bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes in CCG-2961, a Children's Oncology Group Phase 3 Trial for untreated pediatric acute myeloid leukemia: a report from the Children's Oncology Group
Authors: Lange Beverly J. , Smith Franklin O. , Feusner James , Barnard Dorothy R. , Dinndorf Patricia , Feig Stephen , Heerema Nyla A. , Arndt Carola , Arceci Robert J. , Seibel Nita , Weiman Margie , Dusenbery Kathryn , Shannon Kevin , Luna-Fineman Sandra , Gerbing Robert B. , Alonzo Todd A.
Published: November 2007

CCG-2961 incorporated 3 new agents, idarubicin, fludarabine and interleukin-2, into a phase 3 AML trial using intensive-timing remission induction/consolidation and related donor marrow transplantation or high-dose cytarabine intensifi-cation. Among 901 patients under age 21 years, 5-year survival was 52%, and event-free survival was 42%. Survival improved from 44% between 1996 and 1998 to 58% between 2000 and 2002 (P = .005), and treatment-related mortality declined from 19% to 12% (P = .025). Partial replacement of daunomycin with idarubicin in the 5-drug induction combination achieved a remission rate of 88%, similar to historical controls. Postremission survival was 56% in patients randomized to either 5-drug reinduction or fludarabine/cytarabine/idarubicin. For patients with or without a related donor, respective 5-year disease-free survival was 61% and 50% (P = .021); respective survival was 68% and 62% (P = .425). Donor availability conferred no benefit on those with inv(16) or t(8;21) cytogenetics. After cytarabine intensification, patients randomized to interleukin-2 or none experienced similar outcomes. Factors predictive of inferior survival were age more than 16 years, non-white ethnicity, absence of related donor, obesity, white blood cell count more than 100 000 × 109/L, −7/7q−, −5/5q−, and/or complex karyotype. No new agent improved outcomes; experience may have contributed to better results time.
Development of an allele-specific minimal residual disease assay for patients with juvenile myelomonocytic leukemia
Authors: Archambeault Sophie , Flores Nikki J. , Yoshimi Ayami , Kratz Christian P. , Reising Miriam , Fischer Alexandra , Noellke Peter , Locatelli Franco , Sedlacek Petr , Flotho Christian , Zecca Marco , Emanuel Peter D. , Castleberry Robert P. , Niemeyer Charlotte M. , Bader Peter , Loh Mignon L.
Published: November 2007

Juvenile myelomonocytic leukemia is an aggressive and frequently lethal myeloproliferative disorder of childhood. Somatic mutations in NRAS, KRAS, or PTPN11 occur in 60% of cases. Monitoring disease status is difficult because of the lack of characteristic leukemic blasts at diagnosis. We designed a fluorescently based, allele-specific polymerase chain reaction assay called TaqMAMA to detect the most common RAS or PTPN11 mutations. We analyzed peripheral blood and/or bone marrow of 25 patients for levels of mutant alleles over time. Analysis of pre–hematopoietic stem-cell transplantation, samples revealed a broad distribution of the quantity of the mutant alleles. After hematopoietic stem-cell transplantation, the level of the mutant allele rose rapidly in patients who relapsed and correlated well with falling donor chimerism. Simultaneously analyzed peripheral blood and bone marrow samples demonstrate that blood can be monitored for residual disease. Importantly, these assays provide a sensitive strategy to evaluate molecular responses to new therapeutic strategies.
PACAP and its receptor VPAC1 regulate megakaryocyte maturation: therapeutic implications
Authors: Freson Kathleen , Peeters Karen , De Vos Rita , Wittevrongel Christine , Thys Chantal , Hoylaerts Marc F. , Vermylen Jos , Van Geet Chris
Published: November 2007

Megakaryocytes and platelets express the Gs-coupled VPAC1 receptor, for which the pituitary adenylyl cyclase–activating peptide (PACAP) and the vasointestinal peptide (VIP) are agonists. We here demonstrate a regulatory role for VPAC1 signaling during megakaryopoiesis. A total of 2 patients with trisomy 18p with PACAP overexpression and transgenic mice overexpressing PACAP in megakaryocytes have thrombopathy, a mild thrombocytopenia, and a reduced number of mature megakaryocytes in their bone marrow. In vitro differentiation of hematopoietic stem cells from the patient and transgenic mice shows a reduced number of megakaryocyte colonies compared with controls. The addition of PACAP, VIP, or the adenylyl cyclase activator forskolin to CD34+ cells inhibits megakaryocyte differentiation. In contrast, neutralizing monoclonal anti-PACAP (PP1A4) or anti-VPAC1 (23A11) antibodies inhibit cAMP formation and stimulate megakaryopoiesis in a thrombopoietin-independent manner. Moreover, wild-type mice obtain an increased platelet count after subcutaneous injection of PP1A4 or 23A11. These antibodies also elevate platelet numbers in animal models of myelosuppressive therapy and in GATA1-deficient mice with congenital thrombocytopenia. Furthermore, 23A11 stimulates the in vitro megakaryocyte differentiation of both normal and GATA1-deficient human CD34+ cells. Together, our data strongly suggest that VPAC1 signaling tempers normal megakaryopoiesis, and that inhibition of this pathway stimulates megakaryocyte differentiation, enhancing platelet recovery after myelosuppressive therapy and in GATA1 deficiency.
Patterns of airway inflammation and MMP-12 expression in smokers and ex-smokers with COPD
Authors: Babusyte Agne , Stravinskaite Kristina , Jeroch Jolanta , Lötvall Jan , Sakalauskas Raimundas , Sitkauskiene Brigita
Published: November 2007

Background

Smoking activates and recruits inflammatory cells and proteases to the airways. Matrix metalloproteinase (MMP)-12 may be a key mediator in smoke induced emphysema. However, the influence of smoking and its cessation on airway inflammation and MMP-12 expression during COPD is still unknown. We aimed to analyse airway inflammatory cell patterns in induced sputum (IS) and bronchoalveolar lavage (BAL) from COPD patients who are active smokers and who have ceased smoking >2 years ago.

Methods

39 COPD outpatients – smokers (n = 22) and ex-smokers (n = 17) were studied. 8 'healthy' smokers and 11 healthy never-smokers were tested as the control groups. IS and BAL samples were obtained for differential and MMP-12+-macrophages count analysis.

Results

The number of IS neutrophils was higher in both COPD groups compared to both controls. The amount of BAL neutrophils was higher in COPD smokers compared to healthy never-smokers. The number of BAL MMP-12+-macrophages was higher in COPD smokers (1.6 ± 0.3 × 106/ml) compared to COPD ex-smokers, 'healthy' smokers and healthy never-smokers (0.9 ± 0.4, 0.4 ± 0.2, 0.2 ± 0.1 × 106/ml respectively, p < 0.05).

Conclusion

The lower amount of BAL neutrophils in COPD ex-smokers, compared to COPD smokers, suggests positive alterations in alveolar compartment after smoking cessation. Smoking and disease itself may stimulate MMP-12 expression in airway compartments (IS and BAL) from COPD patients.
Revealing biases inherent in recombination protocols
Authors: Chaparro-Riggers Javier F , Loo Bernard LW , Polizzi Karen M , Gibbs Phillip R , Tang Xiao-Song , Nelson Mark J , Bommarius Andreas S
Published: November 2007

Background

The recombination of homologous genes is an effective protein engineering tool to evolve proteins. DNA shuffling by gene fragmentation and reassembly has dominated the literature since its first publication, but this fragmentation-based method is labor intensive. Recently, a fragmentation-free PCR based protocol has been published, termed recombination-dependent PCR, which is easy to perform. However, a detailed comparison of both methods is still missing.

Results

We developed different test systems to compare and reveal biases from DNA shuffling and recombination-dependent PCR (RD-PCR), a StEP-like recombination protocol. An assay based on the reactivation of β-lactamase was developed to simulate the recombination of point mutations. Both protocols performed similarly here, with slight advantages for RD-PCR. However, clear differences in the performance of the recombination protocols were observed when applied to homologous genes of varying DNA identities. Most importantly, the recombination-dependent PCR showed a less pronounced bias of the crossovers in regions with high sequence identity. We discovered that template variations, including engineered terminal truncations, have significant influence on the position of the crossovers in the recombination-dependent PCR. In comparison, DNA shuffling can produce higher crossover numbers, while the recombination-dependent PCR frequently results in one crossover. Lastly, DNA shuffling and recombination-dependent PCR both produce counter-productive variants such as parental sequences and have chimeras that are over-represented in a library, respectively. Lastly, only RD-PCR yielded chimeras in the low homology situation of GFP/mRFP (45% DNA identity level).

Conclusion

By comparing different recombination scenarios, this study expands on existing recombination knowledge and sheds new light on known biases, which should improve library-creation efforts. It could be shown that the recombination-dependent PCR is an easy to perform alternative to DNA shuffling.
High risk HPV types 18 and 16 are potent modulators of oral squamous cell carcinoma phenotypes in vitro
Authors: Reddout Nicole , Christensen Todd , Bunnell Anthony , Jensen Dayne , Johnson Devin , O'Malley Susan , Kingsley Karl
Published: November 2007

Background

Human papillomavirus (HPV) has been confirmed as the primary etiological factor that transforms cervical epithelia into cancer. The presence of HPV in oral cancers suggests that HPV may play a similar role in transforming the oral epithelia. A high degree of variability in the prevalence of HPV in oral cancers has been found, however, raising questions regarding its role in the transformation and development of oral cancers. The goal of this study was to test our hypothesis that high-risk HPV strains HPV16 and HPV18 will alter the phenotype of transformed oral squamous cell carcinoma cell lines, CAL27, SCC-15 and SCC-25 in vitro.

Results

CAL27 cells transfected with HPV18, HPV16, as well as HPV16/18 co-transfectants, demonstrated significant increases in proliferation, adhesion and cell spreading compared with non-transfected controls. These observed differences were correlated with a small level of increased cell survival. SCC-15 cells, however, displayed a differential response to HPV transfection, with only HPV18-transfectants demonstrated changes to proliferation. Interestingly, SCC-25 cells displayed a more complex response, with HPV16-induced increases in cell proliferation, viability and cell spreading, while HPV18- and 16/18-transfectants exhibited reduced adhesion and proliferation.

Conclusion

Determining the potential of specific high-risk HPV strains to alter phenotypic behaviors of already transformed oral carcinomas is a critical step in providing more accurate prognosis and treatment options for oral cancer patients. The identification of differential responses to specific HPV strains among oral cancers suggests a more significant, complex and multifactorial role of HPV, not only in transforming, but also in modulating, the phenotype and treatment responsiveness of precancerous and cancerous oral lesions. This study provides some of the first evidence to help identify the important molecular markers for pathways that could be used to determine the most effective and appropriate treatment plans for oral cancer patients with concomitant oral HPV infections.
Role of the Thyrotropin-Releasing Hormone Stimulation Test in Diagnosis of Congenital Central Hypothyroidism in Infants
Authors: van Tijn David A. , de Vijlder Jan J. M. , Vulsma Thomas
Published: November 2007

Context: A shortage of thyroid hormone during prenatal life and the first years after birth results in a spectrum of neuropsychological disorders, depending on the duration and severity of the deficiency. In the case of congenital hypothyroidism of central origin (CH-C), the majority of patients have multiple pituitary hormone deficiencies (MPHD). This condition poses an additional threat to postnatal central nervous system development, primarily on account of neuroglycopenia due to ACTH/cortisol deficiency with or without additional GH deficiency. Therefore, in CH-C, rapid diagnosis is even more urgent than in congenital hypothyroidism of thyroidal origin.

Objective: In the assessment of hypothalamic-pituitary-thyroid function, we considered the pituitary response to iv administration of TRH (TRH test) pivotal. We evaluated the usefulness of the TRH test in a cohort of infants with neonatal congenital hypothyroidism screening results indicative of CH-C by analyzing the results within the framework of investigations of the anatomical and functional integrity of the hypothalamo-hypophyseal system.

Design and Setting: The study was a Dutch nationwide prospective study (1994–1996). Patients were included if neonatal congenital hypothyroidism screening results were indicative of CH-C and patients could be tested within 3 months of birth.

Patients: Ten male and five female infants with CH-C, detected by neonatal screening, and six infants with false-positive screening results, nonthyroidal illness, or transient hypothyroidism, were included in the study.

Main Outcome Measures: Results of TRH tests, within the framework of extensive endocrinological examinations and cerebral magnetic resonance imaging, were measured.

Results: All patients with type 3 TSH responses to TRH had MPHD, and the majority (67%) of patients with type 2 responses had isolated TSH deficiency.

Conclusions: The TRH test has a pivotal role in the diagnosis of TSH deficiency in young infants. Abnormal TRH test results, especially a type 3 response, urge immediate assessment of integral hypothalamic-pituitary function because the majority of patients have MPHD.
A Prospective Study of the Prevalence of Nonclassical Congenital Adrenal Hyperplasia among Women Presenting with Hyperandrogenic Symptoms and Signs
Authors: Escobar-Morreale Héctor F. , Sanchón Raul , San Millán José L.
Published: November 2007

Context: The diagnosis of the polycystic ovary syndrome requires the exclusion of nonclassical congenital adrenal hyperplasia (NCAH).

Objective: Our objective was to evaluate the actual prevalences of 21-hydroxylase and 11β-hydroxylase deficiencies among women presenting with hyperandrogenic complaints.

Settings: This study was performed at an academic hospital.

Patients: A total of 270 consecutive unselected women presenting with hyperandrogenic symptoms were prospectively recruited.

Interventions: Basal and ACTH-stimulated 11-deoxycortisol and 17-hydroxyprogesterone concentrations were measured.

Main Outcome Measures: The prevalences of 21-hydroxylase and 11β-hydroxylase deficiencies were calculated, and the diagnostic performance of basal serum 17-hydroxyprogesterone levels for the screening of NCAH was evaluated by receiver operating characteristic curve analysis.

Results: Six of the 270 patients had 21-hydroxylase-deficient NCAH that was confirmed by CYP21 genotyping, whereas no patient was diagnosed with 11β-hydroxylase deficiency, for an overall NCAH prevalence of 2.2% (95% confidence limits 0.5–3.9%). According to receiver operating characteristic analysis, a single basal serum 17-hydroxyprogesterone determination has a 0.97 (95% confidence interval: 0.934–1.008) chance of detecting NCAH in hyperandrogenic women. In our experience, the most appropriate cutoff value for the detection of NCAH is a 17-hydroxyprogesterone above 1.7 ng/ml, showing a 100% sensitivity and a 88.6% specificity. Five of the six 21-hydroxylase-deficient NCAH patients carried a severe CYP21 allele requiring genetic counseling and highlighting the importance of excluding this disorder among hyperandrogenic patients.

Conclusions: The prevalence of NCAH among hyperandrogenic patients from Spain is 2.2%. Basal serum 17-hydroxyprogesterone measurements have an excellent diagnostic performance, yet the cutoff value should be established in each laboratory to avoid false-negative results.
Effects of Atorvastatin on Lp(a) and Lipoprotein Profiles in Hemodialysis Patients
Authors: Joy Melanie S , Dornbrook-Lavender Kimberly A , Chin Hyunsook , Hogan Susan L , Denu-Ciocca Cynthia
Published: November 2007

Background:

Dialysis patients have many underlying traditional and nontraditional risk factors that may predispose them to a high prevalence of cardiovascular disease. The effects of statins (eg, atorvastatin) on altering nontraditional lipoprotein measures in dialysis patients have not been extensively investigated.

Objective:

To evaluate the efficacy of atorvastatin compared with a control group in inducing changes in lipoprotein(a) [Lp(a)], apolipoprotein (Apo) A-1, Apo-B, and fibrinogen levels, as well as the conventional lipoprotein profile, in hemodialysis patients over 36 weeks; secondary objectives were to assess changes in C-reactive protein, albumin, and safety measures.

Methods:

Forty-five hemodialysis patients with low-density lipoprotein cholesterol (LDL-C) levels greater than 100 mg/dL were randomized to parallel groups: atorvastatin (n = 19) or no treatment (n = 26). The atorvastatin dose was titrated from 10 mg to achieve an LDL-C goal of 100 mg/dL or less and therapy was continued for 36 weeks. Biochemical and lipoprotein laboratory tests for efficacy outcomes were obtained at baseline, 12 weeks, and 36 weeks.

Results:

The atorvastatin group exhibited clinically significant reductions (mean ± SD) compared with controls in total cholesterol (–21.7 ± 41.7 vs –3.2 ± 40.0 mg/dL, respectively; p = 0.017) and LDL-C (–13.1 ± 32.0 vs –1.1 ± 38.4 mg/dL. respectively; p = 0.056) levels, as well as Lp(a) (–10.6 ± 27 vs 3.5 ± 17.8 mg/dL, respectively; p = 0.046). Statistical analyses included analysis of variance on ranked measures for multivariable modeling and paired t-test to determine changes in efficacy measures between baseline and 36 weeks within groups.

Conclusions:

Atorvastatin was safe and effective in reducing Lp(a), total cholesterol, and LDL-C levels. Given the prevalence of atherosclerosis in hemodialysis patients, therapy aimed at reducing traditional and nontraditional risk factors may be beneficial.
Somatodendritic Release of Glutamate Regulates Synaptic Inhibition in Cerebellar Purkinje Cells via Autocrine mGluR1 Activation
Authors: Duguid Ian C. , Pankratov Yuriy , Moss Guy W. J. , Smart Trevor G.
Published: November 2007

In the cerebellum, the process of retrograde signaling via presynaptic receptors is important for the induction of short- and long-term changes in inhibitory synaptic transmission at interneuron–Purkinje cell (PC) synapses. Endocannabinoids, by activating presynaptic CB1 receptors, mediate a short-term decrease in inhibitory synaptic efficacy, whereas glutamate, acting on presynaptic NMDA receptors, induces a longer-latency sustained increase in GABA release. We now demonstrate that either low-frequency climbing fiber stimulation or direct somatic depolarization of Purkinje cells results in SNARE-dependent vesicular release of glutamate from the soma and dendrites of PCs. The activity-dependent release of glutamate caused the activation of postsynaptic metabotropic glutamate receptor 1 (mGluR1) on PC somatodendritic membranes, resulting in the cooperative release of endocannabinoids and an mGluR1-mediated slow membrane conductance. The activity of excitatory amino acid transporters regulated the spatial spread of glutamate and thus the extent of PC mGluR1 activation. We propose that activity-dependent somatodendritic glutamate release and autocrine activation of mGluR1 on PCs provides a powerful homeostatic mechanism to dynamically regulate inhibitory synaptic transmission in the cerebellar cortex.
Sleep Does Not Benefit Probabilistic Motor Sequence Learning
Authors: Song Sunbin , Howard James H. , Howard Darlene V.
Published: November 2007

It has become widely accepted that sleep-dependent consolidation occurs for motor sequence learning based on studies using finger-tapping tasks. Studies using another motor sequence learning task [the serial response time task (SRTT)] have portrayed a more nuanced picture of off-line consolidation, involving both sleep-dependent and daytime consolidation, as well as modifying influences of explicit awareness. The present study used a variant of the SRTT featuring probabilistic sequences to investigate off-line consolidation. Probabilistic sequences confer two advantages: first, spontaneous explicit awareness does not occur, and second, sequence learning measures are continuous, making it easier to separate general skill from sequence-specific learning. We found that sleep did not enhance general skill or sequence-specific learning. In contrast, daytime enhancement occurred for general skill but not for sequence-specific learning. Overall, these results suggest that motor learning does not always undergo consolidation with sleep.
SynCAMs Organize Synapses through Heterophilic Adhesion
Authors: Fogel Adam I. , Akins Michael R. , Krupp Alexander J. , Stagi Massimiliano , Stein Valentin , Biederer Thomas
Published: November 2007

Synapses are asymmetric cell junctions with precisely juxtaposed presynaptic and postsynaptic sides. Transsynaptic adhesion complexes are thought to organize developing synapses. The molecular composition of these complexes, however, remains incompletely understood, precluding us from understanding how adhesion across the synaptic cleft guides synapse development. Here, we define two immunoglobulin superfamily members, SynCAM 1 and 2, that are expressed in neurons in the developing brain and localize to excitatory and inhibitory synapses. They function as cell adhesion molecules and assemble with each other across the synaptic cleft into a specific, transsynaptic SynCAM 1/2 complex. Additionally, SynCAM 1 and 2 promote functional synapses as they increase the number of active presynaptic terminals and enhance excitatory neurotransmission. The interaction of SynCAM 1 and 2 is affected by glycosylation, indicating regulation of this adhesion complex by posttranslational modification. The SynCAM 1/2 complex is representative for the highly defined adhesive patterns of this protein family, the four members of which are expressed in neurons in divergent expression profiles. SynCAMs 1, 2, and 3 each can bind themselves, yet preferentially assemble into specific, heterophilic complexes as shown for the synaptic SynCAM 1/2 interaction and a second complex comprising SynCAM 3 and 4. Our results define SynCAM proteins as components of novel heterophilic transsynaptic adhesion complexes that set up asymmetric interactions, with SynCAM proteins contributing to synapse organization and function.
Long-Term Plasticity of the Spinal Locomotor Circuitry Mediated by Endocannabinoid and Nitric Oxide Signaling
Authors: Kyriakatos Alexandros , El Manira Abdeljabbar
Published: November 2007

Retrograde signaling by endocannabinoids is known to induce short- and long-term synaptic plasticity, but the significance of this modulation for the activity of neural networks underlying motor behavior is largely unclear. Here, we used the isolated lamprey spinal cord to show that endocannabinoids released by activation of metabotropic glutamate receptor 1 (mGluR1) induce long-term synaptic plasticity during an ongoing locomotor rhythm and how this is translated onto the integrated activity of the spinal circuitry. A brief activation of mGluR1 induces a long-term increase in the locomotor frequency that is mediated by a concomitant long-term depression of midcycle reciprocal inhibition and long-term potentiation of ipsilateral synaptic excitation arising from locomotor circuit interneurons. Blockade of cannabinoid receptors with AM251 prevented the mGluR1-mediated long-term plasticity of both inhibitory and excitatory synaptic transmission, as well as that of the locomotor activity. Similarly, inhibition of nitric oxide signaling blocked the mGluR1-mediated long-term plasticity. These results show that the locomotor circuitry is endowed with a “memory” capacity mediated by a long-term shift in the balance between synaptic inhibition and excitation. This is triggered by activation of mGluR1 and requires subsequent endocannabinoid and nitric oxide signaling.
Diminishing Risk-Taking Behavior by Modulating Activity in the Prefrontal Cortex: A Direct Current Stimulation Study
Authors: Fecteau Shirley , Knoch Daria , Fregni Felipe , Sultani Natasha , Boggio Paulo , Pascual-Leone Alvaro
Published: November 2007

Studies have shown increased risk taking in healthy individuals after low-frequency repetitive transcranial magnetic stimulation, known to transiently suppress cortical excitability, over the right dorsolateral prefrontal cortex (DLPFC). It appears, therefore, plausible that differential modulation of DLPFC activity, increasing the right while decreasing the left, might lead to decreased risk taking, which could hold clinical relevance as excessively risky decision making is observed in clinical populations leading to deleterious consequences. The goal of the present study was to investigate whether risk-taking behaviors could be decreased using concurrent anodal transcranial direct current stimulation (tDCS) of the right DLPFC, which allows upregulation of brain activity, with cathodal tDCS of the left DLPCF, which downregulates activity. Thirty-six healthy volunteers performed the risk task while they received either anodal over the right with cathodal over the left DLPFC, anodal over the left with cathodal over the right DLPFC, or sham stimulation. We hypothesized that right anodal/left cathodal would decrease risk-taking behavior compared with left anodal/right cathodal or sham stimulation. As predicted, during right anodal/left cathodal stimulation over the DLPFC, participants chose more often the safe prospect compared with the other groups. Moreover, these participants appeared to be insensitive to the reward associated with the prospects. These findings support the notion that the interhemispheric balance of activity across the DLPFCs is critical in decision-making behaviors. Most importantly, the observed suppression of risky behaviors suggests that populations with boundless risk-taking behaviors leading to negative real-life consequences, such as individuals with addiction, might benefit from such neuromodulation-based approaches.
Profound Decreases in Dopamine Release in Striatum in Detoxified Alcoholics: Possible Orbitofrontal Involvement
Authors: Volkow Nora D. , Wang Gene-Jack , Telang Frank , Fowler Joanna S. , Logan Jean , Jayne Millard , Ma Yeming , Pradhan Kith , Wong Christopher
Published: November 2007

The value of rewards (natural rewards and drugs) is associated with dopamine increases in the nucleus accumbens and varies as a function of context. The prefrontal cortex has been implicated in the context dependency of rewards and in the fixated high value that drugs have in addiction, although the mechanisms are not properly understood. Here we test the hypothesis that the prefrontal cortex regulates the value of rewards by modulating dopamine increases in nucleus accumbens and that this regulation is disrupted in addicted subjects. We used positron emission tomography to evaluate the activity of the prefrontal cortex (measuring brain glucose metabolism with [18F]fluorodeoxyglucose) and dopamine increases (measured with [11C]raclopride, a D2/D3receptor ligand with binding that is sensitive to endogenous dopamine) induced by the stimulant drug methylphenidate in 20 controls and 20 detoxified alcoholics, most of whom smoked. In all subjects, methylphenidate significantly increased dopamine in striatum. In ventral striatum (where the nucleus accumbens is located) and in putamen, dopamine increases were associated with the rewarding effects of methylphenidate (drug liking and high) and were profoundly attenuated in alcoholics (70 and 50% lower than controls, respectively). In controls, but not in alcoholics, metabolism in orbitofrontal cortex (region involved with salience attribution) was negatively associated with methylphenidate-induced dopamine increases in ventral striatum. These results are consistent with the hypothesis that the orbitofrontal cortex modulates the value of rewards by regulating the magnitude of dopamine increases in the ventral striatum and that disruption of this regulation may underlie the decreased sensitivity to rewards in addicted subjects.
Regulation of Spine Development by Semaphorin3A through Cyclin-Dependent Kinase 5 Phosphorylation of Collapsin Response Mediator Protein 1
Authors: Yamashita Naoya , Morita Asa , Uchida Yutaka , Nakamura Fumio , Usui Hiroshi , Ohshima Toshio , Taniguchi Masahiko , Honnorat Jérôme , Thomasset Nicole , Takei Kohtaro , Takahashi Takuya , Kolattukudy Pappachan , Goshima Yoshio
Published: November 2007

Collapsin response mediator protein 1 (CRMP1) is one of the CRMP family members that mediates signal transduction of axonal guidance and neuronal migration. We show here evidence that CRMP1 is involved in semaphorin3A (Sema3A)-induced spine development in the cerebral cortex. In the cultured cortical neurons fromcrmp1+/−mice, Sema3A increased the density of clusters of synapsin I and postsynaptic density-95, but this increase was markedly attenuated incrmp1−/−mice. This attenuation was also seen incyclin-dependent kinase 5(cdk5)−/−neurons. Furthermore, the introduction of wild-type CRMP1 but not CRMP1-T509A/S522A, (Thr 509 and Ser 522 were replaced by Ala), a mutant that cannot be phosphorylated by Cdk5, intocrmp1−/−neurons rescued the defect in Sema3A responsiveness. The Golgi-impregnation method showed that thecrmp1−/−layer V cortical neurons showed a lower density of synaptic bouton-like structures and that this phenotype had genetic interaction withsema3A. These findings suggest that Sema3A-induced spine development is regulated by phosphorylation of CRMP1 by Cdk5.
A Promising Therapeutic Approach for Multiple Sclerosis: Recombinant T-Cell Receptor Ligands Modulate Experimental Autoimmune Encephalomyelitis by Reducing Interleukin-17 Production and Inhibiting Migration of Encephalitogenic Cells into the CNS
Authors: Sinha Sushmita , Subramanian Sandhya , Proctor Thomas M. , Kaler Laurie J. , Grafe Marjorie , Dahan Rony , Huan Jianya , Vandenbark Arthur A. , Burrows Gregory G. , Offner Halina
Published: November 2007

Recombinant T-cell receptor ligands (RTLs) can prevent and reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in an antigen-specific manner and are currently in clinical trials for treatment of subjects with multiple sclerosis (MS). To evaluate regulatory mechanisms, we designed and tested RTL551, containing the α1 and β1 domains of the I-Abclass II molecule covalently linked to the encephalitogenic MOG-35-55 peptide in C57BL/6 mice. Treatment of active or passive EAE with RTL551 after disease onset significantly reduced clinical signs and spinal cord lesions. Moreover, RTL551 treatment strongly and selectively reduced secretion of interleukin-17 and tumor necrosis factor α by transferred green fluorescent protein-positive (GFP+) MOG-35-55-reactive T-cells and almost completely abrogated existent GFP+ cellular infiltrates in affected spinal cord sections. Reduced inflammation in spinal cords of RTL551-treated mice was accompanied by a highly significant downregulation of chemokines and their receptors and inhibition of VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) expression by endothelial cells. Thus, RTL therapy cannot only inhibit systemic production of encephalitogenic cytokines by the targeted myelin oligodendrocyte glycoprotein-reactive T-cells but also impedes downstream local recruitment and retention of inflammatory cells in the CNS. These findings indicate that targeted immunotherapy of antigen-specific T-cells can result in a reversal of CNS lesion formation and lend strong support to the application of the RTL approach for therapy in MS.
A Novel Role for Extracellular Signal-Regulated Kinase in Maintaining Long-Term Memory-Relevant Excitability Changes
Authors: Cohen-Matsliah Sivan Ida , Brosh Inbar , Rosenblum Kobi , Barkai Edi
Published: November 2007

Pyramidal neurons in the piriform cortex from olfactory-discrimination-trained rats show enhanced intrinsic neuronal excitability that lasts for several days after learning. Such enhanced intrinsic excitability is mediated by long-term reduction in the postburst afterhyperpolarization (AHP), which is generated by repetitive spike firing. AHP reduction is attributable to decreased conductance of a calcium-dependent potassium current, thesIAHP. We have previously shown that such learning-induced AHP reduction is maintained by PKC activation. However, the molecular machinery underlying such long-lasting modulation of intrinsic excitability is yet to be fully described. Here we examine whether the extracellular signal-regulated kinase I/II (ERKI/II) pathway, which is known to be crucial in learning, memory, and synaptic plasticity processes, is instrumental for the long-term maintenance of learning-induced AHP reduction. PD98059 or UO126, which selectively block MEK, the upstream kinase of ERK, increased the AHP in neurons from trained rats but not in neurons from naive and pseudo-trained rats. Consequently, the differences in AHP amplitude and neuronal adaptation between neurons from trained rats and controls were abolished. This effect was not mediated by modulation of basic membrane properties. In accordance with its effect on neuronal excitability, the level of activated ERK in the membranal fraction was significantly higher in piriform cortex samples taken from trained rats. In addition, the PKC activator OAG (1-oleoyl-20acety-sn-glycerol), which was shown to reduce the AHP in neurons from control rats, had no effect on these neurons in the presence of PD98059. Our data show that ERK has a key role in maintaining long-lasting learning-induced enhancement of neuronal excitability.
High-Frequency Deep Brain Stimulation of the Nucleus Accumbens Region Suppresses Neuronal Activity and Selectively Modulates Afferent Drive in Rat Orbitofrontal CortexIn Vivo
Authors: McCracken Clinton B. , Grace Anthony A.
Published: November 2007

High-frequency deep-brain stimulation (DBS) of the nucleus accumbens (NAc) region is an effective therapeutic avenue for patients with treatment-resistant obsessive–compulsive disorder (OCD). Imaging studies suggest that DBS acts by suppressing the aberrant metabolism in the orbitofrontal cortex (OFC) that is a hallmark of OCD; however, little is known about the mechanisms by which this occurs. We examined the effects of 30 min NAc DBS at 130 Hz on spontaneously active OFC neurons and local field potentials (LFPs) in addition to evoked responses elicited by single-pulse stimulation of the NAc or mediodorsal thalamus (MD) in urethane-anesthetized rats. NAc DBS reduced the mean firing rate of OFC neurons, although neurons receiving monosynaptic input from MD were less affected and some putative interneurons were excited by DBS. Single-pulse stimulation of the NAc produced a robust inhibition in OFC neurons that was attenuated after DBS, whereas excitatory responses were unchanged. In contrast, after DBS inhibitory responses evoked from MD were unchanged, whereas excitatory responses were enhanced. NAc-evoked LFP responses were potentiated after DBS, whereas MD-evoked LFP responses were unchanged. NAc DBS also enhanced OFC spontaneous LFP oscillatory activity in the slow (0.5–4 Hz) frequency band. These results suggest that DBS of the NAc region may alleviate OCD symptoms by reducing activity in subsets of OFC neurons, potentially by driving recurrent inhibition though antidromic activation of corticostriatal axon collaterals. Moreover, selective potentiation of input to these inhibitory circuits may also contribute to the therapeutic effects produced by DBS in OCD patients.
Dynamic Contribution of Nestin-Expressing Stem Cells to Adult Neurogenesis
Authors: Lagace Diane C. , Whitman Mary C. , Noonan Michele A. , Ables Jessica L. , DeCarolis Nathan A. , Arguello Amy A. , Donovan Michael H. , Fischer Stephanie J. , Farnbauch Laure A. , Beech Robert D. , DiLeone Ralph J. , Greer Charles A. , Mandyam Chitra D. , Eisch Amelia J.
Published: November 2007

Understanding the fate of adult-generated neurons and the mechanisms that influence them requires consistent labeling and tracking of large numbers of stem cells. We generated a nestin-CreERT2/R26R-yellow fluorescent protein (YFP) mouse to inducibly label nestin-expressing stem cells and their progeny in the adult subventricular zone (SVZ) and subgranular zone (SGZ). Several findings show that the estrogen ligand tamoxifen (TAM) specifically induced recombination in stem cells and their progeny in nestin-CreERT2/R26R-YFP mice: 97% of SGZ stem-like cells (GFAP/Sox2 with radial glial morphology) expressed YFP; YFP+ neurospheres could be generatedin vitroafter recombinationin vivo, and maturing YFP+ progeny were increasingly evident in the olfactory bulb (OB) and dentate gyrus (DG) granule cell layer. Revealing an unexpected regional dissimilarity in adult neurogenesis, YFP+ cells accumulated up to 100 d after TAM in the OB, but in the SGZ, YFP+ cells reached a plateau 30 d after TAM. In addition, most SVZ and SGZ YFP+ cells became neurons, underscoring a link between nestin and neuronal fate. Finally, quantification of YFP+ cells in nestin-CreERT2/R26R-YFP mice allowed us to estimate, for example, that stem cells and their progeny contribute to no more than 1% of the adult DG granule cell layer. In addition to revealing the dynamic contribution of nestin-expressing stem cells to adult neurogenesis, this work highlights the utility of the nestin-CreERT2/R26R-YFP mouse for inducible gene ablation in stem cells and their progenyin vivoin the two major regions of adult neurogenesis.
Diminished Neurosteroid Sensitivity of Synaptic Inhibition and Altered Location of the α4 Subunit of GABAAReceptors in an Animal Model of Epilepsy
Authors: Sun Chengsan , Mtchedlishvili Zakaria , Erisir Alev , Kapur Jaideep
Published: November 2007

In animal models of temporal lobe epilepsy (TLE), neurosteroid sensitivity of GABAAreceptors on dentate granule cells (DGCs) is diminished; the molecular mechanism underlying this phenomenon remains unclear. The current study investigated a mechanism for loss of neurosteroid sensitivity of synaptic GABAAreceptors in TLE. Synaptic currents recorded from DGCs of epileptic animals (epileptic DGCs) were less frequent, larger in amplitude, and less sensitive to allopregnanolone modulation than those recorded from DGCs of control animals (control DGCs). Synaptic currents recorded from epileptic DGCs were less sensitive to diazepam and had altered sensitivity to benzodiazepine inverse agonist RO 15-4513 (ethyl-8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5α][1,4]benzodiazepine-3-carboxylate) and furosemide than those recorded from control DGCs. Properties of synaptic currents recorded from epileptic DGCs appeared similar to those of recombinant receptors containing the α4 subunit. Expression of the α4 subunit and its colocalization with the synaptic marker GAD65 was increased in epileptic DGCs. Location of the α4 subunit in relation to symmetric (inhibitory) synapses on soma and dendrites of control and epileptic DGCs was examined with postembedding immunogold electron microscopy. The α4 immunogold labeling was present more commonly within the synapse in epileptic DGCs compared with control DGCs, in which the subunit was extrasynaptic. These studies demonstrate that, in epileptic DGCs, the neurosteroid modulation of synaptic currents is diminished and α4 subunit-containing receptors are present at synapses and participate in synaptic transmission. These changes may facilitate seizures in epileptic animals.
Karen and Me
Authors: taylor john martin
Published: November 2007

Food writer John Martin Taylor reflects on his relationship with the recently (2007) deceased culinary historian Karen Hess, who was his mentor and friend. He compares their circuitous paths to the food world, and the similarities of their approaches to, and ideas about, the field. Taylor describes their meeting and her continued inspiration to him through the twenty-three years of their friendship.
Fishing with Ulysses and Bacchus: Two Roman Mosaics from Tunisia
Authors: knutson chris
Published: November 2007

The mosaics of Roman Africa drew upon themes from mythology as well as daily life. Even "mythological" scenes can lend insight into real-life activities like food production. One such activity, fishing, is especially prominent in Roman African mosaics. Two mosaics from the so-called "House of Ulysses" in Dougga combine mythological themes with fishing scenes. One mosaic depicts Ulysses' encounter with the Sirens, while the second represents the god Bacchus transforming his would-be kidnappers into dolphins. The fishing scenes are incorporated into the mythological scenes and show fishermen harvesting the adjacent waters. The details of these fishing scenes are striking considering the inland location of Dougga, some 60 miles (100 km) from the sea, in the middle of Roman Africa's agricultural heartland. The inclusion of these fishing scenes in the "House of Ulysses" mosaics suggests that the house's owner had a close connection with the sea, and perhaps alludes to the Roman infrastructure that would have brought marine products to the interior.
The Secret Joys of Chinon
Authors: bowman sharon
Published: November 2007

Far away from the shining poles of France's two major wine regions, Bordeaux and Burgundy, Chinon is hidden away in the Loire Valley. Its wines are just as secret. Are they intellectuals' wines, as Jules Romains wrote, rife with unexpected savors, or are they simple country quaffers? However the wines of Chinon are seen, they must first be seen at all. And once they are on the oenophile's horizon, they require a certain type of gaze. In a world that is witnessing an increasingly technical approach to wine, both in wine tasting and wine making, Chinon's Cabernet Franc charms are atavistic rather than "Parker friendly." Chinon is a bumpy path rather than a streamlined highway, and for those sensitive to its treasures, that is worth its weight in famous names, critics' points and high-alcohol "fruit-bombs."
A moment approach for the almost sure central limit theorem for martingales
Authors: Bercu Bernard , Fort Jean-Claude
Published: November 2007

We prove the almost sure central limit theorem for martingales via an original approach which uses the Carleman moment theorem together with the convergence of moments of martingales. Several statistical applications to autoregressive and branching processes are also provided.
Os Cimicídeos e sua importância em Saúde Pública (Hemiptera-Heteroptera; Cimicidae)
Authors: Forattini Oswaldo Paulo
Published: November 2007

Apresenta-se atualização de conhecimentos sobre insetos da família Cimicidae, ou percevejos, de interesse em saúde pública. Após fornecer elementos de morfologia, externa e interna, dedica-se atenção à biologia e ecologia desses insetos, em especial modo, focalizando o relacionamento com o homem e seu ambiente. As espécies Cimex lectularius e C. hemipterus são tratadas em particular, com revisão dos dados disponíveis sobre o possível papel vetor desses percevejos na transmissão de agentes infecciosos. São apresentados dados sobre a classificação e distribuição geográfica. Fornecem-se dados sobre meios de controle. Inclui chaves para identificação de formas adultas e imaturas, além de vestígios que possam servir de indícios para as atividades de vigilância epidemiológica.
Aplicação de uma metodologia de screening para avaliar a mortalidade por câncer em municípios selecionados do Estado de Minas Gerais, Brasil
Authors: Otero Ubirani B. , Antoniazzi Berenice N. , Veiga Lene H. S. , Turci Silvana R. , Mendonça Gulnar Azevedo e Silva
Published: November 2007

Iniciou-se uma investigação epidemiológica em municípios do sul de Minas Gerais, Brasil, considerando a possibilidade de aumento na incidência de câncer devido a maior exposição à radiação natural em alguns deles. Buscou-se, preliminarmente, conhecer o padrão de mortalidade por câncer, avaliar se existe excesso de óbitos e discutir os possíveis fatores de risco associados a esse aumento. Propõe-se uma metodologia de screening com base na razão de mortalidade padronizada (RMP) para classificar os municípios prioritários em estudos futuros. Os municípios considerados de altíssima prioridade para investigação foram: Andradas - câncer de pulmão em homens [RMP = 208 (106-310)] e fígado em mulheres [RMP = 403 (104-701)]; Poços de Caldas - leucemia em homens e mulheres (RMP = 284 (156-412) e RMP = 211 (111-312), respectivamente); Pouso Alegre - leucemia em homens [RMP = 333 (127-540)] e cânceres hematológicos em mulheres [RMP = 257 (188-396)].Estudos epidemiológicos devem ser conduzidos para avaliar a contribuição da radiação e outros fatores de riscos relacionados ao câncer e assim subsidiar futuras medidas de prevenção e controle.
Associação entre poluição atmosférica e doenças respiratórias e cardiovasculares na cidade de Itabira, Minas Gerais, Brasil
Authors: Braga Alfésio Luís Ferreira , Pereira Luiz Alberto Amador , Procópio Marly , André Paulo Afonso de , Saldiva Paulo Hilário do Nascimento
Published: November 2007

A cidade de Itabira, Minas Gerais, Brasil, está localizada na Serra do Espinhaço, onde existem grandes jazidas de minério de ferro que são extraídas em lavra mecanizada a céu aberto. Este estudo foi realizado para avaliar os efeitos agudos do material particulado inalável (PM10) sobre os atendimentos em pronto-socorro por doenças respiratórias e cardiovasculares no Município de Itabira. Modelos aditivos generalizados de regressão de Poisson foram utilizados, controlando-se para temperatura, umidade e sazonalidades de longa e curta duração. Aumentos de 10µg/m³ no PM10 foram associados com aumentos nos atendimentos de pronto-socorro por doenças respiratórias de 4% (IC95%: 2,2-5,8), no dia e no dia seguinte, para crianças menores de 13 anos, e de 12% (IC95%: 8,5-15,5), nos três dias subseqüentes para os adolescentes entre 13 e 19 anos. Dentre os atendimentos por doenças cardiovasculares, o efeito foi agudo (4%; IC95%: 0,8-8,5), principalmente para os indivíduos com idade entre 45 e 64 anos. Esses resultados mostram que o PM10 gerado principalmente através de mineração a céu aberto pode acarretar prejuízos à saúde da população exposta.
Decreased intelligence in children and exposure to fluoride and arsenic in drinking water
Authors: Rocha-Amador Diana , Navarro Maria Elena , Carrizales Leticia , Morales Raúl , Calderón Jaqueline
Published: November 2007

Recent evidence suggests that fluoride (F) and arsenic (As) may adversely affect intelligence quotient (IQ) scores. We explore the association between exposure to F and As in drinking water and intelligence in children. Three rural communities in Mexico with contrasting levels of F and As in drinking water were studied: Moctezuma (F 0.8±1.4mg/L; As 5.8±1.3µg/L); Salitral (F 5.3±0.9mg/L; As 169±0.9µg/L) and 5 de Febrero (F 9.4±0.9mg/L; As 194±1.3µg/L). The final study sample consisted of 132 children from 6 to 10 years old. After controlling for confounders, an inverse association was observed between F in urine and Performance, Verbal, and Full IQ scores (beta values = -13, -15.6, -16.9, respectively). Similar results were observed for F in drinking water (beta values = -6.7, -11.2, -10.2, respectively) and As in drinking water (beta values= -4.30, -6.40, -6.15, respectively). The p-values for all cases were < 0.001. A significant association was observed between As in urine and Full IQ scores (beta = -5.72, p = 0.003). These data suggest that children exposed to either F or As have increased risks of reduced IQ scores.