bluuebunny/crossref_metadata_2025 huggingface dataset:
Copeptin in the Differential Diagnosis of Hyponatremia
Authors: Fenske Wiebke , Störk Stefan , Blechschmidt Anne , Maier Sebastian G. K. , Morgenthaler Nils G. , Allolio Bruno
Published: November 2008

Background: Treatment of patients with hyponatremia varies widely; thus, convenient diagnostic parameters are needed to guide the correct treatment strategy. This study was designed to evaluate the diagnostic potential of copeptin, the C-terminal part of provasopressin, as a new marker in the differential diagnosis of hyponatremia.

Methods: In this prospective observational study, 106 consecutive hyponatremic patients were classified based on their history, clinical evaluation, and laboratory tests. In patients and 32 healthy control subjects, plasma copeptin concentration and standard biochemical parameters were tested for their utility of diagnosing the syndrome of inappropriate antidiuresis (SIAD).

Results: Four patients (4%) were diagnosed as primary polydipsia, nine (8%) as diuretic-induced hyponatremia, 42 (40%) as SIAD, 29 (27%) as hypovolemic hyponatremia, and 22 patients (21%) as hypervolemic hyponatremia. In controls, a close correlation between plasma copeptin and serum sodium (r2 = 0.62, P < 0.001) or urine osmolality (r2 = 0.39, P = 0.001) was observed. Plasma copeptin levels were significantly higher in patients with hypo- and hypervolemic hyponatremia compared with SIAD (P < 0.005, respectively) and primary polydipsia (P < 0.001). The copeptin to U-Na ratio differentiated accurately between volume-depleted and normovolemic disorders (area under the receiver-operating characteristic curve 0.88, 95% confidence interval 0.81–0.95; P < 0.001), resulting in a sensitivity and specificity of 85 and 87% if a cutoff value of 30 pmol/mmol was used. The combined information of plasma copeptin less than 3 pmol/liter and urine osmolality less than 200 mOsm/kg ensured primary polydipsia in 100% of suspected patients.

Conclusion: Copeptin measurement reliably identifies patients with primary polydipsia but has limited utility in the differential diagnosis of other hyponatremic disorders. In contrast, the copeptin to U-Na ratio is superior to the reference standard in discriminating volume-depleted from normovolemic hyponatremic disorders.
Novel functions of the CD34 family
Authors: Nielsen Julie S. , McNagny Kelly M.
Published: November 2008

For almost 30 years, the cell-surface protein CD34 has been widely used as a marker to assist in the identification and isolation of hematopoietic stem cells (HSCs) and progenitors in preparation for bone-marrow transplantation. In addition, it has increasingly been used as a marker to help identify other tissue-specific stem cells, including muscle satellite cells and epidermal precursors. Despite its utility as a stem-cell marker, however, the function of CD34 has remained remarkably elusive. This is probably because: (1) it is subject to a range of tissue-specific post-transcriptional and post-translational modifications that are expected to alter its function dramatically; (2) the simple interpretation of CD34 gain- and loss-of-function experiments has been confounded by the overlapping expression of the two recently discovered CD34-related proteins podocalyxin and endoglycan; and (3) there has been a glaring lack of robust in vitro and in vivo functional assays that permit the structural and functional analysis of CD34 and its relatives. Here, we provide a brief review of the domain structure, genomic organization, and tissue distribution of the CD34 family. We also describe recent insights from gain- and loss-of-function experiments and improved assays, which are elucidating a fascinating role for these molecules in cell morphogenesis and migration.
A DyI3-catalyzed Mannich-type Reaction of 1-Methylcyclopropanecarboxylate-type Donors for the Stereoselective Synthesis of Pyrrolidines with Quaternary Stereocenters
Authors: Noda Hidetoshi , Wiedemann Sean H , Matsunaga Shigeki , Shibasaki Masakatsu
Published: November 2008

Stereoselective synthesis of functionalized pyrrolidines with all-carbon quaternary stereocenters is described. DyI3 catalyzed the ring opening of cyclopropanecarboxylate equivalents and promoted Mannich-type addition of the resulting α,α-disubstituted enolate intermediates to aryl and isomerizable alkyl imines, giving products in 86–58% yield and >96:4–84:16 diastereoselectivity.
Functionalized Antibodies as Biosensing Materials and Catalysts
Authors: Yamaguchi Hiroyasu , Harada Akira
Published: November 2008

Monoclonal antibodies have been prepared against water-soluble porphyrins, viologen derivatives, and transition-metal complexes, respectively. These monoclonal antibodies were utilized to devise biosensing and catalytic systems.
Synthesis of Stable cis-Dichloro- and cis-Dimethylplatinum(II) Complexes Bearing Bulky Primary Phosphines and Introduction of an Alkyl Group on the Primary Phosphine Ligand
Authors: Sasamori Takahiro , Kawai Masahiro , Takeda Nobuhiro , Tokitoh Norihiro
Published: November 2008

Stable cis-dichloro- and cis-dimethylplatinum(II) complexes bearing bulky primary phosphines, such as BbtPH2 (Bbt = 2,6-bis[bis(trimethylsilyl)methyl]-4-[tris(trimethylsilyl)methyl]phenyl) and TbtPH2 (Tbt = 2,4,6-tris[bis(trimethylsilyl)methyl]phenyl), were synthesized and isolated as stable compounds. The treatment of cis-[PtMe2(PH2Bbt)2] with lithium diisopropylamide (LDA) followed by the addition of an alkyl halide afforded the corresponding alkylated complexes, cis-[PtMe2(PHRBbt)(PH2Bbt)] (R=Me, Et, Bu, etc.). The spectroscopic observation of the intermediacy of the lithiated complex, cis-[PtMe2(PHLiBbt)(PH2Bbt)], has been accomplished.
Catalytic Excavation and Graphitization of Activated Carbon by Cobalt Nanoparticles
Authors: Iwazaki Tomoya , Semba Toshiro , Konishi Shunsuke , Sezai Takahiro , Murakami Yasushi , Sugimoto Wataru , Takasu Yoshio
Published: November 2008

Cobalt nanoparticles loaded on an activated carbon catalytically excavated the activated carbon when it was heat-treated in a 1 atm stream of a mixture of hydrogen and argon gases at high temperature. The BET surface area of the activated carbon decreased from 2210 to 1750 m2 g−1, and the mesopore volume increased from 0.14 to 0.25 cm3 g−1 by heat-treatment at 900 °C for 8 h. As for the XRD pattern of the heat-treated specimen, diffraction peaks from the turbostratic carbon phase were observed. This phase was confirmed by TEM both around the cobalt particles and the walls of the pores formed by the excavation.
Synthesis and Characterization of a Temperature-responsive Amphiphilic Block Copolymer Containing a Liquid Crystalline Unit
Authors: Nishihara Masamichi , Murakami Yoshihiko , Shinoda Takashi , Yamamoto Jun , Yokoyama Masayuki
Published: November 2008

To create a stimuli-responsive micelle, we synthesized a novel temperature-responsive amphiphilic block copolymer, poly(ethylene glycol)-block-poly{6-[4-(4-pyridylazo)phenoxy]hexyl methacrylate} [PEG-b-P(AzoPyl)], by undertaking the RAFT polymerization of an AzoPyl monomer with a PEG macro-RAFT reagent. This block copolymer possesses a liquid crystalline unit derived from a hydrophobic AzoPyl/carboxylic acid complex. The PEG-b-P(AzoPyl/decanoic acid (C9COOH)) complex formed a micelle structure (weight-average diameter = 68 nm). DSC results confirmed that the PEG-b-P(AzoPyl/C9COOH) micellar solution exhibited thermodynamic phase-transition behavior.
Abrupt Spin Transitions and LIESST Effects Observed in FeII Spin-crossover Complexes with Extended π-Conjugated Schiff-base Ligands Having N4O2 Donor Sets
Authors: Kuroda-Sowa Takayoshi , Yu Zhong , Senzaki Yuka , Sugimoto Kunihisa , Maekawa Masahiko , Munakata Megumu , Hayami Shinya , Maeda Yonezo
Published: November 2008

Novel FeII complexes with N4O2 donor sets having extended π-conjugated aromatic rings, [Fe(qnal)2]·CH2Cl2 and [Fe(qnal)2], show abrupt spin transitions at 220 and 265 K, respectively. Both complexes show LIESST effects below 80 K.
ASGBI fellows and surgical specialisation: who is doing what?
Authors: Scott N , Finan P , Shorthouse A , MacFie J
Published: November 2008

Four generations ago a practical textbook of British operative surgery instructed the 'general surgeon' in the techniques of abdominal, orthopaedic, neurosurgical, ophthalmic and facial-maxillary procedures. Inevitable change in the intervening years has seen an evolution of multiple surgical specialties from this corpus, each in turn recognised by appropriate training structures and specialised practice.
Workforce planning in general surgery: problems ahead?
Authors: Davies J , Kallam R , MacFie J
Published: November 2008

One of the factors that led to the Modernising Medical Careers (MMC)/Medical Training Application Service disaster of 2007 was the discrepancy between the numbers of applicants and the actual number of posts available for appointment. In its submission to the Tooke enquiry, the Workforce Review Team stated that 'workforce planning needs to be at the core of any changes to a medical career structure (and that) in general this should be demand, not supply, led'. In an attempt to predict opportunities for general surgery over the next five years we have estimated demand from numbers of consultant appointments advertised and supply from numbers of specialist registrars (national training numbers (NTNs)).
News from the specialist library
Authors: Setterfield Polly , Sams Stefanie
Published: November 2008

During the summer months (if you could call it that), the Specialist Library for Surgery, Theatres and Anaesthesia team have been preparing for the library's expansion into critical care, have published guest editorials and a mini topic review and have delivered an annual evidence update on a surgical topic. We also followed the publication of the final report of Lord Darzi's NHS Next Stage Review with interest as it has a direct bearing on the future of our service. In the article below we provide you with a summary of our recent work and an indication of our future.
Levelling the playing field: the future of the FRCS (Tr & Orth) exam
Authors: Caesar B , David L
Published: November 2008

The processes of formal assessment and examination in the UK have become increasingly convoluted over the past few years, whether at school, in higher education, or as a senior orthopaedic trainee sitting the ISB examination at fellowship level in trauma and orthopaedics. Although rationalising the ever-expanding methods of assessment inflicted upon medical students and postgraduate doctors by various government departments is not within our remit, we can endeavour to shed light on the current issues surrounding the FRCS (Tr & Orth) examination.
Living and learning
Authors: Drake Sharon
Published: November 2008

In September, the Faculty of General Dental Practice (UK) bids farewell to its deputy registrar, Sharon Drake. The FGDP(UK) and indeed dentistry as a whole have seen many changes in the nine years since Sharon joined the Faculty. Here she reflects on some of these changes.
Back to basics
Authors: Black John
Published: November 2008

Ian McDermott, Council member, told Council last year that he gave a tutorial on surgery of the hand to a group of pre-MRCS trainees. He asked them to name the three main nerves that supply the hand and was bemused and horrified that between them they could think of only one. That evening I put the same question to my wife, a holder of that honourable and much-missed qualification, state-registered nurse (SRN). Without hesitation she came up with the answer: median, ulnar and radial. Admittedly she was once an orthopaedic ward sister but what a reflection on declining standards of anatomical knowledge in medical graduates.
Varenicline-Associated Acute Renal Failure
Authors: Bird Matthew L , Vesta YuKimi S
Published: November 2008

Objective:

To report an association between acute renal failure and varenicline.

Case Summary:

A 53-year-old white male with preexisting moderate renal insufficiency was admitted to the hospital for acute renal failure following a change in serum creatinine from 4 mg/dL at baseline to 10.6 mg/dL upon admission. One week prior to admission, the patient started taking varenicline (dose undetermined) for smoking cessation and had been stable on all other medications for 2 months prior to admission. All hospital workup tests were negative for prerenal azotemia, postrenal obstruction, and intrinsic renal disease. Varenicline was discontinued on admission. With no other changes in therapy, the serum creatinine level decreased each day of the patient's 5-day hospitalization to 8.6 mg/dL upon discharge, and it was 6.4 mg/dL at a follow-up appointment 2 weeks after discharge.

Discussion:

Varenicline is a novel medication that is effective for smoking cessation. Adverse effects are generally mild and self-limiting, with gastrointestinal effects most commonly reported. According to the package insert, varenicline does not change creatinine clearance to any appreciable extent, but it should be used with caution in patients with renal impairment. It also states that varenicline can cause acute renal failure rarely; to our knowledge, this is the first published association of varenicline with renal effects. Use of the Naranjo probability scale showed varenicline to be the probable cause of renal dysfunction in this patient because of the temporal relationship and lack of alternative causes.

Conclusions:

Although there was a probable relationship between varenicline and acute renal failure in this patient, the significant benefit of smoking cessation to overall health outweighs the risk of this rare adverse effect. Clinicians should be aware of this potential adverse effect and should monitor renal function upon initiation of varenicline therapy, especially in patients with chronic kidney disease.
Efficiency of solar energy conversion as a function of light intensity
Authors: Varfolomeev Sergei
Published: November 2008

The kinetic model has been developed for disserting the efficiency of solar energy conversion as a function of light intensity. A comparison of theory with experimental results shows that the model provides a satisfactory agreement. We have estimated the essential parameters of photosynthetic systems (the size of the photosynthetic antenna, the rate of electron transport, the correlation between photosynthesis and respiration) that are responsible for reaching the maximum efficiency at "one sun" and "one hundred suns" light illumination intensities. Recommendations for the improvement of photosynthetic system parameters using genetic engineering methods are also provided.
The future of solar photovoltaics: A new challenge for chemical physics
Authors: Shevaleevskiy Oleg
Published: November 2008

In recent times, photovoltaic (PV) technologies for solar energy conversion have gained greater recognition. World production of PV cells and modules over the last five years grew at an average of around 40 % a year. The history of modern PV science started more than half a century ago. However, the period that followed exploited the mid-20th century developments in the basics of solid-state physics and semiconductor science. With only a few exceptions, almost no major achievements were attained during a long period of time. The present paper offers an attempt of a critical retrospective look at the history and current progress of solar PV research from a personal viewpoint. It also addresses the current status of research on conventional solid-state PV devices and compares it with the alternative organic and molecular PV systems. The paper briefly describes the potential of new types of organic and mesoscopic dye-sensitized solar cells (DSCs). The paper shows that chemical physics rather than traditional solid-state physics is expected to lead to exciting challenges in the future of PV science.
Tailoring of metal cluster-like materials for the molecular oxygen reduction reaction
Authors: Alonso-Vante Nicolas
Published: November 2008

Research of nanometer scale range catalysts based on cluster-like mono-, bi-metallic, and chalcogenides for oxygen reduction reaction (ORR) as cathodes, a major challenge for polymer electrolyte membrane fuel cells (PEMFCs) nowadays, for facilitating efficient electron transfer using the carbonyl chemical route is reviewed. A strategy aimed at reducing the amount of expensive catalyst materials, giving the accessibility of non-noble materials and taking into account the activity and selectivity of cathodes for the ORR is devised as well.
Factors affecting light energy conversion in dual fluorophore-nitroxide molecules in solution and a protein
Authors: Likhtenshtein Gertz I.
Published: November 2008

Donor-acceptor structures capable of retaining the charge-photoseparated state during the time long enough for secondary chemical reactions of these charges to occur attract special interest from the viewpoint of the problem of light energy utilization. We proposed dual fluorophore-nitroxide compounds (FNO•) as systems for the conversion of light energy to chemical energy. In these systems, the fluorophore segment in the excited singlet state serves as an electron donor, and the nitroxide segment is an electron acceptor. InFNO•, the photo- and chemical reduction of nitroxide results in the drastic decay of the electron spin resonance (ESR) signal from the nitroxide and the parallel enhancement of fluorescence. The same groups allow one to measure the factors affecting the electron transfer, namely, molecular dynamics and micropolarity of the medium in the vicinity of the donor (by fluorescence technique) and acceptor (by ESR) moieties. We demonstrate that in the dual probes the nitroxide segment is photoreduced to hydroxylamine in solution and in such nanoscale structures as serum albumins. The photoreduction occurs by very weak reducing agents (glycerol, ethanol, ethylene glycol, etc.) without a violation of the fluorophore structure. Therefore, photochemical reactions in the dual compounds with the formation of a reducing agent as hydroxyl amine can be considered as processes of light energy transfer. The nitroxide segment tethered to the donor-bridge-acceptor triad affects the photoseparated charge recombination via the mechanism of spin catalysis. Proficiency of the dual compounds for developing energy conversion systems can be extended by an optimal choice of the participants of the photochemical and -physical processes.
Virtual Adult Ears Reveal the Roles of Acoustical Factors and Experience in Auditory Space Map Development
Authors: Campbell Robert A. A. , King Andrew J. , Nodal Fernando R. , Schnupp Jan W. H. , Carlile Simon , Doubell Timothy P.
Published: November 2008

Auditory neurons in the superior colliculus (SC) respond preferentially to sounds from restricted directions to form a map of auditory space. The development of this representation is shaped by sensory experience, but little is known about the relative contribution of peripheral and central factors to the emergence of adult responses. By recording from the SC of anesthetized ferrets at different age points, we show that the map matures gradually after birth; the spatial receptive fields (SRFs) become more sharply tuned and topographic order emerges by the end of the second postnatal month. Principal components analysis of the head-related transfer function revealed that the time course of map development is mirrored by the maturation of the spatial cues generated by the growing head and external ears. However, using virtual acoustic space stimuli, we show that these acoustical changes are not by themselves responsible for the emergence of SC map topography. Presenting stimuli to infant ferrets through virtual adult ears did not improve the order in the representation of sound azimuth in the SC. But by using linear discriminant analysis to compare different response properties across age, we found that the SRFs of infant neurons nevertheless became more adult-like when stimuli were delivered through virtual adult ears. Hence, although the emergence of auditory topography is likely to depend on refinements in neural circuitry, maturation of the structure of the SRFs (particularly their spatial extent) can be largely accounted for by changes in the acoustics associated with growth of the head and ears.
Glial Chain Migration Requires Pioneer Cells
Authors: Aigouy Benoît , Lepelletier Léa , Giangrande Angela
Published: November 2008

The migration of glial chains along the nerve entails directional and coordinated movement. Despite its importance in the formation of the nervous system, this process remains poorly understood, because of the difficulty of manipulating identified cells. Using confocal time-lapse and cell ablation in the whole animal, we provide direct evidence for a discrete number ofDrosophilaperipheral glial cells acting as pioneers and guiding the rest of the migratory chain. These cells are in direct contact with several follower cells through a very long and stable cytoplasmic extension. The presence of pioneer cells and homotypic interactions at the tip of the chain allows coordinated movement and the formation of a continuous sheath around the nerve. Thesein vivodata open novel perspectives for understanding the cellular bases of vertebrate glial migration in physiological and pathological conditions.
Dissociating the Human Language Pathways with High Angular Resolution Diffusion Fiber Tractography
Authors: Frey Stephen , Campbell Jennifer S. W. , Pike G. Bruce , Petrides Michael
Published: November 2008

The anatomical connectivity of ventrolateral frontal areas 44 and 45, which in the human brain constitute Broca's region, has been revisited on the basis of experimental anatomical tracer evidence in the nonhuman primate that the homologues of areas 44 and 45 have distinct bidirectional corticocortical connections. Here we show, using high angular resolution diffusion imaging in the living human brain, a dissociation between the specific projections from the pars opercularis (area 44) and the pars triangularis (area 45) in the ventrolateral frontal lobe. As in the macaque monkey, area 44 has distinct connections with the rostral inferior parietal lobule via the third branch of the superior longitudinal fasciculus. In contrast, area 45 connects with the superior temporal gyrus, anterior to Heschl's gyrus, via the extreme capsule fiber system. These results highlight the differences in connectivity between areas 44 and 45 which had previously been thought to be uniformly connected with the posterior temporal region via the arcuate fasciculus. We also provide evidence in the human brain that the arcuate fasciculus, as in the macaque monkey brain, connects the posterior superior temporal region with dorsolateral frontal areas 8 and rostral 6 that lie above areas 44 and 45. Thus, monkey and human evidence suggests that the connections of areas 44 and 45 are much more differentiated than had previously been thought and provide the basis for studies searching for their differential contribution in function.
Neuronal Distortions of Reward Probability without Choice
Authors: Tobler Philippe N. , Christopoulos George I. , O'Doherty John P. , Dolan Raymond J. , Schultz Wolfram
Published: November 2008

Reward probability crucially determines the value of outcomes. A basic phenomenon, defying explanation by traditional decision theories, is that people often overweigh small and underweigh large probabilities in choices under uncertainty. However, the neuronal basis of such reward probability distortions and their position in the decision process are largely unknown. We assessed individual probability distortions with behavioral pleasantness ratings and brain imaging in the absence of choice. Dorsolateral frontal cortex regions showed experience dependent overweighting of small, and underweighting of large, probabilities whereas ventral frontal regions showed the opposite pattern. These results demonstrate distorted neuronal coding of reward probabilities in the absence of choice, stress the importance of experience with probabilistic outcomes and contrast with linear probability coding in the striatum. Input of the distorted probability estimations to decision-making mechanisms are likely to contribute to well known inconsistencies in preferences formalized in theories of behavioral economics.
Inflammatory Response in the Hippocampus of PS1M146L/APP751SLMouse Model of Alzheimer's Disease: Age-Dependent Switch in the Microglial Phenotype from Alternative to Classic
Authors: Jimenez Sebastian , Baglietto-Vargas David , Caballero Cristina , Moreno-Gonzalez Ines , Torres Manuel , Sanchez-Varo Raquel , Ruano Diego , Vizuete Marisa , Gutierrez Antonia , Vitorica Javier
Published: November 2008

Although the microglial activation is concomitant to the Alzheimer's disease, its precise role (neuroprotection vs neurodegeneration) has not yet been resolved. Here, we show the existence of an age-dependent phenotypic change of microglial activation in the hippocampus ofPS1xAPPmodel, from an alternative activation state with Aβ phagocytic capabilities (at 6 months) to a classic cytotoxic phenotype (expressing TNF-α and related factors) at 18 months of age. This switch was coincident with high levels of soluble Aβ oligomers and a significant pyramidal neurodegeneration.In vitroassays, using astromicroglial cultures, demonstrated that oligomeric Aβ42 and soluble extracts from 18-month-oldPS1xAPPhippocampus produced a potent TNF-α induction whereas monomeric Aβ42 and soluble extract from 6- or 18-month-old control and 6-month-oldPS1xAPPhippocampi produced no stimulation. This stimulatory effect was avoided by immunodepletion using 6E10 or A11. In conclusion, our results show evidence of a switch in the activated microglia phenotype from alternative, at the beginning of Aβ pathology, to a classical at advanced stage of the disease in this model. This change was induced, at least in part, by the age-dependent accumulation of extracellular soluble Aβ oligomers. Finally, these cytotoxic activated microglial cells could participate in the neuronal lost observed in AD.
Extrasynaptic NR2D-Containing NMDARs Are Recruited to the Synapse during LTP of NMDAR-EPSCs
Authors: Harney Sarah C. , Jane David E. , Anwyl Roger
Published: November 2008

Long-term potentiation of NMDA-receptor-mediated synaptic transmission (NMDAR-LTP) is a little-understood form of plasticity. In the present study, we investigated whether NMDAR-LTP in the dentate gyrus involves recruitment of extrasynaptic NMDARs, because NMDARs are expressed both synaptically and extrasynaptically with evidence for subtype differences at different locations. We show that before induction of NMDAR-LTP, pharmacological inhibition of glutamate transporters resulted in glutamate spillover from the synapse and activation of extrasynaptic NMDARs. After the induction of NMDAR-LTP, such activation of extrasynaptic NMDARs was absent. Activation of extrasynaptic NMDARs after glutamate uptake inhibition also occurred when synaptic NMDARs were inhibited with MK801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate], and this extrasynaptically mediated NMDAR-EPSC was strongly reduced by prior induction of NMDAR-LTP. The extrasynaptic NMDARs were shown to be NR2D-containing, because the activation of extrasynaptic NMDARs by glutamate spillover was prevented by the NR2D-selective antagonists PPDA [(2R*,3S*)-1-(phenanthrenyl-2-carbonyl)piperazine-2,3-dicarboxylic acid] and UBP141. Further studies using selective antagonists for NR2A- and NR2B-containing NMDARs demonstrated that synaptic NMDARs are predominantly NR2A-containing and NR2B-containing receptors, whereas the extrasynaptic NMDARs are complex multimeric receptors with NR2A, NR2B, or NR2D subunits. Our results show that LTP of NMDAR-EPSCs involves movement of NMDARs from an extrasynaptic to a synaptic location and suggest a novel physiological role for extrasynaptic NMDARs.
The Hemopexin Domain of Matrix Metalloproteinase-9 Activates Cell Signaling and Promotes Migration of Schwann Cells by Binding to Low-Density Lipoprotein Receptor-Related Protein
Authors: Mantuano Elisabetta , Inoue Gen , Li Xiaoqing , Takahashi Kazuhisa , Gaultier Alban , Gonias Steven L. , Campana W. Marie
Published: November 2008

Low-density lipoprotein receptor-related protein (LRP-1) is an endocytic receptor for diverse proteins, including matrix metalloproteinase-9 (MMP-9), and a cell-signaling receptor. In the peripheral nervous system (PNS), LRP-1 is robustly expressed by Schwann cells only after injury. Herein, we demonstrate that MMP-9 activates extracellular-signal-regulated kinase (ERK1/2) and Akt in Schwann cells in culture. MMP-9 also promotes Schwann cell migration. These activities require LRP-1. MMP-9-induced cell signaling and migration were blocked by inhibiting MMP-9-binding to LRP-1 with receptor-associated protein (RAP) or by LRP-1 gene silencing. The effects of MMP-9 on Schwann cell migration also were inhibited by blocking the cell-signaling response. An antibody targeting the hemopexin domain of MMP-9, which mediates the interaction with LRP-1, blocked MMP-9-induced cell signaling and migration. Furthermore, a novel glutathione-S-transferase fusion protein (MMP-9-PEX), which includes only the hemopexin domain of MMP-9, replicated the activities of intact MMP-9, activating Schwann cell signaling and migration by an LRP-1-dependent pathway. Constitutively active MEK1 promoted Schwann cell migration; in these cells, MMP-9-PEX had no further effect, indicating that ERK1/2 activation is sufficient to explain the effects of MMP-9-PEX on Schwann cell migration. Injection of MMP-9-PEX into sciatic nerves, 24 h after crush injury, robustly increased phosphorylation of ERK1/2 and Akt. This response was inhibited by RAP. MMP-9-PEX failed to activate cell signaling in uninjured nerves, consistent with the observation that Schwann cells express LRP-1 at significant levels only after nerve injury. These results establish LRP-1 as a cell-signaling receptor for MMP-9, which may be significant in regulating Schwann cell migration and physiology in PNS injury.
Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model
Authors: Ding Yun , Qiao Aimin , Wang Ziqing , Goodwin J. Shawn , Lee Eun-Sook , Block Michelle L. , Allsbrook Matthew , McDonald Michael P. , Fan Guo-Huang
Published: November 2008

Recent studies have revealed that disruption of vitamin A signaling observed in Alzheimer's disease (AD) leads to β-amyloid (Aβ) accumulation and memory deficits in rodents. The aim of the present study was to evaluate the therapeutic effect of all-transretinoic acid (ATRA), an active metabolite of vitamin A, on the neuropathology and deficits of spatial learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, a well established AD mouse model. Here we report a robust decrease in brain Aβ deposition and tau phosphorylation in the blinded study of APP/PS1 transgenic mice treated intraperitoneally for 8 weeks with ATRA (20 mg/kg, three times weekly, initiated when the mice were 5 months old). This was accompanied by a significant decrease in the APP phosphorylation and processing. The activity of cyclin-dependent kinase 5, a major kinase involved in both APP and tau phosphorylation, was markedly downregulated by ATRA treatment. The ATRA-treated APP/PS1 mice showed decreased activation of microglia and astrocytes, attenuated neuronal degeneration, and improved spatial learning and memory compared with the vehicle-treated APP/PS1 mice. These results support ATRA as an effective therapeutic agent for the prevention and treatment of AD.
Nicotinamide Restores Cognition in Alzheimer's Disease Transgenic Mice via a Mechanism Involving Sirtuin Inhibition and Selective Reduction of Thr231-Phosphotau
Authors: Green Kim N. , Steffan Joan S. , Martinez-Coria Hilda , Sun Xuemin , Schreiber Steven S. , Thompson Leslie Michels , LaFerla Frank M.
Published: November 2008

Memory loss is the signature feature of Alzheimer's disease, and therapies that prevent or delay its onset are urgently needed. Effective preventive strategies likely offer the greatest and most widespread benefits. Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance memory and synaptic plasticity. We evaluated the efficacy of nicotinamide, a competitive inhibitor of the sirtuins or class III NAD+-dependent HDACs in 3xTg-AD mice, and found that it restored cognitive deficits associated with pathology. Nicotinamide selectively reduces a specific phospho-species of tau (Thr231) that is associated with microtubule depolymerization, in a manner similar to inhibition of SirT1. Nicotinamide also dramatically increased acetylated α-tubulin, a primary substrate of SirT2, and MAP2c, both of which are linked to increased microtubule stability. Reduced phosphoThr231-tau was related to a reduction of monoubiquitin-conjugated tau, suggesting that this posttranslationally modified form of tau may be rapidly degraded. Overexpression of a Thr231-phospho-mimic tauin vitroincreased clearance and decreased accumulation of tau compared with wild-type tau. These preclinical findings suggest that oral nicotinamide may represent a safe treatment for AD and other tauopathies, and that phosphorylation of tau at Thr231 may regulate tau stability.
A Blocker of N- and T-type Voltage-Gated Calcium Channels Attenuates Ethanol-Induced Intoxication, Place Preference, Self-Administration, and Reinstatement
Authors: Newton Philip M. , Zeng Lily , Wang Victoria , Connolly Jacklyn , Wallace Melisa J. , Kim Chanki , Shin Hee-Sup , Belardetti Francesco , Snutch Terrance P. , Messing Robert O.
Published: November 2008

There is a clear need for new therapeutics to treat alcoholism. Here, we test our hypothesis that selective inhibitors of neuronal calcium channels will reduce ethanol consumption and intoxication, based on our previous studies using knock-out mice and cell culture systems. We demonstrate that pretreatment with the novel mixed N-type and T-type calcium channel antagonist 1-(6,6-bis(4-fluorophenyl)hexyl)-4-(3,4,5-trimethoxybenzyl)piperazine (NP078585) reduced ethanol intoxication. NP078585 also attenuated the reinforcing and rewarding properties of ethanol, measured by operant self-administration and the expression of an ethanol conditioned place preference, and abolished stress-induced reinstatement of ethanol seeking. NP078585 did not affect alcohol responses in mice lacking N-type calcium channels. These results suggest that selective calcium channel inhibitors may be useful in reducing acute ethanol intoxication and alcohol consumption by human alcoholics.
High Intracellular Chloride Slows the Decay of Glycinergic Currents
Authors: Pitt Samantha J. , Sivilotti Lucia G. , Beato Marco
Published: November 2008

The time course of currents mediated by native and recombinant glycine receptors was examined with a combination of rapid agonist applications to outside-out patches and single-channel recording. The deactivation time constant of currents evoked by brief, saturating pulses of glycine is profoundly affected by the chloride concentration on the intracellular side of the cell membrane. Deactivation was threefold slower when intracellular chloride was increased from a low level (10 mm), similar to that observed in living mature neurons, to 131 mm(“symmetrical” chloride, often used in pipette internal solutions). Single-channel analysis revealed that high chloride has its greatest effect on the channel closing rate, slowing it by a factor of 2 compared with the value we estimated in the cell-attached mode (in which the channels are at physiological intracellular chloride concentrations). The same effect of chloride was observed when glycinergic evoked synaptic currents were recorded from juvenile rat spinal motoneuronsin vitro, because the decay time constant was reduced from ∼7 ms to ∼3 ms when cells were dialyzed with 10 mmchloride intracellular recording solution.

Our results indicate that the time course of glycinergic synaptic inhibition in intact neurons is much faster than is estimated by measurements in symmetrical chloride and can be modulated by changes in intracellular chloride concentration in the range that can occur in physiological or pathological conditions.
Treatment of Nelson's syndrome with temozolomide
Authors: Moyes V J , Alusi G , Sabin H I , Evanson J , Berney D M , Kovacs K , Monson J P , Plowman P N , Drake W M
Published: November 2008

A 64-year-old woman was previously treated for Cushing's disease with trans-sphenoidal surgery, external beam radiotherapy and bilateral adrenalectomy. Progression of an aggressive corticotroph adenoma was evident 3 years post-adrenalectomy; involvement of the clivus was treated with surgery and gamma knife radiosurgery. Tumour spread through the skull base, occiput and left ear with persistent facial pain and left ear discharge; progression continued despite second gamma knife treatment. ACTH levels peaked at 2472 and 2265 pmol/l pre- and post-hydrocortisone respectively. Treatment with temozolomide resulted in a significant improvement in symptoms, a reduction of plasma ACTH to 389 pmol/l and regression of tumour on magnetic resonance imaging scan after four cycles of treatment. We propose that temozolomide is an effective and well-tolerated therapeutic tool for the treatment of Nelson's syndrome and a useful addition to the range of therapies available to treat this condition.
Molecular Population Genetics and Evolution of Drosophila Meiosis Genes
Authors: Anderson Jennifer A , Gilliland William D , Langley Charles H
Published: November 2008

While many functional elements of the meiotic process are well characterized in model organisms, the genetic basis of most of the natural phenotypic variation observed in meiotic pathways has not been determined. To begin to address this issue, we characterized patterns of polymorphism and divergence in the protein-coding regions of 33 genes across 31 lines of Drosophila melanogaster and 6 lines of Drosophila simulans. We sequenced genes known to be involved in chromosome segregation, recombination, DNA repair, and related heterochromatin binding. As expected, we found several of the genes to be highly conserved, consistent with purifying selection. However, a subset of genes showed patterns of polymorphism and divergence typical of other types of natural selection. Moreover, several intriguing differences between the two Drosophila lineages were evident: along the D. simulans lineage we consistently found evidence of adaptive protein evolution, whereas along the D. melanogaster lineage several loci exhibited patterns consistent with the maintenance of protein variation.
Construction and Characterization of Deletions With Defined End Points in Drosophila Using P Elements in Trans
Authors: Paré Adam C , Dean Derek M , Ewer John
Published: November 2008

We used P-element transposase-mediated “male recombination” between two P elements in trans to create genetic deletions that removed a number of loci, including the gene encoding the neuropeptide crustacean cardioactive peptide (CCAP). Two classes of recombinant chromosomes were produced. Approximately one-quarter were viable when homozygous or hemizygous, whereas the remaining lines caused homozygous and hemizygous lethality. Preliminary analyses using PCR and CCAP immunohistochemistry suggested that, whereas the DNA of the viable lines was largely intact, most lethal lines contained chromosomal deletions that were roughly bounded by the insertion sites of the two P elements used. Southern blot analyses of select lethal lines showed that the DNA flanking the deletion was indeed grossly intact whereas the intervening DNA could not be detected. Sequencing across the deletion in three of these lethal lines identified a single line bearing intact genomic DNA on either side of the deletion separated by 30 bp of P-element DNA. The method described here suggests a simple procedure for creating deletions with defined end points. Importantly, it can use preexisting P-element insertion strains and does not rely on the use of transposable elements that are engineered to cause specific DNA rearrangements.
A Double-Blind, Placebo-Controlled, Randomized Trial of Montelukast for Acute Bronchiolitis
Authors: Amirav Israel , Luder Anthony S. , Kruger Natalie , Borovitch Yael , Babai Ilan , Miron Dan , Zuker Miriam , Tal Gay , Mandelberg Avigdor
Published: November 2008

BACKGROUND. Cysteinyl leukotrienes are implicated in the inflammation of bronchiolitis. Recently, a specific cysteinyl leukotriene receptor antagonist, montelukast (Singulair [MSD, Haarlem, Netherlands]), has been approved for infants in granule sachets.

OBJECTIVE. Our goal was to evaluate the effect of montelukast on clinical progress and on cytokines in acute bronchiolitis.

METHODS. This was a randomized, placebo-controlled, double-blind, parallel-group study in 2 medical centers. Fifty-three infants (mean age: 3.8 ± 3.5 months) with a first episode of acute bronchiolitis were randomly assigned to receive either 4-mg montelukast sachets or placebo, every day, from hospital admission until discharge. The primary outcome was length of stay, and secondary outcomes included clinical severity score (maximum of 12) and changes in type 1 and 2 cytokine levels (including interleukin4/IFN-γ ratio as a surrogate for the T-helper 2/T-helper 1 ratio) in nasal lavage.

RESULTS. Both groups were comparable at baseline, and cytokine levels correlated positively with disease severity. There were neither differences in length of stay (4.63 ± 1.88 [placebo group] vs 4.65 ± 1.97 days [montelukast group]) nor in clinical severity score and cytokine levels between the 2 groups. No differences in interleukin 4/IFN-γ ratio between the 2 groups were seen. There was a slight tendency for infants in the montelukast group to recover more slowly than those in the placebo group (clinical severity score at discharge: 6.1 ± 2.4 vs 4.8 ± 2.2, respectively).

CONCLUSIONS. Montelukast did not improve the clinical course in acute bronchiolitis. No significant effect of montelukast on the T-helper 2/T-helper 1 cytokine ratio when given in the early acute phase could be demonstrated.
Efecto del nitrato de potasio, fosfato de potasio y ethephon en la inducción floral de la feijoa o goiabeira serrana (Acca sellowiana [O. Berg] Burret)
Authors: Javier Garcia Oskar , Yiovani Dueñez Edgar , Fischer Gerhard , Chaves Bernardo , Camilo Quintero Omar
Published: November 2008

El ensayo se llevó a cabo en la finca El Cortijo (La Vega, Cundinamarca, Colombia [04°55'N y 74°18'W], 2350 m altitud, 17°C temperatura media, 1423 mm precipitación anual, 85% humedad relativa, 1377 horas brillo solar/año). Se utilizaron árboles de feijoa o goiabeira serrana de seis años, Clon 41 ('Quimba'), evaluando fertilizantes foliares KNO3 (Nitrato de Potasio 13-0-46® 1%, 1,5% y 2%) y KH2PO4 (fosfato de potasio; Cosmofoliar 0-32-43®; 0,5%, 0,75% y 1,0%) y la fitohormona ethephon (Ethrel® 48 SL; 100, 150 y 200 mg L-1). Se determinaron el número de botones florales inducidos, flores formadas, además, el porcentaje de flores formadas y nivel de eficacia de los productos inductores. El KH2PO4 al 0,5% obtuvo resultados favorables en cada una de las variables evaluadas, comparado con el 0,75% y 1% del mismo producto y, sin embargo hubo un alto número de flores inducidas y formadas, no se presentaron diferencias significativas con el testigo. Ethephon a 150 mg L-1 en la inducción de botones florales y a 100 mg L-1 en la de formación de flores mostró resultados favorables, pero tampoco pudo superar el testigo por falta de significancia. La respuesta generada por KNO3 mostró una baja inducción de botones florales, y una eficacia negativa en la proporción de flores formadas; asimismo fitotoxicidad, cuando se emplearon concentraciones al 2% de este producto.
Efeitos de mbta [cloridrato de n,n-dietil-2-(4-metilbenziloxi) etilamina] na produtividade e na qualidade dos frutos da laranjeira 'pêra' (Citrus sinensis L. Osbeck)
Authors: Serciloto Chryz Melinski , Castro Paulo Roberto de Camargo e , Tavares Silvio
Published: November 2008

O objetivo deste trabalho foi avaliar os efeitos do biorregulador MBTA [cloridrato de N,N-dietil-2-(4-metilbenziloxi) etilamina] aplicado em diferentes épocas e concentrações na produtividade e qualidade dos frutos da laranjeira 'Pêra'. Em duas safras consecutivas, o MBTA foi aplicado em três diferentes concentrações (8; 16 e 32 mg L-1) e em duas diferentes fases fenológicas (25% e 100% de flores abertas), em árvores cítricas adultas, utilizando um volume de 7 litros de solução por planta, acompanhado do adjuvante Silwett L-77 0,05%. Foram amostrados 20 frutos por planta, em quatro diferentes épocas estudadas, para determinar o teor de sólidos solúveis (SS); acidez titulável (AT); quantidade de sólidos solúveis por caixa de 40,8 kg; pH; rendimento de suco; "ratio" (relação SS/AT), e a massa média dos frutos. Os efeitos do MBTA variaram de acordo com a concentração aplicada e com a fase fenológica de aplicação. O MBTA, na concentração de 8 mg L-1, aplicado com 25% das flores abertas, incrementou o teor de sólidos solúveis, a acidez, a quantidade de sólidos solúveis por caixa de 40,8 kg e a produtividade. Esse mesmo tratamento também reduziu a massa média dos frutos e não alterou o rendimento de suco e o "ratio" do suco dos frutos. O incremento médio foi de 0,49 a 0,65% na concentração de sólidos solúveis, de 0,11 a 0,13 kg na quantidade de sólidos solúveis por caixa de 40,8 kg e de 20,4 kg/planta na produtividade.
Disposição do nematóide Bursaphelenchus cocophilus (Cobb) baujard, em coqueiros portadores da doença anel-vermelho
Authors: Duarte Adriana Guimarães , Lima Ivanildo Soares de , Araújo Júnior Josemildo Verçosa de , Duarte Alexandre Guimarães , Albuquerque Ariane Loudemila Silva de , Cruz Marcelo de Menezes
Published: November 2008

Este trabalho teve o objetivo de conhecer como o nematóide Bursaphelenchus cocophilus tende a se distribuir no interior das plantas de coqueiros em estágios avançados da doença anel-vermelho. Nas amostras de raízes coletadas junto à base da estipe de coqueiros doentes, o número de nematóides foi consideravelmente maior que encontrado em raízes situadas entre um e três metros de distância da estipe. Observou-se que, à medida que se afasta da estipe, a possibilidade de encontrar nematóides na raiz é mínima, de forma que as chances de transmissão da doença, de uma planta para outra, através das raízes, devem ser muito pequenas. Na região do palmito, onde o tecido é mais tenro, é possível encontrar o nematóide tanto nas áreas avermelhadas quanto nas áreas aparentemente sadias. Nos tecidos do pecíolo, foram encontrados nematóides em pequena quantidade. Portanto, práticas profiláticas, visando à desinfecção do facão utilizado na colheita e despalma, devem ser realizadas com a finalidade de eliminar a transmissão da doença. Nenhuma das amostras obtidas dos tecidos da ráquis e dos folíolos estava contaminada. A população de nematóide é mais alta nos excrementos de túneis larvais das regiões apicais do coqueiro, o que confere maior chance de serem transportados para outras plantas, aderidos ao corpo do seu principal vetor, os adultos de Rhynchophorus palmarum.