bluuebunny/crossref_metadata_2025 huggingface dataset:
Interleukin‐1 System in CNS Stress
Authors: BARTFAI TAMAS , SANCHEZ‐ALAVEZ MANUEL , ANDELL‐JONSSON SIV , SCHULTZBERG MARIANNE , VEZZANI ANNAMARIA , DANIELSSON ERIK , CONTI BRUNO
Published: October 2007

Abstract:  Proteins of the interleukin‐1 (IL‐1) system include the secreted agonist IL‐1β, and the receptor antagonist IL‐1ra, both competing for binding to the IL‐1 receptor (IL‐1R). IL‐1β and IL‐1ra are highly inducible under different forms of stress, such as excitatory neurotransmitter excess occurring during seizures, in infection and inflammation, and during neurotrauma. In each of these conditions induction of IL‐1β precedes that of IL‐1ra, resulting in up to 10–20‐fold elevation of IL‐1β concentrations. Consequently, IL‐1β induces the elevation of other proinflammatory molecules, including IL‐6, IL‐1R1, COX2, and iNOS, as well as of IL‐1ra. Elevation of IL‐1ra is of key importance for quenching the inflammatory response at the IL‐1R1 as part of an autoregulatory loop. In seizures, IL‐1ra is a strong anticonvulsant and in IL‐1β‐dependent fever, a powerful antipyretic. In traumatic brain injury (TBI), the ability of patients to mount an IL‐1ra response, as measured in the CSF, strongly correlated with the neurological outcome. Selective induction or pharmacological application of IL‐1ra may be sparing neurons in seizures and neurotrauma.
Cognitive Activation Theory of Stress, Sensitization, and Common Health Complaints
Authors: URSIN HOLGER , ERIKSEN HEGE
Published: October 2007

Abstract:  According to the cognitive activation theory of stress (CATS), a formal system of systematic definitions, the term “stress” is used for stress stimuli, the stress experience, the nonspecific, general stress response, and the experience of the stress response. The stress response is normal, healthy, and necessary alarm. If sustained there may be a risk of illness and disease. The level and duration of the alarm depend on the expectancy of the outcome of stimuli and the specific responses available for coping. The most common health complaints are subjective health complaints like muscle pain, tiredness and mood changes. These are normal aches of short duration and low intensity for most people. For some the pains and complaints are substantial and longlasting with serious implications for functioning. There are no sharp or obvious limits in the distribution of health complaints, separating “normal” and endurable pain and complaints, and intolerable complaints that need professional help. These conditions are most often unspecific, and are the most common reason for encounters with health professionals, and the most frequent reason for sick leave and disability. There is a striking comorbidity for all these conditions. This may be explained by psychobiological sensitization within neural loops, maintained by sustained activation, which has been suggested as a mechanism for these conditions.
Temperature Stress
Authors: HARWOOD JOHN L.
Published: October 2007

Abstract: 
Acanthamoeba castellanii (A. castellanii) is a common soil‐ or water‐borne protozoon that feeds on bacteria by phagocytosis. A. castellanii can grow between 4 and 32°C and has to adapt quickly to chilling in order to survive. We have identified a Δ12‐fatty acid desaturase as key to low temperature adaptation. The activity of this enzyme is mainly increased through gene expression and new protein synthesis. Interestingly, the activity can also be altered independently by dissolved oxygen levels. In addition, we have identified a gene for the Δ12‐desaturase, which, when expressed in yeast, catalyses Δ15‐desaturation also. Moreover, it is also capable of producing very unusual n‐1 polyunsaturated products.
The Catecholamine–Cytokine Balance
Authors: SZELÉNYI J. , VIZI E.S.
Published: October 2007

Abstract: Cytokines are involved both in various immune reactions and in controlling certain events in the central nervous system (CNS). In our earlier studies, it was shown that monoamine neurotransmitters, released in stress situations, represent a tonic sympathetic control on cytokine production and on the balance of proinflammatory/anti‐inflammatory cytokines. Basic and clinical studies have provided evidence that the biophase level of monoamines, determined by the balance of their release and uptake, is involved in the pathophysiology and treatment of depression, while inflammatory mediators might also have a role in its etiology. In this work, we studied the role of changes in norepinephrine (NE) level on the lipopolysaccharide (LPS) evoked tumor necrosis factor (TNF)‐α and interleukin (IL)‐10 response both in the plasma and in the hippocampus of mice. We demonstrated that the LPS induced TNF‐α response is in direct correlation with the biophase level of NE, as it is significantly higher when the release of NE of vesicular origin was completely inhibited in an animal model of depression (reserpine treatment) and it is significantly lower in the case of increasing biophase levels of NE by genetic (NET–KO) or chemical (desipramine) disruption of NE reuptake. IL‐10 was changed inversely to TNF‐α levels only in the desipramine‐treated animals. Our results showed that depression is related both to changes in peripheral and in hippocampal inflammatory cytokine production and to monoamine neurotransmitter levels. Since several anti‐inflammatory drugs also have antidepressant effects, we hypothesized that antidepressants are also able to modulate the LPS‐induced inflammatory response, which might contribute to their antidepressant effect.
Membrane Regulation of the Stress Response from Prokaryotic Models to Mammalian Cells
Authors: VIGH LASZLO , NAKAMOTO HITOSHI , LANDRY JACQUES , GOMEZ‐MUNOZ ANTONIO , HARWOOD JOHN L. , HORVATH IBOLYA
Published: October 2007

Abstract:  “Membrane regulation” of stress responses in various systems is widely studied. In poikilotherms, membrane rigidification could be the first reaction to cold perception: reducing membrane fluidity of membranes at physiological temperatures is coupled with enhanced cold inducibility of a number of genes, including desaturases (see J.L. Harwood's article in this Proceedings volume). A similar role of changes in membrane physical state in heat (oxidative stress, etc.) sensing‐ and signaling gained support recently from prokaryotes to mammalian cells. Stress‐induced remodeling of membrane lipids could influence generation, transduction, and deactivation of stress signals, either through global effects on the fluidity of the membrane matrix, or by specific interactions of boundary (or raft) lipids with receptor proteins, lipases, ion channels, etc. Our data point to membranes not only as targets of stress, but also as sensors in activating a stress response.
Heat Shock Proteins in Cancer
Authors: SHERMAN MICHAEL , MULTHOFF GABRIELE
Published: October 2007

Abstract:  Heat shock proteins (Hsps) are highly conserved and inhabit nearly all subcellular locations where they perform a variety of chaperoning functions including folding and unfolding of nascent polypeptides, proteins, transport of proteins, and support of antigen presentation processes. Apart from their intracellular location Hsps with a molecular weight of 70 kDa (Hsp70) also have been found on the plasma membrane of malignantly transformed cells, on virally/bacterial infected cells and in the extracellular space. Depending on their intra‐ and extracellular location Hsps exert either protection against environmental stress or act as potent stimulators of the immune response. In this review we address the dual function of intracellular and extracellular located small Hsps and members of the Hsp70 family and its immunological consequences for cancer immunity.
Heat Shock Proteins and Protection of the Nervous System
Authors: BROWN IAN R.
Published: October 2007

Abstract:  Manipulation of the cellular stress response offers strategies to protect brain cells from damage induced by ischemia and neurodegenerative diseases. Overexpression of Hsp70 reduced ischemic injury in the mammalian brain. Investigation of the domains within Hsp70 that confers ischemic neuroprotection revealed the importance of the carboxyl‐terminal domain. Arimoclomol, a coinducer of heat shock proteins, delayed progression of amyotrophic lateral sclerosis (ALS) in a mouse model in which motor neurons in the spinal cord and motor cortex degenerate. Celastrol, a promising candidate as an agent to counter neurodegenerative diseases, induced expression of a set of Hsps in differentiated neurons grown in tissue culture. Heat shock “preconditioning” protected the nervous system at the functional level of the synapse and selective overexpression of Hsp70 enhanced the level of synaptic protection. Following hyperthermia, constitutively expressed Hsc70 increased in synapse‐rich areas of the brain where it associates with Hsp40 to form a complex that can refold denatured proteins. Stress tolerance in neurons is not solely dependent on their own Hsps but can be supplemented by Hsps from adjacent glial cells. Hence, application of exogenous Hsps at neural injury sites is an effective strategy to maintain neuronal viability.
Polymorphisms in the IDE-KIF11-HHEX Gene Locus Are Reproducibly Associated with Type 2 Diabetes in a Japanese Population
Authors: Furukawa Yasushi , Shimada Takeshi , Furuta Hiroto , Matsuno Shohei , Kusuyama Akiko , Doi Asako , Nishi Masahiro , Sasaki Hideyuki , Sanke Tokio , Nanjo Kishio
Published: October 2007

Context: A genome-wide association study in the French population has detected that novel single-nucleotide polymorphisms (SNPs) in the IDE-KIF11-HHEX gene locus and the SLC30A8 gene locus are associated with susceptibility to type 2 diabetes.

Objective: We investigated whether SNPs in these loci were associated with type 2 diabetes in Japanese.

Design: Two SNPs, rs7923837 and rs1111875, in the IDE-KIF11-HHEX gene locus and one SNP, rs13266634, in the SLC30A8 gene locus were genotyped in Japanese type 2 diabetic patients (n = 405) and in nondiabetic control subjects (n = 340) using the TaqMan genotyping assay system.

Results: The G allele of rs7923837 was associated with type 2 diabetes [odds ratio 1.66, 95% confidence interval (CI) 1.28–2.15; P = 0.00014], following the same tendency as in the French population of the previous report. Heterozygous and homozygous carriers of the risk allele had odds ratios of 1.57 (95% CI 1.15–2.16; P = 0.0050) and 3.16 (95% CI 1.40–7.16; P = 0.0038) relative to noncarriers. Although the G allele was a major allele (66.5%) in the French population, it was a minor allele (23.8%) in Japanese. The G allele of rs1111875 was also associated with type 2 diabetes (odds ratio 1.42, 95% CI 1.13–1.78; P = 0.0024). Heterozygous and homozygous carriers of the risk allele had odds ratios of 1.31 (95% CI 0.97–1.77; P = 0.0810) and 2.40 (95% CI 1.34–4.32; P = 0.0028) relative to noncarriers. A significant association with type 2 diabetes was not observed for rs13266634.

Conclusions: Polymorphisms in the IDE-KIF11-HHEX gene locus are associated with susceptibility to type 2 diabetes across the boundary of race.
The Expression of Activin-βA- and -βB-Subunits, Follistatin, and Activin Type II Receptors in Fallopian Tubes Bearing an Ectopic Pregnancy
Authors: Refaat Bassem , Amer Saad , Ola Bolarinde , Chapman Neil , Ledger William
Published: October 2007

Context: Ectopic pregnancy is a major cause of maternal morbidity and mortality with increasing incidence worldwide.

Objective: We investigated whether epithelia from Fallopian tubes (FTs) bearing an ectopic pregnancy differ from normal tubes in expression of TGF-β family and related proteins and their receptors.

Methodology: Because it is not possible to collect FTs from women carrying a healthy pregnancy, we studied tissue collected at the time of hysterectomy for benign disease. Women were injected with human chorionic gonadotropin in the days leading up to hysterectomy to produce a state of pseudopregnancy. Pseudopregnancy status was confirmed by the presence of high serum progesterone levels and the decidualization of the endometrium. Fifteen FTs bearing ectopic pregnancy and six pseudopregnant tubes were collected and examined using immunohistochemistry and quantitative RT-PCR.

Results: Immunohistochemistry demonstrated clear staining for the βA- and βB-subunits, type II receptor group comprising the activin type IIA and type IIB receptors, and follistatin, which increased in intensity from the isthmus to the ampulla in both models. However, the intensity of expression of these molecules was stronger in the ectopic pregnancy group when compared with the pseudopregnant group. Quantitative RT-PCR showed significant decrease in mRNA levels of βA-subunit, activin type IIA and IIB receptors, and follistatin in ectopic group (P < 0.05) but no changes in βB-subunit (P > 0.05). Overall, there was an apparent paradox of high concentration of protein but low mRNA expression.

Conclusion: Activin-A may stimulate tubal decidualization and trophoblast invasion. A better understanding of the mechanism by which an embryo implants in the tubal epithelium may lead to improved methods for early diagnosis and/or management of ectopic pregnancy.
A novel role for Lsc/p115 RhoGEF and LARG in regulating RhoA activity downstream of adhesion to fibronectin
Authors: Dubash Adi D. , Wennerberg Krister , García-Mata Rafael , Menold Marisa M. , Arthur William T. , Burridge Keith
Published: October 2007

Adhesion of cells to extracellular matrix proteins such as fibronectin initiates signaling cascades that affect cell morphology, migration and survival. Some of these signaling pathways involve the Rho family of GTPases, such as Cdc42, Rac1 and RhoA, which play a key role in regulating the organization of the cytoskeleton. Although significant advances have been made in understanding how Rho proteins control cytoskeletal architecture, less is known about the signals controlling activation of the GTPases themselves. The focus of this study was to determine which guanine nucleotide exchange factor(s) are responsible for activation of RhoA downstream of adhesion to fibronectin. Using an affinity pulldown assay for activated exchange factors, we show that the RhoA-specific exchange factors Lsc/p115 RhoGEF and LARG are activated when cells are plated onto fibronectin, but not other exchange factors such as Ect2 or Dbl. Knockdown of Lsc and LARG together significantly decreases RhoA activation and formation of stress fibers and focal adhesions downstream of fibronectin adhesion. Similarly, overexpression of a catalytically inactive mutant of Lsc/p115 RhoGEF inhibits RhoA activity and formation of stress fibers and focal adhesions on fibronectin. These data establish a previously uncharacterized role for the exchange factors Lsc/p115 RhoGEF and LARG in linking fibronectin signals to downstream RhoA activation.
Distinct kinetic and mechanical properties govern ALCAM-mediated interactions as shown by single-molecule force spectroscopy
Authors: te Riet Joost , Zimmerman Aukje W. , Cambi Alessandra , Joosten Ben , Speller Sylvia , Torensma Ruurd , van Leeuwen Frank N. , Figdor Carl G. , de Lange Frank
Published: October 2007

The activated leukocyte cell adhesion molecule (ALCAM) mediates dynamic homotypic and heterotypic cellular interactions. Whereas homotypic ALCAM-ALCAM interactions have been implicated in the development and maintenance of tissue architecture and tumor progression, heterotypic ALCAM-CD6 interactions act to initiate and stabilize T-cell–dendritic-cell interactions affecting T-cell activation. The ability to resist the forces acting on the individual bonds during these highly dynamic cellular contacts is thought to be crucial for the (patho)physiology of ALCAM-mediated cell adhesion. Here, we used atomic force microscopy to characterize the relationship between affinity, avidity and the stability of ALCAM-mediated interactions under external loading, at the single-molecule level. Disruption of the actin cytoskeleton resulted in enhanced ALCAM binding avidity, without affecting the tensile strength of the individual bonds. Force spectroscopy revealed that the ALCAM-CD6 bond displayed a significantly higher tensile strength, a smaller reactive compliance and an up to 100-fold lower dissociation rate in the physiological force window in comparison to the homotypic interaction. These results indicate that homotypic and heterotypic ALCAM-mediated adhesion are governed by significantly distinct kinetic and mechanical properties, providing novel insight into the role of ALCAM during highly dynamic cellular interactions.
Absence of keratin 19 in mice causes skeletal myopathy with mitochondrial and sarcolemmal reorganization
Authors: Stone Michele R. , O'Neill Andrea , Lovering Richard M. , Strong John , Resneck Wendy G. , Reed Patrick W. , Toivola Diana M. , Ursitti Jeanine A. , Omary M. Bishr , Bloch Robert J.
Published: October 2007

Intermediate filaments, composed of desmin and of keratins, play important roles in linking contractile elements to each other and to the sarcolemma in striated muscle. We examined the contractile properties and morphology of fast-twitch skeletal muscle from mice lacking keratin 19. Tibialis anterior muscles of keratin-19-null mice showed a small but significant decrease in mean fiber diameter and in the specific force of tetanic contraction, as well as increased plasma creatine kinase levels. Costameres at the sarcolemma of keratin-19-null muscle, visualized with antibodies against spectrin or dystrophin, were disrupted and the sarcolemma was separated from adjacent myofibrils by a large gap in which mitochondria accumulated. The costameric dystrophin-dystroglycan complex, which co-purified with γ-actin, keratin 8 and keratin 19 from striated muscles of wild-type mice, co-purified with γ-actin but not keratin 8 in the mutant. Our results suggest that keratin 19 in fast-twitch skeletal muscle helps organize costameres and links them to the contractile apparatus, and that the absence of keratin 19 disrupts these structures, resulting in loss of contractile force, altered distribution of mitochondria and mild myopathy. This is the first demonstration of a mammalian phenotype associated with a genetic perturbation of keratin 19.
The chemokine SDF1 controls multiple steps of myogenesis through atypical PKCζ
Authors: Ödemis Veysel , Boosmann Karina , Dieterlen Maja Theresa , Engele Jürgen
Published: October 2007

Mice deficient in the SDF1-chemokine-receptor CXCR4, exhibit severe defects of secondary limb myogenesis. To further elucidate the role of SDF1 in muscle development, we have now analyzed putative effects of this chemokine on proliferation, migration and myogenic differentiation of mouse C2C12 myogenic progenitor/myoblast cells. In addition, we have characterized the signaling pathways employed by SDF1-CXCR4 to control myogenesis. We found that SDF1 stimulates proliferation and induces migration of C2C12 cells with a potency similar to that of FGF2 and HGF, which both represent prototypical extracellular regulators of myogenesis. In addition, SDF1 inhibits myogenic differentiation in both C2C12 cells and primary myoblasts, as assessed by MyoD, myosin heavy chain and/or myogenin expression. Regarding signaling pathways, C2C12 cells responded to SDF1 with activation (phosphorylation) of Erk and PKCζ, whereas even after prolonged SDF1 treatment for up to 120 minutes, levels of activated Akt, p38 and PKCα or PKCβ remained unaffected. Preventing activation of the classic MAP kinase cascade with the Erk inhibitor UO126 abolished SDF1-induced proliferation and migration of C2C12 cells but not the inhibitory action of SDF1 on myogenic differentiation. Moreover, the effects of SDF1 on proliferation, migration and differentiation of C2C12 cells were all abrogated in the presence of myristoylated PKCζ peptide pseudosubstrate and/or upon cellular depletion of PKCζ by RNA interference. In conclusion, our findings unravel a previously unknown role of CXCR4-PKCζ signaling in myogenesis. The potent inhibitory effects of SDF1 on myogenic differentiation point to a major function of CXCR4-PKCζ signaling in the control of secondary muscle growth.
Dictyostelium Hip1r contributes to spore shape and requires epsin for phosphorylation and localization
Authors: Repass Shannon Lea , Brady Rebecca J. , O'Halloran Theresa J.
Published: October 2007

Clathrin-coated pits assemble on the plasma membrane to select and sequester proteins within coated vesicles for delivery to intracellular compartments. Although a host of clathrin-associated proteins have been identified, much less is known regarding the interactions between clathrin-associated proteins or how individual proteins influence the function of other proteins. In this study, we present evidence of a functional relationship between two clathrin-associated proteins in Dictyostelium, Hip1r and epsin. Hip1r-null cells form fruiting bodies that yield defective spores that lack the organized fibrils typical of wild-type spores. This spore coat defect leads to formation of round, rather than ovoid, spores in Hip1r-null cells that exhibit decreased viability. Like Hip1r-null cells, epsin-null cells also construct fruiting bodies with round spores, but these spores are more environmentally robust. Double-null cells that harbor deletions in both epsin and Hip1r form fruiting bodies, with spores identical in shape and viability to Hip1r single-null cells. In the growing amoeba, Hip1r is phosphorylated and localizes to puncta on the plasma membrane that also contain epsin. Both the phosphorylation state and localization of Hip1r into membrane puncta require epsin. Moreover, expression of the N-terminal ENTH domain of epsin is sufficient to restore both the phosphorylation and the restricted localization of Hip1r within plasma membrane puncta. The results from this study reveal a novel interaction between two clathrin-associated proteins during cellular events in both growing and developing Dictyostelium cells.
In vivo analysis of undocked connexin43 gap junction hemichannels in ovarian granulosa cells
Authors: Tong Dan , Li Tony Y. , Naus Kathryn E. , Bai Donglin , Kidder Gerald M.
Published: October 2007

Connexin43 (Cx43, encoded by Gja1) is required for ovarian follicle development in the mouse. It is strongly expressed in granulosa cells, in which it forms intercellular gap junction channels that couple the cells metabolically. However, recent evidence indicates that undocked gap junction hemichannels can also have physiological roles such as mediating the release of small messenger molecules, including ATP. In this study, the presence of undocked Cx43 hemichannels in granulosa cells was revealed by dye uptake induced either by mechanical stimulation or by the reduction of extracellular divalent cations, both of which are known triggers for hemichannel opening. ATP release was also detected, and could be abolished by connexin-channel blockers. None of these putative hemichannel-mediated activities were detected in Cx43-deficient granulosa cells. Therefore, we hypothesized that hemichannels account for the essential role of Cx43 in folliculogenesis. To test this, a Cx43 mutant lacking the conserved cysteines on the extracellular loops (cys-less Cx43), reported to form hemichannels but not intercellular channels, was retrovirally expressed in Cx43-deficient granulosa cells. The infected cells were then combined with wild-type oocytes to make reaggregated ovaries, which were grafted into host kidneys. Although re-introduction of wild-type Cx43 rescued folliculogenesis, introduction of cys-less Cx43 did not. Therefore, although Cx43 gap junction hemichannels might play a role in ovarian folliculogenesis, their contribution does not supplant the need for intercellular gap junction channels.
Mitochondrial DNA replication during differentiation of murine embryonic stem cells
Authors: Facucho-Oliveira Joao M. , Alderson Jon , Spikings Emma C. , Egginton Stuart , St. John Justin C.
Published: October 2007

Oxidative phosphorylation (OXPHOS), the intracellular process that generates the majority of the ATP of a cell through the electron-transfer chain, is highly dependent on proteins encoded by the mitochondrial genome (mtDNA). MtDNA replication is regulated by the nuclear-encoded mitochondrial transcription factor A (TFAM) and the mitochondrial-specific DNA polymerase gamma, which consists of a catalytic (POLG) and an accessory (POLG2) subunit. Differentiation of pluripotent embryonic stem cells (ESCs) into specific cell types requires expansion of discrete populations of mitochondria and mtDNA replication to meet the specific metabolic requirements of the cell. We determined by real-time PCR that expression of pluripotent markers is reduced before the upregulation of Polg, Polg2 and Tfam in spontaneously differentiating R1 murine (m)ESCs, along with transient increases in mtDNA copy number. In D3 mESCs, the initial transient increase did not take place. However, precursors of neuronal and cardiomyocyte differentiation were positive for both POLG and TFAM. Similar-stage ESCs also showed active mtDNA replication, identified by 5-bromo-2′-deoxy-uridine labelling, as mtDNA copy number increased. Retinoic-acid-induced differentiation resulted in more consistent patterns of replication and upregulation of Polg, Polg2 and Tfam, whereas siRNA knockdown demonstrated that steady-state expression of POLG is essential for maintaining pluripotency.
NCAM is ubiquitylated, endocytosed and recycled in neurons
Authors: Diestel Simone , Schaefer Daniel , Cremer Harold , Schmitz Brigitte
Published: October 2007

The neural cell adhesion molecule NCAM plays an important role during neural development and in the adult brain. To study the intracellular trafficking of NCAM in neurons, two major isoforms, NCAM140 or NCAM180, were expressed in primary cortical neurons and in the rat B35 neuroblastoma cell line. NCAM was endocytosed and subsequently recycled to the plasma membrane, whereas only a minor fraction was degraded in lysosomes. In cortical neurons, endocytosis of NCAM was detected in the soma, neurites and growth cones in a developmentally regulated fashion. Furthermore, we found that NCAM is mono-ubiquitylated at the plasma membrane and endocytosis was significantly increased in cells overexpressing ubiquitin. Therefore, we propose that ubiquitylation represents an endocytosis signal for NCAM.
Compliance with National Guidelines for the Management of Drug–Drug Interactions in Dutch Community Pharmacies
Authors: Buurma Henk , Schalekamp Tom , Egberts Antoine CG , Smet Peter AGM De
Published: October 2007

Background:

Pharmacists contribute to the detection and prevention of drug therapy–related problems, including drug–drug interactions. Little is known about compliance with pharmacy practice guidelines for the management of drug–drug interaction alerts.

Objective:

To measure the compliance of community pharmacists with Dutch guidelines for the management of drug–drug interactions and to determine patient- and prescriber-related determinants for noncompliance.

Methods:

Sixteen clinically relevant drug–drug interactions were included in the study based on certain described criteria. From June to August 2005, Dutch pharmacists (N = 149) collected alerts occurring in daily patient care for these interactions as well as information related to the patient, the alert itself, the prescriber, and the management of the alert. Noncompliance was measured by comparing the management executed by the pharmacy with the national guidelines.

Results:

Overall compliance with the guidelines was 69.3% (n = 423), with large differences between the various drug–drug interactions. Male sex (OR 2.25; 95% CI 1.52 to 3.31), oldest age (>75 y; OR 1.97; 95% CI 1.03 to 3.75), and polypharmacy (>7 medications; OR 2.35; 95% CI 1.46 to 3.80) were associated with a higher probability for noncompliance with the guidelines. Prescriber-related variables had no significant influence on guideline compliance. Substitution of one of the involved agents, recommended for most of the drug–drug Interactions, was executed in a small minority of cases. The outcome of interaction management, such as substitution, dose reduction, or temporary stop of one of the agents, was frequently inconsistent with the guidelines. Compliance rates were partly influenced by the ultimate decision made by the prescriber. In that way, pharmacies' compliance was not solely assessed. However, in only 22.5% of the cases was the drug–drug interaction presented to the prescriber.

Conclusions:

Noncompliance with Dutch guidelines for the management of drug–drug interaction alerts is common in community pharmacies. Further research into underlying reasons for noncompliance is warranted, such as the relation between pharmacist and prescriber in this context.
Patient Evaluation of a Community Pharmacy Medications Management Service
Authors: Tinelli Michela , Bond Christine , Blenkinsopp Alison , Jaffray Mariesha , Watson Margaret , Hannaford Philip
Published: October 2007

Background:

A patient-centered approach is increasingly recognized as an important component in the evaluation of healthcare services.

Objective:

To assess patient satisfaction with, attitudes toward, and expectations of or experience with community pharmacy in genera), and to evaluate the effect of the community pharmacy–led medications management service on these factors.

Methods:

Postal questionnaire surveys were completed at baseline and after 12 months (follow-up) as part of a randomized controlled trial of the service. The setting was 9 primary care organizations in England. Patients with coronary heart disease were recruited from general practice registers and randomly allocated to the intervention (pharmacy-led medications management service) or control group.

Results:

Survey response rates at baseline and follow-up were 88.4% (1232/1394) and 80.1% (1085/1355), respectively. The respondents indicated that they wanted pharmacists to provide dispensing, medications review, advice on medications and health, private consultation areas, and short visit times. At follow-up, intervention patients were more likely than control patients (p < 0.01) to rate the service provided by their pharmacist with a higher level of satisfaction, and most intervention patients stated a preference for seeing their physician to discuss their medications, although this was less marked than in control patients (76% vs 85%; p < 0.01). Intervention patients were also more willing than control patients to ask the pharmacist questions that they would be unable to ask a physician (20% vs 11%, respectively; p < 0.01), to ask the pharmacist questions about their medications (32% vs 18%, respectively; p < 0.01), and to recommend this practice to others (51% vs 40%, respectively; p < 0.01).

Conclusions:

Pharmacist intervention was associated with significant and positive changes in patient satisfaction. While patients probably continue to prefer a physician-led service, they value aspects of a pharmacy service. Patients generally preferred discussing medications with the family physician, but experiencing the community pharmacy-led service resulted in an attitudinal shift toward the pharmacist. These findings suggest a benefit in developing the community pharmacist's role as a reviewer of, and adviser on, patients' medications.
Impact of Patient and Plan Design Factors on Switching to Preferred Statin Therapy
Authors: Cox Emily R , Kulkarni Amit , Henderson Rochelle
Published: October 2007

Background:

Changing formulary status is a common strategy to encourage greater use of lower-cost brand and generic drugs.

Objective:

To examine the relationship between patient and plan design factors and formulary adherence after the formulary status change of atorvastatin.

Methods:

We conducted a cross-sectional, cohort study of patients enrolled in one of 2139 commercial (no Medicare or Medicaid) plans that offer a 3-tier benefit design and changed atorvastatin from formulary to nonformulary status on January 1,2006. Adults on atorvastatin therapy who were receiving targeted communications in the fourth quarter of 2005 were included for analysis. We used bivariate and multivariate logistic regression analyses to examine the relationship between covariates and formulary adherence for patients receiving atorvastatin through retail or home delivery (HD) pharmacies.

Results:

A total of 211,083 patients met the study inclusion criteria, and more than 42% switched from atorvastatin to a formulary statin (33.1% retail, 51.6% HD). Patient-related factors that consistently and positively predicted switching across retail and HD channels included female sex, prior statin switching, and member outreach to the pharmacy benefit manager through telephone or Web use. Plan design factors that positively influenced switching to the preferred agent included step therapy, brand preferred/nonpreferred copayment differential, and among retail users, receipt of a rapid response education letter. Adoption of step therapy and the rapid-response program in retail settings increased the odds of switching by 1.3. Compared with patients who were paying a differential of $10 or less in retail channels, those who were paying $11–15, $16–20, and $21 and higher had increased odds of switching of 35% (95% CI 1.31 to 1.39), 41% (95% CI 1.37 to 1.46), and 80% (95% CI 1.74 to 1.86), respectively. In HD, compared with patients who were paying a differential of $15 or less, those who were paying $16–30, $31–40, and $41 and higher had increased odds of switching to a formulary preferred agent of 20% (95% CI 1.17 to 1.23), 23% (95% CI 1.19 to 1.26), and 59% (95% CI 1.55 to 1.64), respectively.

Conclusions:

Through appropriate program and plan design, plan sponsors’ impact on formulary adoption is maximized.
DVD Reviews
Authors: Udden James , Kramer Gary M , Bitel Anton , Scatton-Tessier Michelle , Broomer Stephen , Stanek Tom , Joll Harry
Published: October 2007

Yi Yi (A One and a Two) (2000)

Cinema 16: European Short Films (2007)

Clean, Shaven (1993)

Eric Rohmer's Six Moral Tales The Criterion Collection. 2006 ISBN: 1-55940-989-4. 99.95

The Bakery Girl of Monceau (La Boulangre de Monceau, 1962)

Suzanne's Career (La Carrire de
Suzanne, 1963)

My Night at Maud's (Ma nuit chez Maud, 1969)

La Collectionneuse (1969)

Claire's Knee (Le Genou de Claire, 1970)

Love in the After-noon (L'Amour, laprs-midi, 1972)

R.W. Paul: The Collected Films, 18951908

Echoes of Forgotten Places: Urban Exploration, Industrial
Archeology, and the Aesthetics of Decay, (2005)

Army in the Shadows (L'Arme des ombres, 1969)
Festival Reviews
Authors: Lumholdt Jan
Published: October 2007

What a Swell Party This Was
Jan Lumholdt turns ten as Cannes turns 60
Biochemical and hormonal composition, cytological examination of thyroid cyst fluid, and comparison according to gender and color of cyst fluid
Authors: Demirci Hüseyin , Erdamar Hüsamettin , Bukan Neslihan , Dikmen Kürşat , Karakoç Ayhan , Arslan Metin
Published: October 2007

Clin Chem Lab Med 2007;45:1517–22.
Reliability assessment of glucose measurement by HemoCue analyser in a neonatal intensive care unit
Authors: Bellini Carlo , Serra Giovanni , Risso Domenico , Mazzella Massimo , Bonioli Eugenio
Published: October 2007

Clin Chem Lab Med 2007;45:1549–54.
Analysis of ferritin genes in Parkinson disease
Authors: Foglieni Barbara , Ferrari Francesca , Goldwurm Stefano , Santambrogio Paolo , Castiglioni Emanuela , Sessa Maria , Antonietta Volontè Maria , Lalli Stefania , Galli Carlo , Wang Xin-Sheng , Connor James , Sironi Francesca , Canesi Margherita , Biasiotto Giorgio , Pezzoli Gianni , Levi Sonia , Ferrari Maurizio , Arosio Paolo , Cremonesi Laura
Published: October 2007

Clin Chem Lab Med 2007;45:1450–6.
Association of a 27-bp repeat polymorphism in intron 4 of endothelial constitutive nitric oxide synthase gene with myocardial infarction in Tunisian patients
Authors: Jemaa Riadh , Kallel Amani , Ben Ali Samir , Omar Souheil , Chabrak Sonia , Elasmi Monia , Haj Taieb Sameh , Sanhaji Haïfa , Feki Moncef , Mechmeche Rachid , Kaabachi Naziha
Published: October 2007

Clin Chem Lab Med 2007;45:1476–80.
Multimers and adiponectin gene 276G>T polymorphism in the Japanese population residing in rural areas
Authors: Ishibashi Kiyomi , Takamura Noboru , Aoyagi Kiyoshi , Yamasaki Hironori , Abiru Norio , Nakazato Mio , Kamihira Shimeru , Maeda Takahiro
Published: October 2007

Clin Chem Lab Med 2007;45:1457–63.
Impact of rosiglitazone on the expression of β3-AR in the stable cell lines expressed β3-AR gene
Authors: Zhao Xin , Hu Min-Yu , Huang Qiong , Tang Zhong-Yang , Dai Xing-Ping , Yin Ji-Ye , Zhang Feng , Zhou Hong-Hao , Liu Zhao-Qian
Published: October 2007

Clin Chem Lab Med 2007;45:1511–6.
Altered angiogenesis in preeclampsia: evaluation of a new test system for measuring placental growth factor
Authors: Schmidt Markus , Dogan Canan , Birdir Cahid , Callies Rainer , Kuhn Ulrich , Gellhaus Alexandra , Janetzko Alfred , Kimmig Rainer , Kasimir-Bauer Sabine
Published: October 2007

Clin Chem Lab Med 2007;45:1504–10.
Utility of PFA-100® closure time vs. optical aggregometry in assessing the efficacy of platelet membrane glycoprotein IIb/IIIa antagonists in vitro
Authors: Stegnar Mojca , Božič Mojca , Dolenc Marija Sollner , Anderluh Petra Štefanič , Kikelj Danijel
Published: October 2007

Clin Chem Lab Med 2007;45:1542–8.
Current state and future directions of neurochemical biomarkers for Alzheimer's disease
Authors: de Jong Daniëlle , Kremer Berry P.H. , Olde Rikkert Marcel G.M. , Verbeek Marcel M.
Published: October 2007

In this comprehensive review, we summarize the current state-of-the-art of neurochemical biomarkers for Alzheimer's disease. Predominantly, these biomarkers comprise cerebrospinal fluid biomarkers directly related to the pathophysiology of this disorder (such as amyloid β protein, tau protein). We particularly pay attention to the innovations in this area that have been made in technological aspects during the past 5 years (e.g., multiplex analysis of biomarkers, proteomics), to the discovery of novel, potential biomarkers (e.g., amyloid β oligomers, isoprostanes), and to the extension of this research towards identification of biomarkers in plasma.

Clin Chem Lab Med 2007;45:1421–34.
Use of SELDI-TOF mass spectrometry for identification of new biomarkers: potential and limitations
Authors: Kiehntopf Michael , Siegmund Robert , Deufel Thomas
Published: October 2007

Surface-enhanced laser desorption time of flight mass spectrometry (SELDI-TOF-MS) is an important proteomic technology that is immediately available for the high throughput analysis of complex protein samples. Over the last few years, several studies have demonstrated that comparative protein profiling using SELDI-TOF-MS breaks new ground in diagnostic protein analysis particularly with regard to the identification of novel biomarkers. Importantly, researchers have acquired a better understanding also of the limitations of this technology and various pitfalls in biomarker discovery. Bearing these in mind, great emphasis must be placed on the development of rigorous standards and quality control procedures for the pre-analytical as well as the analytical phase and subsequent bioinformatics applied to analysis of the data. To avoid the risk of false-significant results studies must be designed carefully and control groups accurately selected. In addition, appropriate tools, already established for analysis of highly complex microarray data, need to be applied to protein profiling data. To validate the significance of any candidate biomarker derived from pilot studies in appropriately designed prospective multi-center studies is mandatory; reproducibility of the clinical results must be shown over time and in different diagnostic settings. SELDI-TOF-MS-based studies that are in compliance with these requirements are now required; only a few have been published so far. In the meantime, further evaluation and optimization of both technique and marker validation strategies are called for before MS-based proteomic algorithms can be translated into routine laboratory testing.

Clin Chem Lab Med 2007;45:1435–49.
Changes of the EPSP Waveform Regulate the Temporal Window for Spike-Timing-Dependent Plasticity
Authors: Fuenzalida Marco , Fernandez de Sevilla David , Buño Washington
Published: October 2007

Using spike-timing-dependent plasticity (STDP) protocols that consist of pairing an EPSP and a postsynaptic backpropagating action potential (BAP), we investigated the contribution of the changes in EPSP waveform induced by the slow Ca2+-dependent K+-mediated afterhyperpolarization (sAHP) in the regulation of long-term potentiation (LTP). The “temporal window” between Schaffer collateral EPSPs and BAPs in CA1 pyramidal neurons required to induce LTP was narrowed by a reduction of the amplitude and decay time constant of the EPSP, which could be reversed with cyclothiazide. The EPSP changes were caused by the increased conductance induced by activation of the sAHP. Therefore, the EPSP waveform and its regulation by the sAHP are central in determining the duration of the temporal window for STDP, thus providing a possible dynamic regulatory mechanism for the encoding of cognitive processes.
Gastrin-Releasing Peptide Mediates Light-Like Resetting of the Suprachiasmatic Nucleus Circadian Pacemaker through cAMP Response Element-Binding Protein andPer1Activation
Authors: Gamble Karen L. , Allen Gregg C. , Zhou Tongrong , McMahon Douglas G.
Published: October 2007

Circadian rhythmicity in the primary mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN) of the hypothalamus, is maintained by transcriptional and translational feedback loops among circadian clock genes. Photic resetting of the SCN pacemaker involves induction of the clock genesPeriod1(Per1) andPeriod2(Per2) and communication among distinct cell populations. Gastrin-releasing peptide (GRP) is localized to the SCN ventral retinorecipient zone, from where it may communicate photic resetting signals within the SCN network. Here, we tested the putative role of GRP as an intra-SCN light signal at the behavioral and cellular levels, and we also tested whether GRP actions are dependent on activation of the cAMP response element-binding protein (CREB) pathway andPer1. In vivomicroinjections of GRP to the SCN regions ofPer1::green fluorescent protein (GFP) mice during the late night inducedPer1::GFP throughout the SCN, including a limited population of arginine vasopressin-immunoreactive (AVP-IR) neurons. Blocking spike-mediated communication with tetrodotoxin did not disrupt overallPer1::GFP induction but did reduce induction within AVP-IR neurons.In vitroGRP application resulted in persistent increases in the spike frequency ofPer1::GFP-induced neurons. Blocking endogenousPer1with antisense oligodeoxynucleotides inhibited GRP-induced increases in spike frequency. Furthermore, inhibition of CREB-mediated gene activation with decoy oligonucleotides blocked GRP-induced phase shifts of PER2::luciferase rhythms in SCN slices. Altogether, these results indicate that GRP communicates phase resetting signals within the SCN network via both spike-dependent and spike-independent mechanisms, and that activation of the CREB pathway andPer1are key steps in mediating downstream events in GRP resetting of SCN neurons.
Neural Stem Cells Improve Memory in an Inducible Mouse Model of Neuronal Loss
Authors: Yamasaki Tritia R. , Blurton-Jones Mathew , Morrissette Debbi A. , Kitazawa Masashi , Oddo Salvatore , LaFerla Frank M.
Published: October 2007

Neuronal loss is a major pathological outcome of many common neurological disorders, including ischemia, traumatic brain injury, and Alzheimer disease. Stem cell-based approaches have received considerable attention as a potential means of treatment, although it remains to be determined whether stem cells can ameliorate memory dysfunction, a devastating component of these disorders. We generated a transgenic mouse model in which the tetracycline-off system is used to regulate expression of diphtheria toxin A chain. After induction, we find progressive neuronal loss primarily within the hippocampus, leading to specific impairments in memory. We find that neural stem cells transplanted into the brain after neuronal ablation survive, migrate, differentiate and, most significantly, improve memory. These results show that stem cells may have therapeutic value in diseases and conditions that result in memory loss.
Dissociable Performance on Scene Learning and Strategy Implementation after Lesions to Magnocellular Mediodorsal Thalamic Nucleus
Authors: Mitchell Anna S. , Baxter Mark G. , Gaffan David
Published: October 2007

Monkeys with aspiration lesions of the magnocellular division of the mediodorsal thalamus (MDmc) are impaired in object-in-place scene learning, object recognition, and stimulus-reward association. These data have been interpreted to mean that projections from MDmc to prefrontal cortex are required to sustain normal prefrontal function in a variety of task settings. In the present study, we investigated the extent to which bilateral neurotoxic lesions of the MDmc impair a preoperatively learnt strategy implementation task that is impaired by a crossed lesion technique that disconnects the frontal cortex in one hemisphere from the contralateral inferotemporal cortex. Postoperative memory impairments were also examined using the object-in-place scene memory task. Monkeys learnt both strategy implementation and scene memory tasks separately to a stable level preoperatively. Bilateral neurotoxic lesions of the MDmc, produced by 10 × 1 μl injections of a mixture of ibotenate and NMDA did not affect performance in the strategy implementation task. However, new learning of object-in-place scene memory was substantially impaired. These results provide new evidence about the role of the magnocellular mediodorsal thalamic nucleus in memory processing, indicating that interconnections with the prefrontal cortex are essential during new learning, but are not required when implementing a preoperatively acquired strategy task. Thus, not all functions of the prefrontal cortex require MDmc input. Instead, the involvement of MDmc in prefrontal function may be limited to situations in which new learning must occur.
Cognitive Signals in the Primate Motor Thalamus Predict Saccade Timing
Authors: Tanaka Masaki
Published: October 2007

We often generate movements without any external event that immediately triggers them. How the brain decides the timing of self-initiated movements remains unclear. Previous studies suggest that the basal ganglia–thalamocortical pathways play this role, but the subcortical signals that determine movement timing have not been identified. The present study reports that a subset of thalamic neurons predicts the timing of self-initiated saccadic eye movements. When monkeys made a saccade in response to the fixation point (FP) offset in the traditional memory saccade task, neurons in the ventrolateral and the ventroanterior nuclei of the thalamus exhibited a gradual buildup of activity that peaked around the most probable time of the FP offset; however, neither the timing nor the magnitude of neuronal activity correlated with saccade latencies, suggesting that the brain is unlikely to have used this information to decide the times of saccades in the traditional memory saccade task. In contrast, when monkeys were required to make a self-timed saccade within a fixed time interval after an external cue, the same neurons again exhibited a strong buildup of activity that preceded saccades by several hundred milliseconds, showing a close correlation between the times of neuronal activity and the times of self-initiated saccades. The results suggest that neurons in the motor thalamus carry subjective time information, which is used by cortical networks to determine the timing of self-initiated saccades.