Biomedical subjects

E Becker

Publications and source records attributed to E Becker.

At least 19 recordsLinked to original sources

PubMed2002

Prevalence, incidence and stability of premenstrual dysphoric disorder in the community.

BACKGROUND: Despite an abundance of clinical research on premenstrual and menstrual symptoms, few epidemiological data provide estimates of the prevalence, incidence, co-morbidity, stability and correlates of premenstrual dysphoric disorder (PMDD) in the community. AIMS: To describe the prevalence, incidence, 12 co-morbidity factors and correlates of threshold and subthreshold PMDD in a community sample of young women. METHODS: Findings are based on prospective-longitudinal community survey of 1488 women aged 14-24, who were followed-up over a period of 48 months (follow-up, N = 1,251) as part of the EDSP sample. Diagnostic assessments were based on the Composite International Diagnostic Interview (CIDI) and its 12-month PMDD diagnostic module administered by clinical interviewers. Diagnoses were calculated using DSM-IV algorithms, but daily ratings of symptoms, as required, were not available. RESULTS: The baseline 12-month prevalence of DSM-IV PMDD was 5.8%. Application of the diagnostic exclusion rules with regard to concurrent major depression and dysthymia decreased the rate only slightly (5.3%). An additional 18.6 % were 'near-threshold' cases, mostly because they failed to meet the mandatory impairment criterion. Over the follow-up period only few new PMDD cases were observed: cumulative lifetime incidence was 7.4%. PMDD syndrome was stable across 48 months with < 10% complete remissions among baseline PMDD cases. The 12-month and lifetime co-morbidity rates were high (anxiety disorders 47.4%, mood disorders 22.9%; somatoform 28.4%), only 26.5 % had no other mental disorder. Particularly high odds ratios were found with nicotine dependence and PTSD. In terms of correlates increased rates of 4-weeks impairment days, high use of general health and mental health services, and increased rates of suicide attempts were found. CONCLUSION: In this sample of adolescents and young adults, premenstrual symptoms were widespread. However, DSM-IV PMDD was considerably less prevalent. PMDD is a relatively stable and impairing condition, with high rates of health service utilization, increased suicidality and substantial co-morbidity.

Adolescent↗

PubMed2001

beta-adrenergic receptor blockers restore cardiac calcium release channel (ryanodine receptor) structure and function in heart failure.

BACKGROUND: beta-Adrenergic receptor blockade is one of the most effective treatments for heart failure, a leading cause of mortality worldwide. The use of beta-adrenergic receptor blockers in patients with heart failure is counterintuitive, however, because they are known to decrease contractility in normal hearts. The ryanodine receptor (RyR2) on cardiac sarcoplasmic reticulum is the key calcium release channel required for excitation-contraction coupling. In failing hearts, the stoichiometry and function of the RyR2 macromolecular complex is altered. Decreased levels of phosphatases (PP1 and PP2A) and hyperphosphorylation by protein kinase A result in dissociation of the regulatory protein FKBP12.6 and channels with increased open probability. METHODS AND RESULTS: Here, we show that systemic oral administration of a beta-adrenergic receptor blocker reverses protein kinase A hyperphosphorylation of RyR2, restores the stoichiometry of the RyR2 macromolecular complex, and normalizes single-channel function in a canine model of heart failure. CONCLUSIONS: These results may, in part, explain the improved cardiac function observed in heart failure patients treated with beta-adrenergic receptor blockers.

Adrenergic beta-Antagonists↗

PubMed2001

Domain mapping of human PEX5 reveals functional and structural similarities to Saccharomyces cerevisiae Pex18p and Pex21p.

PEX5 functions as an import receptor for proteins with the type-1 peroxisomal targeting signal (PTS1). Although PEX5 is not involved in the import of PTS2-targeted proteins in yeast, it is essential for PTS2 protein import in mammalian cells. Human cells generate two isoforms of PEX5 through alternative splicing, PEX5S and PEX5L, and PEX5L contains an additional insert 37 amino acids long. Only one isoform, PEX5L, is involved in PTS2 protein import, and PEX5L physically interacts with PEX7, the import receptor for PTS2-containing proteins. In this report we map the regions of human PEX5L involved in PTS2 protein import, PEX7 interaction, and targeting to peroxisomes. These studies revealed that amino acids 1-230 of PEX5L are required for PTS2 protein import, amino acids 191-222 are sufficient for PEX7 interaction, and amino acids 1-214 are sufficient for targeting to peroxisomes. We also identified a 21-amino acid-long peptide motif of PEX5L, amino acids 209-229, that overlaps the regions sufficient for full PTS2 rescue activity and PEX7 interaction and is shared by Saccharomyces cerevisiae Pex18p and Pex21p, two yeast peroxins that act only in PTS2 protein import in yeast. A mutation in PEX5 that changes a conserved serine of this motif abrogates PTS2 protein import in mammalian cells and reduces the interaction of PEX5L and PEX7 in vitro. This peptide motif also lies within regions of Pex18p and Pex21p that interact with yeast PEX7. Based on these and other results, we propose that mammalian PEX5L may have acquired some of the functions that yeast Pex18p and/or Pex21p perform in PTS2 protein import. This hypothesis may explain the essential role of PEX5L in PTS2 protein import in mammalian cells and its lack of importance for PTS2 protein import in yeast.

Amino Acid Sequence↗

PubMed2001

Development of potential iron chelators for the treatment of Friedreich's ataxia: ligands that mobilize mitochondrial iron.

Friedreich's ataxia (FA) is a crippling neurodegenerative disease that is due to iron (Fe) overload within the mitochondrion. One therapeutic intervention may be the development of a chelator that could remove mitochondrial Fe. We have implemented the only well characterized model of mammalian mitochondrial Fe overload to examine the Fe chelation efficacy of novel chelators of the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) class. In this model we utilize reticulocytes treated with the haem synthesis inhibitor succinylacetone which results in mitochondrial Fe-loading. Our experiments demonstrate that in contrast to desferrioxamine, several of the PCIH analogues show very high activity at mobilizing (59)Fe from (59)Fe-loaded reticulocytes. Further studies on these ligands in animals are clearly warranted considering their potential to treat FA.

Animals↗

PubMed2001

Prevalence and epidemiologic correlates of atypical squamous cells of undetermined significance in women at low risk for cervical cancer.

Our aim was to determine the prevalence and epidemiologic correlates of atypical squamous cells of undetermined significance (ASCUS) in a population at low risk for cervical cancer in Porto Alegre, Brazil. Sociodemographic data and gynecological and obstetrical history from 977 women screened at an outpatient clinic were recorded. Specimens were collected for Papanicolaou cervical cytology, colposcopy, and biopsy (if indicated). Sixty-two (6.3%) patients presented ASCUS, 21 (2.1%) presented low-grade squamous intraepithelial lesions, and 6 (0.6%) presented high-grade lesions. Presence of human papillomavirus (HPV) DNA in cervical cells (odds ratio (OR) = 1.57; confidence interval (CI) 95% = 1.11-2.23), history of HPV infection (OR = 3.12; CI 95% = 1.22-7.96), and becoming sexually active at 18 yr or younger (OR = 1.70; CI 95% = 1.15-2.51) were independently associated with ASCUS. ASCUS patients reported HPV infections and presented HPV DNA in cervical cells more often than did patients with normal cytology; therefore, they should be carefully monitored to ensure early detection of cancer precursor lesions and prevention of cervical cancer.

Adolescent↗

PubMed2001

Frataxin: its role in iron metabolism and the pathogenesis of Friedreich's ataxia.

Friedreich's ataxia (FA) is a severe neurodegenerative condition with an incidence of 1:50000 in the European population. In 97% of patients this disease is due to an intronic GAA triplet repeat expansion in the FRDA gene resulting in a marked decrease in its expression. The protein encoded by this gene is known as frataxin which is found within the mitochondrion. Upon deletion of the homologous gene (YFH1) in the yeast, there was an accumulation of iron (Fe) within the mitochondrion. When the YFH1 gene was reintroduced back into the yeast cell Fe was exported out of the mitochondrion and into the cytosol. Evidence that human frataxin is also involved in mitochondrial Fe-overload comes from studies in FA patients that have shown an accumulation of Fe within the heart. While the precise role of human frataxin remains to be determined, the molecule appears to be involved indirectly in regulating the export and/or import of mitochondrial Fe. The finding of mitochondrial Fe-overload suggests that the use of specific Fe chelators which can permeate the mitochondrion may have potential in the treatment of this disease.

Friedreich Ataxia↗

PubMed2001

Risk of disease in siblings of patients with hereditary hemochromatosis.

BACKGROUND: Parents of hereditary hemochromatosis (HH) homozygote patients, who are predominantly HH heterozygotes, have been found to have an increased risk of colonic neoplasia, diabetes, stroke death, stomach cancer and leukemia. The health histories of siblings of HH patients are reported. METHODS: Individuals homozygous for HH were mailed questionnaires concerning the health histories of their siblings. Spouses of the HH homozygotes were asked to complete accompanying questionnaires concerning their siblings. The frequencies of serious illness and, when specified, each reported disease were determined by zygosity, odds ratios and 95% confidence intervals estimated. RESULTS: Data were available for 279 siblings known to be HH homozygotes (HHs), and 1,265 other siblings of HH patients, who are predominantly hemochromatosis heterozygotes (HHhet). Controls consisted of 1,338 spouse siblings in whom only the general population prevalence of HH homozygosity and heterozygosity existed. Odds ratios comparing HH strata to controls were elevated for serious illness (1.12 in HHhet, 1.71 in HHs), diabetes (0.78, 2.45), arthritis (2.10, 1.69), and hepatoma (1.06, 11.96). CONCLUSIONS: There was a significant trend for increased risk of serious illness among siblings of HH patients with increasing exposure to the HH gene, especially for diabetes, arthritis and hepatoma.

Arthritis↗

PubMed2000

Eosinophils maintain their capacity to signal and release eosinophil cationic protein upon repetitive stimulation with the same agonist.

Eosinophils contain in their granules eosinophil cationic protein (ECP) and other basic proteins that have been implicated in immunity to parasites and pathophysiology of chronic allergic responses. In a model of eosinophil degranulation, we show that eosinophils release ECP upon short-term GM-CSF priming and stimulation with either platelet-activating factor (PAF) or the anaphylatoxin C5a, but not eotaxin. Restimulation with the same agonist (PAF or C5a) was unsuccessful as assessed by monitoring intracellular calcium concentration and ECP release. In contrast, upon an intermediate washing step, eosinophils rapidly transduced PAF and C5a signals followed by significant ECP releases. Ligand-binding studies demonstrated that only a proportion of PAF receptors is internalized upon cell stimulation and that washing of the cells removes the agonist from the cell surface. Upon repetitive stimulation, eosinophils with less than 50% of the original ECP content were obtained. Such eosinophils did not increase cellular ECP levels even in the presence of the eosinophil survival factor GM-CSF in overnight cultures. In vivo studies revealed that eosinophils always express detectable amounts of ECP under chronic inflammatory conditions. In conclusion, we have shown that eosinophils maintain their capacity to degranulate upon repetitive stimulation with the same agonist as long as the receptor is not occupied from a previous stimulation. The cellular content of ECP appears to be a no limiting factor in the case of repetitive stimulation, implying that mature eosinophils may not require a significant ECP resynthesis.

Blood Proteins↗

PubMed2000

Neuroectodermal and endodermal expression of the ascidian Cdx gene is separated by metamorphosis.

Ascidians are a group of invertebrate chordates that exhibit a biphasic life history, with chordate-specific structures developing during embryogenesis (dorsal neural tube and notochord) and metamorphosis (pharyngeal gill slits and endostyle). Here we characterize the expression of a caudal/Cdx gene homologue, Hec-Cdx, from the ascidian Herdmania curvata. Vertebrate Cdx genes are expressed at gastrulation and in the posterior of the developing neural tube and endoderm. Hec-Cdx expression is initiated at the earliest stages of gastrulation, with peaks in RNA abundance occurring first during neurulation and tailbud extension and then in 3- to 5-day-old juveniles. Hec-Cdx is expressed in a pair of cells in the anterior lip of the blastopore in the late gastrula which form the most posterior portion of the neural plate. During tailbud formation expression is maintained in and solely restricted to these cells. During metamorphosis expression is localized to the intestine of the juvenile. These data, along with data for the H. curvata Otx gene, suggest that the evolution of the novel ascidian biphasic body plan was not accompanied by a deployment of these genes into new pathways but by a temporal separation of tissue-specific expression.

Amino Acid Sequence↗

PubMed2000

A comparison of different postures for scaffold end-frame disassembly.

Overexertion and fall injuries comprise the largest category of nonfatal injuries among scaffold workers. This study was conducted to identify the most favourable scaffold end-frame disassembly techniques and evaluate the associated slip potential by measuring whole-body isometric strength capability and required coefficient of friction (RCOF) to reduce the incidence of injury. Forty-six male construction workers were used to study seven typical postures associated with scaffold end-frame disassembly. An analysis of variance (ANOVA) showed that the isometric forces (334.4-676.3 N) resulting from the seven postures were significantly different (p < 0.05). Three of the disassembly postures resulted in considerable biomechanical stress to workers. The symmetric front-lift method with hand locations at knuckle height would be the most favourable posture; at least 93% of the male construction worker population could handle the end frame with minimum overexertion risk. The static RCOF value resulting from this posture during the disassembly phase was less than 0.2, thus the likelihood of a slip should be low.

Accidental Falls↗

PubMed2000

Nck-interacting Ste20 kinase couples Eph receptors to c-Jun N-terminal kinase and integrin activation.

The mammalian Ste20 kinase Nck-interacting kinase (NIK) specifically activates the c-Jun amino-terminal kinase (JNK) mitogen-activated protein kinase module. NIK also binds the SH3 domains of the SH2/SH3 adapter protein Nck. To determine whether Nck functions as an adapter to couple NIK to a receptor tyrosine kinase signaling pathway, we determined whether NIK is activated by Eph receptors (EphR). EphRs constitute the largest family of receptor tyrosine kinases (RTK), and members of this family play important roles in patterning of the nervous and vascular systems. In this report, we show that NIK kinase activity is specifically increased in cells stimulated by two EphRs, EphB1 and EphB2. EphB1 kinase activity and phosphorylation of a juxtamembrane tyrosine (Y594), conserved in all Eph receptors, are both critical for NIK activation by EphB1. Although pY594 in the EphB1R has previously been shown to bind the SH2 domain of Nck, we found that stimulation of EphB1 and EphB2 led predominantly to a complex between NIK/Nck, p62(dok), RasGAP, and an unidentified 145-kDa tyrosine-phosphorylated protein. Tyrosine-phosphorylated p62(dok) most probably binds directly to the SH2 domain of Nck and RasGAP and indirectly to NIK bound to the SH3 domain of Nck. We found that NIK activation is also critical for coupling EphB1R to biological responses that include the activation of integrins and JNK by EphB1. Taken together, these findings support a model in which the recruitment of the Ste20 kinase NIK to phosphotyrosine-containing proteins by Nck is an important proximal step in the signaling cascade downstream of EphRs.

Adaptor Proteins, Signal Transducing↗

PubMed1999

The biologically active iron chelators 2-pyridylcarboxaldehyde isonicotinoylhydrazone, 2-pyridylcarboxaldehyde benzoylhydrazone monohydrate and 2-furaldehyde isonicotinoylhydrazone.

In the crystal structures of the respective title compounds, C12H10N4O, C13H11N3O.H2O and C11H9N3O2, variations in the torsion angles of the aromatic pyridyl and benzoyl groups are observed, and the disposition of the heterocyclic aldehyde is shown to be influenced by the ring size of this group.

Crystallography, X-Ray↗

PubMed1999

Neurotrophins and their receptors in the tench retina during optic nerve regeneration.

To understand the role of neurotrophins in the visual system, we investigated the distribution of both neurotrophins and their receptors within the retina of a fish that has the capacity to spontaneously regenerate its optic nerve axons after lesion. Intact retinas and retinas from tench, whose optic nerve had been crushed, were analyzed by immunohistochemistry and in situ hybridization. Trk receptors were mainly immunolocalized in cells of the inner nuclear and ganglion cell layers, a distribution coincident with that of their mRNAs. Nerve growth factor (NGF) immunoreactivity was detected exclusively in Müller cell processes, and brain-derived neurotrophic factor (BDNF) was found in both neuronal bodies and Müller cell processes. Neurotrophin-3 (NT-3) was detected in most of the cell nuclei, and neurotrophin-4/5 (NT-4/5) was localized in fibers and in a few cells in the inner retina. An increase in both TrkA protein and mRNA was detected during axonal regeneration within the retinal ganglion cell layer, reaching a maximum 30 days postcrush and returning to normal levels by day 90, when optic nerve regeneration is almost completed in this fish. None of the other neurotrophins and receptors showed appreciable changes. The heterogeneous distribution patterns of neurotrophins and their receptors in fish retina, their differences from the distribution observed in other species, and the TrkA changes after optic nerve crush suggest an important role for these molecules in the normal physiology of the fish retina and during the regeneration process.

Animals↗

PubMed1999

A Drosophila TNF-receptor-associated factor (TRAF) binds the ste20 kinase Misshapen and activates Jun kinase.

Two families of protein kinases that are closely related to Ste20 in their kinase domain have been identified - the p21-activated protein kinase (Pak) and SPS1 families [1-3]. In contrast to Pak family members, SPS1 family members do not bind and are not activated by GTP-bound p21Rac and Cdc42. We recently placed a member of the SPS1 family, called Misshapen (Msn), genetically upstream of the c-Jun amino-terminal (JNK) mitogen-activated protein (MAP) kinase module in Drosophila [4]. The failure to activate JNK in Drosophila leads to embryonic lethality due to the failure of these embryos to stimulate dorsal closure [5-8]. Msn probably functions as a MAP kinase kinase kinase kinase in Drosophila, activating the JNK pathway via an, as yet, undefined MAP kinase kinase kinase. We have identified a Drosophila TNF-receptor-associated factor, DTRAF1, by screening for Msn-interacting proteins using the yeast two-hybrid system. In contrast to the mammalian TRAFs that have been shown to activate JNK, DTRAF1 lacks an amino-terminal 'Ring-finger' domain, and overexpression of a truncated DTRAF1, consisting of only its TRAF domain, activates JNK. We also identified another DTRAF, DTRAF2, that contains an amino-terminal Ring-finger domain. Msn specifically binds the TRAF domain of DTRAF1 but not that of DTRAF2. In Drosophila, DTRAF1 is thus a good candidate for an upstream molecule that regulates the JNK pathway by interacting with, and activating, Msn. Consistent with this idea, expression of a dominant-negative Msn mutant protein blocks the activation of JNK by DTRAF1. Furthermore, coexpression of Msn with DTRAF1 leads to the synergistic activation of JNK. We have extended some of these observations to the mammalian homolog of Msn, Nck-interacting kinase (NIK), suggesting that TRAFs also play a critical role in regulating Ste20 kinases in mammals.

Amino Acid Sequence↗

PubMed1999

Development of novel aroylhydrazone ligands for iron chelation therapy: 2-pyridylcarboxaldehyde isonicotinoyl hydrazone analogs.

Previous studies have demonstrated that aroylhydrazone iron (Fe) chelators of the pyridoxal isonicotinoyl hydrazone (PIH) class have high Fe chelation efficacy both in vitro and in vivo. Depending on their design, these drugs may have potential as agents for the treatment of Fe overload disease or cancer. Considering the high potential of this class of ligands, we have synthesized seven novel aroylhydrazones in an attempt to identify Fe chelators more efficient than desferrioxamine (DFO) and more soluble than those of the PIH class. These compounds belong to a new series of tridentate chelators known as the 2-pyridylcarboxaldehyde isonicotinoyl hydrazones (PCIH). In this study we have examined the Fe chelation efficacy and antiproliferative activity of these chelators including their effects on the expression of genes (WAF1 and GADD45) known to be important in mediating cell cycle arrest at G1/S. From seven chelators synthesized, three ligands, namely 2-pyridylcarbox-aldehyde benzoyl hydrazone (PCBH), 2-pyridylcarboxaldehyde m-bromobenzoyl hydrazone (PCBBH), and 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone (PCTH), showed greater Fe chelation activity than DFO and comparable or greater efficiency than PIH. These ligands were highly effective at both mobilizing 59Fe from cells and preventing 59Fe uptake from 59Fe-transferrin and caused a marked increase in the RNA-binding activity of the iron-regulatory proteins (IRP). Our studies have also demonstrated that compared with the cytotoxic Fe chelator, 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), these ligands have far less effect on cellular growth and 3H-thymidine, 3H-leucine, or 3H-uridine incorporation. In addition, in contrast to 311, which markedly increased WAF1 and GADD45 mRNA expression, PCBH and PCTH did not have any effect, whereas PCBBH increased the expression of GADD45 mRNA. Collectively, these results demonstrate the potential of several of these ligands as agents for the management of Fe overload disease.

Biological Transport, Active↗

PubMed1998

Increased levels of TrkA in the regenerating retinal ganglion cells of fish.

Retinal ganglion cells of the fish have the spontaneous capacity to regenerate after nerve crush, a phenomenon known to be facilitated by nerve growth factor (NGF). We have studied the high-affinity NGF receptor TrkA, during the regeneration of the tench (Tinca tinca L.) optic nerve, using immunocytochemical techniques. TrkA-like immunoreactivity increased during the regeneration of the retinal ganglion cells. The increase is followed by a change in the subcellular distribution from perinuclear in control cells to cytoplasmic and perinuclear in regenerating ones. This increase was observed when antibodies against the extracellular domain of TrkA were used; no changes in TrkA-like immunoreactivity were observed with antibodies against the intracellular domain of TrkA. We thus conclude that modulation of TrkA is involved in the regeneration of fish retinal ganglion cells.

3T3 Cells↗

PubMed1998

Development of survival responsiveness to brain-derived neurotrophic factor, neurotrophin 3 and neurotrophin 4/5, but not to nerve growth factor, in cultured motoneurons from chick embryo spinal cord.

During embryonic development, most neuronal populations undergo a process usually referred to as naturally occurring neuronal death. For motoneurons (MTNs) of the lumbar spinal cord of chick embryos, this process takes place in a well defined period of time, between embryonic days 6 and 10 (E6-E10). Neurotrophins (NTs) are the best characterized family of neurotrophic factors and exert their effects through activation of their specific Trk receptors. In vitro and in vivo studies have demonstrated that rodent motoneurons survive in response to BDNF, NT3, and NT4/5. In contrast, the trophic dependencies of chicken motoneurons have been difficult to elucidate, and various apparently conflicting reports have been published. In the present study, we describe how freshly isolated motoneurons from E5.5 chick embryos did not respond to any neurotrophin in vitro. Yet, because motoneurons were maintained alive in culture in the presence of muscle extract, they developed a delayed specific survival response to BDNF, NT3, and NT4/5 that is clearly dose-dependent, reaching saturation at doses of 100 pg/ml. This trophic response correlated with increasing expression of the corresponding functional receptors TrkB and TrkC. Moreover, TrkB receptor is able to become autophosphorylated and to activate classical intracellular signaling pathways such as the extracellular signal-regulated protein kinase when it is stimulated with its cognate ligand BDNF. Therefore, our results reconcile the reported differences between in vivo and in vitro studies on the ability of chicken MTNs to respond to some members of the neurotrophin family of trophic factors.

Animals↗

PubMed1998

Cell cycle phase-specific surface expression of nerve growth factor receptors TrkA and p75(NTR).

Expression of the nerve growth factor (NGF) receptors TrkA and p75(NTR) was found to vary at the surface of PC12 cells in a cell cycle phase-specific manner. This was evidenced by using flow cytometric and microscopic analysis of cell populations labeled with antibodies to the extracellular domains of both receptors. Differential expression of these receptors also was evidenced by biotinylation of surface proteins and Western analysis, using antibodies specific for the extracellular domains of TrkA and p75(NTR). TrkA is expressed most strongly at the cell surface in M and early G1 phases, whereas p75(NTR) is expressed mainly in late G1, S, and G2 phases. This expression reflects the molecular and cellular responses to NGF in specific phases of the cell cycle; in the G1 phase NGF elicits both the anti-mitogenic effect, i.e., inhibition of the G1 to S transition, and the differentiation response whereas a survival effect is provoked elsewhere in the cell cycle. A model is proposed relating these responses to the surface expression of the two receptors. These observations open the way for novel approaches to the investigation of the mechanism of NGF signal transduction.

Animals↗