bluuebunny/crossref_metadata_2025 huggingface dataset:
Intraoperative fluid optimization using stroke volume variation in high risk surgical patients: results of prospective randomized study
Authors: Benes Jan , Chytra Ivan , Altmann Pavel , Hluchy Marek , Kasal Eduard , Svitak Roman , Pradl Richard , Stepan Martin
Published: June 2010

Introduction

Stroke volume variation (SVV) is a good and easily obtainable predictor of fluid responsiveness, which can be used to guide fluid therapy in mechanically ventilated patients. During major abdominal surgery, inappropriate fluid management may result in occult organ hypoperfusion or fluid overload in patients with compromised cardiovascular reserves and thus increase postoperative morbidity. The aim of our study was to evaluate the influence of SVV guided fluid optimization on organ functions and postoperative morbidity in high risk patients undergoing major abdominal surgery.

Methods

Patients undergoing elective intraabdominal surgery were randomly assigned to a Control group (n = 60) with routine intraoperative care and a Vigileo group (n = 60), where fluid management was guided by SVV (Vigileo/FloTrac system). The aim was to maintain the SVV below 10% using colloid boluses of 3 ml/kg. The laboratory parameters of organ hypoperfusion in perioperative period, the number of infectious and organ complications on day 30 after the operation, and the hospital and ICU length of stay and mortality were evaluated. The local ethics committee approved the study.

Results

The patients in the Vigileo group received more colloid (1425 ml [1000-1500] vs. 1000 ml [540-1250]; P = 0.0028) intraoperatively and a lower number of hypotensive events were observed (2[1-2] Vigileo vs. 3.5[2-6] in Control; P = 0.0001). Lactate levels at the end of surgery were lower in Vigileo (1.78 ± 0.83 mmol/l vs. 2.25 ± 1.12 mmol/l; P = 0.0252). Fewer Vigileo patients developed complications (18 (30%) vs. 35 (58.3%) patients; P = 0.0033) and the overall number of complications was also reduced (34 vs. 77 complications in Vigileo and Control respectively; P = 0.0066). A difference in hospital length of stay was found only in per protocol analysis of patients receiving optimization (9 [8-12] vs. 10 [8-19] days; P = 0.0421). No difference in mortality (1 (1.7%) vs. 2 (3.3%); P = 1.0) and ICU length of stay (3 [2-5] vs. 3 [0.5-5]; P = 0.789) was found.

Conclusions

In this study, fluid optimization guided by SVV during major abdominal surgery is associated with better intraoperative hemodynamic stability, decrease in serum lactate at the end of surgery and lower incidence of postoperative organ complications.

Trial registration

Current Controlled Trials ISRCTN95085011.
Increased metallothionein gene expression, zinc, and zinc-dependent resistance to apoptosis in circulating monocytes during HIV viremia
Authors: Raymond Andrea D , Gekonge Bethsebah , Giri Malavika S , Hancock Aidan , Papasavvas Emmanouil , Chehimi Jihed , Kossevkov Andrew V , Nicols Calen , Yousef Malik , Mounzer Karam , Shull Jane , Kostman Jay , Showe Louise , Montaner Luis J
Published: June 2010

Differential expression of metallothionein genes and high intracellular zinc promote monocyte survival during HIV infection.

Circulating monocytes exhibit an apoptotic resistance phenotype during HIV viremia in association with increased MT expression. MTs are known to play an important role in zinc metabolism and immune function. We now show, in a cross-sectional study using peripheral monocytes, that expression of MT1 isoforms E, G, H, and X is increased significantly in circulating monocyte cells from HIV+ subjects during chronic viremic episodes as compared with uninfected subjects. This increase in expression is also observed during acute viremia following interruption of suppressive ART. Circulating monocytes from HIV+ donors were also found to have elevated zinc importer gene Zip8 expression in conjunction with elevated intracellular zinc levels in contrast to CD4+T-lymphocytes. In vitro HIV-1 infection studies with elutriated MDM confirm a direct relation between HIV-1 infection and increased MDM MT1 (isoform G) gene expression and increased intracellular zinc levels. A direct link between elevated zinc levels and apoptosis resistance was established using a cell-permeable zinc chelator TPEN, which reversed apoptosis resistance effectively in monocytes from HIV-infected to levels comparable with uninfected controls. Taken together, increases in MT gene expression and intracellular zinc levels may contribute directly to maintenance of an immune-activated monocyte by mediating an increased resistance to apoptosis during active HIV-1 viremia.
Dendritic cells interact with CD4 T cells in intestinal mucosa
Authors: Inman Charlotte F , Singha Sakon , Lewis Marie , Bradley Ben , Stokes Chris , Bailey Mick
Published: June 2010

Dendritic cells interact with T cells in intestinal mucosa in an MHCII-dependent manner, suggesting presentation outside organized lymphoid tissue may be important in determining T cell phenotype.

Absence of lymph nodes in nonmammalian species, expression of MHCII by APCs in the periphery, and the recent findings that T cells can change their polarization status after presentation in the lymph nodes imply a role for MHCII-mediated presentation outside the organized lymphoid tissue. This study shows that MHCII+ ECs and DCs from the intestinal mucosa of the pig can present antigen to T cells in vitro. In vivo, APCs colocalize with T cells in pig and mouse intestinal mucosa. In the pig, endothelium is involved in these interactions in neonates but not in adults, indicating different roles for stromal and professional APCs in the neonate compared with the adult. The ratio of expression of DQ and DR MHCII locus products was lower on ECs than on other mucosal APCs, indicating that the two types of cells present different peptide sets. Adult nonendothelial APCs expressed a higher ratio of DQ/DR than in neonates. These results suggest that mucosal DCs can present antigen locally to primed T cells and that stromal APCs are recruited to these interactions in some cases. This raises the possibility that local presentation may influence T cell responses at the effector stage after initial presentation in the lymph node.
A newly identified bacterial cell-penetrating peptide that reduces the transcription of pro-inflammatory cytokines
Authors: Rüter Christian , Buss Christoph , Scharnert Julia , Heusipp Gerhard , Schmidt M. Alexander
Published: June 2010

Cell-permeable proteins, also called cell-penetrating peptides (CPPs), have the ability to cross cellular membranes, either alone or in association with bioactive cargo. We identified the Yersinia protein YopM as a novel bacterial cell-permeable protein. Here, we describe the ability of isolated recombinant YopM to enter host cells without a requirement for additional factors. This autonomous translocation of YopM was confirmed in several cell types, indicating that it is an intrinsic property of YopM. Using truncated versions of YopM, we show that either of the two N-terminal α-helices of YopM mediates translocation into the cells. Furthermore, the two α-helices are also able to deliver heterologous cargo, such as GFP or YopE. In addition, we found that, after entering the cells, YopM is functional and efficiently downregulates the transcription of pro-inflammatory cytokines (such as tumor necrosis factor-α and interleukins 12, 15 and 18). This finding suggests the potential use of YopM as a tool for protein delivery. Furthermore, it can lead to important advances in understanding and evaluating the intracellular and molecular function of YopM without the need for infection with Yersinia.
Visualization of Ins(1,4,5)P3 dynamics in living cells: two distinct pathways for Ins(1,4,5)P3 generation following mechanical stimulation of HSY-EA1 cells
Authors: Nezu Akihiro , Tanimura Akihiko , Morita Takao , Tojyo Yosuke
Published: June 2010

In the present study, the contribution of inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] generation on the mechanical-stimulation-induced Ca2+ response was investigated in HSY-EA1 cells. Mechanical stimulation induced a local increase in the cytosolic concentration of Ins(1,4,5)P3 ([IP3]i), as indicated by the Ins(1,4,5)P3 biosensor LIBRAvIII. The area of this increase expanded like an intracellular Ins(1,4,5)P3 wave as [IP3]i increased in the stimulated region. A small transient [IP3]i increase was subsequently seen in neighboring cells. The phospholipase C inhibitor U-73122 abolished these Ins(1,4,5)P3 responses and resultant Ca2+ releases. The purinergic receptor blocker suramin completely blocked increases in [IP3]1 and the Ca2+ release in neighboring cells, but failed to attenuate the responses in mechanically stimulated cells. These results indicate that generation of Ins(1,4,5)P3 in response to mechanical stimulation is primarily independent of extracellular ATP. The speed of the mechanical-stimulation-induced [IP3]i increase was much more rapid than that induced by a supramaximal concentration of ATP (1 mM). The contribution of the Ins(1,4,5)P3-induced Ca2+ release was larger than that of Ca2+ entry in the Ca2+ response to mechanical stimulation in HSY-EA1 cells.
Constant regulation of both the MPF amplification loop and the Greatwall-PP2A pathway is required for metaphase II arrest and correct entry into the first embryonic cell cycle
Authors: Lorca Thierry , Bernis Cyril , Vigneron Suzanne , Burgess Andrew , Brioudes Estelle , Labbé Jean-Claude , Castro Anna
Published: June 2010

Recent results indicate that regulating the balance between cyclin-B–Cdc2 kinase, also known as M-phase-promoting factor (MPF), and protein phosphatase 2A (PP2A) is crucial to enable correct mitotic entry and exit. In this work, we studied the regulatory mechanisms controlling the cyclin-B–Cdc2 and PP2A balance by analysing the activity of the Greatwall kinase and PP2A, and the different components of the MPF amplification loop (Myt1, Wee1, Cdc25) during the first embryonic cell cycle. Previous data indicated that the Myt1-Wee1-Cdc25 equilibrium is tightly regulated at the G2-M and M-G1 phase transitions; however, no data exist regarding the regulation of this balance during M phase and interphase. Here, we demonstrate that constant regulation of the cyclin-B–Cdc2 amplification loop is required for correct mitotic division and to promote correct timing of mitotic entry. Our results show that removal of Cdc25 from metaphase-II-arrested oocytes promotes mitotic exit, whereas depletion of either Myt1 or Wee1 in interphase egg extracts induces premature mitotic entry. We also provide evidence that, besides the cyclin-B–Cdc2 amplification loop, the Greatwall-PP2A pathway must also be tightly regulated to promote correct first embryonic cell division. When PP2A is prematurely inhibited in the absence of cyclin-B–Cdc2 activation, endogenous cyclin-A–Cdc2 activity induces irreversible aberrant mitosis in which there is, first, partial transient phosphorylation of mitotic substrates and, second, subsequent rapid and complete degradation of cyclin A and cyclin B, thus promoting premature and rapid exit from mitosis.
Control of ciliogenesis by FOR20, a novel centrosome and pericentriolar satellite protein
Authors: Sedjaï Fatima , Acquaviva Claire , Chevrier Véronique , Chauvin Jean-Paul , Coppin Emilie , Aouane Aicha , Coulier François , Tolun Aslihan , Pierres Michel , Birnbaum Daniel , Rosnet Olivier
Published: June 2010

Cilia and flagella are evolutionary conserved organelles that generate fluid movement and locomotion, and play roles in chemosensation, mechanosensation and intracellular signalling. In complex organisms, cilia are highly diversified, which allows them to perform various functions; however, they retain a 9+0 or 9+2 microtubules structure connected to a basal body. Here, we describe FOR20 (FOP-related protein of 20 kDa), a previously uncharacterized and highly conserved protein that is required for normal formation of a primary cilium. FOR20 is found in PCM1-enriched pericentriolar satellites and centrosomes. FOR20 contains a Lis1-homology domain that promotes self-interaction and is required for its satellite localization. Inhibition of FOR20 expression in RPE1 cells decreases the percentage of ciliated cells and the length of the cilium on ciliated cells. It also modifies satellite distribution, as judged by PCM1 staining, and displaces PCM1 from a detergent-insoluble to a detergent-soluble fraction. The subcellular distribution of satellites is dependent on both microtubule integrity and molecular motor activities. Our results suggest that FOR20 could be involved in regulating the interaction of PCM1 satellites with microtubules and motors. The role of FOR20 in primary cilium formation could therefore be linked to its function in regulating pericentriolar satellites. A role for FOR20 at the basal body itself is also discussed.
The keratin-filament cycle of assembly and disassembly
Authors: Kölsch Anne , Windoffer Reinhard , Würflinger Thomas , Aach Til , Leube Rudolf E.
Published: June 2010

Continuous and regulated remodelling of the cytoskeleton is crucial for many basic cell functions. In contrast to actin filaments and microtubules, it is not understood how this is accomplished for the third major cytoskeletal filament system, which consists of intermediate-filament polypeptides. Using time-lapse fluorescence microscopy of living interphase cells, in combination with photobleaching, photoactivation and quantitative fluorescence measurements, we observed that epithelial keratin intermediate filaments constantly release non-filamentous subunits, which are reused in the cell periphery for filament assembly. This cycle is independent of protein biosynthesis. The different stages of the cycle occur in defined cellular subdomains: assembly takes place in the cell periphery and newly formed filaments are constantly transported toward the perinuclear region while disassembly occurs, giving rise to diffusible subunits for another round of peripheral assembly. Remaining juxtanuclear filaments stabilize and encage the nucleus. Our data suggest that the keratin-filament cycle of assembly and disassembly is a major mechanism of intermediate-filament network plasticity, allowing rapid adaptation to specific requirements, notably in migrating cells.
In vivo cellular adaptation to ER stress: survival strategies with double-edged consequences
Authors: Tsang Kwok Yeung , Chan Danny , Bateman John F. , Cheah Kathryn S. E.
Published: June 2010

Disturbances to the balance of protein synthesis, folding and secretion in the endoplasmic reticulum (ER) induce stress and thereby the ER stress signaling (ERSS) response, which alleviates this stress. In this Commentary, we review the emerging idea that ER stress caused by abnormal physiological conditions and/or mutations in genes that encode client proteins of the ER is a key factor underlying different developmental processes and the pathology of diverse diseases, including diabetes, neurodegeneration and skeletal dysplasias. Recent studies in mouse models indicate that the effect of ERSS in vivo and the nature of the cellular strategies induced to ameliorate pathological ER stress are crucial factors in determining cell fate and clinical disease features. Importantly, ERSS can affect cellular proliferation and the differentiation program; cells that survive the stress can become ‘reprogrammed’ or dysfunctional. These cell-autonomous adaptation strategies can generate a spectrum of context-dependent cellular consequences, ranging from recovery to death. Secondary effects can include altered cell–extracellular-matrix interactions and non-cell-autonomous alteration of paracrine signaling, which contribute to the final phenotypic outcome. Recent reports showing that ER stress can be alleviated by chemical compounds suggest the potential for novel therapeutic approaches.
Interplay between BCL10, MALT1 and IκBα during T-cell-receptor-mediated NFκB activation
Authors: Carvalho Gabrielle , Le Guelte Armelle , Demian Catherine , Vazquez Aimé , Gavard Julie , Bidère Nicolas
Published: June 2010

T-cell-receptor (TCR) signalling to NFκB requires the assembly of a large multiprotein complex containing the serine/threonine kinase CK1α, the scaffold protein CARMA1, the heterodimer BCL10-MALT1 (the CBM complex) and the IκB kinase complex (IKK). Although the mechanisms regulating recruitment and activation of IKK within the CBM microenvironment have been extensively studied, there is little understanding of how IKK subsequently binds and phosphorylates IκBα, the inhibitor of NFκB, to promote IκBα ubiquitylation and proteasomal degradation. Here, we show that BCL10, MALT1 and IKK inducibly associate with IκBα in a complex that is physically distinct from the early CK1α-CBM signalosome. This IκBα-containing complex probably maturates from the CBM, because siRNA-based knockdown of CARMA1, CK1α and BCL10 hampered its assembly, leading to a reduction in NFκB activation. By contrast, CK1α normally recruited both BCL10 and ubiquitylated species of MALT1 when IκBα levels were reduced. However, knockdown of IκBα led to an altered ubiquitylation profile of BCL10-MALT1 combined with a defect in MALT1 reorganisation within large cytoplasmic structures, suggesting that, following stimulation, IκBα might also participate in MALT1 recycling. Altogether, our data suggest a two-step mechanism to connect active IKK to IκBα, and further unveil a potential role for IκBα in resetting TCR-mediated signalling.
Regulation of store-operated Ca2+ entry during the cell cycle
Authors: Arredouani Abdelilah , Yu Fang , Sun Lu , Machaca Khaled
Published: June 2010

Cytoplasmic Ca2+ signals are central to numerous cell physiological processes, including cellular proliferation. Historically, much of the research effort in this area has focused on the role of Ca2+ signals in cell-cycle progression. It is becoming clear, however, that the relationship between Ca2+ signaling and the cell cycle is a ‘two-way street’. Specifically, Ca2+-signaling pathways are remodeled during M phase, leading to altered Ca2+ dynamics. Such remodeling probably better serves the large variety of functions that cells must perform during cell division compared with during interphase. This is clearly the case during oocyte meiosis, because remodeling of Ca2+ signals partially defines the competence of the egg to activate at fertilization. Store-operated Ca2+ entry (SOCE) is a ubiquitous Ca2+-signaling pathway that is regulated during M phase. In this Commentary, we discuss the latest advances in our understanding of how SOCE is regulated during cell division.
Teaching Modeling in Management Science
Authors: Powell Stephen G.
Published: June 2010

This essay discusses how we can most effectively teach Management Science to students in MBA or similar programs who will be, at best, part-time practitioners of these arts. I take as a working hypothesis the radical proposition that the heart of Management Science itself is not the impressive array of tools that have been built up over the years (optimization, simulation, decision analysis, queuing, and so on) but rather the art of reasoning logically with formal models. I believe it is necessary with this group of students to teach basic modeling skills, and in fact it is only when such students have these basic skills as a foundation that they are prepared to acquire the more sophisticated skills needed to employ Management Science. In this paper I present a hierarchy of modeling skills, from numeracy skills through sophisticated Management Science skills, as a framework within which to plan courses for the occasional practitioner.
Who Wants to See a $Million Error?
Authors: Rump Christopher M.
Published: June 2010

Inspired by the popular television show “Who Wants to Be a Millionaire?”, this case discusses the monetary decisions contestants face on a game consisting of 15 increasingly difficult multiple choice questions. Since the game continues as long as a contestant answers correctly, this case, at its core, is one of sequential decision analysis, amenable to analysis via stochastic dynamic programming. The case is also suitable for a course dealing with single decision analysis, allowing for discussion of utility theory and Bayesian probability revision. In developing a story line for the case, the author has sprinkled in much background material on probability and statistics. This material is placed in a historical context, illuminating some of the influential scholars involved in the development of these subjects as well as the birth of operations research and the management sciences.
Teaching Revenue Management at the Cornell University School of Hotel Administration
Authors: Anderson Chris K. , Kimes Sherri , Carroll Bill
Published: June 2010

The Cornell University School of Hotel Administration was one of the first in the world to offer a university course in revenue management (starting in 1994) and currently offers five courses related to revenue management: Yield Management, Restaurant Revenue Management, Managing Hospitality Distribution Strategies, Hospitality Pricing and Analysis, and Nontraditional Revenue Management. In addition, the school offers undergraduate and graduate concentrations and executive education courses in revenue management. In recent years, about 10%–15% of our graduates have obtained jobs in revenue management and distribution. In the following paper we discuss the evolution of the teaching of revenue management at Cornell providing descriptions of the courses we teach as well as insight into how this content may be delivered at other institutions.
Teaching Demand Management and Price Optimization in the MBA Program at the Carnegie Mellon University Tepper School of Business
Authors: Secomandi Nicola
Published: June 2010

In this paper, I describe the course Demand Management and Price Optimization that I have taught in the MBA program at the Carnegie Mellon University Tepper School of Business during the past five years. I focus on my experience in teaching this course, which has significantly evolved over time from essentially a revenue management course to a course that emphasizes quantitative models that address features falling at the interface between the operations and marketing functions of a firm. I hope that prospective instructors of similar courses will find this discussion useful and informative in making their own choices regarding how to structure their courses.
The Customer Valuations Game as a Basis for Teaching Revenue Management
Authors: Talluri Kalyan
Published: June 2010

I describe the customer valuations game, a simple intuitive game that can serve as a foundation for teaching revenue management. The game requires little or no preparation, props, or software; takes about two hours to play (and hence can be finished in one session); and illustrates the formation of classical (airline and hotel) revenue management mechanisms such as advanced purchase discounts, booking limits, and fixed multiple prices. I use the game to introduce revenue management and to develop revenue management forecasting and optimization concepts stemming from it. The game is particularly suited for nontechnical audiences.
Case Article—Revenue Management at Harrah's Entertainment, Inc.
Authors: Agrawal Narendra , Cohen Morris A. , Gans Noah
Published: June 2010

Harrah's Entertainment operates a highly diversified network of gambling facilities in the United States and the United Kingdom. This case introduces students to Harrah's use of price controls for hotel revenue management: how it works, how it integrates with Harrah's Total Rewards loyalty card, and how it might be changed. Within the context of a course on revenue management or service operations, the case can be used effectively to discuss principles of revenue management and to demonstrate the use of a number of quantitative analysis techniques to design and optimize revenue management systems.

Case Teaching Note: Interested Instructors please see the Instructor Materials page for access to the restricted materials. To maintain the integrity and usefulness of cases published in ITE, unapproved distribution of the case teaching notes and other restricted materials to any other party is prohibited.
The Role of Colesevelam Hydrochloride in Hypercholesterolemia and Type 2 Diabetes Mellitus
Authors: Brunetti Luigi , Hermes-DeSantis Evelyn R
Published: June 2010

Objective:

To evaluate the safety and efficacy of colesevelam hydrochloride for the treatment of hypercholesterolemia and type 2 diabetes mellitus.

Data Sources:

Literature retrieval was accessed through MEDLINE/PubMed (1950–March 2010), Web of Science (1980–March 2010), and International Pharmaceutical Abstracts (1977–March 2010) using the terms colesevelam, dyslipidemia, hypercholesterolemia, and type 2 diabetes mellitus. References from publications identified were reviewed for additional resources. In addition, abstracts presented at the most recent (2009) American Diabetes Association, American Association of Clinical Endocrinologists, and European Association for the Study of Diabetes annual meetings were searched for relevant original research.

Study Selection and Data Extraction:

All articles in English identified from the data sources were evaluated. All relevant studies evaluating the safety and efficacy of colesevelam in hypercholesterolemia and/or type 2 diabetes mellitus were included. Priority was placed on data obtained from human randomized controlled trials.

Data Synthesis:

Seventeen clinical trials were reviewed and evaluated. Of the clinical trials evaluating colesevelam in hypercholesterolemia, 3 evaluated monotherapy, 4 evaluated combination therapy with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, and 6 evaluated combination therapy with other lipid-lowering therapies. In the type 2 diabetes mellitus trials, colesevelam was evaluated in combination with metformin, sulfonylureas, insulin, and rosiglitazone and sitagliptin. A review of the clinical trials provided evidence that colesevelam monotherapy effectively reduces low-density lipoprotein cholesterol (LDL-C). Additionally, the use of colesevelam in combination with other lipid-lowering therapies further reduces LDL-C. Colesevelam also effectively reduces hemoglobin A1c in patients with type 2 diabetes mellitus. The safety and tolerability of colesevelam appear to be improved from that of older-generation bile acid sequestrants, with adverse effects similar to those with placebo in monotherapy and type 2 diabetes mellitus trials.

Conclusions:

Colesevelam is a safe and effective option for the treatment of hypercholesterolemia and type 2 diabetes mellitus. It can fulfill a useful role in combination with HMG-CoA reductase inhibitors for hypercholesterolemia and should be considered in patients with type 2 diabetes mellitus with concomitant hypercholesterolemia.
A Population Study of the Frequency of High-Dose Acetaminophen Prescribing and Dispensing
Authors: Albertson Timothy E , Walker Victor M , Stebbins Marilyn R , Ashton Elisa W , Owen Kelly P , Sutter Mark E
Published: June 2010

Background:

Recurrent intake of 4 g/day or more of acetaminophen has been associated with elevation of serum alanine aminotransferase (ALT) levels in 30–40% of the exposed population and may result in hepatotoxicity.

Objective:

To describe the frequency that patients are prescribed acetaminophen doses that exceed 4 g/day across a large population.

Methods:

Using California's Medicaid (MediCal) fee-for-service population, pharmacy claims including over-the-counter (OTC) medications were examined for prescriptions that could result in acetaminophen doses of 4 g/day or more. The period studied, October 2004 through September 2005, was before the Part D pharmacy benefit was available to dually eligible Medicare patients when all prescriptions were covered by the MediCal claims process.

Results:

During the pre-Part D evaluation period, approximately 3.27 million beneficiaries were enrolled in the fee-for-service MediCal program. A total of 192,716 (5.9%) were potentially exposed to at least 1 day of 4 g/day or more of acetaminophen. Of those, 769 patients were potentially exposed to at least 1 day of 16 g/day or more. A total of 2664 beneficiaries were dispensed prescriptions and OTC products that, if taken as directed, would have resulted in more than 100 days of acetaminophen doses of 4 g/day or more during the study year.

Conclusions:

Despite electronic systems designed to warn dispensing pharmacists of duplications of drug class and cumulative excessive doses, potentially toxic amounts of acetaminophen are commonly prescribed and dispensed to this population. Better systems, increased awareness, and education of patients, prescribers, and pharmacists are needed to reduce this potential toxic exposure.
Pitfalls Associated with the Use of Liquid Chromatography–Tandem Mass Spectrometry in the Clinical Laboratory
Authors: Vogeser Michael , Seger Christoph
Published: June 2010

BACKGROUND

Novel mass spectrometric techniques such as atmospheric pressure ionization and tandem mass spectrometry have substantially extended the spectrum of clinical chemistry methods during the past decade. In particular, liquid chromatography tandem–mass spectrometry (LC-MS/MS) has become a standard tool in research laboratories as well as in many clinical laboratories. Although LC-MS/MS has features that suggest it has a very high analytical accuracy, potential sources of inaccuracy have recently been identified.

CONTENT

The sources of inaccuracy in LC-MS/MS methods used in the routine quantification of small molecules are described and discussed. Inaccuracy of LC-MS/MS methods can be related to the process of ionization through the insource transformation of conjugate metabolites or target analytes and may also be attributable to ionization matrix effects that have a differential impact on target analytes and internal-standard compounds. Inaccuracy can also be associated with the process of ion selection, which mainly occurs when compounds from the sample matrix share mass transitions with a target analyte. In individual assays, most potential sources of inaccuracy can be controlled by sufficient LC separation–based sample workup before MS analysis.

LC-MS/MS methods should undergo rigorous and systematic validation before introduction into patient care.
Ten Research Questions for Family Therapy
Authors: Carr Alan
Published: June 2010

A growing evidence‐base shows that family therapy works, but many gaps in our knowledge remain about the conditions under which family therapy is effective and how it works. In this paper, ten critical research questions about family therapy that need to be addressed are considered. In short these are:

Is family therapy as effective in community settings as it is in specialist clinics?

For what problems is family therapy cost‐effective?

Does family therapy work for under‐researched problems and populations?

Do social‐constructionist and narrative approaches to family therapy work?

Can family therapy protocols be enhanced for non‐responders?

Can family therapy be combined with other psychotherapies to effectively treat specific problems?

Can family therapy be combined with pharmacotherapy to effectively treat specific problems?

What specific factors contribute to the effectiveness of family therapy with particular problems?

What common factors contribute to the effectiveness of family therapy?

What therapist and client factors contribute to the effectiveness of family therapy?
Family‐Based Treatment for Adolescents With Bulimia Nervosa
Authors: Grange Daniel Le
Published: June 2010

Family‐based treatment has for at least two decades now come to be seen as the treatment of choice for adolescents with anorexia nervosa (AN). Yet, involving the parents in the treatment for adolescents with bulimia nervosa (BN) have remained largely unexplored. We have recently adapted manualised family‐based treatment for adolescent AN (FBT‐AN) to a large group of adolescents with BN (FBT‐BN). This manuscript will highlight the key tenets of manualised FBT‐BN, briefly describe the three treatment phases, and summarise the main differences of this model in its application for AN versus BN. Finally, reference will be made to the first randomised controlled trial of FBT‐BN showing preliminary support for the parents' involvement in the treatment of adolescent BN.
Innovating through community capacity in traditional knowledge and Ethno medicine: a case study from Tamil Nadu (India)
Authors: Torri Maria-Costanza
Published: June 2010

This article looks at innovation as a product of the interaction between scientific and indigenous knowledge (IK). The innovation process raises questions about how knowledge on medicinal plants (MPs) is acquired, commoditized and politicized. By invoking the experiences of two related
Indian non-governmental organizations (NGOs), the article examines attempts made to promote IK in MPs through botanical knowledge and knowledge based on policies of biodiversity conservation, global health and development. The case studies further help shed light on how local knowledge is
reinvented to fit into new global networks. Making traditional medicine (TRM) more visible through NGOs helps promote IK in MPs; it also has the effect of disbanding TRM from embodied knowledge and daily practices.
Combating Vigilance Decrement in a Single-Operator Radar Platform
Authors: Alves Erin E. , Kelsey Christopher M.
Published: June 2010

FEATURE AT A GLANCE: Our research was aimed at validating the staffing concept for a single-operator radar station. Our review of empirical research revealed causality and impact of operator fatigue and the vigilance decrement. We concluded that the single-operator platform was appropriate for the monitoring task, and we imposed subsequent standards for staffing and shift length. We propose several methodologies for the prediction, assessment, and abatement of fatigue for extended vigilant shift work.
Subjective health status in men and women with congenital adrenal hyperplasia: a population-based survey in Norway
Authors: Nermoen Ingrid , Husebye Eystein S , Svartberg Johan , Løvås Kristian
Published: June 2010

Background

Patients with classical congenital adrenal hyperplasia (CAH) require life-long corticosteroid therapy, with uncertain health outcome. Investigations of subjective health status in unselected populations of adult patients are needed.

Objective

To identify all adult Norwegian patients with CAH and obtain population-based data on subjective and psychological health status, working ability and fertility.

Patients, methods and design

Classical CAH patients were identified through search in electronic diagnosis registries at all the university hospitals in Norway. The diagnosis was verified by scrutiny of medical records. The patients were invited to a questionnaire survey including medical history, and the Short Form-36 (SF-36) and Quality of Life Scale questionnaires. The questionnaire responses and fertility data were compared with normative data.

Results

We identified 104 adult patients (101 alive) with classical CAH (63% female), yielding overall incidence at 1/20 000 live births (1/16 000 in females). Seventy-two (72%) responded; median age 38 years (range 18–72). All the SF-36 scales were significantly impaired, most pronounced for general health and vitality perception. Working disability was reported by 19% of the patients, compared with 10% in the general population. The female patients were often single, and the CAH women had only 21% of the expected number of children compared with the general population.

Conclusion

In this population-based survey of patients with classical CAH, we found that subjective health status and working ability were impaired, and that fertility was reduced in females. There is a need for improvement of the medical treatment and the general care of this patient group.
Nested Association Mapping for Identification of Functional Markers
Authors: Guo Baohong , Sleper David A , Beavis William D
Published: June 2010

Identification of functional markers (FMs) provides information about the genetic architecture underlying complex traits. An approach that combines the strengths of linkage and association mapping, referred to as nested association mapping (NAM), has been proposed to identify FMs in many plant species. The ability to identify and resolve FMs for complex traits depends upon a number of factors including frequency of FM alleles, magnitudes of their genetic effects, disequilibrium among functional and nonfunctional markers, statistical analysis methods, and mating design. The statistical characteristics of power, accuracy, and precision to identify FMs with a NAM population were investigated using three simulation studies. The simulated data sets utilized publicly available genetic sequences and simulated FMs were identified using least-squares variable selection methods. Results indicate that FMs with simple additive genetic effects that contribute at least 5% to the phenotypic variability in at least five segregating families of a NAM population consisting of recombinant inbred progeny derived from 28 matings with a single reference inbred will have adequate power to accurately and precisely identify FMs. This resolution and power are possible even for genetic architectures consisting of disequilibrium among multiple functional and nonfunctional markers in the same genomic region, although the resolution of FMs will deteriorate rapidly if more than two FMs are tightly linked within the same amplicon. Finally, nested mating designs involving several reference parents will have a greater likelihood of resolving FMs than single reference designs.
Gene Duplication, Gene Conversion and the Evolution of the Y Chromosome
Authors: Connallon Tim , Clark Andrew G
Published: June 2010

Nonrecombining chromosomes, such as the Y, are expected to degenerate over time due to reduced efficacy of natural selection compared to chromosomes that recombine. However, gene duplication, coupled with gene conversion between duplicate pairs, can potentially counteract forces of evolutionary decay that accompany asexual reproduction. Using a combination of analytical and computer simulation methods, we explicitly show that, although gene conversion has little impact on the probability that duplicates become fixed within a population, conversion can be effective at maintaining the functionality of Y-linked duplicates that have already become fixed. The coupling of Y-linked gene duplication and gene conversion between paralogs can also prove costly by increasing the rate of nonhomologous crossovers between duplicate pairs. Such crossovers can generate an abnormal Y chromosome, as was recently shown to reduce male fertility in humans. The results represent a step toward explaining some of the more peculiar attributes of the human Y as well as preliminary Y-linked sequence data from other mammals and Drosophila. The results may also be applicable to the recently observed pattern of tetraploidy and gene conversion in asexual, bdelloid rotifers.
Patterns and Processes of Genome-Wide Divergence Between North American and AfricanDrosophila melanogaster
Authors: Yukilevich Roman , Turner Thomas L , Aoki Fumio , Nuzhdin Sergey V , True John R
Published: June 2010

Genomic tools and analyses are now being widely used to understand genome-wide patterns and processes associated with speciation and adaptation. In this article, we apply a genomics approach to the model organism Drosophila melanogaster. This species originated in Africa and subsequently spread and adapted to temperate environments of Eurasia and the New World, leading some populations to evolve reproductive isolation, especially between cosmopolitan and Zimbabwean populations. We used tiling arrays to identify highly differentiated regions within and between North America (the United States and Caribbean) and Africa (Cameroon and Zimbabwe) across 63% of the D. melanogaster genome and then sequenced representative fragments to study their genetic divergence. Consistent with previous findings, our results showed that most differentiation was between populations living in Africa vs. outside of Africa (i.e., “out-of-Africa” divergence), with all other geographic differences being less substantial (e.g., between cosmopolitan and Zimbabwean races). The X chromosome was much more strongly differentiated than the autosomes between North American and African populations (i.e., greater X divergence). Overall differentiation was positively associated with recombination rates across chromosomes, with a sharp reduction in regions near centromeres. Fragments surrounding these high FST sites showed reduced haplotype diversity and increased frequency of rare and derived alleles in North American populations compared to African populations. Nevertheless, despite sharp deviation from neutrality in North American strains, a small set of bottleneck/expansion demographic models was consistent with patterns of variation at the majority of our high FST fragments. Although North American populations were more genetically variable compared to Europe, our simulation results were generally consistent with those previously based on European samples. These findings support the hypothesis that most differentiation between North America and Africa was likely driven by the sorting of African standing genetic variation into the New World via Europe. Finally, a few exceptional loci were identified, highlighting the need to use an appropriate demographic null model to identify possible cases of selective sweeps in species with complex demographic histories.
Regulation of Odor Receptor Genes in Trichoid Sensilla of the Drosophila Antenna
Authors: Miller Carson J , Carlson John R
Published: June 2010

This study concerns the problem of odor receptor gene choice in the fruit fly Drosophila melanogaster. From a family of 60 Odor receptor genes, only one or a small number are selected for expression by each olfactory receptor neuron. Little is known about how an olfactory receptor neuron selects a receptor, or how the nucleotide sequences flanking a receptor gene dictate its expression in a particular neuron. Previous investigation has primarily concerned the maxillary palp, the simpler of the fly's two olfactory organs. Here we focus on genes encoding four antennal receptors that respond to fly odors in an in vivo expression system. To investigate the logic of odor receptor expression, we carry out a genetic analysis of their upstream regulatory sequences. Deletion analysis reveals that relatively short regulatory regions are sufficient to confer expression in the appropriate neurons, with limited if any misexpression. We find evidence for both positive and negative regulation. Multiple repressive functions restrict expression to the antenna, to a region of the antenna, and to neurons. Through deletion and base substitution mutagenesis we identify GCAATTA elements and find evidence that they act in both positive and negative regulation.
YNot a Dead End: Epistatic Interactions BetweenY-Linked Regulatory Polymorphisms and Genetic Background Affect Global Gene Expression inDrosophila melanogaster
Authors: Jiang Pan-Pan , Hartl Daniel L , Lemos Bernardo
Published: June 2010

The Y chromosome, inherited without meiotic recombination from father to son, carries relatively few genes in most species. This is consistent with predictions from evolutionary theory that nonrecombining chromosomes lack variation and degenerate rapidly. However, recent work has suggested a dynamic role for the Y chromosome in gene regulation, a finding with important implications for spermatogenesis and male fitness. We studied Y chromosomes from two populations of Drosophila melanogaster that had previously been shown to have major effects on the thermal tolerance of spermatogenesis. We show that these Y chromosomes differentially modify the expression of hundreds of autosomal and X-linked genes. Genes showing Y-linked regulatory variation (YRV) also show an association with immune response and pheromone detection. Indeed, genes located proximal to the euchromatin–heterochromatin boundary of the X chromosome appear particularly responsive to Y-linked variation, including a substantial number of odorant-binding genes. Furthermore, the data show significant regulatory interactions between the Y chromosome and the genetic background of autosomes and X chromosome. Altogether, our findings support the view that interpopulation, Y-linked regulatory polymorphisms can differentially modulate the expression of many genes important to male fitness, and they also point to complex interactions between the Y chromosome and genetic background affecting global gene expression.
QIP, a Protein That Converts Duplex siRNA Into Single Strands, Is Required for Meiotic Silencing by Unpaired DNA
Authors: Xiao Hua , Alexander William G , Hammond Thomas M , Boone Erin C , Perdue Tony D , Pukkila Patricia J , Shiu Patrick K T
Published: June 2010

RNA interference (RNAi) depends on the production of small RNA to regulate gene expression in eukaryotes. Two RNAi systems exist to control repetitive selfish elements in Neurospora crassa. Quelling targets transgenes during vegetative growth, whereas meiotic silencing by unpaired DNA (MSUD) silences unpaired genes during meiosis. The two mechanisms require common RNAi proteins, such as RNA-directed RNA polymerases, Dicers, and Argonaute slicers. We have previously demonstrated that, while Quelling depends on the redundant dicer activity of DCL-1 and DCL-2, only DCL-1 is required for MSUD. Here, we show that QDE-2-interacting protein (QIP), an exonuclease that is important for the production of single-stranded siRNA during Quelling, is also required for MSUD. QIP is crucial for sexual development and is shown to colocalize with other MSUD proteins in the perinuclear region.
Inferring Bacterial Genome Flux While Considering Truncated Genes
Authors: Hao Weilong , Golding G Brian
Published: June 2010

Bacterial gene content variation during the course of evolution has been widely acknowledged and its pattern has been actively modeled in recent years. Gene truncation or gene pseudogenization also plays an important role in shaping bacterial genome content. Truncated genes could also arise from small-scale lateral gene transfer events. Unfortunately, the information of truncated genes has not been considered in any existing mathematical models on gene content variation. In this study, we developed a model to incorporate truncated genes. Maximum-likelihood estimates (MLEs) of the new model reveal fast rates of gene insertions/deletions on recent branches, suggesting a fast turnover of many recently transferred genes. The estimates also suggest that many truncated genes are in the process of being eliminated from the genome. Furthermore, we demonstrate that the ignorance of truncated genes in the estimation does not lead to a systematic bias but rather has a more complicated effect. Analysis using the new model not only provides more accurate estimates on gene gains/losses (or insertions/deletions), but also reduces any concern of a systematic bias from applying simplified models to bacterial genome evolution. Although not a primary purpose, the model incorporating truncated genes could be potentially used for phylogeny reconstruction using gene family content.