bluuebunny/crossref_metadata_2025 huggingface dataset:
Human resources requirements for highly active antiretroviral therapy scale-up in Malawi
Authors: Muula Adamson S , Chipeta John , Siziya Seter , Rudatsikira Emmanuel , Mataya Ronald H , Kataika Edward
Published: December 2007

Background

Twelve percent of the adult population in Malawi is estimated to be HIV infected. About 15% to 20% of these are in need of life saving antiretroviral therapy. The country has a public sector-led antiretroviral treatment program both in the private and public health sectors. Estimation of the clinical human resources needs is required to inform the planning and distribution of health professionals.

Methods

We obtained data on the total number of patients on highly active antiretroviral treatment program from the Malawi National AIDS Commission and Ministry of Health, HIV Unit, and the number of registered health professionals from the relevant regulatory bodies. We also estimated number of health professionals required to deliver highly active antiretroviral therapy (HAART) using estimates of human resources from the literature. We also obtained data from the Ministry of Health on the actual number of nurses, clinical officers and medical doctors providing services in HAART clinics. We then made comparisons between the human resources situation on the ground and the theoretical estimates based on explicit assumptions.

Results

There were 610 clinicians (396 clinical officers and 214 physicians), 44 pharmacists and 98 pharmacy technicians and 7264 nurses registered in Malawi. At the end of March 2007 there were 85 clinical officer and physician full-time equivalents (FTEs) and 91 nurse FTEs providing HAART to 95,674 patients. The human resources used for the delivery of HAART comprised 13.9% of all clinical officers and physicians and 1.1% of all nurses. Using the estimated numbers of health professionals from the literature required 15.7–31.4% of all physicians and clinical officers, 66.5–199.3% of all pharmacists and pharmacy technicians and 2.6 to 9.2% of all the available nurses. To provide HAART to all the 170,000 HIV infected persons estimated as clinically eligible would require 4.7% to 16.4% of the total number of nurses, 118.1% to 354.2% of all the available pharmacists and pharmacy technicians and 27.9% to 55.7% of all clinical officers and physicians. The actual number of health professionals working in the delivery of HAART in the clinics represented 44% to 88.8% (for clinical officers and medical doctors) and 13.6% and 47.6% (for nurses), of what would have been needed based on the literature estimation.

Conclusion

HAART provision is a labour intensive exercise. Although these data are insufficient to determine whether HAART scale-up has resulted in the weakening or strengthening of the health systems in Malawi, the human resources requirements for HAART scale-up are significant. Malawi is using far less human resources than would be estimated based on the literature from other settings. The impact of HAART scale-up on the overall delivery of health services should be assessed.
Hypoxia transcriptionally induces macrophage-inflammatory protein-3α/CCL-20 in primary human mononuclear phagocytes through nuclear factor (NF)-κB
Authors: Battaglia Florinda , Delfino Silvana , Merello Elisa , Puppo Maura , Piva Roberto , Varesio Luigi , Bosco Maria Carla
Published: December 2007

Hypoxia, a condition of low oxygen tension, occurring in many pathological processes, modifies the mononuclear phagocyte transcriptional profile. Here, we demonstrate hypoxic up-regulation of the CCL20 chemokine in primary human monocytes (Mn) and macrophages. mRNA induction was paralleled by protein secretion and dependent on gene transcription activation. Functional studies of the CCL20 promoter using a series of 5′-deleted and mutated reporter constructs demonstrated the requirement for the NF-κB-binding site located at position –92/–82 for gene transactivation by hypoxia, as 1) transcription was abrogated by a 3-bp mutation of the NF-κB motif; 2) three copies of the wild-type NF-κB-binding site conferred hypoxia responsiveness to a minimal heterologous promoter; and 3) hypoxia increased specific NF-κB binding to this sequence. Furthermore, we provide evidence of the specific role of a single NF-κB family member, p50, in mediating CCL20 gene transcription in hypoxic Mn. p50 homodimers were the only detectable NF-κB complexes binding the cognate κB site on the CCL20 promoter upon hypoxia exposure, and NF-κBp50 knockdown by lentiviral-mediated short hairpin RNA interference resulted in complete binding inhibition. NF-κBp50 overexpression in transient cotransfection studies promoted CCL20 gene transactivation, which was abrogated by mutation of the –92/–82 κB site. Moreover, nuclear expression of the other NF-κB family members was inhibited in hypoxic Mn. In conclusion, this study characterizes a previously unrecognized role for hypoxia as a transcriptional inducer of CCL20 in human mononuclear phagocytes and highlights the importance of the NF-κB pathway in mediating this response, with potential implications for inflammatory disease and cancer pathogenesis.
Constitutive activation of SHP2 protein tyrosine phosphatase inhibits ICSBP-induced transcription of the gene encoding gp91PHOX during myeloid differentiation
Authors: Zhu Chunliu , Lindsey Stephan , Konieczna Iwonna , Eklund Elizabeth A
Published: December 2007

The IFN consensus sequence-binding protein (ICSBP; also referred to as IFN regulatory factor 8) is a transcription factor which is expressed in myeloid and B cells. In previous studies, we found that ICSBP activated transcription of the gene encoding gp91PHOX (the CYBB gene), a rate-limiting component of the phagocyte respiratory burst oxidase expressed exclusively after the promyelocyte stage of myelopoiesis. Previously, we found that CYBB transcription was dependent on phosphorylation of specific ICSBP tyrosine residues. Since ICSBP is tyrosine-phosphorylated during myelopoiesis, this provided a mechanism of differentiation stage-specific CYBB transcription. In the current studies, we found that ICSBP was a substrate for Src homology-containing tyrosine phosphatase 2 (SHP2-PTP) in immature myeloid cells but not during myelopoiesis. Therefore, SHP2-PTP inhibited CYBB transcription and respiratory burst activity in myeloid progenitor cells by dephosphorylating ICSBP. In contrast, we found that ICSBP was a substrate for a leukemia-associated, constitutively active mutant form of SHP2, described previously, throughout differentiation. Consistent with this, constitutive SHP2 activation blocked ICSBP-induced CYBB transcription and respiratory burst activity in differentiating myeloid cells. ICSBP-deficiency and constitutive SHP2 activation have been described in human myelodysplastic syndromes. As these two abnormalities may coexist, our results identified a potential molecular mechanism for impaired phagocyte function in this malignant myeloid disease.
Pseudo-3D imaging of a low-slip-rate, active normal fault using shallow geophysical methods: The Geleen fault in the Belgian Maas River valley
Authors: Vanneste Kris , Verbeeck Koen , Petermans Toon
Published: December 2007

In a detailed site survey for paleoseismic trenching, we applied shallow geophysical prospecting techniques, including ground-penetrating radar (GPR), electric resistivity tomography (ERT), and resistivity mapping to identify, locate, and visualize in 3D the Geleen fault, an active normal fault bordering the Roer Valley graben in northeast Belgium. Because of a low slip rate, the geomorphic expression of this fault is very faint in the relatively young deposits of the Maas River valley. ERT profiles show the fault as a broad, near-vertical anomaly characterized by sharp lateral resistivity contrasts, with an associated vertical offset of sediment layers. We observed offsets of [Formula: see text] and [Formula: see text] for the base and top, respectively, of a middle-late Pleistocene fluvial gravel layer. Shallow ERT and GPR profiles indicate that younger sediments are also affected by faulting, but the amount and sense of offset appear to be conflicting: ERT profiles show a near-surface, high-resistivity layer with an apparent reverse offset, and GPR profiles portray the fault as a sharp and laterally consistent disruption of reflectors, often without a clearly identifiable offset. Resistivity maps at different depths map the fault as a narrow, linear, lateral resistivity gradient matching the anomalies observed with other techniques. This method proved to be efficient in determining the precise position and orientation of dip-slip faults, and could potentially be very useful for the identification of lateral changes in fault geometry, such as splays and step-overs. Subsequent trenching confirmed the presence of a normal fault at the location predicted by the geophysical survey. Correlation with the sediments exposed on the trench walls demonstrated that, close to the surface, resistivity and dielectric permittivity contrasts mostly occur in a postdepositional soil, which developed differently on either side of the fault. This explains why shallow geophysical variations do not reflect the true fault offset.
A 2.5D finite-element-modeling difference method for marine CSEM modeling in stratified anisotropic media
Authors: Kong F. N. , Johnstad S. E. , Røsten T. , Westerdahl H.
Published: December 2007

We have developed a 2.5D finite-element modeling (FEM) method for marine controlled-source electromagnetic (CSEM) applications in stratified anisotropic media. The main feature of the method is that delta sources are used to solve the governing partial differential equations for cases with and without a resistive target and to obtain the difference of these two solutions as the scattered field from the target. The total field is then the sum of the analytical background field calculated with a 1D modeling method and the difference or scattered field mentioned above. Compared with a conventional direct solution (using delta sources directly in a 2.5D formulation), the new method has smaller near-field error as a result of the source singularity and smaller boundary reflections. The new method does not require a dense mesh in the source region, which thereby reduces the total number of variables to be solved. In this way, the modeling time can be kept within a few minutes for some cases. We show that the maximum relative error of the calculation can be kept within 2% for targets at depths of approximately [Formula: see text]. The method is valid for stratified anisotropic media. The anisotropic modeling examples show that (1) marine CSEM is predominantly sensitive to target vertical resistivity and not to target horizontal resistivity, provided that the targets are thin, horizontal, high-resistivity layers and (2) marine CSEM is sensitive to the horizontal resistivity of the conductive sediments surrounding the target (e.g., the overburden).
Early Detection of Insulin Sensitivity and β-Cell Function with Simple Tests Indicates Future Derangements in Late Pregnancy
Authors: Lapolla A. , Dalfrà M. G. , Mello G. , Parretti E. , Cioni R. , Marzari C. , Masin M. , Ognibene A. , Messeri G. , Fedele D. , Mari A. , Pacini G.
Published: December 2007

Objective: Insulin sensitivity and secretion during early and late pregnancy were assessed in women with normal glucose tolerance and gestational diabetes mellitus (GDM).

Research Design and Methods: The oral glucose tolerance test (OGTT) was performed in 903 women at 16–20th gestational week, of whom 37 had GDM (GDM1 group), and 859 repeated the OGTT at wk 26–30. At the second test, 55 had GDM (GDM2 group); the others remained normotolerant (ND group). Insulin sensitivity from OGTT (as quantitative insulin sensitivity check index and OGTT insulin sensitivity) and β-cell function (as the ratio of the areas under the insulin and glucose concentration curves, adjusted for insulin sensitivity) were assessed in both tests.

Results: In early pregnancy the quantitative insulin sensitivity check index was not different in the three groups, whereas OGTT insulin sensitivity was lowest in GDM2, intermediate in GDM1, and highest in ND. In late pregnancy both indices were reduced in GDM compared with ND and lower than in early pregnancy. In early pregnancy GDM1, but not GDM2, had lower β-cell function than ND. During the late visit, GDM2 also showed impaired β-cell function compared with ND; furthermore, the adaptation to the increase to insulin resistance from early to late pregnancy was defective in GDM2.

Conclusions: In early pregnancy insulin sensitivity, as assessed from the OGTT but not from fasting measurements, is impaired in women who developed GDM. β-Cell function impairment is evident only when GDM is manifest and is characterized by inappropriate adaptation to the pregnancy induced increase in insulin resistance.
Preimplantation Genetic Diagnosis for Severe Albright Hereditary Osteodystrophy
Authors: Lietman Steven A. , Goldfarb James , Desai Nina , Levine Michael A.
Published: December 2007

Context: Preimplantation genetic diagnosis (PGD) enables the selection of embryos without mutations for implantation and has not been described to our knowledge for mutations in GNAS. Phocomelia in a patient with Albright hereditary osteodystrophy (AHO) has also not been previously described.

Objective: The aim of this study was to identify a GNAS mutation in a patient with a severe form of AHO and pseudohypoparathyroidism type 1a with phocomelia and to perform PGD on embryos derived by in vitro fertilization to deliver an unaffected infant.

Design: A proband and his family are described clinically, the GNAS gene was sequenced to identify a novel mutation in the proband, and PGD was performed on embryos.

Setting: The setting was in a tertiary-care hospital.

Patients: The patients were from a single family in which the proband has a severe form of AHO.

Interventions: Interventions were PGD and in vitro fertilization.

Main Outcome Measures: The main outcome measures were the clinical phenotypes and GNAS gene sequences of the proband, embryos, and family members.

Results: After PGD, three genotypically normal embryos were transferred back to the mother. Pregnancy ensued, and a healthy male infant was delivered at 36.5 wk gestation. The GNAS genes in the baby were confirmed as wild-type, and the infant is free of any signs of AHO.

Conclusions: We describe herein a proband with AHO and severe skeletal deformities (including phocomelia) related to a novel GNAS mutation and the delivery of a male infant with homozygous normal GNAS genotype after PGD.
Synthesis, Structure, and Properties of Alkaline-earth-substituted Tungstogermanate: [K2.5(H2O)1.5]2H3[Ca2(GeW11O39)(H2O)5]2·7H2O
Authors: Wang Jingping , Han Ruijuan , Du Xiaodi , Niu Jingyang
Published: December 2007

A novel alkaline-earth-metal-substituted tungstogermanate derivative [K2.5(H2O)1.5]2H3[Ca2(GeW11O39)(H2O)5]2·7H2O (1) has been synthesized and characterized by IR, UV spectroscopy, ICP, TG, electrochemical behavior, and X-ray diffraction. The title compound consists of an infinite 2D arrangement built up of [α-GeW11O39]8− anions connected by alkaline earth metal cation CaII.
Note—Further Improvements on Base-Stock Approximations for Independent Stochastic Lead Times with Order Crossover
Authors: Robinson Lawrence W. , Bradley James R.
Published: December 2007

When inventory replenishments can arrive in a different sequence than the one in which they were placed, it is important to use the shortfall distribution to set the base-stock level. Because the exact shortfall distribution is quite difficult to compute, heuristics are commonly used in its stead. Bradley and Robinson [Bradley, J. R., L. W. Robinson. 2005. Improved base-stock approximations for independent stochastic lead times with order crossover. Manufacturing Service Oper. Management 7 319–329.] developed an upper bound on the variance of the number of outstanding orders that they used within a normal approximation of the shortfall distribution. In this short note, we tighten their upper bound and use it within a beta approximation of the shortfall distribution to derive a policy whose costs average only 0.05% above that of the optimal.
On the Choice-Based Linear Programming Model for Network Revenue Management
Authors: Liu Qian , van Ryzin Garrett
Published: December 2007

Gallego et al. [Gallego, G., G. Iyengar, R. Phillips, A. Dubey. 2004. Managing flexible products on a network. CORC Technical Report TR-2004-01, Department of Industrial Engineering and Operations Research, Columbia University, New York.] recently proposed a choice-based deterministic linear programming model (CDLP) for network revenue management (RM) that parallels the widely used deterministic linear programming (DLP) model. While they focused on analyzing “flexible products”—a situation in which the provider has the flexibility of using a collection of products (e.g., different flight times and/or itineraries) to serve the same market demand (e.g., an origin-destination connection)—their approach has broader implications for understanding choice-based RM on a network. In this paper, we explore the implications in detail. Specifically, we characterize optimal offer sets (sets of available network products) by extending to the network case a notion of “efficiency” developed by Talluri and van Ryzin [Talluri, K. T., G. J. van Ryzin. 2004. Revenue management under a general discrete choice model of consumer behavior. Management Sci. 50 15–33.] for the single-leg, choice-based RM problem. We show that, asymptotically, as demand and capacity are scaled up, only these efficient sets are used in an optimal policy. This analysis suggests that efficiency is a potentially useful approach for identifying “good” offer sets on networks, as it is in the case of single-leg problems. Second, we propose a practical decomposition heuristic for converting the static CDLP solution into a dynamic control policy. The heuristic is quite similar to the familiar displacement-adjusted virtual nesting (DAVN) approximation used in traditional network RM, and it significantly improves on the performance of the static LP solution. We illustrate the heuristic on several numerical examples.
Load-Based POLCA: An Integrated Material Control System for Multiproduct, Multimachine Job Shops
Authors: Vandaele Nico , Van Nieuwenhuyse Inneke , Claerhout Diederik , Cremmery Rony
Published: December 2007

This article proposes a supporting framework for the implementation of the material control system POLCA (paired-cell overlapping loops of cards with authorization). The POLCA system is particularly appropriate for environments that involve highly variable demand and large product variety, which force small batch (or even one-of-a-kind) production. We propose a load-based version of the POLCA control system (LB-POLCA), which determines the POLCA parameters (release authorizations, allowed workloads in the loops) according to an advanced resources planning (ARP) system that adequately captures the stochastic behavior of the production system and enables fine-tuning and high-level optimization of the manufacturing lot sizes. We also discuss the implementation of an electronic LB-POLCA system in a metal shop of Spicer Off-Highway Products Division, a subsidiary of the Dana Corporation.
Characterization of Globin RNA Interference in Gene Expression Profiling of Whole-Blood Samples
Authors: Wright Christopher , Bergstrom Donald , Dai Hongyue , Marton Matthew , Morris Mark , Tokiwa George , Wang Yanqun , Fare Thomas
Published: December 2007

Background: Blood-based biomarker discovery with gene expression profiling has been hampered by interference from endogenous, highly abundant α- and β-globin transcripts. We describe a means to quantify the interference of globin transcripts on profiling and the effectiveness of globin transcript mitigation by (a) defining and characterizing globin interference, (b) reproducing globin interference with synthetic transcripts, and (c) using ROC curves to measure sensitivity and specificity for a protocol for removing α- and β-globin transcripts.

Methods: We collected blood at 2 sites and extracted total RNA in PreAnalytiX PAXgene tubes. As a reference for characterizing interference, we supplemented aliquots of total RNA with synthesized globin transcripts and total RNA from human brain. Selected aliquots were processed with Ambion GLOBINclear to remove globin transcripts. All aliquots were labeled and hybridized to Agilent DNA microarrays by means of pooling schemes designed to quantify the mitigation of globin interference and to titrate gene expression signatures. Quantitative reverse transcription–PCR data were generated for comparison with microarray results.

Results: Our supplementation and pooling strategy for comparing the microarray data among samples demonstrated that mitigation could reduce an interference signature of >1000 genes to approximately 200. Analysis of samples of endogenous globin transcripts supplemented with brain RNA indicated that results obtained with the GLOBINclear treatment approach those of peripheral blood mononuclear cell preparations.

Conclusion: We confirmed that both the absolute concentrations of globin transcripts and differences in transcript concentrations within a sample set are factors that cause globin interference (Genes Immun 2005;6:588–95). The methods and transcripts we have developed may be useful for quantitatively characterizing globin mRNA interference and its mitigation.
Plasma Uric Acid and the Risk of Type 2 Diabetes in a Chinese Community
Authors: Chien Kuo-Liong , Chen Ming-Fong , Hsu Hsiu-Ching , Chang Wei-Tien , Su Ta-Chen , Lee Yuan-Teh , Hu Frank B
Published: December 2007

Background: Previous cross-sectional studies have shown hyperuricemia to be prevalent among individuals with metabolic syndrome, but the evidence from prospective studies of an association between uric acid and diabetes risk is limited. We prospectively investigated the association between plasma concentrations of uric acid and the incidence of type 2 diabetes in Chinese individuals.

Methods: We conducted a community-based prospective cohort study of 2690 participants (age range, 35–97 years) in the Chin-Shan Community Cardiovascular Cohort Study, who were found to be free of diabetes and cardiovascular disease during baseline assessment at study entry in 1990. During a median 9.0-year follow-up, 548 participants developed type 2 diabetes.

Results: High plasma uric acid concentrations were associated with a higher prevalence of metabolic syndrome. After adjustment for age, sex, body mass index, and other covariates, the relative risks (RR) of diabetes according to uric acid quintile were 1.11, 1.29, 1.40, and 1.63 [95% confidence interval (CI), 1.20–2.23; P for trend <0.001]. After additional adjustment for metabolic syndrome, the RR for comparing the participants in the fifth and first uric acid quintiles was 1.40 (95% CI, 1.02–1.92; P for trend = 0.027). In joint analyses, participants who were in the highest uric acid quintile and also had metabolic syndrome had a 3.3-fold greater risk of diabetes (95% CI, 2.27–4.94) than those in the lowest uric acid quintile and without metabolic syndrome.

Conclusions: These findings suggest a modest positive association between plasma uric acid concentration and the incidence of type 2 diabetes in Chinese individuals. The association between hyperuricemia and diabetes was partly mediated through the metabolic syndrome.
The role of universities in the evolution of the Triple Helix culture of innovation network: The case of Malaysia
Authors: Razak Azley Abd , Saad Mohammed
Published: December 2007

Using a qualitative and a case study approach, this paper examines the role of the Malaysian universities and their social relationships with government and industry in the light of the statist, laissez-faire and hybrid characters of the Triple Helix model. Most Malaysian universities
are positioned within the statist and laissezfaire variants of the Triple Helix model, where the government is invariably a dominant actor. Overall, universities in Malaysia have made efforts to see social relationships evolve; however, there are still issues to be addressed and difficulties
to be overcome with respect to such questions as commercialisation and procedures that would need to evolve within the university for transition to hybrid Triple Helix culture to take root.
Differential Trafficking of AMPA and NMDA Receptors during Long-Term Potentiation in Awake Adult Animals
Authors: Williams Joanna M. , Guévremont Diane , Mason-Parker Sara E. , Luxmanan Carthika , Tate Warren P. , Abraham Wickliffe C.
Published: December 2007

Despite a wealth of evidencein vitrothat AMPA receptors are inserted into the postsynaptic membrane during long-term potentiation (LTP), it remains unclear whether this occursin vivoat physiological concentrations of receptors. To address the issue of whether native AMPA or NMDA receptors undergo such trafficking during LTP in the adult brain, we examined the synaptic and surface expression of glutamate receptor subunits during the early induction phase of LTP in the dentate gyrus of awake adult rats. Induction of LTP was accompanied by a rapid NMDA receptor-dependent increase in surface expression of glutamate receptor 1–3 (GluR1–3) subunits. However, in the postsynaptic density fraction only GluR1 accumulated. GluR2/3-containing AMPA receptors, in contrast, were targeted exclusively to extrasynaptic sites in a protein synthesis-dependent manner. NMDA receptor subunits exhibited a delayed accumulation, both at the membrane surface and in postsynaptic densities, that was dependent on protein synthesis. These data suggest that trafficking of native GluR1-containing AMPA receptors to synapses is important for early-phase LTP in awake adult animals, and that this increase is followed homeostatically by a protein synthesis-dependent trafficking of NMDA receptors.
The EphA4 Receptor Regulates Neuronal Morphology through SPAR-Mediated Inactivation of Rap GTPases
Authors: Richter Melanie , Murai Keith K. , Bourgin Caroline , Pak Daniel T. , Pasquale Elena B.
Published: December 2007

Eph receptors play critical roles in the establishment and remodeling of neuronal connections, but the signaling pathways involved are not fully understood. We have identified a novel interaction between the C terminus of the EphA4 receptor and the PDZ domain of the GTPase-activating protein spine-associated RapGAP (SPAR). In neuronal cells, this binding mediates EphA4-dependent inactivation of the closely related GTPases Rap1 and Rap2, which have recently been implicated in the regulation of dendritic spine morphology and synaptic plasticity. We show that SPAR-mediated inactivation of Rap1, but not Rap2, is critical for ephrin-A-dependent growth cone collapse in hippocampal neurons and decreased integrin-mediated adhesion in neuronal cells. Distinctive effects of constitutively active Rap1 and Rap2 on the morphology of growth cones and dendritic spines support the idea that these two GTPases have different functions in neurons. Together, our data implicate SPAR as an important signaling intermediate that links the EphA4 receptor with Rap GTPase function in the regulation of neuronal morphology.
Neural Substrates of Abstinence-Induced Cigarette Cravings in Chronic Smokers
Authors: Wang Ze , Faith Myles , Patterson Freda , Tang Kathy , Kerrin Kia , Wileyto E. Paul , Detre John A. , Lerman Caryn
Published: December 2007

Craving is a hallmark of drug dependence, including dependence on nicotine. Many studies have examined the neural substrates of cravings elicited by smoking-related cues. Less is known about the neural basis of unprovoked, abstinence-induced cravings, despite the contributions of such cravings to smoking relapse. To fill this gap, we used arterial spin labeled (ASL) perfusion magnetic resonance imaging to characterize the neural substrates of abstinence-induced cravings to smoke. Fifteen chronic smokers were scanned during a resting state on two separate occasions: (1) smoking satiety and (2) abstinence (after ≥12 h of smoking deprivation), in counterbalanced order. Smoking abstinence state (vs satiety) was associated with increased cerebral blood flow (CBF) in anterior cingulate cortex (ACC)/medial orbitofrontal cortex (OFC) and left OFC. Abstinence-induced cravings to smoke were predicted by CBF increases (abstinence minus satiety) in the right OFC, right dorsolateral prefrontal cortex, occipital cortex, ACC, ventral striatum/nucleus accumbens, thalamus, amygdala, bilateral hippocampus, left caudate, and right insula. These data suggest that increased activation in the brain's visuospatial and reward circuitry underlies abstinence-induced cravings to smoke, and thereby, may be important in relapse.
Vigorous Motor Activity inCaenorhabditis elegansRequires Efficient Clearance of Dopamine Mediated by Synaptic Localization of the Dopamine Transporter DAT-1
Authors: McDonald Paul W. , Hardie Shannon L. , Jessen Tammy N. , Carvelli Lucia , Matthies Dawn Signor , Blakely Randy D.
Published: December 2007

The catecholamine dopamine (DA) functions as a powerful modulatory neurotransmitter in both invertebrates and vertebrates. As in man, DA neurons in the nematodeCaenorhabditis elegansexpress a cocaine-sensitive transporter (DAT-1), presumably to regulate synaptic DA signaling and limit DA spillover to extrasynaptic sites, although evidence supporting this is currently lacking. In this report, we describe and validate a novel and readily quantifiable phenotype, swimming-induced paralysis (SWIP) that emerges in DAT-1-deficient nematodes when animals exert maximal physical activity in water. We verify the dependence of SWIP on DA biosynthesis, vesicular packaging, synaptic release, and on the DA receptor DOP-3. Using DAT-1 specific antibodies and GFP::DAT-1 fusions, we demonstrate a synaptic enrichment of DAT-1 that is achieved independently of synaptic targeting of the vesicular monoamine transporter (VMAT). Importantly,dat-1deletions and point mutations that disrupt DA uptake in culturedC. elegansneurons and/or impact DAT-1 synaptic localizationin vivogenerate SWIP. SWIP assays, along within vivoimaging of wild-type and mutant GFP::DAT-1 fusions identify a distal COOH terminal segment of the transporter as essential for efficient somatic export, synaptic localization andin vivoDA clearance. Our studies provide the first description of behavioral perturbations arising from altered trafficking of DATsin vivoin any organism and support a model whereby endogenous DA actions inC. elegansare tightly regulated by synaptic DAT-1.
Synaptic Strength of Individual Spines Correlates with Bound Ca2+–Calmodulin-Dependent Kinase II
Authors: Asrican Brent , Lisman John , Otmakhov Nikolai
Published: December 2007

Both synaptic strength and spine size vary from spine to spine, but are strongly correlated. This gradation is regulated by activity and may underlie information storage. Ca2+-calmodulin-dependent kinase II (CaMKII) is critically involved in the regulation of synaptic strength and spine size. The high amount of the kinase in the postsynaptic density has suggested that the kinase has a structural role at synapses. We demonstrated previously that the bound amount of CaMKIIα in spines persistently increases after induction of long-term potentiation, prompting the hypothesis that this amount may correlate with synaptic strength. To test this hypothesis we combined two recently developed methods, two-photon uncaging of glutamate for determining the EPSC of individual spines (uEPSC) and quantitative microscopy for measuring bound CaMKIIα in the same spines. We found that under basal conditions the relative bound amount of CaMKIIα varied over a 10-fold range and positively correlated with the uEPSC. Both the bound amount of CaMKIIα in spines and uEPSC also positively correlated with spine size. Interestingly, the bound CaMKIIα fraction (bound/total CaMKIIα in spines) remained remarkably constant across all spines. The results are consistent with the hypothesis that bound CaMKII serves as a structural organizer of postsynaptic molecules and thereby may be involved in maintaining spine size and synaptic strength.
The G59S Mutation in p150gluedCauses Dysfunction of Dynactin in Mice
Authors: Lai Chen , Lin Xian , Chandran Jayanth , Shim Hoon , Yang Wan-Jou , Cai Huaibin
Published: December 2007

The G59S missense mutation at the conserved microtubule-binding domain of p150glued, a major component of dynein/dynactin complex, has been linked to an autosomal dominant form of motor neuron disease (MND). To study how this mutation affects the function of the dynein/dynactin complex and contributes to motor neuron degeneration, we generated p150gluedG59S knock-in mice. We found that the G59S mutation destabilizes p150gluedand disrupts the function of dynein/dynactin complex, resulting in early embryonic lethality of homozygous knock-in mice. Heterozygous knock-in mice, which developed normally, displayed MND-like phenotypes after 10 months of age, including excessive accumulation of cytoskeletal and synaptic vesicle proteins at neuromuscular junctions, loss of spinal motor neurons, increase of reactive astrogliosis, and shortening of gait compared with wild-type littermates and age-matched p150gluedheterozygous knock-out mice. Our findings indicate that the G59S mutation in p150gluedabrogates the normal function of p150gluedand accelerates motor neuron degeneration.
The Impact of Catechol-O-Methyltransferase and Dopamine D4 Receptor Genotypes on Neurophysiological Markers of Performance Monitoring
Authors: Krämer Ulrike M. , Cunillera Toni , Càmara Estela , Marco-Pallarés Josep , Cucurell David , Nager Wido , Bauer Peter , Schüle Rebecca , Schöls Ludger , Rodriguez-Fornells Antoni , Münte Thomas F.
Published: December 2007

Dynamic adaptations of one's behavior by means of performance monitoring are a central function of the human executive system, that underlies considerable interindividual variation. Converging evidence from electrophysiological and neuroimaging studies in both animals and humans hints at the importance of the dopaminergic system for the regulation of performance monitoring. Here, we studied the impact of two polymorphisms affecting dopaminergic functioning in the prefrontal cortex [catechol-O-methyltransferase (COMT) Val108/158Met and dopamine D4 receptor (DRD4) single-nucleotide polymorphism (SNP)-521] on neurophysiological correlates of performance monitoring. We applied a modified version of a standard flanker task with an embedded stop-signal task to tap into the different functions involved, particularly error monitoring, conflict detection and inhibitory processes. Participants homozygous for the DRD4Tallele produced an increased error-related negativity after both choice errors and failed inhibitions compared withC-homozygotes. This was associated with pronounced compensatory behavior reflected in higher post-error slowing. No group differences were seen in the incompatibility N2, suggesting distinct effects of the DRD4 polymorphism on error monitoring processes. Additionally, participants homozygous for the COMTValallele, with a thereby diminished prefrontal dopaminergic level, revealed increased prefrontal processing related to inhibitory functions, reflected in the enhanced stop-signal-related components N2 and P3a. The results extend previous findings from mainly behavioral and neuroimaging data on the relationship between dopaminergic genes and executive functions and present possible underlying mechanisms for the previously suggested association between these dopaminergic polymorphisms and psychiatric disorders as schizophrenia or attention deficit hyperactivity disorder.
TASK Channels Determine pH Sensitivity in Select Respiratory Neurons But Do Not Contribute to Central Respiratory Chemosensitivity
Authors: Mulkey Daniel K. , Talley Edmund M. , Stornetta Ruth L. , Siegel Audra R. , West Gavin H. , Chen Xiangdong , Sen Neil , Mistry Akshitkumar M. , Guyenet Patrice G. , Bayliss Douglas A.
Published: December 2007

Central respiratory chemoreception is the mechanism by which the CNS maintains physiologically appropriate pH and PCO2via control of breathing. A prominent hypothesis holds that neural substrates for this process are distributed widely in the respiratory network, especially because many neurons that make up this network are chemosensitivein vitro. We and others have proposed that TASK channels (TASK-1, K2P3.1 and/or TASK-3, K2P9.1) may serve as molecular sensors for central chemoreception because they are highly expressed in multiple neuronal populations in the respiratory pathway and contribute to their pH sensitivityin vitro. To test this hypothesis, we examined the chemosensitivity of two prime candidate chemoreceptor neuronsin vitroand tested ventilatory responses to CO2using TASK channel knock-out mice. The pH sensitivity of serotonergic raphe neurons was abolished in TASK channel knock-outs. In contrast, pH sensitivity of neurons in the mouse retrotrapezoid nucleus (RTN) was fully maintained in a TASK null background, and pharmacological evidence indicated that a K+channel with properties distinct from TASK channels contributes to the pH sensitivity of rat RTN neurons. Furthermore, the ventilatory response to CO2was completely retained in single or double TASK knock-out mice. These data rule out a strict requirement for TASK channels or raphe neurons in central respiratory chemosensation. Furthermore, they indicate that a non-TASK K+current contributes to chemosensitivity of RTN neurons, which are profoundly pH-sensitive and capable of driving respiratory output in response to local pH changesin vivo.
Avaliação da radioiodoterapia com doses fixas de 10 e 15 mCi em pacientes com doença de graves
Authors: Canadas Viviane , Vilar Lucio , Moura Eliane , Brito Ana , Castellar Ênio
Published: December 2007

As opções terapêuticas para a hipertireoidismo da doença de Graves são as drogas antitireoidianas, a cirurgia e o radioiodo, porém nenhuma delas é considerada ideal pois não atuam diretamente na etiopatogênese da doença. O radioiodo vem sendo cada vez mais utilizado como primeira escolha, sendo um tratamento definitivo, seguro e de fácil administração. Há autores que preferem doses mais altas para induzir deliberadamente o hipotireoidismo, enquanto outros recomendam doses mais baixas que, a curto prazo, implicam menor incidência de hipotireoidismo e maior de eutireoidismo. Não há consenso sobre o melhor esquema de doses fixas a ser utilizado, sendo esse o principal enfoque deste estudo, no qual comparamos doses de 10 e 15 mCi. Dos 164 pacientes analisados, 61 (37,2%) foram submetidos a 10 mCi e 103 (62,8%), a 15 mCi de 131I. Na análise longitudinal, observou-se que a remissão do hipertireoidismo foi estatisticamente diferente no sexto mês (p < 0,001), sendo maior no grupo em que foi empregada a dose de 15 mCi. Contudo, foi semelhante nos dois grupos após 12 e 24 meses. É possível concluir que doses fixas de 10 e 15 mCi promovem semelhante remissão do hipertireoidismo após 12 meses de tratamento. A remissão do hipertireoidismo não teve associação com idade, sexo ou uso prévio de drogas antitireoidianas.
Increased diagnostic probability of subclinical cushing’s syndrome in a population sample of overweight adult patients with type 2 diabetes mellitus
Authors: Caetano Maria Silvia S. , Silva Regina do Carmo , Kater Claudio E.
Published: December 2007

Endogenous Cushing’s Syndrome (CS) is unusual. Patients with subclinical CS (SCS) present altered cortisol dynamics without obvious manifestations. CS occurs in 2-3% of obese poorly controlled diabetics. We studied 103 overweight adult outpatients with type 2 diabetes to examine for cortisol abnormalities and SCS. All collected salivary cortisol at 23:00 h and salivary and serum cortisol after a 1 mg dexamethasone suppression test (DST). Patients whose results were in the upper quintile for each test (253 ng/dL, 47 ng/dL, and 1.8 mg/dL, respectively for the 23:00 h and post-DST saliva and serum cortisol) were re-investigated. Average values from the upper quintile group were 2.5-fold higher than in the remaining patients. After a confirmatory 2 mg x 2 day DST the investigation for CS was ended for 61 patients with all normal tests and 33 with only one (false) positive test. All 8 patients who had two abnormal tests had subsequent normal 24h-urinary cortisol, and 3 of them were likely to have SCS (abnormal cortisol tests and positive imaging). However, a final diagnosis could not to be confirmed by surgery or pathology. Although not confirmatory, the results of this study suggest that the prevalence of SCS is considerably higher in populations at risk than in the general population.
Apo B/Apo A-I ratio in central and peripheral arterial diseases
Authors: Lima Luciana M. , Carvalho Maria das Graças , Sabino Adriano de P. , Mota Ana P.L. , Fernandes Ana P. , Sousa Marinez O.
Published: December 2007

BACKGROUND: The apo B/apo A-I ratio represents the balance between atherogenic particles, rich in apo B, and the antiatherogenic ones, apo A-I rich. This study investigated the association between atherosclerotic diseases in different anatomical sites and apo B/apo A-I ratio. METHODS: Lipids, lipoproteins, and apolipoproteins A-I and B were assessed in 30 subjects with coronary artery disease (CAD), 26 with ischemic stroke (IS), 30 with peripheral arterial obstructive disease (PAOD), and 38 healthy subjects (controls). RESULTS: HDLc and Apo A-I were significantly lower in PAOD and CAD groups, respectively, than in other groups. Significantly higher levels of triglycerides were observed for CAD and PAOD groups than for controls. Apo B was significantly higher in IS group than in control and PAOD groups. The apo B/apo A-I ratio showed significantly higher in CAD and IS groups when compared to control and PAOD groups (p < 0.001). CONCLUSION: The apo B/apo A-I ratio was important for identifying an increased trend for coronary and cerebral atherosclerosis. In spite of the increased trend for apo B/apo A-I ratio in IS and CAD groups, the studied variables cannot be considered in an isolated way, given as those parameters were analyzed together by a binary logistic regression, no association has been demonstrated.
Discordant results in Tc-99m tetrofosmin and Tc-99m sestamibi parathyroid scintigraphies
Authors: Duarte Paulo Schiavom , Domingues Fernanda C. , Costa Michele Santi , Brandão Cynthia , Oliveira Marco A.C. de , Vieira José G.H.
Published: December 2007

Parathyroid scintigraphies have been used to detect pathological parathyroid glands either before as well as after the parathyroid resection surgery in patients with hyperparathyroidism. One of the most utilized techniques to perform the studies is the double-phase images with Tc-99m sestamibi, which has been shown to be very accurate in the localization of enlarged parathyroid glands. Similar to Tc-99m sestamibi, Tc-99m tetrofosmin is a radiopharmaceutical initially developed to perform myocardial perfusion study that has been used to perform parathyroid scintigraphies. Although most of the papers suggest that the overall sensitivities of both radiopharmaceuticals are similar, there are some papers questioning the accuracy of Tc-99m tetrofosmin to detect abnormal parathyroid glands. In the present article, we report a case with discordant results by both methods.
Aplicação parcelada de calcário na cultura do algodoeiro
Authors: Ferraz Carlos A. M. , Rodrigues Filho Francisco S. O. , Cia Edivaldo , Silva Nélson Machado Da , Sabino Nelson P.
Published: December 2007

Ensaios de campo foram conduzidos por um período de seis anos agrícolas, de 1967/68 a 1972/73, em latossolo roxo, no Centro Experimental de Campinas para estudar os efeitos de diferentes modos de aplicação de calcário e seu efeito residual na cultura do algodoeiro. Os tratamentos comparados foram os seguintes: sem aplicação de calcário; dose total de calcário aplicada no primeiro ano; metade da dose aplicada no primeiro ano e metade no segundo; um terço da dose aplicada no primeiro ano, um terço no segundo e um terço no terceiro; metade da dose aplicada no primeiro ano e metade no terceiro ano. Todos os tratamentos em presença de uma adubação mineral NPK. A dose total de calcário foi de 4,5 t/ha. A avaliação do efeito da aplicação de calcário foi feita pela produção de algodão em caroço, pelas características de produção (peso de 1 capulho, peso de 100 sementes e porcentagem de fibra) e pelas características tecnológicas de fibra (comprimento, uniformidade, Pressley e Micronaire). Os resultados revelam que houve efeito significativo devido à aplicação de calcário sobre a produção do algodoeiro, não tendo sido, no entanto, detectado efeito entre os diferentes modos de parcelamentos estudados. Os aumentos de produção variaram de 18 a 25%, em relação à testemunha sem calcário. O efeito residual do calcário foi significativo apenas para as aplicações feitas metade da dose no 1.° ano e metade no 2.° e um terço da dose em cada ano, em relação à testemunha sem calcário; os demais tratamentos não diferiram dessa testemunha. Não foi verificado efeito da aplicação de calcário, nem efeito residual, sobre as características de produção e tecnológicas da fibra.
Competição de cultivares de feijoeiro em Mococa e Monte Alegre do Sul
Authors: Almeida Luiz D'Artagnan de , Bulisani Eduardo Antônio , Alves Sebastião , Rocha Túlio Ribeiro da
Published: December 2007

Visando à escolha de melhores cultivares de feijoeiro para cultivo na época denominada "das águas", para a região Serrana da Mantiqueira no Estado de São Paulo, foram instalados durante quatro anos ensaios de competição de cultivares em solo podzólico vermelho-amarelo, Orto nos Municípios de Mococa e Monte Alegre do Sul, Foram testados os cultivares carioca, bico-de-ouro, rosinha G-2, pintado, chumbinho-opaco, preto G-l e rico-230. Em média das oito experiências, o cultivar carioca apresentou produção significativamente maior que as demais. Pintado, chumbinho-opaco e rico-23 formaram um grupo intermediário. Bico-de-ouro, preto G-l e rosinha G-2 foram os de menor produção. Em Mococa o cultivar carioca apresentou produção significativamente superior aos demais; já em Monte Alegre do Sul sua produção foi, no entanto, semelhante à do rico-23 e pintado. Devido ao seu comportamento, o cultivar carioca pode ser recomendado para plantio na região.
Melhoramento do cafeeiro: XXXVII - Observações sobre a resistência do cafeeiro ao bicho-mineiro
Authors: Medina Filho H. P. , Carvalho A. , Mônaco L. C.
Published: December 2007

Diversos cultivares, híbridos e retrocruzamentos no gênero Coffea foram, avaliados, em condições de campo, quanto à resistência ao ataque pelo bicho-mineiro. Entre as espécies diplóides observou-se acentuada variabilidade quanto ao grau de infestação. As espécies C. eugenioides, C. dewevrei, C. racemosa, C. liberica, C. kapakata apresentaram reduzida porcentagem de folhas atacadas, enquanto C. stenophylla mostrou-se praticamente imune. As espécies C. canephora e C. congensis revelaram-se suscetíveis. Altos índices de infestação foram também verificados para os cultivares e variedades de C. arabica, com exceção da variedade mokka. Não se verificaram diferenças de infestação em plantas com graus variáveis de ploidía, as quais apresentam a espessura variável da lâmina foliar ou com folhas de tamanhos diferentes. O exame das populações híbridas sugere que a resistência ao ataque pelo bicho-mineiro seja de natureza dominante, não se podendo tirar conclusões sobre o número de genes envolvidos. Considerações sobre o tipo de ação gênica controlando essas características e sugestões para o aproveitamento dessa resistência ao melhoramento de C. arabica e C. canephora são discutidas.