bluuebunny/crossref_metadata_2025 huggingface dataset:
Numbers needed to treat calculated from responder rates give a better indication of efficacy in osteoarthritis trials than mean pain scores
Authors: Moore R Andrew , Moore Owen A , Derry Sheena , McQuay Henry J
Published: April 2008

Introduction

Osteoarthritis trials usually report average changes in visual analogue scale (VAS) pain, and examine the difference between treatment and placebo. We investigated whether dichotomous responder analysis provides a more informative interpretation of drug efficacy.

Methods

Merck supplied the number of patients who, by 6 weeks, had achieved pain relief compared with a baseline of 0% or more, 10% or more, 20% or more, and so on at equal intervals up to 90% or more. These different levels of pain relief were used to distinguish different definitions of responders, for example at least 50% pain relief from baseline. Numbers and percentages of patients achieving each level were identified. Information was sought from a dose–response trial over 6 weeks in osteoarthritis using placebo and using etoricoxib at 5, 10, 30 and 60 mg daily.

Results

With placebo, the proportions of patients achieving at least 20%, 50% and 70% pain relief over baseline at 6 weeks were 30%, 11% and 2%. With 60 mg etoricoxib the equivalent percentages were 74%, 49% and 29%. The numbers needed to treat for 30 mg and 60 mg etoricoxib to produce at least 50% pain relief at 6 weeks compared with placebo were 4.2 (95% confidence interval 3.8 to 8.6) and 2.6 (2.0 to 3.9), respectively. Levels of pain relief of 50% and above discriminated best between different doses of etoricoxib.

Conclusion

Responder analysis seemed to be more sensitive than examination of average changes in VAS pain scores. Validation would require calculations to be performed on a set of trials using individual patient data not available in publications.
Risk factors for the development of nosocomial pneumonia and mortality on intensive care units: application of competing risks models
Authors: Wolkewitz Martin , Vonberg Ralf Peter , Grundmann Hajo , Beyersmann Jan , Gastmeier Petra , Bärwolff Sina , Geffers Christine , Behnke Michael , Rüden Henning , Schumacher Martin
Published: April 2008

Introduction

Pneumonia is a very common nosocomial infection in intensive care units (ICUs). Many studies have investigated risk factors for the development of infection and its consequences. However, the evaluation in most of theses studies disregards the fact that there are additional competing events, such as discharge or death.

Methods

A prospective cohort study was conducted over 18 months in five intensive care units at one university hospital. All patients that were admitted for at least 2 days were included, and surveillance of nosocomial pneumonia was conducted. Various potential risk factors (baseline- and time-dependent) were evaluated in two competing risks models: the acquisition of nosocomial pneumonia and discharge (dead or alive; model 1) and for the risk of death in the ICU and discharge alive (model 2).

Results

Patients from 1,876 admissions were included. A total of 158 patients developed nosocomial pneumonia. The main risk factors for nosocomial pneumonia in the multivariate analysis in model 1 were: elective surgery (cause-specific hazard ratio = 1.95; 95% CI 1.33 to 2.85) or emergency surgery (1.59; 95% CI 1.10 to 2.28) prior to ICU admission, usage of a nasogastric tube (3.04; 95% CI 1.25 to 7.37) and mechanical ventilation (5.90; 95% CI 2.47 to 14.09). Nosocomial pneumonia prolonged the length of ICU stay but was not directly associated with a fatal outcome (p = 0.55).

Conclusion

More studies using competing risk models, which provide more accurate data compared to naive survival curves or logistic models, should be carried out to verify the impact of risk factors and patient characteristics for the acquisition of nosocomial infections and infection-associated mortality.
Growth Hormone Decreases Visceral Fat and Improves Cardiovascular Risk Markers in Women with Hypopituitarism: A Randomized, Placebo-Controlled Study
Authors: Beauregard Catherine , Utz Andrea L. , Schaub Amber E. , Nachtigall Lisa , Biller Beverly M. K. , Miller Karen K. , Klibanski Anne
Published: April 2008

Context: Data regarding gender-specific efficacy of GH on critical endpoints are lacking. There are no randomized, placebo-controlled studies of physiological GH therapy solely in women.

Objective: Our objective was to determine the effects of physiological GH replacement on cardiovascular risk markers and body composition in women with GH deficiency (GHD).

Design: This was a 6-month, randomized, placebo-controlled, double-blind study.

Setting: The study was conducted at the General Clinical Research Center.

Study Participants: 43 women with GHD due to hypopituitarism were included in the study.

Intervention: Study participants were randomized to receive GH (goal mid-normal serum IGF-1) or placebo.

Main Outcome Measures: Cardiovascular risk markers, including high-sensitivity C-reactive protein, tissue plasminogen activator, and body composition, including visceral adipose tissue by cross-sectional computed tomography, were measured.

Results: Mean daily GH dose was 0.67 mg. The mean IGF-1 sd score increased from −2.5 ± 0.3 to −1.4 ± 0.9 (GH) (P < 0.0001 vs. placebo). High-sensitivity C-reactive protein decreased by 38.2 ± 9.6% (GH) vs.18.2 ± 6.0% (placebo) (P = 0.03). Tissue plasminogen activator and total cholesterol decreased, and high-density lipoprotein increased. Homeostasis model assessment-insulin resistance and other markers were unchanged. Body fat decreased [−5.1 ± 2.0 (GH) vs. 1.9 ± 1.0% (placebo); P = 0.002] as did visceral adipose tissue [−9.0 ± 5.9 (GH) vs. 4.3 ± 2.7% (placebo); P = 0.03]. Change in IGF-1 level was inversely associated with percent change in visceral adipose tissue (r = −0.61; P = 0.002), total body fat (r = −0.69; P < 0.0001), and high-sensitivity C-reactive protein (r = −0.51; P = 0.003).

Conclusions: Low-dose GH replacement in women with GHD decreased total and visceral adipose tissue and improved cardiovascular markers, with a relatively modest increase in IGF-1 levels and without worsening insulin resistance.
Inhibition of CYP21A2 Enzyme Activity Caused by Novel Missense Mutations Identified in Brazilian and Scandinavian Patients
Authors: Soardi F. C. , Barbaro M. , Lau I. F. , Lemos-Marini S. H. V. , Baptista M. T. M. , Guerra-Junior G. , Wedell A. , Lajic S. , de Mello M. P.
Published: April 2008

Background: Most patients with 21-hydroxylase deficiency carry CYP21A1P-derived mutations, but an increasing number of novel and rare mutations have been reported in disease-causing alleles.

Objective: Functional effects of three novel (p.G56R, p.L107R, p.L142P) and one recurrent (p.R408C) CYP21A2 mutations were investigated. The degree of enzyme impairment caused by p.H62L alone or combined to p.P453S was also analyzed.

Design: The study included 10 Brazilian and two Scandinavian patients. To determine the deleterious role of each mutant protein, in vitro assays were performed in transiently transfected COS-1 cells. For a correct genotype-phenotype correlation, the enzymatic activities were evaluated toward the two natural substrates, 17-hydroxyprogesterone and progesterone.

Results: Low levels of residual activities obtained for p.G56R, p.L107R, p.L142P, and p.R408C mutants classified them as classical congenital adrenal hyperplasia mutations, whereas the p.H62L showed an activity within the range of nonclassical mutations. Apparent kinetic constants for p.H62L confirmed the nonclassical classification as the substrate binding capacity was within the same magnitude for mutant and normal enzymes. A synergistic effect was observed for the allele bearing the p.H62L+p.P453S combination because it caused a significant reduction in the enzymatic activity.

Conclusions: We describe the functional analysis of five rare missense mutations identified in Brazilian and Scandinavian patients. The p.G56R, p.L107R, and p.L142P are reported for the first time. Most probably these novel mutations are closer to null than the p.I172N, but for the p.G56R, that might not be the case, and the p.H62L is definitely a nonclassical mutation.
Support for active citizenship and public service performance: an empirical analysis of English local authorities
Authors: Andrews Rhys , Cowell Richard , Downe James
Published: April 2008

Government efforts to increase civic engagement are predicated, in part, on the belief that this will lead to better public services. This assumption is tested by analysing the impact of different approaches to supporting active citizenship in English local authorities on their recorded service performance in 2005. Performance and support for active citizenship are modelled using data drawn from a national survey and secondary sources. The results suggest that councils which aim to promote understanding of citizenship among the public are more likely to have higher service performance, but that those which aim to increase citizen engagement in local governance are associated with lower performance in deprived areas.
Professional self-regulation in a changing architecture of governance: comparing health policy in the UK and Germany
Authors: Kuhlmann Ellen , Allsop Judith
Published: April 2008

This chapter compares transformations in professional self-regulation in the UK and Germany through the lens of governance. We introduce an expanded concept of governance that includes national configurations of state–;profession relationships and places selfregulation in the context of other forms of governance. The analysis shows that a general trend towards network governance plays out differently. In the UK, a plural structure of network governance and stakeholder arrangements is emerging in the context of stateled change. In Germany, partnership governance between sickness funds and medical associations shape the transformations and act as a barrier towards the entry of new players.
Daptomycin-Induced Acute Renal and Hepatic Toxicity Without Rhabdomyolysis
Authors: Abraham George , Finkelberg Dmitry , Spooner Linda M
Published: April 2008

Objective:

To report a case of a patient who experienced acute renal and hepatic toxicity following administration of daptomycin and review previously published case reports of renal and hepatic dysfunction with daptomycin.

Case Summary:

A 35-year-old man receiving daptomycin 4 mg/kg (275 mg) intravenously once daily (started 5 wk prior to presentation for presumed osteomyelitis) presented to the emergency department with elevations in serum creatinine and hepatic transaminase levels. He did not experience creatine kinase (CK) elevation or rhabdomyolysis. Following discontinuation of daptomycin, his renal and hepatic function improved.

Discussion:

To our knowledge, this is the first case of daptomycin-induced hepatotoxicity with acute renal failure in the absence of rhabdomyolysis and CK abnormalities. Previously published case reports described patients with a variety of elevations in liver function tests, serum creatinine, and CK with daptomycin. In our patient, the acute renal and hepatic toxicity was probable according to the Naranjo probability scale.

Conclusions:

Although daptomycin is a well-tolerated antibacterial agent, clinicians should consider periodic monitoring of liver function and renal function tests to identify potential adverse effects.
Very Late Stent Thrombosis After Dual Antiplatelet Therapy Discontinuation in a Patient with a History of Acute Stent Thrombosis
Authors: Bhatt Snehal H , Hauser Thomas H
Published: April 2008

Objective:

To describe a case of very late stent thrombosis after dual antiplatelet discontinuation in a patient with a previous history of stent thrombosis.

Case Summary:

A 62-year-old man with a history of coronary artery disease, multiple acute coronary syndromes requiring percutaneous coronary interventions with multiple stent placements, and acute stent thrombosis resulting in ST segment elevation myocardial infarction presented to the hospital with chest pain. The chest pain was not relieved by 4 sublingual nitroglycerin tablets. Five days prior to his presentation, the patient had been instructed to discontinue both aspirin and clopidogrel in preparation for a left ankle fusion procedure. He was taken to the cardiac catheterization laboratory where he was found to have thrombosis in a sirolimus-eluting stent placed more than 3 years ago. Thrombectomy and balloon angioplasty were performed, and the patient completed his hospital course without complications.

Discussion:

Stent thrombosis associated with drug-eluting stents is a complicated pathophysiologic phenomenon with multiple patient-, procedure-, and device-related factors. Application of these risk factors to quantify the risk of stent thrombosis as they apply to a single patient is unknown. Discontinuation of recommended dual antiplatelet therapy with aspirin plus a thienopyridine has been identified as a major risk factor for stent thrombosis, but the optimal duration of dual antiplatelet therapy remains unknown. Current recommendations suggest extending dual antiplatelet therapy beyond one year in patients with low bleeding risk.

Conclusions:

Given the overall data at this time and the severity of stent thrombosis, it seems prudent to continue dual antiplatelet therapy with aspirin indefinitely plus a thienopyridine for at least one year, with continuation beyond one year on a case-by-case basis depending on the risks of in-stent thrombosis and bleeding. In patients with a low risk of bleeding, indefinite continuation of dual antiplatelet therapy may be reasonable.
Appropriate Use of Dopamine Agonists and Levodopa in Restless Legs Syndrome in an Ambulatory Care Setting
Authors: Molokwu Ogochukwu Chidozie
Published: April 2008

Background:

Dopaminergic agents are the mainstay therapy for the management of restless tegs syndrome (RLS). There are no clear guidelines on RLS management, and no study has evaluated the appropriate use of dopaminergic agents in RLS.

Objective:

To evaluate the appropriateness of use of dopaminergic agents in RLS management in an ambulatory care setting based on the most current scientific evidence.

Methods:

A retrospective drug utilization evaluation was conducted in patients who received levodopa or dopamine agonist for RLS from July 1, 2006, to July 31, 2007. Patients’ medical records were reviewed and data were collected on demographics; comorbidities; laboratory values; doses of levodopa or dopamine agonists; prescribing physician's specialty; and use of alcohol, tobacco, and caffeine. RESULTS: A total of 27 patients were included in the study for data collection and analysis. Twenty-two (81%) patients were on levodopa and 5 (19%) were on ropinirole. RLS severity was documented in only 2 (7%) patients. Serum ferritin levels and transferrin-iron saturation (Tsat) percentages were not obtained in 18 (67%) and 20 (74%) of the patients, respectively. Two (7%) patients had ferritin levels less than 50 ng/mL, and 7 (26%) patients had ferritin levels greater than 50 ng/mL. Fourteen (52%) patients were taking concurrent antidepressants and 6 (22%) were taking sedating antihistamines. Alcohol and tobacco use was documented in 2 (7%) and 8 (30%) patients, respectively. Twenty-six (96%) of the prescribing physicians were primary care providers.

Conclusions:

The findings of this study confirm the need for provider education about the appropriate use of levodopa and dopamine agonists in patients with RLS. Appropriate use of these drugs may help decrease unnecessary adverse effects, complications, and costs.
Effects of a Mixture of Growth Factors and Proteins on the Development of the Osteogenic Phenotype in Human Alveolar Bone Cell Cultures
Authors: de Oliveira Paulo Tambasco , de Oliva Marcos Andrade , Amarú Maximiano William Marcatti , Vasconcelos Sebastião Karen Elaine , Crippa Grasiele Edilaine , Ciancaglini Pietro , Beloti Márcio Mateus , Nanci Antonio , Rosa Adalberto Luiz
Published: April 2008

Strategies to promote bone repair have included exposure of cells to growth factor (GF) preparations from blood that generally include proteins as part of a complex mixture. This study aimed to evaluate the effects of such a mixture on different parameters of the development of the osteogenic phenotype in vitro. Osteoblastic cells were obtained by enzymatic digestion of human alveolar bone and cultured under standard osteogenic conditions until subconfluence. They were subcultured on Thermanox coverslips up to 14 days. Treated cultures were exposed during the first 7 days to osteogenic medium supplemented with a GFs + proteins mixture containing the major components found in platelet extracts [platelet-derived growth factor-BB, transforming growth factor (TGF)-β1, TGF-β2, albumin, fibronectin, and thrombospondin] and to osteogenic medium alone thereafter. Control cultures were exposed only to the osteogenic medium. Treated cultures exhibited a significantly higher number of adherent cells from day 4 onward and of cycling cells at days 1 and 4, weak alkaline phosphatase (ALP) labeling, and significantly decreased levels of ALP activity and mRNA expression. At day 14, no Alizarin red–stained nodular areas were detected in cultures treated with GFs + proteins. Results were confirmed in the rat calvaria–derived osteogenic cell culture model. The addition of bone morphogenetic protein 7 or growth and differentiation factor 5 to treated cultures upregulated Runx2 and ALP mRNA expression, but surprisingly, ALP activity was not restored. These results showed that a mixture of GFs + proteins affects the development of the osteogenic phenotype both in human and rat cultures, leading to an increase in the number of cells, but expressed a less differentiated state.
Long-Distance Retrograde Effects of Botulinum Neurotoxin A
Authors: Antonucci Flavia , Rossi Chiara , Gianfranceschi Laura , Rossetto Ornella , Caleo Matteo
Published: April 2008

Botulinum neurotoxins (designated BoNT/A–BoNT/G) are bacterial enzymes that block neurotransmitter release by cleaving essential components of the vesicle fusion machinery. BoNT/A, which cleaves SNAP-25 (synaptosomal-associated protein of 25 kDa), is extensively exploited in clinical medicine to treat neuromuscular pathologies, facial wrinkles, and various types of pain. It is widely assumed that BoNT/A remains at the synaptic terminal and its effects are confined to the injection site. Here we demonstrate that catalytically active BoNT/A is retrogradely transported by central neurons and motoneurons and is then transcytosed to afferent synapses, in which it cleaves SNAP-25. SNAP-25 cleavage by BoNT/A was observed in the contralateral hemisphere after unilateral BoNT/A delivery to the hippocampus. Appearance of cleaved SNAP-25 resulted in blockade of hippocampal activity in the untreated hemisphere. Injections of BoNT/A into the optic tectum led to the appearance of BoNT/A-truncated SNAP-25 in synaptic terminals within the retina. Cleaved SNAP-25 also appeared in the facial nucleus after injection of the toxin into rat whisker muscles. Experiments excluded passive spread of the toxin and demonstrated axonal migration and neuronal transcytosis of BoNT/A. These findings reveal a novel pathway of BoNT/A trafficking in neurons and have important implications for the clinical uses of this neurotoxin.
Cyclin-Dependent Kinase 5 Phosphorylation of Human Septin SEPT5 (hCDCrel-1) Modulates Exocytosis
Authors: Amin Niranjana D. , Zheng Ya-Li , Kesavapany Sashi , Kanungo Jyotshnabala , Guszczynski Tad , Sihag Ram K. , Rudrabhatla Parvathi , Albers Wayne , Grant Philip , Pant Harish C.
Published: April 2008

Cyclin-dependent kinase 5 (Cdk5) is predominantly expressed in the nervous system, where it is involved in neuronal migration, synaptic transmission, and survival. The role of Cdk5 in synaptic transmission is mediated by regulating the cellular functions of presynaptic proteins such as synapsin, Munc18, and dynamin 1. Its multifunctional role at the synapse is complex and probably involves other novel substrates. To explore this possibility, we used a yeast two-hybrid screen of a human cDNA library with p35 as bait and isolated human septin 5 (SEPT5), known also as hCDCrel-1, as an interacting clone. Here we report that p35 associates with SEPT5 in GST (glutathioneS-transferase)-pull-down and coimmunoprecipitation assays. We confirmed that Cdk5/p35 phosphorylates SEPT5in vitroandin vivoand identified S327 of SEPT5 as a major phosphorylation site. A serine (S)-to-alanine (A) 327 mutant of SEPT5 bound syntaxin more efficiently than SEPT5 wild type. Additionally, coimmunoprecipitation from synaptic vesicle fractions and Cdk5 wild-type and knock-out lysates showed that phosphorylation of septin 5 by Cdk5/p35 decreases its binding to syntaxin-1. Moreover, mutant nonphosphorylated SEPT5 potentiated regulated exocytosis more than the wild type when each was expressed in PC12 cells. These data suggest that Cdk5 phosphorylation of human septin SEPT5 at S327 plays a role in modulating exocytotic secretion.
InDRG11Knock-Out Mice, Trigeminal Cell Death Is Extensive and Does Not Account for Failed Brainstem Patterning
Authors: Jacquin Mark F. , Arends Joop J. A. , Xiang Chuanxi , Shapiro Lee A. , Ribak Charles E. , Chen Zhou-Feng
Published: April 2008

A previous study (Ding et al., 2003) showed that the homeodomain transcription factorDRG11is necessary for pattern formation in the trigeminal nucleus principalis (PrV), the requisite brainstem nucleus for development of the whisker-to-barrel cortex pathway. However, it is not known howDRG11contributes to pattern formation. Anatomical studies were performed inDRG11knock-out (−/−) andDRG11/Baxdouble −/− mice to test the hypotheses thatDRG11is required for neuronal survival in the V pathway and that PrV cell death is sufficient to explain pattern alterations. At birth,DRG11−/−mice had equivalent cell loss in the V ganglion, PrV, and spinal V subnucleus interpolaris (SpVi). Because whisker-related patterns were normal in the SpVi, cell death would not appear to explain failed pattern formation in the mutant PrV. Electron microscopy revealed exuberant apoptosis and necrosis as the mechanisms of PrV cell death occurring in the late prenatal and newbornDRG11−/−, when such cell death was up to six times more prevalent than normal.DRG11heterozygote andBax−/−mice were crossed in an attempt to dissociate PrV patterning anomalies from exuberant apoptosis inDRG11−/−mice. BothDRG11−/−andDRG11/Baxdouble −/− mutants lacked whisker-related patterning in their PrV, despiteBax−/−-induced rescue of V ganglion and PrV cells. Thus, apoptotic cell death is not a sufficient cause of failed pattern formation in the PrV of theDRG11−/−. A signaling pathway involvingDRG11may, therefore, be the elusive PrV pattern maker.
Intermediate Progenitors in Adult Hippocampal Neurogenesis: Tbr2 Expression and Coordinate Regulation of Neuronal Output
Authors: Hodge Rebecca D. , Kowalczyk Thomas D. , Wolf Susanne A. , Encinas Juan M. , Rippey Caitlin , Enikolopov Grigori , Kempermann Gerd , Hevner Robert F.
Published: April 2008

Neurogenesis in the adult hippocampus is a highly regulated process that originates from multipotent progenitors in the subgranular zone (SGZ). Currently, little is known about molecular mechanisms that regulate proliferation and differentiation in the SGZ. To study the role of transcription factors (TFs), we focused on Tbr2 (T-box brain gene 2), which has been implicated previously in developmental glutamatergic neurogenesis. In adult mouse hippocampus, Tbr2 protein andTbr2-GFP(green fluorescent protein) transgene expression were specifically localized to intermediate-stage progenitor cells (IPCs), a type of transit amplifying cells. The Tbr2+ IPCs were highly responsive to neurogenic stimuli, more than doubling after voluntary wheel running. Notably, the Tbr2+ IPCs formed cellular clusters, the average size of which (Tbr2+ cells per cluster) likewise more than doubled in runners. Conversely, Tbr2+ IPCs were selectively depleted by antimitotic drugs, known to suppress neurogenesis. After cessation of antimitotic treatment, recovery of neurogenesis was paralleled by recovery of Tbr2+ IPCs, including a transient rebound above baseline numbers. Finally, Tbr2 was examined in the context of additional TFs that, together, define a TF cascade in embryonic neocortical neurogenesis (Pax6 → Ngn2 → Tbr2 → NeuroD → Tbr1). Remarkably, the same TF cascade was found to be linked to stages of neuronal lineage progression in adult SGZ. These results suggest that Tbr2+ IPCs play a major role in the regulation of adult hippocampal neurogenesis, and that a similar transcriptional program controls neurogenesis in adult SGZ as in embryonic cerebral cortex.
Functional Gradients of Auditory Sensitivity along the Anterior Ectosylvian Sulcus of the Cat
Authors: Las Liora , Shapira Ayelet-Hashahar , Nelken Israel
Published: April 2008

Determining the spatial direction of sound sources is one of the major computations performed by the auditory system. The anterior ectosylvian sulcus (AES) of cat cortex is known to be important for sound localization. However, there are contradicting reports as to the spatial response properties of neurons in AES: whereas some studies found narrowly tuned neurons, others reported mostly spatially widely tuned neurons. We hypothesized that this is the result of a nonhomogenous distribution of the auditory neurons in this area. To test this possibility, we recorded neuronal activity along the AES, together with a sample of neurons from primary auditory cortex (A1) of cats in response to pure tones and to virtual acoustic space stimuli. In all areas, most neurons responded to both types of stimuli. Neurons located in posterior AES (pAES) showed special response properties that distinguished them from neurons in A1 and from neurons in anterior AES (aAES). The proportion of space-selective neurons among auditory neurons was significantly higher in pAES (82%) than in A1 (72%) and in aAES (60%). Furthermore, whereas the large majority of A1 neurons responded preferentially to contralateral sounds, neurons in pAES (and to a lesser extent in aAES) had their spatial selectivity distributed more homogenously. In particular, 28% of the space-selective neurons in pAES had highly modulated frontal receptive fields, against 8% in A1 and 17% in aAES. We conclude that in cats, pAES contains a secondary auditory cortical field which is specialized for spatial processing, in particular for the representation of frontal space.
Somatostatin Receptor Subtype 4 Couples to the M-Current to Regulate Seizures
Authors: Qiu Cuie , Zeyda Thomas , Johnson Brian , Hochgeschwender Ute , de Lecea Luis , Tallent Melanie K.
Published: April 2008

The K+M-current (IM, Kv7) is an important regulator of cortical excitability, and mutations in these channels cause a seizure disorder in humans. The neuropeptide somatostatin (SST), which has antiepileptic properties, augmentsIMin hippocampal CA1 pyramidal neurons. We used SST receptor knock-out mice and subtype-selective ligands to investigate the receptor subtype that couples toIMand mediates the antiepileptic effects of SST. Using pentylenetetrazole as a chemoconvulsant,SST2,SST3, andSST4receptor knock-out mice all had shorter latencies to different seizure stages and increased seizure severity when compared with wild-type mice. However, the most robust differences were observed in theSST4knock-outs. When seizures were induced by systemic injection of kainate, onlySST4knock-outs showed an increase in seizure sensitivity. We next examined the action of SST and subtype-selective SST agonists on electrophysiological parameters in hippocampal slices of wild-type and receptor knock-out mice. SST2and SST4appear to mediate the majority of SST inhibition of epileptiform activity in CA1. SST lacked presynaptic effects in mouse CA1, in contrast to our previous findings in rat. SST increasedIMin CA1 pyramidal neurons of wild-type andSST2knock-out mice, but notSST4knock-out mice. Using M-channel blockers, we found that SST4coupling to M-channels is critical to its inhibition of epileptiform activity. This is the first demonstration of an endogenous enhancer ofIMthat is important in controlling seizure activity. SST4receptors could therefore be an important novel target for developing new antiepileptic and antiepileptogenic drugs.
Glutamatergic Contributions to Nicotinic Acetylcholine Receptor Agonist-Evoked Cholinergic Transients in the Prefrontal Cortex
Authors: Parikh Vinay , Man Kingson , Decker Michael W. , Sarter Martin
Published: April 2008

Because modulation of cortical cholinergic neurotransmission has been hypothesized to represent a necessary mechanism mediating the beneficial cognitive effects of nicotine and nicotinic acetylcholine receptor (nAChR) subtype-selective agonists, we used choline-sensitive microelectrodes for the real-time measurement of ACh releasein vivo, to characterize cholinergic transients evoked by nicotine and the α4β2*-selective nAChR partial agonist 2-methyl-3-(2-(S)-pyrrolindinylmethoxy)pyridine dihydrochloride (ABT-089), a clinically effective cognition enhancer. In terms of cholinergic signal amplitudes, ABT-089 was significantly more potent than nicotine in evoking ACh cholinergic transients. Moreover, cholinergic signals evoked by ABT-089 were characterized by faster signal rise time and decay rate. The nAChR antagonist mecamylamine attenuated the cholinergic signals evoked by either compound. Cholinergic signals evoked by ABT-089 were more efficaciously attenuated by the relatively β2*-selective nAChR antagonist dihydro-β-erythroidine. The α7 antagonist methyllycaconitine did not affect choline signal amplitudes but partly attenuated the relatively slow decay rate of nicotine-evoked cholinergic signals. Furthermore, the AMPA receptor antagonist DNQX as well as the NMDA receptor antagonist APV more potently attenuated cholinergic signals evoked by ABT-089. Using glutamate-sensitive microelectrodes to measure glutamatergic transients, ABT-089 was more potent than nicotine in evoking glutamate release. Glutamatergic signals were highly sensitive to tetrodotoxin-induced blockade of voltage-regulated sodium channels. Together, the present evidence indicates that compared with nicotine, ABT-089 evokes more potent and sharper cholinergic transients in prefrontal cortex. Glutamatergic mechanisms necessarily mediate the cholinergic effects of nAChR agonists in the prefrontal cortex.
Protein 600 Is a Microtubule/Endoplasmic Reticulum-Associated Protein in CNS Neurons
Authors: Shim Su Yeon , Wang Jian , Asada Naoyuki , Neumayer Gernot , Tran Hong Chi , Ishiguro Kei-ichiro , Sanada Kamon , Nakatani Yoshihiro , Nguyen Minh Dang
Published: April 2008

There is an increasing body of literature pointing to cytoskeletal proteins as spatial organizers and interactors of organelles. In this study, we identified protein 600 (p600) as a novel microtubule-associated protein (MAP) developmentally regulated in neurons. p600 exhibits the unique feature to interact with the endoplasmic reticulum (ER). Silencing of p600 by RNA interference (RNAi) destabilizes neuronal processes in young primary neurons undergoing neurite extension and containing scarce staining of the ER marker Bip. Furthermore,in uteroelectroporation of p600 RNAi alters neuronal migration, a process that depends on synergistic actions of microtubule dynamics and ER functions. p600-depleted migrating neurons display thin, crooked, and “zigzag” leading process with very few ER membranes. Thus, p600 constitutes the only known MAP to associate with the ER in neurons, and this interaction may impact on multiple cellular processes ranging from neuronal development to neuronal maturation and plasticity.
RPM-1, aCaenorhabditis elegansProtein That Functions in Presynaptic Differentiation, Negatively Regulates Axon Outgrowth by Controlling SAX-3/robo and UNC-5/UNC5 Activity
Authors: Li Haichang , Kulkarni Gauri , Wadsworth William G.
Published: April 2008

Changes in axon outgrowth patterns are often associated with synaptogenesis. Members of the conserved Pam/Highwire/RPM-1 protein family have essential functions in presynaptic differentiation. Here, we show thatCaenorhabditis elegansRPM-1 negatively regulates axon outgrowth mediated by the guidance receptors SAX-3/robo and UNC-5/UNC5. Loss-of-functionrpm-1mutations cause a failure to terminate axon outgrowth, resulting in an overextension of the longitudinal PLM axon. We observe that PLM overextension inrpm-1mutants is suppressed bysax-3andunc-5loss-of-function mutations. PLM axon overextension is also induced by SAX-3 overexpression, and the length of extension is enhanced by loss ofrpm-1function or suppressed by loss ofunc-5function. We also observe that loss ofrpm-1function in genetic backgrounds sensitized for guidance defects disrupts ventral AVM axon guidance in a SAX-3-dependent manner and enhances dorsal guidance of DA and DB motor axons in an UNC-5-dependent manner. Loss ofrpm-1function alters expression of the green fluorescent protein (GFP)-tagged proteins, SAX-3::GFP and UNC-5::GFP. RPM-1 is known to regulate axon termination through two parallel genetic pathways; one involves the Rab GEF (guanine nucleotide exchange factor) GLO-4, which regulates vesicular trafficking, and another that involves the F-box protein FSN-1, which mediates RPM-1 ubiquitin ligase activity. We show thatglo-4but notfsn-1mutations affect axon guidance in a manner similar to loss ofrpm-1function. Together, the results suggest that RPM-1 regulates axon outgrowth affecting axon guidance and termination by controlling the trafficking of the UNC-5 and SAX-3 receptors to cell membranes.
Presynaptic Calcium Channel Localization and Calcium-Dependent Synaptic Vesicle Exocytosis Regulated by the Fuseless Protein
Authors: Long A. Ashleigh , Kim Eunju , Leung Hung-Tat , Woodruff Elvin , An Lingling , Doerge R. W. , Pak William L. , Broadie Kendal
Published: April 2008

A systematic forward geneticDrosophilascreen for electroretinogram mutants lacking synaptic transients identified thefuseless(fusl) gene, which encodes a predicted eight-pass transmembrane protein in the presynaptic membrane. Nullfuslmutants display >75% reduction in evoked synaptic transmission but, conversely, an approximately threefold increase in the frequency and amplitude of spontaneous synaptic vesicle fusion events. These neurotransmission defects are rescued by a wild-typefusltransgene targeted only to the presynaptic cell, demonstrating a strictly presynaptic requirement for Fusl function. Defects in FM dye turnover at the synapse show a severely impaired exo-endo synaptic vesicle cycling pool. Consistently, ultrastructural analyses reveal accumulated vesicles arrested in clustered and docked pools at presynaptic active zones. In the absence of Fusl, calcium-dependent neurotransmitter release is dramatically compromised and there is little enhancement of synaptic efficacy with elevated external Ca2+concentrations. These defects are causally linked with severe loss of the Cacophony voltage-gated Ca2+channels, which fail to localize normally at presynaptic active zone domains in the absence of Fusl. These data indicate that Fusl regulates assembly of the presynaptic active zone Ca2+channel domains required for efficient coupling of the Ca2+influx and synaptic vesicle exocytosis during neurotransmission.
Brain Chromatin Remodeling: A Novel Mechanism of Alcoholism
Authors: Pandey Subhash C. , Ugale Rajesh , Zhang Huaibo , Tang Lei , Prakash Anand
Published: April 2008

The treatment of alcoholism requires the proper management of ethanol withdrawal symptoms, such as anxiety, to prevent further alcohol use and abuse. In this study, we investigated the potential role of brain chromatin remodeling, caused by histone modifications, in alcoholism. We found that the anxiolytic effects produced by acute alcohol were associated with a decrease in histone deacetylase (HDAC) activity and increases in acetylation of histones (H3 and H4), levels of CREB (cAMP-responsive element binding) binding protein (CBP), and neuropeptide Y (NPY) expression in the amygdaloid brain regions of rats. However, the anxiety-like behaviors during withdrawal after chronic alcohol exposure were associated with an increase in HDAC activity and decreases in acetylation of H3 and H4, and levels of both CBP and NPY in the amygdala. Blocking the observed increase in HDAC activity during alcohol withdrawal with the HDAC inhibitor, trichostatin A, rescued the deficits in H3 and H4 acetylation and NPY expression (mRNA and protein levels) in the amygdala (central and medial nucleus of amygdala) and prevented the development of alcohol withdrawal-related anxiety in rats as measured by the elevated plus maze and light/dark box exploration tests. These results reveal a novel role for amygdaloid chromatin remodeling in the process of alcohol addiction and further suggest that HDAC inhibitors may be potential therapeutic agents in treating alcohol withdrawal symptoms.
Acapulco in Dreams and Reality
Authors: Niblo Stephen R. , Niblo Diane M.
Published: April 2008

This article is an exploration of the development of Acapulco, primarily in the twentieth century. It looks at the political economy of the resort and its importance to the Mexican model of development. It also examines the myths, tourist promotion, and the place of Acapulco in popular culture.

Este artículo es una exploración del desarrollo de Acapulco, principalmente en el siglo veinte. Se estudia la economía política de ese centro turístico y su importancia para el modelo mexicano de desarrollo. Examina también los mitos, la promoción turística, y el lugar de Acapulco en la cultura popular.
Efficient Control of Population Structure in Model Organism Association Mapping
Authors: Kang Hyun Min , Zaitlen Noah A , Wade Claire M , Kirby Andrew , Heckerman David , Daly Mark J , Eskin Eleazar
Published: April 2008

Genomewide association mapping in model organisms such as inbred mouse strains is a promising approach for the identification of risk factors related to human diseases. However, genetic association studies in inbred model organisms are confronted by the problem of complex population structure among strains. This induces inflated false positive rates, which cannot be corrected using standard approaches applied in human association studies such as genomic control or structured association. Recent studies demonstrated that mixed models successfully correct for the genetic relatedness in association mapping in maize and Arabidopsis panel data sets. However, the currently available mixed-model methods suffer from computational inefficiency. In this article, we propose a new method, efficient mixed-model association (EMMA), which corrects for population structure and genetic relatedness in model organism association mapping. Our method takes advantage of the specific nature of the optimization problem in applying mixed models for association mapping, which allows us to substantially increase the computational speed and reliability of the results. We applied EMMA to in silico whole-genome association mapping of inbred mouse strains involving hundreds of thousands of SNPs, in addition to Arabidopsis and maize data sets. We also performed extensive simulation studies to estimate the statistical power of EMMA under various SNP effects, varying degrees of population structure, and differing numbers of multiple measurements per strain. Despite the limited power of inbred mouse association mapping due to the limited number of available inbred strains, we are able to identify significantly associated SNPs, which fall into known QTL or genes identified through previous studies while avoiding an inflation of false positives. An R package implementation and webserver of our EMMA method are publicly available.
Immunomodulator therapy migration in relapsing remitting multiple sclerosis: a study of 152 cases
Authors: Jordy Sergio Semeraro , Tilbery Charles Peter , Fazzito Mirella Martins
Published: April 2008

BACKGROUND: Since 1997, immunological modulators have been used for treatment of Relapsing Remitting Multiple Sclerosis (RRMS) in the Multiple Sclerosis Attendance and Treatment Center (CATEM) with significant alterations in this disease natural history. AIM: To add data on the experience of CATEM for the treatment of RRMS patients that had immunomodulators. METHOD: RRMS patients that received continuously immunomodulator drugs were evaluated on adherence, migration, withdrawal and progression rates. The patients were divided in three groups by the period of immunomodulators intake. RESULTS: There were registered in Group 1 withdrawal in 98 patients (25%) and adherence in 292 cases (74%); Group 2 interruption of therapy in 140 patients, 92 (31%) due to progression for PSMS, 14 (5%) for pregnancy, withdrawal in 34 (11%), adherence in 88%; Group 3 progression in 41 (26%), pregnancy in 3 (2%) withdrawal in 42 (27%) and adherence in 72%. The migration rate was about one third (31.57%) and the principal cause was therapeutic failure; the mean migrating time was 0.5-2.5 years in group 3. CONCLUSION: Immunomodulatory treatment for RRMS patients may have significant levels of failure and side effects; the adherence was compatible with the international literature.
Normative study of tympanic infrared thermometry: a non-invasive index of asymmetric cerebral activity
Authors: Landa Danielle Cicarini de , Brasil-Neto Joaquim P. , Boechat-Barros Raphael , Uribe Carlos
Published: April 2008

Human and primate studies have demonstrated that performance of tasks that induce asymmetrical physiological activation of the cerebral hemispheres leads to a reduction of tympanic temperature (TT) ipsilateral to the most active hemisphere. It is possible that diseases that interfere in an asymmetrical fashion with the degree of cerebral activity cause similar TT changes. There are not, however, normative studies of the acceptable interaural difference in TT in normal subjects at rest. This study was done to establish normative values for interaural TT values measured by means of infrared tympanic thermometry in resting normal subjects not engaged in any specific task. TT values were measured in 47 normal volunteers (20 men and 27 women, aged 39.38±12.57 years old) at rest; mean interaural differences of TT were calculated. Mean right ear TT was 36.85±0.50ºC and mean left ear TT was 36.74±0.57ºC; these values are in agreement with those already reported in the literature. Mean interaural TT difference was 0.25ºC (SD 0.21ºC). These findings indicate that maximal normal values for interaural TT differences, with confidence levels of 99% and 95%, are, respectively, 0.88 and 0.67ºC. The value of interaural differences of TT as a marker of asymmetrical hemispheric activity in neurological patients will have to be established by additional studies.
A brief historical note on the classification of nerve fibers
Authors: Manzano Gilberto M. , Giuliano Lydia M.P. , Nóbrega João A.M.
Published: April 2008

This is a brief review of the literature focused on the articles that formed the basis for the classification of the nerve fibers. Mention is also made to the origin of the nomenclature of the different motoneurons (a, b and g).
Trajetória e tendências dos cursos de enfermagem no Brasil
Authors: Teixeira Elizabeth , Vale Eucléia Gomes , Fernandes Josicelia Dumêt , De Sordi Mara Regina Lemes
Published: April 2008

O texto analisa a trajetória da educação em enfermagem no Brasil; analisa as tendências dos cursos de graduação (1991-2004) e traça um perfil do estudante de graduação de enfermagem que participou do Exame Nacional de Cursos (ENADE), em 2004. Para traçar o referido perfil são utilizados 18 indicadores sócio-familiares e acadêmicos dos respondentes do questionário do aluno. Apontam-se algumas perspectivas e desafios à educação em enfermagem no país, com vistas a subsidiar educadores e educandos na sua prática acadêmica.
A equipe de enfermagem e Maslow: (in)satisfações no trabalho
Authors: Vitória Regis Lorena Fagundes Ladeia , Porto Isaura Setenta
Published: April 2008

Este texto busca compreender as insatisfações da equipe de Enfermagem no trabalho. Propomos a associação com a teoria das necessidades humanas de Abraham Maslow como um meio de sistematizar e entender as situações recorrentes ao dia-a-dia e prática da Enfermagem. As necessidades estruturam-se hierarquicamente em fisiológicas, segurança, social, auto-estima e auto-realização indicando o grau de satisfação (da enfermidade à plenitude) de um indivíduo ou grupo. A vantagem desta abordagem consiste em podermos utilizar da solidez, profundidade e riqueza da teoria de Maslow em situações concretas e particulares da equipe de Enfermagem.
O método mãe-canguru sob o olhar problematizador de uma equipe neonatal
Authors: Costa Roberta , Monticelli Marisa
Published: April 2008

Este artigo tem como objetivo relatar a experiência do desenvolvimento de um processo educativo com uma equipe de saúde neonatal, sobre as potencialidades do Método Mãe-Canguru na assistência ao recém-nascido e família, a partir do referencial teórico-metodológico problematizador. Foram desenvolvidas doze oficinas, visando proporcionar ao grupo de profissionais a oportunidade de refletir sobre sua realidade, analisá-la de forma crítica, buscando compreendê-la e transformá-la. Os resultados apontaram a necessidade da criação de espaços para reflexões entre os profissionais da equipe neonatal sobre sua prática, possibilitando a transformação do modelo assistencial vigente e favorecendo o cuidado integral e individualizado aos recém-nascidos pré-termos e suas famílias.
Em busca de uma visão antropológica no Programa de Saúde da Família
Authors: Cortez Elaine Antunes , Tocantins Florence Romijn
Published: April 2008

Este estudo tem como objetivos: Analisar o Programa Saúde da Família enquanto estratégia de reorientação da atenção básica; Discutir a visão antropológica de saúde correlacionando-a com o PSF. Verificamos que existem dois elementos que são fundamentais no direcionamento do PSF, o conceitual e o estrutural, que influenciam diretamente no âmbito institucional e, por conseguinte no cuidado. Considerando-se os fortes fatores que facilitam a mudança no processo de saúde e doença, as perspectivas que devem ser sinalizadas devem ser apoiadas na busca de uma visão antropológica de saúde como ferramenta para a efetivação de fato da Estratégia Saúde da Família, de forma que possamos oferecer com uma assistência/cuidado prestado de qualidade.
Assistência de enfermagem a um paciente portador de Diabetes Mellitus
Authors: Faeda Alessandra , Leon Cassandra Genoveva Rosales Martins Ponce de
Published: April 2008

Trata-se de um estudo de caso, desenvolvido num Centro de Saúde, do Distrito Federal, com o propósito de relatar a Assistência de Enfermagem a um paciente com Diabetes Mellitus. Para desenvolver este estudo foi aplicado o Processo de Enfermagem, nas etapas: Coleta de Dados; Diagnósticos de Enfermagem; Planejamento; Intervenções e Avaliação da Assistência proporcionada. Os Diagnósticos encontrados foram: Controle Ineficaz do Regime Terapêutico; Adaptação prejudicada; Imagem Corporal perturbada e Risco para Integridade da Pele Prejudicada. O Planejamento da Assistência de enfermagem visou principalmente contribuir para a adesão ao tratamento e diminuir riscos potenciais, fazendo uso da educação para saúde. Com a interação e o uso da comunicação terapêutica, observou-se uma pequena mudança nos hábitos de vida do paciente.