-3, and E, and their accumulation is rate-limiting for progression from the G1 to S phase. The 'mitotic or G2 cyclins', which include cyclin A and cyclin B, are involved in the control of G2/M transition and mitosis. The cyclins bind to and activate the CDK, which leads to phosphorylation (and then inhibition) of the tumor suppressor protein, pRb. pRb controls commitment to progress from the G1 to S phase, at least in part by repressing the activity of the E2F transcription factors known to promote cell proliferation. Both the D-type cyclins and their partner kinases CDK4/6 have proto-oncogenic properties, and their activity is carefully regulated at multiple levels including negative control by two families of CDK inhibitors. While members of the INK4 family (p16INK4A, p15INK4B, p18INK4C, p19INK4D) interact specifically with CDK4 and CDK6, the CIP/KIP inhibitors p21CIP1/WAF1, p27KIP1 and p57KIP2 inhibit a broader spectrum of CDK. The interplay between p16INK4A, cyclin D/CDK, and pRb/E2F together constitute a functional unit collectively known as the 'pRb pathway'. Each of the major components of this mechanism may become deregulated in cancer, and accumulating evidence points to the 'pRb pathway' as a candidate obligatory target in multistep oncogenesis of possibly all human tumor types. FUTURE PROSPECTS AND PROJECTS: Major advances in the understanding of cell cycle regulation mechanisms provided a better knowledge of the molecular interactions involved in human cancer. This progress has led to the promotion of new therapeutic agents presently in clinical trials or under development. Moreover, the components of the cell cycle are probably involved in other non-cancerous diseases and their role must be defined.

Animals↗

PubMed1989

Psychiatric investigations among American Indians and Alaska natives: a critical review.

This review of psychiatric investigations among Native Americans opens with a discussion of the dominant theoretical perspectives in psychiatric anthropology in order to provide an analytic framework with which to assess the substantive findings of researchers in the field. Studies of culture-specific disorders, service utilization and patient population studies, psychiatric epidemiological studies, and studies designed to test the validity of certain diagnostic instruments are scrutinized for evidence of the nature of the role of indigenous cultures in the manifestations of psychiatric disorders among these populations. The review reveals that a universalist theoretical perspective, which tends to obscure the role of local interpretations in the phenomenology of psychiatric illness, dominates this field of inquiry. Nonetheless, evidence has accumulated which indicates the importance of native understandings for a more reliable and valid explanation of the nature of mental disorder among these peoples. The inadequacies of our current knowledge are examined and suggestions for directions in future work are presented in the concluding section. Recommendations include the direct investigation of the local meanings of the signs, symptoms, and syndromes of Western psychiatry; the concentrated search for potentially unique and powerful local signs of distress; and the study of the culturally-constituted social processes of illness.

Anthropology↗

PubMed2004

Assessing cadmium distribution applying neutron radiography in moss trophical levels, located in Szarvasko, Hungary.

The measuring station of the 10 MW VVR-SM research reactor at the Budapest Neutron Centre (Hungary) was used to perform dynamic neutron radiography (DNR), which was, to our best knowledge, the first time, in a Tortella tortuosa biotope. In the conducted study, two trophical levels, moss and spider Thomisidae sp. juv., were examined. Cadmium penetration routes, distribution and accumulation zones were visualized in the leafy gametophyte life cycle of Tortella tortuosa and in the organs of the spider.

Air Pollutants↗