bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptome transfer produces a predictable cellular phenotype
Authors: Sul Jai-Yoon , Wu Chia-wen K. , Zeng Fanyi , Jochems Jeanine , Lee Miler T. , Kim Tae Kyung , Peritz Tiina , Buckley Peter , Cappelleri David J. , Maronski Margaret , Kim Minsun , Kumar Vijay , Meaney David , Kim Junhyong , Eberwine James
Published: April 2009

Cellular phenotype is the conglomerate of multiple cellular processes involving gene and protein expression that result in the elaboration of a cell's particular morphology and function. It has been thought that differentiated postmitotic cells have their genomes hard wired, with little ability for phenotypic plasticity. Here we show that transfer of the transcriptome from differentiated rat astrocytes into a nondividing differentiated rat neuron resulted in the conversion of the neuron into a functional astrocyte-like cell in a time-dependent manner. This single-cell study permits high resolution of molecular and functional components that underlie phenotype identity. The RNA population from astrocytes contains RNAs in the appropriate relative abundances that give rise to regulatory RNAs and translated proteins that enable astrocyte identity. When transferred into the postmitotic neuron, the astrocyte RNA population converts 44% of the neuronal host cells into the destination astrocyte-like phenotype. In support of this observation, quantitative measures of cellular morphology, single-cell PCR, single-cell microarray, and single-cell functional analyses have been performed. The host-cell phenotypic changes develop over many weeks and are persistent. We call this process of RNA-induced phenotype changes, transcriptome-induced phenotype remodeling.
Short article: Distractor interference in focused attention tasks is not mediated by attention capture
Authors: Gronau Nurit , Cohen Asher , Ben-Shakhar Gershon
Published: April 2009

Distractor stimuli possessing information that is relevant for a task (henceforth, task-relevant distractors) often interfere with task performance. The interference by task-relevant distractors is observed even when distractors are positioned outside the main attentional focus. We investigated whether such interference is due to an attention capture by the distractors. Participants responded to a target colour while ignoring word distractors positioned within (Experiment 1) or outside (Experiments 2 and 3) the attentional focus. The words carried task-relevant information in their colour and personally significant information in their content. Because personally significant information affects performance only when positioned in an attended region, it was used as a marker for the locus of the attentional focus. As expected, when distractors were attended, both task-relevant and personally significant information affected performance. However, when distractors were unattended, only task-relevant information caused interference, suggesting that attention did not shift to the distractors’ location. We discuss possible accounts for interference effects in focused-attention tasks.
Local News Anchors' Contributions to Newscasts
Authors: Bradshaw Katherine A. , Foust James C. , Bernt Joseph P.
Published: April 2009

No social scientist has paused to discover exactly what, if anything, local television news anchors contribute to the newscast beyond their obvious on-air performance, and the assertion that has categorized anchors as gatherers in the research literature hasn't been tested. With clear consonance, however, these researchers found that local television news anchors regularly complete news gatherer, news manager, and news performer tasks; they cross work roles to participate in multiple activities in the news process. Although this study doesn't answer why anchors complete some tasks, the results of this study do call into question the usefulness of the work roles typology of gatherer and manager, and the relationship of work roles to the news-factory analogy. Because anchors cross work roles and work under conflicting sets of norms—journalism and business or entertainment—there are implications for the understanding of the role anchors play in balancing those norms in the final on-air product. A survey of 895 top local anchors resulted in 451 usable surveys, for a 50.4% response rate. Future research about local television news workers should account for anchors as a separate group and not categorize them merely as news gatherers or merely as performers.
Privileged to Be on Camera: Sports Broadcasters Assess the Role of Social Identity in the Profession
Authors: Hardin Marie , Genovese Jason , Yu Nan
Published: April 2009

Drawing on a survey of sports broadcasters in top markets, the authors use the theoretical lens of privilege to examine career paths of white men, women, and racial minorities and their views about social identity as influential in their career success. Those most privileged by gender (male) and race (white) least often acknowledged it. They were also less likely to believe women and minorities faced discrimination. Women and racial minorities were more likely to view their social identity as a reason they were hired, suggesting they might view themselves as “quota hires.” The authors discuss the practical implications of the findings and provide suggestions for the profession and for further research.
Dynein light chain regulates axonal trafficking and synaptic levels of Bassoon
Authors: Fejtova Anna , Davydova Daria , Bischof Ferdinand , Lazarevic Vesna , Altrock Wilko D. , Romorini Stefano , Schöne Cornelia , Zuschratter Werner , Kreutz Michael R. , Garner Craig C. , Ziv Noam E. , Gundelfinger Eckart D.
Published: April 2009

Bassoon and the related protein Piccolo are core components of the presynaptic cytomatrix at the active zone of neurotransmitter release. They are transported on Golgi-derived membranous organelles, called Piccolo-Bassoon transport vesicles (PTVs), from the neuronal soma to distal axonal locations, where they participate in assembling new synapses. Despite their net anterograde transport, PTVs move in both directions within the axon. How PTVs are linked to retrograde motors and the functional significance of their bidirectional transport are unclear. In this study, we report the direct interaction of Bassoon with dynein light chains (DLCs) DLC1 and DLC2, which potentially link PTVs to dynein and myosin V motor complexes. We demonstrate that Bassoon functions as a cargo adapter for retrograde transport and that disruption of the Bassoon–DLC interactions leads to impaired trafficking of Bassoon in neurons and affects the distribution of Bassoon and Piccolo among synapses. These findings reveal a novel function for Bassoon in trafficking and synaptic delivery of active zone material.
The Mating-specific Gα Interacts with a Kinesin-14 and Regulates Pheromone-induced Nuclear Migration in Budding Yeast
Authors: Zaichick Sofia V. , Metodiev Metodi V. , Nelson Scott A. , Durbrovskyi Oleksii , Draper Edward , Cooper John A. , Stone David E.
Published: April 2009

As a budding yeast cell elongates toward its mating partner, cytoplasmic microtubules connect the nucleus to the cell cortex at the growth tip. The Kar3 kinesin-like motor protein is then thought to stimulate plus-end depolymerization of these microtubules, thus drawing the nucleus closer to the site where cell fusion and karyogamy will occur. Here, we show that pheromone stimulates a microtubule-independent interaction between Kar3 and the mating-specific Gα protein Gpa1 and that Gpa1 affects both microtubule orientation and cortical contact. The membrane localization of Gpa1 was found to polarize early in the mating response, at about the same time that the microtubules begin to attach to the incipient growth site. In the absence of Gpa1, microtubules lose contact with the cortex upon shrinking and Kar3 is improperly localized, suggesting that Gpa1 is a cortical anchor for Kar3. We infer that Gpa1 serves as a positional determinant for Kar3-bound microtubule plus ends during mating.
Growth hormone resistance in severe heart failure resolves after cardiac transplantation
Authors: Lund Lars H. , Freda Pamela , Williams Jill J. , LaManca John J. , LeJemtel Thierry H. , Mancini Donna M.
Published: April 2009

Aims

Severe heart failure (HF) is associated with cachexia; this is often reversed post cardiac transplantation (HTx) with frequent development of obesity. Growth hormone (GH) resistance is common in HF and may contribute to cachexia. Whether GH resistance resolves post HTx is unknown. We aimed to confirm that HF is associated with GH resistance and to test the hypothesis that GH resistance resolves post HTx.

Methods and results

We measured GH, insulin‐like growth factor‐1 (IGF‐1), and body composition in 10 HF patients awaiting HTx, in 18 patients 11 ± 8 months post HTx, and seven controls. Body mass index was 23.5 ± 3.2 in HF patients and 29.3 ± 5.7 post HTx. HTx patients had gained 14 ± 8 kg since HTx. GH was elevated in HF (control: 0.21 ± 0.25; HF: 1.13 ± 1.19; HTx: 0.11 ± 0.13 ng/mL; P < 0.007), while IGF‐1 was higher in HTx (control: 114 ± 57; HF: 94 ± 52; HTx: 190 ± 106 ng/mL; P < 0.02). HTx had higher total body and abdominal fat %.

Conclusion

GH resistance is present in severe HF and resolves post HTx. These findings should be confirmed through larger trials.
The acoustic dead zone: theoretical vs. empirical estimates, and its effect on density measurements of semi-demersal fish
Authors: Mello L. G. S. , Rose G. A.
Published: April 2009

Mello, L. G. S., and Rose, G. A. 2009. The acoustic dead zone: theoretical vs. empirical estimates, and its effect on density measurements of semi-demersal fish. – ICES Journal of Marine Science, 66: 1364–1369. The height of the acoustic dead zone, the region near the seabed where fish cannot be resolved acoustically, was calculated both theoretically (DZt) and empirically (DZe). The DZe was based on measurements of depth and trawl geometry from sensors (SCANMAR) mounted on a bottom trawl deployed during a survey off Newfoundland and Labrador in winter 2007. Acoustic data were acquired while trawling, using a 38-kHz echosounder (Simrad EK500) with a hull-mounted transducer. The DZe was calculated as the difference between the trawl-footrope depth and the corresponding acoustically sensed, seabed depth. EK500 and SCANMAR estimates of seabed depth were significantly different. The fish caught were mostly Atlantic cod (Gadus morhua). The estimates of DZe ranged between 2.0 and 3.5 m and were greater than DZt by 0.1–0.9 m in more than half the cases. Three values of acoustically derived cod densities were estimated for each tow, without dead-zone correction and with corrections for DZt and DZe. When compared with DZt corrections, DZe resulted in negative (6–12%) and positive (9–35%) corrections to cod density. A general linear model revealed that the seabed depth gradient, standard deviation of estimated fish density in the dead zone, and wind direction and force explained 85% of the difference between DZt and DZe estimates. These factors affected the detection of the seabed and biased acoustically derived indices of demersal-fish abundance.
Many ways to be small: different environmental regulators of size generate distinct scaling relationships inDrosophila melanogaster
Authors: Shingleton Alexander W. , Estep Chad M. , Driscoll Michael V. , Dworkin Ian
Published: April 2009

Static allometries, the scaling relationship between body and trait size, describe the shape of animals in a population or species, and are generated in response to variation in genetic or environmental regulators of size. In principle, allometries may vary with the different size regulators that generate them, which can be problematic since allometric differences are also used to infer patterns of selection on morphology. We test this hypothesis by examining the patterns of scaling inDrosophila melanogastersubjected to variation in three environmental regulators of size: nutrition, temperature and rearing density. Our data indicate that different environmental regulators of size do indeed generate different patterns of scaling. Consequently, flies that are ostensibly the same size may have very different body proportions. These data indicate that trait size is not simply a read-out of body size, but that different environmental factors may regulate body and trait size, and the relationship between the two, through different developmental mechanisms. It may therefore be difficult to infer selective pressures that shape scaling relationships in a wild population without first elucidating the environmental and genetic factors that generate size variation among members of the population.
A longirostrine tyrannosauroid from the Early Cretaceous of China
Authors: Li Daqing , Norell Mark A. , Gao Ke-Qin , Smith Nathan D. , Makovicky Peter J.
Published: April 2009

The fossil record of tyrannosauroid theropods is marked by a substantial temporal and morphological gap between small-bodied, Barremian taxa, and extremely large-bodied taxa from the latest Cretaceous. Here we describe a new tyrannosauroid,
Xiongguanlong baimoensis
n. gen. et sp., from the Aptian–Albian Xinminpu Group of western China that represents a phylogenetic, morphological, and temporal link between these disjunct portions of tyrannosauroid evolutionary history.
Xiongguanlong
is recovered in our phylogenetic analysis as the sister taxon to Tyrannosauridae plus
Appalachiosaurus
, and marks the appearance of several tyrannosaurid hallmark features, including a sharp parietal sagittal crest, a boxy basicranium, a quadratojugal with a flaring dorsal process and a flexed caudal edge, premaxillary teeth bearing a median lingual ridge, and an expanded axial neural spine surmounted by distinct processes at its corners.
Xiongguanlong
is characterized by a narrow and elongate muzzle resembling that of
Alioramus
. The slender, unornamented nasals of
Xiongguanlong
are inconsistent with recent hypotheses of correlated progression in tyrannosauroid feeding mechanics, and suggest more complex patterns of character evolution in the integration of feeding adaptations in tyrannosaurids. Body mass estimates for the full-grown holotype specimen of
Xiongguanlong
fall between those of Late Cretaceous tyrannosaurids and Barremian tyrannosauroids, suggesting that the trend of increasing body size observed in North American Late Cretaceous Tyrannosauridae may extend through the Cretaceous history of Tyrannosauroidea though further phylogenetic work is required to corroborate this.
Polycomb protein Ezh2 regulates pancreatic β-cell Ink4a/Arf expression and regeneration in diabetes mellitus
Authors: Chen Hainan , Gu Xueying , Su I-hsin , Bottino Rita , Contreras Juan L. , Tarakhovsky Alexander , Kim Seung K.
Published: April 2009

Proliferation of pancreatic islet β cells is an important mechanism for self-renewal and for adaptive islet expansion. Increased expression of the Ink4a/Arf locus, which encodes the cyclin-dependent kinase inhibitor p16INK4a and tumor suppressor p19Arf, limits β-cell regeneration in aging mice, but the basis of β-cell Ink4a/Arf regulation is poorly understood. Here we show that Enhancer of zeste homolog 2 (Ezh2), a histone methyltransferase and component of a Polycomb group (PcG) protein complex, represses Ink4a/Arf in islet β cells. Ezh2 levels decline in aging islet β cells, and this attrition coincides with reduced histone H3 trimethylation at Ink4a/Arf, and increased levels of p16INK4a and p19Arf. Conditional deletion of β-cell Ezh2 in juvenile mice also reduced H3 trimethylation at the Ink4a/Arf locus, leading to precocious increases of p16INK4a and p19Arf. These mutant mice had reduced β-cell proliferation and mass, hypoinsulinemia, and mild diabetes, phenotypes rescued by germline deletion of Ink4a/Arf. β-Cell destruction with streptozotocin in controls led to increased Ezh2 expression that accompanied adaptive β-cell proliferation and re-establishment of β-cell mass; in contrast, mutant mice treated similarly failed to regenerate β cells, resulting in lethal diabetes. Our discovery of Ezh2-dependent β-cell proliferation revealed unique epigenetic mechanisms underlying normal β-cell expansion and β-cell regenerative failure in diabetes pathogenesis.
Frontiers in Neuropharmacotherapy Part I: Alzheimer’s Disease and Epilepsy
Authors: Chappell Jill C. , Cohen Henry
Published: April 2009

Cholinesterase inhibitors, and particularly donepezil, are the standard of care in the management of Alzheimer’s disease. Newer agents, such as rivastigmine, galantamine, and metrifonate, provide therapeutic alternatives but have advantages and disadvantages compared with donepezil. Clinical studies and continued research of the pathophysiology of Alzheimer’s disease help define the role of both the newer agents and the original cholinesterase inhibitor, tacrine. Therapies with other mechanisms of action, such as estrogen and nonsteroidal anti-inflammatory drugs (NSAIDs), are also being actively investigated for their effects on cognition. Since 1993, 8 new antiepileptic drugs have been approved by the FDA, including felbamate, gabapentin, lamotrigine, topiramate, tiagabine, and 3 recently introduced agents, oxcarbazepine, levetiracetam, and zonisamide. These second-generation agents are generally more tolerable and have fewer drug interactions than traditional antiepileptics, and some provide alternative mechanisms that may be beneficial in the management of refractory epileptic disorders. However, until clinical experience with the newer antiepileptics accumulates and well-designed comparative trials are conducted, a review of individual studies of the safety and efficacy of the newer agents helps provide the basis for treatment decisions. New information regarding traditional therapies, including new formulations and updated treatment guidelines, also assist clinicians in optimizing antiepileptic therapy.
Acute Renal Failure and the Critically Ill Patient
Authors: Alexander Earnest , Boucher Bradley A.
Published: April 2009

Acute renal failure (ARF) is a complication frequently observed in critically ill patients. This review provides details regarding the epidemiology and overall care of the ARF patient. ARF is defined and classified based on etiology. These classifications are prerenal azotemia, ischemic ARF, and postrenal azotemia. Examples of drug-induced nephrotoxicity are also outlined. Clinical presentation and diagnostic criteria of ARF are differentiated among the major ARF classes, and management strategies are outlined. These management strategies include preventive, supportive, pharmacologic, and nonpharmacologic interventions. Current standards of practice and investigational therapies are also discussed. Pharmacokinetic monitoring and dosing regimen adjustments in ARF patients with and without renal replacement therapy are reviewed. Finally, a prognostic evaluation of ARF in critically ill patients is provided based on current knowledge of the disease state and treatment options.
Frontiers in Gastroenterology
Authors: Reilly Joseph , Bini Edmund J.
Published: April 2009

There have been a number of exciting advancements and changes in the gastroenterology field over the last few years. A new mesalamine formulation, balsalazide disodium, is now available for the treatment of ulcerative colitis (UC). Balsalazide may be utilized as first line therapy for patients with UC, or patients who are intolerant to other mesalamine preparations. In the area of irritable bowel syndrome, alosetron was removed from the market after reports that it was associated with severe constipation and death, although a causal relationship could not be established. Published data examines the risk of certain medications and the development of reflux disease and esophageal adenocarcinoma.

Also, new proton pump inhibitors (PPIs) are available, esomeprazole, as well as alternate methods of administration for others. The first intravenous PPI, pantoprazole, is available in the United States, although currently there is a paucity of data regarding its efficacy. Peptic ulcer disease is also discussed, including Helicobacter pylori resistance, nonsteroidal anti-inflammatory drugs, and the treatment of bleeding ulcers. With pegylated interferon, progress in the treatment of hepatitis C offers promise for many patients. This review will highlight many recent changes in gastroenterology an offer a perspective on how disease management has changed.
Necrotizing Fasciitis Caused by Group A Streptococcus: Case Report and Therapy Update
Authors: Larose-Pierre Margareth , Scrivens John J. , Norwood Daryl , Rappa Leonard
Published: April 2009

Necrotizing fasciitis is a life-threatening infection that affects the fascia and fat tissue underlying the skin. The diagnosis is often difficult because subcutaneous changes may not be readily apparent. Toxin-producing bacteria are usually the cause, with group A streptococcus (GAS) or Streptococcus pyogenes being responsible for a significant portion of the morbidity and mortality associated with this infection. The mortality rate associated with necrotizing fasciitis varies between 30% and 60%. Toxic shock-like syndrome and multisystem organ failure are the usual causes of death. Early diagnosis and surgery have been associated with decreased morbidity and mortality, and appropriate antimicrobial (eg, penicillin plus clindamycin) and supportive therapy is of utmost importance. Intravenous immunoglobulin and hyperbaric oxygen therapy may be beneficial in treating the infection; however, these 2 therapies require further research. Clinicians need to familiarize themselves with the disease and the different treatment modalities to be able to make the appropriate therapeutic decision. The optimal treatment of necrotizing fasciitis still remains a challenge today. This article presents an illustrative case with a brief overview of necrotizing fasciitis, and the current therapeutic modalities used in the management of the disease.
New Directions in the Treatment of Cancer: Inhibition of Signal Transduction
Authors: Finley Rebecca S.
Published: April 2009

In recent years, it has become increasingly apparent that proteins regulated by activated oncogenes or mutated tumor suppressor genes are responsible for the transformation of normal cells to malignant cells as well as for malignant characteristics such as uncontrolled cellular proliferation and the development of metastases. These proteins may be soluble factors, receptors on cell surfaces, or intracellular enzymes that produce signals that stimulate cellular development or proliferation. This process is called signal transduction .In many cases, increased amounts of these proteins have been demonstrated in cancer cells (over normal cells) and have been found to carry prognostic significance. New approaches in cancer treatment are being designed to block such proteins; this approach is termed signal transduction inhibition. !Specific protein targets that anticancer therapies have been developed to inhibit include epidermal growth factor receptors, tyrosine kinase, farnesyl transferase, and various promoters of angiogenesis.
Prevention of Chemotherapy Medication Errors
Authors: Kloth Dwight D.
Published: April 2009

Prevention of medication errors has long been a concern of pharmacists in all practice settings, including specialty treatment and research centers. Oncology pharmacists have always been particularly aware of this concern because many of the cytotoxic drug therapy regimens we use are already at the maximum tolerated doses, thus leaving no margin for error. During the past 10 years, catastrophic chemotherapy medication errors have occurred in some of the finest hospitals and cancer centers in the United States, bringing unprecedented public and governmental awareness of the risk of such errors. In addition, the March 2000 report by the Institute of Medicine of the National Academy of Sciences, To Err Is Human: Building a Safer Health System, has prompted legislative and executive branch reaction at the federal level aimed toward reducing medical errors of all types, including medication errors.

The purpose of this article is to review the types and causes of catastrophic chemotherapy medication errors that have occurred in oncology and to discuss tools and methods aimed at improving the safety of medication use, particularly chemotherapy, in the United States.
Pharmacological Review of Postoperative Hypertension
Authors: Lewis Kelly S.
Published: April 2009

Postoperative hypertension is an acute, transient increase in blood pressure that develops within 30 to 90 minutes following a surgical procedure and typically lasts for 4 to 8 hours after surgery. It is defined as a systolic blood pressure greater than 160 mm Hg or a diastolic blood pressure greater than 90 mm Hg. The increase in blood pressure is primarily due to increased systemic vascular resistance brought about by reflex changes in humoral factors, including increased levels of catecholamines, renin, and serotonin as well as alterations in baroreceptor function and carotid reflexes. Potential complications of untreated postoperative hypertension include depressed left ventricular performance, increased myocardial oxygen demand resulting in ischemic episodes, cerebrovascular accidents, arrhythmias, and suture line disruption and bleeding. Despite longstanding recognition that high blood pressure is a frequent complication after surgery, formal guidelines for the treatment of postoperative hypertension have not been developed. Postoperative hypertension is a pathophysiological state that requires rapid assessment and appropriate treatment. Several pharmacologic agents are available to achieve and maintain normotension after surgery, including nitrovasodilators (nitroglycerin and sodium nitroprusside), adrenergic blocking agents, and dihydroperidine calcium channel antagonists. Angiotensin-converting enzyme inhibitors and fenoldopam also have been used. Each has its own distinct mechanism of action and adverse effect profile. In cardiac surgery, nicardipine is as effective as nitrovasodilators and offers coronary selectivity. In patients who are hypertensive after neurosurgical procedures, avoid direct-acting vasodilators, which may exacerbate increased intracranial pressure; β-adrenergic receptor antagonists and ACEIs are the preferred agents in these patients. More data are needed to define roles and benefits of fenoldopam in managing postoperative hypertension.
A Case of Topical Benzocaine-Induced Methemoglobinemia
Authors: Granko Robert P.
Published: April 2009

The author reports a case of topical benzocaine-induced methemoglobinemia. Benzocaine is a topical anesthetic commonly used during minor surgical and cannulation procedures. Although not widely reported, benzocaine has the potential to induce severe or life-threatening methemoglobinemia. Clinical practitioners should be cognizant of this complication associated with benzocaine use and its appropriate management. The following report describes a case of topical benzocaine-induced methemoglobinemia in a 74-year-old, Caucasian woman who had undergone transesophageal echocardiography and who received topical benzocaine for local anesthesia. Ten minutes after the administration of benzocaine, her oxygen saturation levels decreased to 71%, requiring immediate attention. Co-oximetry (multiple wavelength spectrophotometry) measured methemoglobin levels indicated the presence of methemoglobinemia. The patient was subsequently treated with 60 mg of intravenous methylene blue. Within 10 minutes, the patient’s condition had improved. The primary etiology of methemoglobinemia is from exposure to oxidizing agents. Benzocaine is an oxidizing agent commonly used as a topical anesthetic. Topically applied benzocaine, in the patient described here and in other reported cases, produced elevated methemoglobin levels requiring treatment with a reducing agent. Methylene blue, within a specified dosage range, can serve as a reducing agent to reverse the effects of topically applied benzocaine-induced methemoglobinemia.
Current Trends in the Treatment of Acute and Chronic Myelogenous Leukemia
Authors: Stull Dawn Marie
Published: April 2009

Acute myelogenous and chronic myelogenous leukemia are uniformly fatal if left untreated. Treatment with conventional chemotherapeutic agents results in a cure for a small percentage of patients and substantial toxicities in all patients that receive treatment. The first of a new generation of “targeted therapies” has recently been introduced. It is hoped that these agents will demonstrate enhanced efficacy and a decreased toxicity profile. Gemtuzumab ozogamicin (Mylotarg™) is the first antibody-targeted therapy approved for use in patients with acute myelogeneous leukemia, arsenic trioxide (Trisenox®) has demonstrated efficacy in patients with acute promyelocytic leukemia, and imatinib mesylate (Gleevec™) has proven efficacy in patients with chronic myelogenous leukemia. Initially, these agents were granted FDA approval for use in those who were refractory to or intolerant of conventional treatment options. Research is ongoing to further define the full therapeutic potential of these agents and to discover additional targeted therapies with increased efficacy.
Management of Candidiasis in Critically Ill Patients
Authors: Pai Manjunath P. , Danziger Larry H. , Pendland Susan L.
Published: April 2009

Fungal infections have been increasing at an alarming rate in critically ill patients. Candida is now the fourth most common pathogen isolated from the bloodstream and is associated with significant morbidity, mortality, and economic consequences. Novel antifungals have been developed in recent years to provide alternatives to amphotericin B, which continues to be the standard therapy for most invasive fungal infections. These alternatives include lipid-based amphotericin B, ketoconazole, fluconazole, itraconazole, caspofungin, and potentially voriconazole. Optimal therapy for the various forms of candidiasis remains controversial. A standardized antifungal susceptibility testing method for Candida isolates has been developed to assist drug selection, but its clinical relevance remains to be determined. The relative susceptibility of Candida isolates can be estimated by the species. Specifically, C krusei is resistant to azoles, C glabrata may be resistant to azoles, and C lusitaniae may be resistant to amphotericin B Candida infections can affect any organ system, and the diagnosis of such infections remains difficult. The Infectious Diseases Society of America recently developed guidelines for the management of candidiasis. This review includes a brief discussion of systemically administered antifungal agents and provides a synopsis of the practice guidelines for the management of candidiasis.
Liability Implications of Innovative Drug Therapy: The Significance of Clinical Guidelines in Establishing the Legal Standard of Care
Authors: Brushwood David B.
Published: April 2009

The use of the clinical practice guideline (CPG) has become widespread in contemporary health care. For some health care providers, there may be a perceived “safe haven” from liability for strict compliance with a relevant CPG. Pointing to an objective standard, such as a CPG, the health care provider may feel secure in defending care that was provided to a patient, when called to account for a bad outcome. The benefit of any CPG is that it standardizes practice at an acceptably high level. The complimentary risk of a CPG is that it may stifle innovation based on newly discovered or newly appreciated data that were not considered when the CPG was developed. The trend in malpractice law is to recognize a CPG as relevant to the applicable standard of care, but not to equate a CPG with the standard of care. In fact, an outdated CPG may fail to reflect the standard of care, if new scientific or medical knowledge has been validated. The health care provider who adheres to an outdated CPG is at greater risk of liability than the health care provider who spurns the outdated CPG in favor of innovative practice based on valid new information. Innovation, as opposed to experimentation, is recognized as a necessary component of competent health care. The health care provider who adheres to outdated traditional medicine, spurning new developments validated by evidence, has clearly expanded exposure to liability.
Extended-Interval Dosing of Aminoglycoside Antibiotics in Critically Ill Patients
Authors: Fish Douglas N.
Published: April 2009

Although aminoglycosides remain an essential part of therapy of severe gram-negative infections in critically ill patients, the use of extended-interval aminoglycoside dosing (EIAD) in this population is highly controversial. The rationale for EIAD is based on major pharmacodynamic characteristics of the aminoglycosides, which include concentration-dependent bactericidal effects, postantibiotic effect, and adaptive resistance. Alterations in the pharmacokinetics of aminoglycosides in the critically ill have been well documented, including changes in both drug distribution and elimination. These pharmacokinetic alterations may prevent critically ill patients from realizing the potential benefits of EIAD by reducing serum concentrations achieved by recommended EIAD regimens and may perhaps place patients at risk of therapeutic failure. Although numerous studies of EIAD have been conducted, there is a lack of data specifically concerning the efficacy and safety of EIAD in the critically ill. The most appropriate methods for monitoring EIAD in this population are also not clearly established. There are thus many questions regarding the suitability of EIAD in the critically ill. This article briefly reviews the rationale for EIAD and data related to the pharmacokinetics, efficacy, safety, and clinical monitoring of EIAD in critically ill patients. Considerations and recommendations for use of EIAD in the critically ill are provided.
Management of Chemotherapy-Induced Nausea and Vomiting
Authors: Rosen Robyn H.
Published: April 2009

Nausea and vomiting are among the most distressing adverse effects of cancer chemotherapy. They can lead to both physical and psychological complications if uncontrolled. The exact mechanism for chemotherapy-induced nausea and vomiting is not known; it is thought to occur through numerous neuronal pathways acting on different sites. Chemotherapy-induced nausea and vomiting are broken down into 3 phases: acute, delayed, and anticipatory. The incidence of each phase depends largely on the chemotherapy agent used and is primarily treated with different antiemetic agents. Pharmacists can assist in optimizing antiemetic use by selecting appropriate antiemetics based on the emetogenicity of the cancer treatment and helping to individualize therapy to each patient’s specific needs.
Vacuolar H+‐ATPase inhibitors overcome Bcl‐xL‐mediated chemoresistance through restoration of a caspase‐independent apoptotic pathway
Authors: Sasazawa Yukiko , Futamura Yushi , Tashiro Etsu , Imoto Masaya
Published: April 2009

The anti‐apoptotic oncoproteins Bcl‐2 and Bcl‐xL play crucial roles in tumorigenesis and chemoresistance, and are thus therapeutic cancer targets. We searched for small molecules that disturbed the anti‐apoptotic function of Bcl‐2 or Bcl‐xL, and found vacuolar H+‐ATPase (V‐ATPase) inhibitors, such as bafilomycin A1 (BMA), that showed such activity. Bcl‐xL‐overexpressing Ms‐1 cells displayed resistance to anticancer drugs, but underwent apoptosis following treatment with a combination of V‐ATPase inhibitors at doses similar to those that caused inhibitory activities of V‐ATPase. We investigated the apoptosis mechanism induced by cotreatment of Bcl‐xL‐overexpressing Ms‐1 cells with BMA as a V‐ATPase inhibitor and taxol (TXL) as an anticancer drug. With BMA, TXL triggered mitochondrial membrane potential loss and cytochrome c release, whereas downstream caspase activation was not observed. In contrast, pronounced nuclear translocation of mitochondrial apoptosis‐inducing factor and endonuclease G, known as effectors of caspase‐independent apoptosis, was observed with BMA and TXL cotreatment. Moreover, depletion of apoptosis‐inducing factor and endonuclease G using each siRNA significantly rescued cells from BMA‐ and TXL‐induced apoptosis. Hence, the apoptosis‐inducing factor‐ and endonuclease G‐dependent pathway was critical for apoptosis induction by BMA and TXL cotreatment. Our data suggest that V‐ATPase inhibitors could not only suppress anti‐apoptotic Bcl‐2 nor Bcl‐xL but could also facilitate the caspase‐independent apoptotic pathway. V‐ATPase inhibition will be a promising therapeutic approach for Bcl‐2‐ or Bcl‐xL‐overexpressing malignancies. (Cancer Sci 2009)
Significance of nitroimidazole compounds and hypoxia‐inducible factor‐1 for imaging tumor hypoxia
Authors: Kizaka‐Kondoh Shinae , Konse‐Nagasawa Hideko
Published: April 2009

A tumor‐specific microenvironment is characterized by hypoxia, in which oxygen tension is considerably lower than in normal tissues. The hypoxic status of various solid tumors has been attributed as an indicator of adverse prognosis due to tumor progression toward a more malignant phenotype with increased metastatic potential and resistance to treatment. Various exogenous and endogenous markers for hypoxia are currently available and studied in relation to each other, tumor architecture, and tumor microenvironment. Over the last few decades, various methods have been suggested to assess the level of oxygenation in solid tumors. Among them, nitroimidazole compounds have provided promising information on tumor hypoxia. To quantify the extent of hypoxia requires that nitroimidazole binding be primarily dependent on oxygen concentration as well as nitroreductase levels in the tumor cells. Furthermore, recent progress in molecular biology has highlighted a transcription factor, hypoxia‐inducible factor (HIF)‐1, whose activity is induced by hypoxia. HIF‐1 plays a central role in malignant progression by inducing the expression of various genes, whose functions are strongly associated with malignant alteration of the entire tumor. The cellular changes induced by HIF‐1 are extremely important therapeutic targets of cancer therapy, particularly in the therapy against refractory cancers. In this review, we will discuss the significance of pimonidazole and HIF‐1 as exogenous and endogenous hypoxia markers, respectively, as well as their evaluation and imaging of tumor hypoxia. (Cancer Sci 2009)
Antitumor activity of a dual epidermal growth factor receptor and ErbB2 kinase inhibitor MP‐412 (AV‐412) in mouse xenograft models
Authors: Suzuki Tsuyoshi , Fujii Akihiro , Ohya Junichi , Nakamura Hideo , Fujita Fumiko , Koike Masako , Fujita Masahide
Published: April 2009

Although epidermal growth factor receptor (EGFR) kinase inhibitors are effective for the treatment of non‐small cell lung cancer (NSCLC), the emergence of mutations resistant to these inhibitors, such as T790M, has become a clinical problem. Recently, ErbB2 mutations have also been identified in a small number of NSCLC patients. Therefore, novel therapies to overcome these mutations are desirable. We describe the antitumor activity of MP‐412 (AV‐412), a dual EGFR/ErbB2 kinase inhibitor, against three lung cancer models with EGFR and ErbB2 mutations and also against various human xenografts with overexpression of these receptors. MP‐412 inhibited phosphorylation of EGFR and its downstream signaling in NCI‐H1650 and NCI‐H1975 cell lines, which harbor the E746‐A750 deletion and L858R + T790M point mutations, respectively, in EGFR. MP‐412 inhibited the growth of these cell lines in vitro and in vivo, whereas the precedent kinase inhibitors lapatinib, erlotinib, and gefitinib were ineffective against NCI‐H1975 cells in vivo. Furthermore, MP‐412 inhibited ErbB2 signaling in the NCI‐H1781 cell line, which harbors the G776V,C insertion in ErbB2, and correlated with its antiproliferation activity. When its antitumor spectrum was further explored in several cancer types overexpressing EGFR or ErbB2, MP‐412 showed potent activity in KPL‐4 and DU145 xenografts, in which lapatinib was ineffective. MP‐412 also inhibited tumor models in which conventional chemotherapies were less effective. These results suggest that MP‐412 is a potent dual inhibitor with the potential for treating solid cancers that overexpress EGFR or ErbB2, including NSCLC cells harboring mutations resistant to the first generation of kinase inhibitors. (Cancer Sci 2009)
Genome‐wide identification of quantitative trait loci for carcass composition and meat quality in a large‐scale White Duroc × Chinese Erhualian resource population
Authors: Ma J. , Ren J. , Guo Y. , Duan Y. , Ding N. , Zhou L. , Li L. , Yan X. , Yang K. , Huang L. , Song Y. , Xie J. , Milan D. , Huang L.
Published: April 2009

Carcass and meat quality traits are economically important in pigs. In this study, 17 carcass composition traits and 23 meat quality traits were recorded in 1028 F2 animals from a White Duroc × Erhualian resource population. All pigs in this experimental population were genotyped for 194 informative markers covering the entire porcine genome. Seventy‐seven genome‐wide significant quantitative trait loci (QTL) for carcass traits and 68 for meat quality were mapped to 34 genomic regions. These results not only confirmed many previously reported QTL but also revealed novel regions associated with the measured traits. For carcass traits, the most prominent QTL was identified for carcass length and head weight at 57 cM on SSC7, which explained up to 50% of the phenotypic variance and had a 95% confidence interval of only 3 cM. Moreover, QTL for kidney and spleen weight and lengths of cervical vertebrae were reported for the first time in pigs. For meat quality traits, two significant QTL on SSC5 and X were identified for both intramuscular fat content and marbling score in the longissimus muscle, while three significant QTL on SSC1 and SSC9 were found exclusively for IMF. Both LM and the semimembranous muscle showed common QTL for colour score on SSC4, 5, 7, 8, 13 and X and discordant QTL on other chromosomes. White Duroc alleles at a majority of QTL detected were favourable for carcass composition, while favourable QTL alleles for meat quality originated from both White Duroc and Erhualian.
CAF in the country: implementing the Common Assessment Framework in a rural area
Authors: Adamson Sue , Deverell Catherine
Published: April 2009

This paper discusses aspects of the implementation of the Common Assessment Framework (CAF) in the UK, introduced under the Change for Children Programme and designed to facilitate early intervention and improve multi‐agency working. The study area was rural in character and findings are compared with evaluation of early CAF implementation which focused primarily on urban areas. The study provided lessons for practice, many of which resonate particularly with rural problems identified in the international literature. There may be advantages in rural areas in ease of involvement of families in processes, in early awareness of practitioners of difficulties in families and in depth of relationships with families. These in turn may support early intervention. Disadvantages centre around resource issues, those of skills and confidence and lack of contact with and therefore distrust of other agencies.
Observations on the spawning behaviour of male and female adult sea trout, Salmo trutta L., using radio‐telemetry
Authors: EVANS D.M.
Published: April 2009

Abstract  The spawning behaviour of adult sea trout, Salmo trutta L., was studied using 174 MHz radio transmitters inserted into the stomachs. Sea trout were captured near the spawning beds and tracked prior to, during and after spawning. Ascent into the spawning river was shown to be linked to increases in flow for some fish but not others; the latter fish tended to move at night. Female sea trout were shown to spawn over 1–3 days, with preference for spawning during darkness, before leaving rapidly as kelts. Size was shown to be important in determining dominance among males, with up to 10 males accompanying one female. Males were shown to spawn with more than one female, and to leave and re‐enter the river on a number of occasions.
Diet composition of largemouth black bass, Micropterus salmoides (Lacepède), in southern Portuguese reservoirs: its relation to habitat characteristics
Authors: GODINHO F. N. , FERREIRA M. T.
Published: April 2009

Abstract  During the summer of 1990 the diet of Micropterus salmoides (Lacepède) was studied in four southern Portuguese reservoirs. The dominant food items were insects (especially Odonata and Ephemeroptera naiads, and Odonata and Hemiptera adults), the crayfish, Procambarus clarkii (Girard), and pumpkinseed sunfish, Lepomis gibbosus (L.). There was an increase in the consumption of L. gibbosus as bass changed from 100–200 mm total length to over 200 mm, and a corresponding decline in the insect and crayfish components. Carp, Cyprinus carpio L., and other benthic cyprinids were absent from the stomach contents. The association between the different prey consumed and the habitat characteristics are discussed in relation to the feeding ecology of largemouth bass, an exotic species in Portugal.
Influence of statin treatment on platelet inhibition by clopidogrel – a randomized comparison of rosuvastatin, atorvastatin and simvastatin co‐treatment
Authors: Malmström R. E. , Östergren J. , Jørgensen L. , Hjemdahl P. ,   for the CASTOR investigators
Published: April 2009

Objectives.  Possible interactions between clopidogrel and atorvastatin, simvastatin or rosuvastatin (a ‘non‐CYP3A4’ metabolized statin) were investigated in a randomized prospective study using sensitive and specific ex vivo platelet function tests.

Methods.  Patients with coronary artery disease participating in a double‐blind study comparing lipid‐lowering effects of atorvastatin (20–80 mg OD; n = 22) and rosuvastatin (10–40 mg OD; n = 24) were studied before and after 2 weeks treatment with clopidogrel 75 mg OD after completed statin dose titration. In addition, 23 patients were randomized to open‐label simvastatin 40 mg OD.

Results.  Clopidogrel inhibited 10 μmol L−1 ADP‐induced platelet aggregation by 40 ± 27%, 57 ± 28% and 51 ± 29%, respectively, in patients on rosuvastatin, atorvastatin and simvastatin treatment. The other platelet tests yielded similar results. No dose‐dependent effects of rosuvastatin or atorvastatin co‐treatment on clopidogrel efficacy were observed.

Conclusions.  Treatment with CYP3A4 metabolized statins, atorvastatin or simvastatin, did not attenuate the platelet inhibitory effect of clopidogrel maintenance treatment compared with the non‐CYP3A4 metabolized, rosuvastatin.
A fratricidal mechanism is responsible for eDNA release and contributes to biofilm development of Enterococcus faecalis
Authors: Thomas Vinai Chittezham , Hiromasa Yasuaki , Harms Nathan , Thurlow Lance , Tomich John , Hancock Lynn E.
Published: April 2009

Extracellular DNA (eDNA), a by‐product of cell lysis, was recently established as a critical structural component of the Enterococcus faecalis biofilm matrix. Here, we describe fratricide as the governing principle behind gelatinase (GelE)‐mediated cell death and eDNA release. GFP reporter assays confirmed that GBAP (gelatinase biosynthesis‐activating pheromone) quorum non‐responders (GelE–SprE–) were a minority subpopulation of prey cells susceptible to the targeted fratricidal action of the quorum responsive predatorial majority (GelE+SprE+). The killing action is dependent on GelE, and the GelE producer population is protected from self‐destruction by the co‐production of SprE as an immunity protein. Targeted gene inactivation and protein interaction studies demonstrate that extracellular proteases execute their characteristic effects following downstream interactions with the primary autolysin, AtlA. Finally, we address a mechanism by which GelE and SprE may modify the cell wall affinity of proteolytically processed AtlA resulting in either a pro‐ or anti‐lytic outcome.