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Selected Abstracts1140915445 Increased numbers of FoxP3+ cells in vaginal mucus from normal pregnant mice suggest early antigen-specific tolerance mechanism during pregnancyAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2006C Thuere The fetal survival within the maternal uterus is thought to be due to a transient immunological tolerance, being CD4+CD25+ T regulatory cells (Tregs) crucial players. Former studies confirmed diminished total numbers of this unique population in abortion-prone mice (DBA/2J-mated CBA/J females) as compared to a control with normal pregnancy outcome (BALB/c-mated CBA/J females) and suggested that Tregs act in an antigen-specific fashion. This hypothesis led us to investigate the kinetics of Tregs during pregnancy (day 0, 2, 5, 8, 10 or 12 of pregnancy) in abortion-prone mice and the control group. Our data confirmed diminished number of Tregs in immunological relevant organs such as lymph nodes and thymus within the abortion-prone mice. The enormous augmentation in the number of FoxP3+ cells in vaginal mucus already on day 0.5 after conception, followed by increased Tregs levels at early pregnancy stages, suggest, that Tregs need to be activated by male antigens for being protective. Notably, the abortion-prone mice displayed again a lower total amount of Tregs as compared to the control. Similar progesterone levels in spite of different pregnancy outcome reinforce the theory of antigen specificity of pregnancy-induced Tregs. The antigen presentation would take place in the periphery e.g. in vaginal mucus, the first site of contact with paternal antigens, directly after insemination. Interestingly the transfer of Tregs from normal pregnant mice at this time point prevented fetal rejection. Our results suggest the crucial role of Tregs already shortly after conception. [source] Using the SWAP-200 in a personality-disordered forensic population: is it valid, reliable and useful?CRIMINAL BEHAVIOUR AND MENTAL HEALTH, Issue 1 2005Luisa E. Marin-Avellan Background Treatment and risk management of forensic patients relies heavily on diagnosing psychopathology, yet the reliability of clinical diagnoses of personality disorder has been found to be only fair to low. Structured instruments for the global assessment of personality disorder are infrequently used in clinical assessments possibly due to their limited validity and clinical utility. Aims/methods The Shedler-Westen Assessment Procedure-200 (SWAP-200) was developed in an effort to address these limitations. Although good reliability and validity in relation to clinicians' diagnosis of personality disorder has been reported, to date the validity of this instrument has not been assessed in relation to other standardized instruments or in a personality-disordered, forensic population. This study aims to establish the reliability and validity of the SWAP-200 against other diagnostic instruments and measures of interpersonal functioning in a personality disordered forensic population. Results This paper reports the results of 30 subjects from a high secure hospital in the UK who were assessed with the SWAP-200, the Structured Clinical Interview for DSM-IV Personality Disorders (SCID-II), the Adult Attachment Interview (AAI) and the Chart of Interpersonal Reactions in Closed Living Environments (CIRCLE). Preliminary results suggest that the SWAP-200 is a reliable instrument for the diagnosis of personality disorder in forensic patients. Conclusions Although the small sample size allows only preliminary conclusions about the validity of this instrument, early results show a reduction of the diagnosis of comorbidity compared with the SCID-II, together with an increased number of expected associations between independent measures of interpersonal functioning and categories of personality disorder. Copyright © 2005 Whurr Publishers Ltd. [source] Risk evaluation and type of treatment of multiple dental trauma episodes to permanent teethDENTAL TRAUMATOLOGY, Issue 5 2000U. Glendor Abstract , Studies have shown that some children and adolescents are effected only once with a dental trauma, while others seem to be accident-prone and suffer from multiple dental trauma episodes (MDTE). Studies have also shown that dental traumas mostly affect upper permanent and medial incisors. Less is known about treatment consequences related to teeth with repeated dental trauma episodes. The aim was therefore to evaluate the risk of MDTE to permanent teeth among children and adolescents by age and gender and to compare types of dental treatment modalities used for patients with one episode and those with MDTE and with single and repeated traumatized teeth. The study was based on a random sample of 83 Danish 6,18-year-old children and adolescents born in 1970 who suffered from dental trauma episodes. All patients were followed during a 12-year period (1976,1988). Forty-one of the patients were registered with MDTE with a range of 2,7 episodes and a mean of 2.9 episodes/patient (SD=1.1). The mean age at single and MDTE was 11.4 years (SD=3.6) and 8.6 years (SD=2.1), respectively. No significant differences were found between age at first episode and the number of MDTE per patient. The number of patients with MDTE was significantly higher among those who suffered their first trauma episode in the age interval 6,10 years than in the age interval 11,18 years (P<0.001). A survival analysis showed that the risk of sustaining another trauma episode increased by 14.9,30.3% when the first trauma occurred before the age of 11, compared to 0,7.4% after the age of 10. The risk of sustaining multiple injuries was 8.4 times higher when the first trauma episode occurred at 9 years of age, compared with those occurring at age 12. The survival analysis also showed that for every new trauma episode, the interval between them became closer. Forty-five per cent of the MDTE affected teeth had already sustained an injury. With an increased number of trauma episodes per patient followed an increase in the number of follow-ups, filling therapy, information and prosthetics, whereas the rates of endodontics, surgery, and consultations were unchanged or even decreased. [source] The histopathology of alopecia areata in vertical and horizontal sectionsDERMATOLOGIC THERAPY, Issue 4 2001David A. Whiting Alopecia areata (AA) is a relatively common disease affecting 1.7% of Americans by the age of 50 years. The diagnosis is usually made on clinical grounds. In some cases the diagnosis is elusive and biopsies are necessary. In other cases biopsies are useful from a prognostic point of view to determine whether there are enough follicles left for possible future regrowth. In view of the active research being conducted into AA, biopsies provide valuable material for further investigation. The diagnosis of AA is improved by the use of horizontal sections in addition to or instead of vertical sections of scalp biopsies. The histopathologic features favoring the diagnosis of AA include peribulbar and intrabulbar mononuclear infiltrates, degenerative changes in the hair matrix, decreased numbers of terminal anagen follicles, increased numbers of terminal catagen and telogen follicles, an increased number of follicular stelae, an increased number of miniaturized vellus hair follicles, and pigment incontinence of hair bulbs and follicular stelae. Follicular counts with horizontal sections are particularly helpful in making the diagnosis of AA when the biopsy has been taken between acute episodes and the characteristic peribulbar inflammatory infiltrate is absent. [source] Increased number of offspring in first degree relatives of psychotic individuals: a partial explanation for the persistence of psychotic illnessesACTA PSYCHIATRICA SCANDINAVICA, Issue 6 2009M. Weiser Objective:, As patients with psychotic illness have fewer offspring than controls, the persistence of psychotic illness is puzzling. We hypothesized that unaffected first-degree relatives of patients have more offspring than controls. Method:, Probands were 4904, individuals with non-affective psychotic disorders identified from a hospitalization registry. Unaffected first degree relatives and matched controls were identified from the Israeli Population Registry. The number of offspring of unaffected parents, biological siblings and controls was ascertained. Results:, Unaffected parents of psychotic patients had more offspring/person than controls; 4.5 ± 2.7 vs. 3.4 ± 2.2, P = 0.000. Unaffected parents from familial psychosis families (more than one affected family member) had 1.83 more offspring than controls; unaffected parents from non-familial psychosis families had 0.97 more offspring than controls (both P < 0.001). Conclusion:, These findings might imply that genes which increase susceptibility for schizophrenia may be associated with increased number of offspring, perhaps supplying a partial explanation for the persistence of psychosis. [source] Degradation in insulin sensitivity with increasing severity of the metabolic syndrome in obese postmenopausal womenDIABETES OBESITY & METABOLISM, Issue 3 2006A. D. Karelis Aim:, We investigated the relationship between insulin sensitivity and the graded increase in the number of features of the metabolic syndrome in a cross-sectional sample of obese postmenopausal women. We hypothesized that insulin sensitivity would deteriorate with an increased number of metabolic syndrome phenotypes. Methods:, Insulin sensitivity was measured in 75 obese postmenopausal women (age: 57.3 ± 5.3 years; BMI: 32.8 ± 4.5 kg/m2) by using both the hyperinsulinaemic,euglycaemic clamp and the homeostasis model assessment (HOMA-IR). Features of the metabolic syndrome included visceral fat (>130 cm2), HDL-cholesterol (<1.29 mmol/l), fasting triglycerides (,1.7 mmol/l), blood pressure (,130/,85 mmHg) and fasting glucose (,6.1 mmol/l). Participants were classified into three categories based on the presence of metabolic syndrome phenotypes: 0,1 vs. 2 vs. ,3 features of the metabolic syndrome. Results:, We found that insulin sensitivity decreased in a graded fashion (12.19 ± 3.2 vs. 11.80 ± 2.3 vs. 9.29 ± 2.6 mg/min/FFM) and HOMA-IR increased in a similar manner (2.95 ± 1.1 vs. 3.28 ± 1.3 vs. 4.65 ± 2.2), as the number of features of the metabolic syndrome increased from 0,1 to ,3. When insulin sensitivity was statistically adjusted for visceral fat (as measured by computed tomography) and plasma triglycerides, the differences among groups were abolished. Conclusions:, These findings suggest that a decreased insulin sensitivity is associated with increased features of the metabolic syndrome in obese postmenopausal women and that visceral fat as well as plasma triglyceride accumulation might be potential mediators of this relationship. [source] Effects of acute hyperglycaemia on anorectal motor and sensory function in diabetes mellitusDIABETIC MEDICINE, Issue 2 2004A. Russo Abstract Aims To determine the effects of acute hyperglycaemia on anorectal motor and sensory function in patients with diabetes mellitus. Methods In eight patients with Type 1, and 10 patients with Type 2 diabetes anorectal motility and sensation were evaluated on separate days while the blood glucose concentration was stabilized at either 5 mmol/l or 12 mmol/l using a glucose clamp technique. Eight healthy subjects were studied under euglycaemic conditions. Anorectal motor and sensory function was evaluated using a sleeve/sidehole catheter, incorporating a barostat bag. Results In diabetic subjects hyperglycaemia was associated with reductions in maximal (P < 0.05) and plateau (P < 0.05) anal squeeze pressures and the rectal pressure/volume relationship (compliance) during barostat distension (P < 0.01). Hyperglycaemia had no effect on the perception of rectal distension. Apart from a reduction in rectal compliance (P < 0.01) and a trend (P = 0.06) for an increased number of spontaneous anal sphincter relaxations, there were no differences between the patients studied during euglycaemia when compared with healthy subjects. Conclusions In patients with diabetes, acute hyperglycaemia inhibits external anal sphincter function and decreases rectal compliance, potentially increasing the risk of faecal incontinence. Diabet. Med. 21, 176,182 (2004) [source] Cytologic diagnosis of pancreatic endocrine tumors by endoscopic ultrasound-guided fine-needle aspiration: A reviewDIAGNOSTIC CYTOPATHOLOGY, Issue 9 2006Fuju Chang M.D., Ph.D. Abstract Precise localization and diagnosis of pancreatic endocrine tumors (PETs) is important, because pancreatic PETs have different clinical and biological behavior and treatment modalities than do exocrine pancreatic tumors. In contrast to the much more common exocrine adenocarcinomas, cytologic studies of PET are relatively rare and many cytopathologists lack experience with the cytomorphologic features of these tumors. During the last 10 yr, endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) has matured into an accurate, highly sensitive, and cost-effective modality for the preoperative localization of pancreatic PETs. This has resulted in an increased number of PETs first sampled as cytology specimens. This manuscript focuses on the cytomorphologic features most suggestive of pancreatic PETs, differential diagnosis, and diagnostic pitfalls of PETs. The technical development of EUS-guided FNA and the ancillary studies for pancreatic PETs are also reviewed. The data summarized in this review indicate that EUS-FNA is a valuable method in the recognition of pancreatic PETs and in most cases cytopathologists could reach a correct diagnosis of these tumors, including their hormone producing capability on aspirated cytologic material. Diagn. Cytopathol. 2006;34:649,658. © 2006 Wiley-Liss, Inc. [source] The capacity of Australian ED to absorb the projected increase in intern numbersEMERGENCY MEDICINE AUSTRALASIA, Issue 2 2010Anthony Chong Abstract As a reaction to the medical workforce shortage in Australia, a large expansion of undergraduate medical education has occurred through the provision of funding of additional medical student places. As a consequence, the number of medical graduates is anticipated to increase by as much as 90% with a peak in numbers anticipated in 2012. With ED already under pressure, this increase has serious implications for ED, particularly the delivery of intern and student teaching. This integrated review describes potential challenges that might arise from the predicted increase in intern numbers working in ED. A structured literature search was conducted from which 44 directly relevant articles were identified. We discuss the possible impact of an increased number of medical graduates on emergency medical staff, education, supervision and feedback to interns, and given the potential impacts on the education of junior doctors; we review the purpose and implementation of the Australian Curriculum framework for Junior Doctors in relation to their learning requirements. Although there is consensus by most postgraduate bodies that the core emergency term in emergency medicine should be retained, the impact of increased intern numbers might dramatically affect the clinical experiences, supervision and educational resources in the ED. This might necessitate cultural changes in medical education and ED function. [source] Pharmaceutical metabolites in the environment: Analytical challenges and ecological risks,ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 12 2009Mary D. Celiz Abstract The occurrence of human and veterinary pharmaceuticals in the environment has been a subject of concern for the past decade because many of these emerging contaminants have been shown to persist in soil and water. Although recent studies indicate that pharmaceutical contaminants can pose long-term ecological risks, many of the investigations regarding risk assessment have only considered the ecotoxicity of the parent drug, with very little attention given to the potential contributions that metabolites may have. The scarcity of available environmental data on the human metabolites excreted into the environment or the microbial metabolites formed during environmental biodegradation of pharmaceutical residues can be attributed to the difficulty in analyzing trace amounts of previously unknown compounds in complex sample matrices. However, with the advent of highly sensitive and powerful analytical instrumentations that have become available commercially, it is likely that an increased number of pharmaceutical metabolites will be identified and included in environmental risk assessment. The present study will present a critical review of available literature on pharmaceutical metabolites, primarily focusing on their analysis and toxicological significance. It is also intended to provide an overview on the recent advances in analytical tools and strategies to facilitate metabolite identification in environmental samples. This review aims to provide insight on what future directions might be taken to help scientists in this challenging task of enhancing the available data on the fate, behavior, and ecotoxicity of pharmaceutical metabolites in the environment. [source] Airway inflammation in Michigan pleasure horses: prevalence and risk factorsEQUINE VETERINARY JOURNAL, Issue 4 2006N. E. Robinson Summary Reasons for performing study: Although subclinical airway inflammation is thought to be common in horses, there is little information on its prevalence and none on risk factors. Objective: To determine the prevalence and risk factors for an increased number of inflammatory cells and for mucus accumulation in the trachea of pleasure horses. Methods: Horses (n = 266) in stables (n = 21) in Michigan were examined endoscopically, once in winter and once in summer 2004. Visible tracheal mucoid secretions were graded 0,5 and inflammatory cell numbers counted in a tracheal lavage sample. Information collected about each horse included age, gender, presence of cough, percent time indoors and source of roughage. The repeated measures were analysed by generalised estimating equations and linear mixed models. Results: Horses eating hay, especially from round bales, had the most neutrophils, whereas horses feeding from pasture had the fewest. Being female and being outdoors in winter were associated with increased numbers of inflammatory cells. Older horses had fewer macrophages than young horses. More than 70% of horses had >20% neutrophils in tracheal lavage. Twenty percent of horses had a mucus accumulation score >1; 17% had both a mucus score >1 and >20% neutrophils. The significant risk factors for mucus accumulation >1 were age >15 years, feeding on hay as compared to pasture, and being outdoors for more than 80% time in winter. Even though mucus accumulation score >1 was a risk factor for cough, only half of such horses coughed. Cough and mucus accumulation were associated with increased number of neutrophils. Conclusions: In comparison to pasture feeding, hay feeding, particularly from round bales, was associated with an increased number of neutrophils in the airway. Being outdoors in winter was associated with increased numbers of inflammatory cells and with mucus accumulation. Because 70% of horses have >20% neutrophils, this value should not be used as the sole indicator of airway inflammation. Potential relevance: The study reinforces the importance of hay feeding and older age as risk factors for inflammatory airway disease. Horses that do not have ,heaves' may be best kept indoors when winters are cold. [source] Iron enhances endothelial cell activation in response to Cytomegalovirus or Chlamydia pneumoniae infectionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 10 2006A. E. R. Kartikasari Abstract Background, Chronic inflammation has been implemented in the pathogenesis of inflammatory diseases like atherosclerosis. Several pathogens like Chlamydia pneumoniae (Cp) and cytomegalovirus (CMV) result in inflammation and thereby are potentially artherogenic. Those infections could trigger endothelial activation, the starting point of the atherogenic inflammatory cascade. Considering the role of iron in a wide range of infection processes, the presence of iron may complicate infection-mediated endothelial activation. Materials and methods, Endothelial intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelial selectin (E-selectin) expression were measured using flow cytometry, as an indication of endothelial activation. Cytotoxicity was monitored using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Immunostaining was applied to measure Cp and CMV infectivity to endothelial cells. Results, An increased number of infected endothelial cells in a monolayer population leads to a raised expression of adhesion molecules of the whole cell population, suggesting paracrine interactions. Iron additively up-regulated Cp-induced VCAM-1 expression, whereas synergistically potentiated Cp-induced ICAM-1 expression. Together with CMV, iron also enhanced ICAM-1 and VCAM-1 expression. These iron effects were observed without modulation of the initial infectivity of both microorganisms. Moreover, the effects of iron could be reversed by intracellular iron chelation or radical scavenging, conforming modulating effects of iron on endothelial activation after infections. Conclusions, Endothelial response towards chronic infections depends on intracellular iron levels. Iron status in populations positive for Cp or CMV infections should be considered as a potential determinant for the development of atherosclerosis. [source] PRECLINICAL STUDY: FULL ARTICLE: Repeated ethanol administration modifies the temporal structure of sucrose intake patterns in mice: effects associated with behavioral sensitizationADDICTION BIOLOGY, Issue 3 2010Raúl Pastor ABSTRACT Neuroadaptations supporting behavioral sensitization to abused drugs are suggested to underlie pathological, excessive motivation toward drugs and drug-associated stimuli. Drug-induced sensitization has also been linked to increased appetitive responses for non-drug, natural reinforcers. The present research investigated whether ethanol (EtOH)-induced neural changes, inferred from psychomotor sensitization, can modify consumption and intake dynamics for the natural reinforcer, sucrose. The effects of EtOH-induced sensitization in mice on the temporal structure of sucrose intake patterns were measured using a lickometer system. After sensitization, sucrose intake dynamics were measured for 1 hour daily for 7 days and indicated more rapid initial approach and consumption of sucrose in EtOH-sensitized groups; animals showed a shorter latency to the first intake bout and an increased number of sucrose bottle licks during the initial 15 minutes of the 1-hour sessions. This effect was associated with increased frequency and size of bouts. For the total 1-hour session, sucrose intake and bout dynamics were not different between groups, indicating a change in patterns of sucrose intake but not total consumption. When sensitization was prevented by the ,-aminobutyric acid B receptor agonist, baclofen, the increased rate of approach and consumption of sucrose were also prevented. Thus, EtOH-induced sensitization, and not the mere exposure to EtOH, was associated with changes in sucrose intake patterns. These data are consistent with current literature suggesting an enhancing effect of drug-induced sensitization on motivational processes involved in reinforcement. [source] CCL17 transgenic mice show an enhanced Th2-type response to both allergic and non-allergic stimuliEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2006Yuichiro Tsunemi Dr. Abstract CC chemokine ligand (CCL)17 is implicated in the pathogenesis of atopic dermatitis (AD). To study the effect of CCL17 produced by keratinocytes (KC) during inflammation, we created transgenic (Tg) mice in which CCL17 is overexpressed in KC. Th2-type contact hypersensitivity (CHS) was enhanced and Th1-type CHS was suppressed in these mice. Increased numbers of CC chemokine receptor (CCR)4+ cells and mast cells infiltrated in Tg mice. Levels of IL-4 mRNA were higher and those of IFN-, mRNA were lower in both acute and chronic CHS. Higher levels of serum IgE were observed after CHS. Numbers of CCR4+ cells among PBMC were increased in Tg mice challenged acutely on the trunk. Chronic irritation with croton oil induced dermatitis and an elevation of serum IgE levels. Tg mice showed enhanced ear swelling after tape stripping. CCL17 was thought to modify the inflammation caused by sensitizing reagents as well as irritant reagents by attracting CCR4+ cells into the lesional skin and creating a Th2-dominant condition. AD-like conditions such as increased number of mast cells and elevated levels of serum IgE were observed. Thus, CCL17 may participate in the pathogenesis of skin diseases such as AD by regulating both allergic and irritant inflammation. [source] Metabolic syndrome and three of its components as risk factors for recurrent ischaemic stroke presenting as large-vessel infarctionEUROPEAN JOURNAL OF NEUROLOGY, Issue 8 2008C.-W. Liou Background and purpose:, Although a clear protocol for reduction of recurrent ischaemic stroke (RIS) has been established, few studies have compared the stroke subtype distribution and risk factors between RIS and first-ever stroke (FES). Methods:, This one-year hospital-based study enrolled 587 FES and 475 RIS patients. Patients were categorized into four stroke subtypes according to a modified TOAST stroke subtype classification system. Risk factor profiles were compared between the two major stroke groups and between the corresponding four subtypes to discriminate the significant risk factors for RIS. Results:, A multivariate regression analysis identified hypertension (OR, 1.87; 95% CI, 1.34,2.62), diabetes mellitus (DM) (OR, 1.57; 95% CI, 1.22,2.02), low high-density lipoprotein (LHDL) (OR, 1.43; 95% CI, 1.08,1.88) and older age as significant RIS risk factors. The significance of the former three RIS factors was further recognized in its large-vessel subtype. Moreover, metabolic syndrome was significantly more common in the recurrent stroke group (P = 0.01), including its large-vessel subtype (P = 0.04). Progressively increasing odds ratios from 1.49 to 2.02, in accordance with increased number of diagnostic components of metabolic syndrome for recurrent large-vessel ischaemic stroke, were noted. Conclusions:, Metabolic syndrome likely plays a crucial role in the development of RIS, including large-vessel infarction in modern-day Taiwan. [source] Functional dentate gyrus neurogenesis in a rapid kindling seizure modelEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2006Paul D. Smith Abstract Neurogenesis in the adult mammalian hippocampus resulting in long-term persistence of new neurons with features of capacity for functional activation is recognized. Many stimuli are capable of increasing the rate of neurogenesis, including seizure activity. Whether these insults result in an increased number of new functionally active neurons over and above the baseline rate of neurogenesis is not known. The rapid electrical amygdala kindling (REAK) model of seizures isolates the effects of seizures alone in the absence of neuronal death and the resulting seizures induce expression of c-Fos in the vast majority of dentate gyrus (DG) granule cells. C57BL/6 mice were exposed to REAK then injected with bromodeoxyuridine (BrDU) to label dividing cells, then re-exposed to REAK after a delay period to allow detection of functional activation in new neurons by measurement c-Fos expression in response to seizures. Adult subgranular zone cells migrated into the DG granule cell layer (GCL), assumed a neuronal phenotype and demonstrated seizure-dependent responsiveness. Larger absolute numbers of new neurons demonstrating seizure-dependent activation were found in the GCL of previously kindled mice. Seizures are capable of increasing the number of new neurons with the capacity for functional activation laid down in the postseizure period and incorporated into seizure-activated circuitry. [source] Genetic engineering of mouse embryonic stem cells by Nurr1 enhances differentiation and maturation into dopaminergic neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2002Sangmi Chung Abstract Nurr1 is a transcription factor critical for the development of midbrain dopaminergic (DA) neurons. This study modified mouse embryonic stem (ES) cells to constitutively express Nurr1 under the elongation factor-1, promoter. The Nurr1-expression in ES cells lead to up-regulation of all DA neuronal markers tested, resulting in about a 4- to 5-fold increase in the proportion of DA neurons. In contrast, other neuronal and glial markers were not significantly changed by Nurr1 expression. It was also observed that there was an additional 4-fold increase in the number of DA neurons in Nurr1-expressing clones following treatment with Shh, FGF8 and ascorbic acid. Several lines of evidence suggest that these neurons may represent midbrain DA neuronal phenotypes; firstly, they coexpress midbrain DA markers such as aromatic l -amino acid decarboxylase, calretinin, and dopamine transporter, in addition to tyrosine hydroxylase and secondly, they do not coexpress other neurotransmitters such as GABA or serotonin. Finally, consistent with an increased number of DA neurons, the Nurr1 transduction enhanced the ability of these neurons to produce and release DA in response to membrane depolarization. This study demonstrates an efficient genetic manipulation of ES cells that facilitates differentiation to midbrain DA neurons, and it will serve as a framework of genetic engineering of ES cells by key transcription factor to regulate their cell fate. [source] Injury induced c-Jun expression and phosphorylation in the dopaminergic nigral neurons of the rat: correlation with neuronal death and modulation by glial-cell-line-derived neurotrophic factorEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2001Elisabetta Vaudano Abstract This study was designed to determine whether induction and phosphorylation of the transcription factor c-Jun is associated with lesion-induced death of dopaminergic neurons of the substantia nigra pars compacta, and if this cellular response is modulated by glial-cell-line-derived neurotrophic factor. In adult rats, delayed dopaminergic neuron cell death induced by intrastriatal 6-hydroxydopamine injection led to a marked increase in the number of both c-Jun- and phosphorylated c-Jun-immunoreactive nuclei in the substantia nigra pars compacta. The response was maximal before any significant loss of nigral neurons could be detected (on day 7 post lesion) and was confined to the dopaminergic neurons. Similarly, 6-hydroxydopamine lesion of the striatal dopaminergic terminals or excitotoxic lesion of the striatal target neurons in neonatal rats resulted in an increased number of c-Jun- and phosphorylated c-Jun-immunoreactive nigral nuclei that preceded the loss of nigral dopaminergic neurons. By contrast, after an excitotoxic lesion of the striatal target neurons in the adult rat, resulting in atrophy but not cell death of the nigral dopaminergic neurons, no upregulation of either c-Jun or phosphorylated c-Jun was found. A single injection of 10 µg of glial-cell-line-derived-neurotrophic factor given at day 3 after the intrastriatal 6-hydroxydopamine lesion reduced the number of c-Jun- and phosphorylated c-Jun-immunoreactive nuclei in the substantia nigra and protected the dopaminergic neurons from the ensuing cell death. We conclude that c-Jun induction and phosphorylation may be involved in the cellular events leading to death of nigral dopaminergic neurons in vivo and that this response can be modulated by glial-cell-line-derived-neurotrophic factor. [source] Enlarged cholinergic forebrain neurons and improved spatial learning in p75 knockout miceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2000Ursula Greferath Abstract The p75 low affinity neurotrophin receptor (p75) can induce apoptosis in various neuronal and glial cell types. Because p75 is expressed in the cholinergic neurons of the basal forebrain, p75 knockout mice may be expected to show an increased number of neurons in this region. Previous studies, however, have produced conflicting results, suggesting that genetic background and choice of control mice are critical. To try to clarify the conflicting results from previous reports, we undertook a further study of the basal forebrain in p75 knockout mice, paying particular attention to the use of genetically valid controls. The genetic backgrounds of p75 knockout and control mice used in this study were identical at 95% of loci. There was a small decrease in the number of cholinergic basal forebrain neurons in p75 knockout mice at four months of age compared with controls. This difference was no longer apparent at 15 months due to a reduction in numbers in control mice between the ages of 4 and 15 months. Cholinergic cell size in the basal forebrain was markedly increased in p75 knockout mice compared with controls. Spatial learning performance was consistently better in p75 knockout mice than in controls, and did not show any deterioration with age. The results indicate that p75 exerts a negative influence on the size of cholinergic forebrain neurons, but little effect on neuronal numbers. The markedly better spatial learning suggests that the function, as well as the size, of cholinergic neurons is negatively modulated by p75. [source] Infiltrating cells and related cytokines in lesional skin of patients with chronic idiopathic urticaria and positive autologous serum skin testEXPERIMENTAL DERMATOLOGY, Issue 5 2003M. Caproni Abstract:, In approximately one-third of patients with chronic idiopathic urticaria (CIU), autoantibodies against the high-affinity IgE receptor and/or against IgE can be detected and a wheal-and-flare response can be provoked by the intradermal injection of autologous serum (ASST). In this study we aimed to further characterize the inflammatory response observed in the subgroup of CIU patients with positive ASST and serum-evoked histamine-release in vitro from basophils in comparison with unaffected skin and healthy donors. An immunohistochemical analysis of infiltrating cells (CD4, MPO, EG1, EG2, tryptase), cytokines (IL-4, IL-5, IFN-,), chemokines and chemokine receptors (IL-8, CCR3, CXCR3), and adhesion molecules (ICAM-1, VCAM-1, ELAM-1) was performed on seven selected patients (four males and three females; median age: 45 years; range: 22,57) and five healthy donors. Cytokine evaluation was also performed in five psoriatic patients to obtain an additional control. In spontaneous wheals we observed an increased number of CD4+ T lymphocytes when compared with the controls, and an increased number of neutrophils and eosinophils, whereas mast cells did not show a significant variation. A significant expression for IL-4 and IL-5 could only be observed in lesional skin, while IFN-, showed a slight expression in the same site. Chemokine receptors CCR3 and CXCR3 did not show a defined polarized response in either lesional or unaffected skin. An increased expression of all cellular adhesion molecules (CAMs) studied was detected in spontaneous wheals. The lack of a significant difference in the expression of tryptase + mast cells, T lymphocytes, IL-8, CXCR3 and CCR3, a few CAMs between the lesional and unaffected skin of CIU patients suggests a wide immunological activation that involves not only lesional tissues, but possibly extends to the whole of the skin's immune system. [source] Prevalence and diversity of insertion sequences in the genome of Bacillus thuringiensis YBT-1520 and comparison with other Bacillus cereus group membersFEMS MICROBIOLOGY LETTERS, Issue 1 2010Ning Qiu Abstract Members of the Bacillus cereus group are closely related bacteria that exhibit highly divergent pathogenic properties. Sequencing of Bacillus thuringiensis ssp. kurstaki strain YBT-1520 revealed an increased number of insertion sequences (ISs) compared with those of the published B. cereus group genomes. Although some of these ISs have been observed and summarized in B. thuringiensis previously, a genomic characterization of their content is required to reveal their distribution and evolution. The result shows that the larger number of transposase coding genes on YBT-1520 chromosome is mainly caused by the amplification of IS231C, IS232A and ISBth166. Some functional genes have been disrupted through the insertion of ISs, preferentially IS231C. By comparing the Southern hybridization profiles of different B. thuringiensis strains, the existence of ISBth166 was mainly found in serovar kurstaki and the recent expansion of IS231C between different kurstaki isolates was suggested. In addition to revealing the ISs profile in YBT-1520 as well as the comparison in the B. cereus group, this study will contribute to further comparative analyses of multiple B. thuringiensis strains aimed at understanding the IS-mediated genomic rearrangements among them. [source] A statistical method for scanning the genome for regions with rare disease allelesGENETIC EPIDEMIOLOGY, Issue 5 2010Chad GarnerArticle first published online: 21 JUN 2010 Abstract Studying the role of rare alleles in common disease has been prevented by the impractical task of determining the DNA sequence of large numbers of individuals. Next-generation DNA sequencing technologies are being developed that will make it possible for genetic studies of common disease to study the full frequency spectrum of genetic variation, including rare alleles. This report describes a method for scanning the genome for disease susceptibility regions that show an increased number of rare alleles among a sample of disease cases versus an ethnically matched sample of controls. The method was based on a hidden Markov model and the statistical support for a disease susceptibility region characterized by rare alleles was measured by a likelihood ratio statistic. Due to the lack of empirical data, the method was evaluated through simulation. The performance of the method was tested under the null and alternative hypotheses under a range of sequence generating and hidden Markov models parameters. The results showed that the statistical method performs well at identifying true disease susceptibility regions and that performance was primarily affected by the amount of variation in the neutral sequence and the number of rare disease alleles found in the disease susceptibility region. Genet. Epidemiol. 34: 386,395, 2010. © 2010 Wiley-Liss, Inc. [source] Proliferation of progenitor cells in the adult rat brain correlates with the presence of vimentin-expressing astrocytesGLIA, Issue 4 2001Gérard Alonso Abstract It is well established that proliferation of progenitor cells persists within the hippocampal dentate gyrus (DG) and the subventricular zone of the lateral ventricle (SVZ) in the adult brain. The aim of the present study was to determine whether the rate of cell proliferation within these germinative zones could be correlated to the occurrence of a particular glial environment. The cell proliferation marker bromodeoxyuridine (BrdU) was administrated to rats under different physiological and experimental conditions known to modify the rate of progenitor cell proliferation. Within both germinative zones, BrdU-labeled nuclei were associated with cell bodies immunostained for the neuronal marker polysialylated neural cell adhesion molecule, but not for the glial markers glial fibrillary acidic protein (GFAP) or vimentin (VIM). In all the rats examined, however, proliferating (BrdU-labeled) cells always exhibited close relationships with immature-like astrocytes that expressed both GFAP and VIM. There was a dramatic decrease of cell proliferation in the DG from both the aged rats and the corticosterone-treated adult rats that was correlated with a decreased expression of vimentin by the astrocytes present in this region. In contrast, both cell proliferation and vimentin expression were only slightly affected in the SVZ from these two treatment groups. Conversely, after either adrenalectomy or a surgical lesion through the lateral hippocampus, the increase in cell proliferation observed in the DG was correlated to the occurrence of an increased number of GFAP and VIM double immunostained structures in these regions. All together, these data suggest that immature-like astrocytes present in the germinative zones may provide a microenvironment involved in sustaining the proliferation of progenitor cells. GLIA 34:253,266, 2001. © 2001 Wiley-Liss, Inc. [source] Notch2 signaling promotes biliary epithelial cell fate specification and tubulogenesis during bile duct development in mice,HEPATOLOGY, Issue 3 2009Jan S. Tchorz Intrahepatic bile duct (IHBD) development begins with the differentiation of hepatoblasts into a single continuous biliary epithelial cell (BEC) layer, called the ductal plate. During ductal plate remodeling, tubular structures arise at distinct sites of the ductal plate, forming bile ducts that dilate into the biliary tree. Alagille syndrome patients, who suffer from bile duct paucity, carry Jagged1 and Notch2 mutations, indicating that Notch2 signaling is important for IHBD development. To clarify the role of Notch2 in BEC differentiation, tubulogenesis, and BEC survival, we developed a mouse model for conditional expression of activated Notch2 in the liver. We show that expression of the intracellular domain of Notch2 (Notch2ICD) differentiates hepatoblasts into BECs, which form additional bile ducts in periportal regions and ectopic ducts in lobular regions. Additional ducts in periportal regions are maintained into adulthood and connect to the biliary tight junction network, resulting in an increased number of bile ducts per portal tract. Remarkably, Notch2ICD-expressing ductal plate remnants were not eliminated during postnatal development, implicating Notch2 signaling in BEC survival. Ectopic ducts in lobular regions did not persist into adulthood, indicating that local signals in the portal environment are important for maintaining bile ducts. Conclusion: Notch2 signaling regulates BEC differentiation, the induction of tubulogenesis during IHBD development, and BEC survival. (HEPATOLOGY 2009.) [source] Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude modelINTERNATIONAL JOURNAL OF CANCER, Issue 1 2005Eunyoung Chun Abstract Inhibition of angiogenesis is emerging as a promising strategy for the treatment of cancer. In our study reported here, the effects of 4 highly potent methionine aminopeptidase 2 (MetAP2) inhibitors, IDR-803, IDR-804, IDR-805 and CKD-732 (designed by structure-based molecular modeling), on angiogenesis and tumor growth were assessed. Concentrations of these inhibitors as low as 2.5 nM were able to inhibit the growth of human umbilical vein endothelial cells (HUVEC) by as much as 50%, arresting growth in the G1 stage of mitosis. An intracellular accumulation of p21WAF1/Cip1 protein was also observed. Furthermore, at higher concentrations (25 nM) of these 4 MetAP2 inhibitors, a significant induction of apoptosis was apparent in the same HUVEC cultures. As a result of these findings, the possible anticancer effects of these inhibitors were examined, utilizing the SNU-398 hepatoma cell line. Interestingly, pretreatment with these inhibitors led to an increased number of apoptotic cells of up to 60% or more, compared to untreated controls. Moreover, utilizing an in vivo xenografted murine model, these inhibitors suppressed the growth of engrafted tumor. In conclusion, these 4 inhibitory compounds potently exert an antiangiogenic effect to inhibit the growth of cancers in vivo and could potentially be useful for the treatment of a variety of cancers. © 2004 Wiley-Liss, Inc. [source] 8q24 Copy number gains and expression of the c- myc mRNA stabilizing protein CRD-BP in primary breast carcinomasINTERNATIONAL JOURNAL OF CANCER, Issue 1 2003Panayotis Ioannidis Abstract The coding region determinant binding protein (CRD-BP) was isolated by virtue of its high affinity to the c- myc mRNA coding region stability determinant and shown to shield this message from nucleolytic attack, prolonging its half-life. CRD-BP is normally expressed during fetal life but is also activated de novo in tumors. Considering that aberrant CRD-BP expression may represent an additional mechanism interfering with c- myc regulation, we screened 118 primary breast carcinomas for CRD-BP expression, 60 of which had also been analyzed by comparative genomic hybridization (CGH). Copy number gains encompassing 8q24, the chromosome band that contains the c- myc locus, were detected in 48.3% (29/60) of tumors, whereas gains involving band 17q21, which contains the CRD-BP locus, were observed in 18.3% (11/60) of tumors. CRD-BP expression was detected in 58.5% (69/118) of tumors, implying mechanisms of activation alternative to gene amplification. Altogether, some 75% of the tumors had alterations pertaining to c- myc since they either harbored 8q24 gains and/or expressed CRD-BP. Significant associations were detected between CRD-BP expression and the absence of estrogen receptors (p = 0.005) and between the presence of 8q24 gains and an increased number of genomic changes as measured by CGH (p = 0.0017). Tumors were divided into 4 groups according to CRD-BP expression and 8q24 gains. The odds for tumors having both characteristics to be classified as poorly differentiated (grade III vs. grade I and II) were 19.6 times the corresponding odds for tumors neither expressing CRD-BP nor harboring 8q24 gains. For tumors either harboring 8q24 gains only or expressing CRD-BP alone, the corresponding odds were 6.4 and 3, respectively. © 2002 Wiley-Liss, Inc. [source] Performance comparison of some dynamical and empirical downscaling methods for South Africa from a seasonal climate modelling perspectiveINTERNATIONAL JOURNAL OF CLIMATOLOGY, Issue 11 2009Willem A. Landman Abstract The ability of advanced state-of-the-art methods of downscaling large-scale climate predictions to regional and local scale as seasonal rainfall forecasting tools for South Africa is assessed. Various downscaling techniques and raw general circulation model (GCM) output are compared to one another over 10 December-January-February (DJF) seasons from 1991/1992 to 2000/2001 and also to a baseline prediction technique that uses only global sea-surface temperature (SST) anomalies as predictors. The various downscaling techniques described in this study include both an empirical technique called model output statistics (MOS) and a dynamical technique where a finer resolution regional climate model (RCM) is nested into the large-scale fields of a coarser GCM. The study addresses the performance of a number of simulation systems (no forecast lead-time) of varying complexity. These systems' performance is tested for both homogeneous regions and for 963 stations over South Africa, and compared with each other over the 10-year test period. For the most part, the simulations method outscores the baseline method that uses SST anomalies to simulate rainfall, therefore providing evidence that current approaches in seasonal forecasting are outscoring earlier ones. Current operational forecasting approaches involve the use of GCMs, which are considered to be the main tool whereby seasonal forecasting efforts will improve in the future. Advantages in statistically post-processing output from GCMs as well as output from RCMs are demonstrated. Evidence is provided that skill should further improve with an increased number of ensemble members. The demonstrated importance of statistical models in operation capacities is a major contribution to the science of seasonal forecasting. Although RCMs are preferable due to physical consistency, statistical models are still providing similar or even better skill and should still be applied. Copyright © 2008 Royal Meteorological Society [source] Performance issues of bandwidth management in ATM networksINTERNATIONAL JOURNAL OF COMMUNICATION SYSTEMS, Issue 2 2003Christos Bouras Abstract In our days, efficient management of the available network resources becomes a critical issue, both from a functional point of view (so that users can be provided with the bandwidth they need), and an economical point of view (so that carriers can satisfactorily and efficiently serve as many customers as possible and at the same time increase their revenue). In this paper we consider a bandwidth control scheme (i.e. managed bandwidth service) for an ATM network infrastructure which is applied to the Greek research and technology network (GRNET). We present some methods that we have tested (in a simulation setting) in order to increase the efficiency of the system and the utilization of the available bandwidth. More specifically, we consider a bandwidth-resizing algorithm for virtual paths, in order to keep the allocated bandwidth very close to the bandwidth actually used. This leads to an increased number of accepted requests and better network utilization. We, also, use the simulation results in order to get an estimation of the effective bandwidth for VBR paths that can be used in call admission. Finally, we consider a semi-offline scheme where requests are gathered and considered for acceptance in regular intervals. Simulation results show an increase in the utilization of resources. As a further improvement, we allow connections to be allocated a little before or after the time initially requested. This leads to further improvement in network utilization. All the improvement schemes were tested with the ATM-TN simulator and the results look promising. Copyright © 2003 John Wiley & Sons, Ltd. [source] On optimal cell planning: Case study for a DCS 1800 systemINTERNATIONAL JOURNAL OF COMMUNICATION SYSTEMS, Issue 9 2001Stavroula Bouzouki Abstract Micro and pico cell planning strategies are adopted in personal communication systems (PCS) in order to increase their capacity. The usage of the upper UHF band in combination with greater bandwidth is already proposed by telecom engineers in order to achieve the promised service quality and data rates. These strategies are characterized by an increased number of cells in specific geographical areas with the corresponding operating base transceiving stations (BTS) located at relatively low heights above the street level. In this case, the cell planning procedure in linear streets under line-of-sight (LOS) conditions needs further study concerning the technical characteristics of the PCS. In this paper, the propagation characteristics of a DCS 1800 system are investigated on a theoretical and experimental basis in a specific geographical area (center of Patras City in Northern Pelloponesse). An improved RF propagation model is proposed in order to determine the propagation path losses occurring under certain multipath fading conditions. Hence an optimum determination of a system's cellular area can be achieved. Copyright © 2001 John Wiley & Sons, Ltd. [source] Gambogic acid induces apoptosis by regulating the expression of Bax and Bcl-2 and enhancing caspase-3 activity in human malignant melanoma A375 cellsINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 2 2009Xiaoyuan Xu Objectives, To investigate the effect of a Chinese traditional medicine, gambogic acid (GA), on human malignant melanoma (MM) A375 cells and to study the mechanism of apoptosis induced by GA. Methods, A375 cells were treated with GA at different doses and for different times, and their proliferation and viability were detected by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis induced by GA in A375 cells was observed by annexin-V/propidium iodide doubling staining flow cytometry assay and Hoechst staining. To further determine the molecular mechanism of apoptosis induced by GA, the changes in expression of Bcl-2 and Bax were detected by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot, and caspase-3 activity was measured by fluorescence resonance energy transfer (FRET) probe. Results, After incubation with GA, A375 cell proliferation was dramatically inhibited in a dose-dependent manner. After these cells had been exposed to GA for 24, 36 and 48 h, the IC50 values were 1.57 ± 0.05, 1.31 ± 0.20, and 1.12 ± 0.19 µg/mL, respectively. Treatment of A375 cells with GA (2.5,7.5 µg/mL) for 36 h resulted in an increased number of early apoptotic cells, which ranged from 27.6% to 41.9%, in a dose-dependent manner, compared with only 3.5% apoptotic cells in the non-GA-treated group. An increase in Bax and decrease in Bcl-2 expression were found by real-time RT-PCR and Western blot. Caspase-3 activity was increased in a dose-dependent manner, observed by FRET probe. Conclusion, GA can inhibit the proliferation of A375 cells and induce their apoptosis, which may be related to the up-regulation of the Bax/Bcl-2 ratio and caspase-3 activity. [source] | |||||||||||||||||||||||||||||||||||||||||||