bluuebunny/crossref_metadata_2025 huggingface dataset:
Two-dimensional gel proteome reference map of blood monocytes
Authors: Jin Ming , Diaz Philip T , Bourgeois Tran , Eng Charis , Marsh Clay B , Wu Haifeng M
Published: September 2006

Background:

Blood monocytes play a central role in regulating host inflammatory processes through chemotaxis, phagocytosis, and cytokine production. However, the molecular details underlying these diverse functions are not completely understood. Understanding the proteomes of blood monocytes will provide new insights into their biological role in health and diseases.

Results:

In this study, monocytes were isolated from five healthy donors. Whole monocyte lysates from each donor were then analyzed by 2D gel electrophoresis, and proteins were detected using Sypro Ruby fluorescence and then examined for phosphoproteomes using ProQ phospho-protein fluorescence dye. Between 1525 and 1769 protein spots on each 2D gel were matched, analyzed, and quantified. Abundant protein spots were then subjected to analysis by mass spectrometry. This report describes the protein identities of 231 monocyte protein spots, which represent 164 distinct proteins and their respective isoforms or subunits. Some of these proteins had not been previously characterized at the protein level in monocytes. Among the 231 protein spots, 19 proteins revealed distinct modification by protein phosphorylation.

Conclusion:

The results of this study offer the most detailed monocyte proteomic database to date and provide new perspectives into the study of monocyte biology.
Pseudomyxoma peritonei – a revisit: report of 2 cases and literature review
Authors: Li Chunyanca , Kanthan Rani , Kanthan SC
Published: September 2006

Background

Pseudomyxoma peritonei (PMP) is a rare, chronic, relapsing, diagnostically challenging and poorly understood disease characterized by disseminated mucinous ascites and peritoneal implants.

Case presentation

We report two cases of PMP that represent the two biological variants of d isseminated p eritoneal a denom ucinosis (DPAM) – the benign variant and the p eritoneal m ucinous c arcinoma tosis (PMCA) – the malignant variant, both of which were characterized by multiple relapses and progression of the disease despite aggressive management.

Conclusion

Even with a better understanding and recent advances in the management of these cases, PMP remains an enigmatic disease with a protracted clinical course characterized by multiple recurrences despite surgery and/or chemotherapy. Recognition of PMP as a delayed consequence years later should alert all surgeons to be extremely vigilant when treating mucinous neoplasms of the appendix, with special care being directed towards adequate excision and thorough debridement at the initial diagnosis.
Molecular signatures induced by interleukin-2 on peripheral blood mononuclear cells and T cell subsets
Authors: Jin Ping , Wang Ena , Provenzano Maurizio , Deola Sara , Selleri Silvia , Ren Jiaqiang , Voiculescu Sonia , Stroncek David , Panelli Monica C , Marincola Francesco M
Published: August 2006

Experimentally, interleukin-2 (IL-2) exerts complex immunological functions promoting the proliferation, survival and activation of T cells on one hand and inducing immune regulatory mechanisms on the other. This complexity results from a cross talk among immune cells which sways the effects of IL-2 according to the experimental or clinical condition tested. Recombinant IL-2 (rIL-2) stimulation of peripheral blood mononuclear cells (PBMC) from 47 donors of different genetic background induced generalized T cell activation and anti-apoptotic effects. Most effects were dependent upon interactions among immune cells. Specialized functions of CD4 and CD8 T cells were less dependent upon and often dampened by the presence of other PBMC populations. In particular, cytotoxic T cell effector function was variably affected with a component strictly dependent upon the direct stimulation of CD8 T cells in the absence of other PBMC. This observation may provide a roadmap for the interpretation of the discrepant biological activities of rIL-2 observed in distinct pathological conditions or treatment modalities.
HIV-1 replication in cell lines harboring INI1/hSNF5 mutations
Authors: Sorin Masha , Yung Eric , Wu Xuhong , Kalpana Ganjam V
Published: September 2006

Background

INI1/hSNF5 is a cellular protein that directly interacts with HIV-1 integrase (IN). It is specifically incorporated into HIV-1 virions. A dominant negative mutant derived from INI1 inhibits HIV-1 replication. Recent studies indicate that INI1 is associated with pre-integration and reverse transcription complexes that are formed upon viral entry into the target cells. INI1 also is a tumor suppressor, biallelically deleted/mutated in malignant rhabdoid tumors. We have utilized cell lines derived from the rhabdoid tumors, MON and STA-WT1, that harbor either null or truncating mutations of INI1 respectively, to assess the effect of INI1 on HIV-1 replication.

Results

We found that while HIV-1 virions produced in 293T cells efficiently transduced MON and STA-WT1 cells, HIV-1 particle production was severely reduced in both of these cells. Reintroduction of INI1 into MON and STA-WT1 significantly enhanced the particle production in both cell lines. HIV-1 particles produced in MON cells were reduced for infectivity, while those produced in STA-WT1 were not. Further analysis indicated the presence of INI1 in those virions produced from STA-WT1 but not from those produced from MON cells. HIV-1 produced in MON cells were defective for synthesis of early and late reverse transcription products in the target cells. Furthermore, virions produced in MON cells were defective for exogenous reverse transcriptase activity carried out using exogenous template, primer and substrate.

Conclusion

Our results suggest that INI1-deficient cells exhibit reduced particle production that can be partly enhanced by re-introduction of INI1. Infectivity of HIV-1 produced in some but not all INI1 defective cells, is affected and this defect may correlate to the lack of INI1 and/or some other proteins in these virions. The block in early events of virion produced from MON cells appears to be at the stage of reverse transcription. These studies suggest that presence of INI1 or some other host factor in virions and reverse transcription complexes may be important for early events of HIV-1 replication.
Regression analysis with categorized regression calibrated exposure: some interesting findings
Authors: Dalen Ingvild , Buonaccorsi John P , Laake Petter , Hjartåker Anette , Thoresen Magne
Published: September 2006

Background

Regression calibration as a method for handling measurement error is becoming increasingly well-known and used in epidemiologic research. However, the standard version of the method is not appropriate for exposure analyzed on a categorical (e.g. quintile) scale, an approach commonly used in epidemiologic studies. A tempting solution could then be to use the predicted continuous exposure obtained through the regression calibration method and treat it as an approximation to the true exposure, that is, include the categorized calibrated exposure in the main regression analysis.

Methods

We use semi-analytical calculations and simulations to evaluate the performance of the proposed approach compared to the naive approach of not correcting for measurement error, in situations where analyses are performed on quintile scale and when incorporating the original scale into the categorical variables, respectively. We also present analyses of real data, containing measures of folate intake and depression, from the Norwegian Women and Cancer study (NOWAC).

Results

In cases where extra information is available through replicated measurements and not validation data, regression calibration does not maintain important qualities of the true exposure distribution, thus estimates of variance and percentiles can be severely biased. We show that the outlined approach maintains much, in some cases all, of the misclassification found in the observed exposure. For that reason, regression analysis with the corrected variable included on a categorical scale is still biased. In some cases the corrected estimates are analytically equal to those obtained by the naive approach. Regression calibration is however vastly superior to the naive method when applying the medians of each category in the analysis.

Conclusion

Regression calibration in its most well-known form is not appropriate for measurement error correction when the exposure is analyzed on a percentile scale. Relating back to the original scale of the exposure solves the problem. The conclusion regards all regression models.
SIV escape mutants in rhesus macaques vaccinated with NEF-derived lipopeptides and challenged with pathogenic SIVmac251
Authors: Villefroy Pascale , Letourneur Franck , Coutsinos Zoe , Mortara Lorenzo , Beyer Christian , Gras-Masse Helene , Guillet Jean-Gerard , Bourgault-Villada Isabelle
Published: September 2006

Background

Emergence of viral variants that escape CTL control is a major hurdle in HIV vaccination unless such variants affect gene regions that are essential for virus replication. Vaccine-induced multispecific CTL could also be able to control viral variants replication. To explore these possibilities, we extensively characterized CTL responses following vaccination with an epitope-based lipopeptide vaccine and challenge with pathogenic SIVmac251. The viral sequences corresponding to the epitopes present in the vaccine as well as the viral loads were then determined in every macaque following SIV inoculation.

Results

In most cases, the emergence of several viral variants or mutants within vaccine CTL epitopes after SIV challenge resulted in increased viral loads except for a single macaque, which showed a single escape viral variant within its 6 vaccine-induced CTL epitopes.

Conclusion

These findings provide a better understanding of the evolution of CD8+ epitope variations after vaccination-induced CTL expansion and might provide new insight for the development of an effective HIV vaccine.
Circulating viral core and E1 antigen levels as supplemental markers for HCV Chronic hepatitis
Authors: El Awady Mostafa K , El Abd Yasmine S , Shoeb Hussein A , Tabll Ashraf A , Hosny AlaaElDin MS , El Shenawy Reem M , Atef Khaled , Bader El Din Noha G , Bahgat Mahmoud M
Published: September 2006

The performance of polyclonal monospecific rabbit anti-sera raised against synthetic peptides derived from conserved HCV sequences of genotype 4 was evaluated for efficient detection of viral core and E1 antigens in circulating immune complexes (ICs) precipitated from 65 serum samples of HCV patients. The infection was established in those patients by the presence of HCV RNA in their sera. A novel enzyme-linked immunosorbent assay (ELISA) was developed for the detection of HCV core and E1 antigen in serum samples. Western blot analyses were used to demonstrate the presence of the core and E1 target antigen in serum samples. The mean OD readings of both core and E1 antigens were significantly higher (P < 0.05) among the viremic patients when compared to controls. Also a significant positive correlation (P < 0.05, r = 0.98) between the values of both core and E1 was recorded. Western blot analysis based on monospecific antibodies against core and E1 recognized the 38-kDa and 88 -kDa bands respectively in the sera of all infected patients. No specific reaction was observed with the sera from uninfected individuals. Interestingly the results of core and E1 antigen levels displayed no positive correlation with the HCV copy number as measured by bDNA. Liver enzymes (ALT and AST) showed a moderate positive correlation (r = 0.44 and 0.47 respectively) with the viral core antigens level. The same trend holds true for E1 (r = 0.43 and 0.64 for ALT and AST respectively). HCV load in infected patients revealed extremely poor correlation with serum ALT and AST levels (r = 0.022 and 0.002 respectively). In conclusion we present a new combination of serological tools correlating with liver enzyme levels that could be utilized as supplemental tests to viral load testing. Also, a sensitive and specific immunoassay was developed for the detection of HCV core and E1 in human serum. This test can be applied for laboratory diagnosis of HCV infection.
Natural products that reduce rotavirus infectivity identified by a cell-based moderate-throughput screening assay
Authors: Shaneyfelt Mark E , Burke Anna D , Graff Joel W , Jutila Mark A , Hardy Michele E
Published: September 2006

Background

There is widespread interest in the use of innate immune modulators as a defense strategy against infectious pathogens. Using rotavirus as a model system, we developed a cell-based, moderate-throughput screening (MTS) assay to identify compounds that reduce rotavirus infectivity in vitro, toward a long-term goal of discovering immunomodulatory agents that enhance innate responses to viral infection.

Results

A natural product library consisting of 280 compounds was screened in the assay and 15 compounds that significantly reduced infectivity without cytotoxicity were identified. Time course analysis of four compounds with previously characterized effects on inflammatory gene expression inhibited replication with pre-treatment times as minimal as 2 hours. Two of these four compounds, α-mangostin and 18-β-glycyrrhetinic acid, activated NFκB and induced IL-8 secretion. The assay is adaptable to other virus systems, and amenable to full automation and adaptation to a high-throughput format.

Conclusion

Identification of several compounds with known effects on inflammatory and antiviral gene expression that confer resistance to rotavirus infection in vitro suggests the assay is an appropriate platform for discovery of compounds with potential to amplify innate antiviral responses.
Presynaptic Regulation of the Inhibitory Transmission by GluR5-Containing Kainate Receptors in Spinal Substantia Gelatinosa
Authors: Xu Hui , Wu Long-Jun , Zhao Ming-Gao , Toyoda Hiroki , Vadakkan Kunjumon I , Jia Yongheng , Pinaud Raphael , Zhuo Min
Published: September 2006

GluR5-containing kainate receptors (KARs) are known to be involved in nociceptive transmission. Our previous work has shown that the activation of presynaptic KARs regulates GABAergic and glycinergic synaptic transmission in cultured dorsal horn neurons. However, the role of GluR5-containing KARs in the modulation of inhibitory transmission in the spinal substantia gelatinosa (SG) in slices remains unknown. In the present study, pharmacological, electrophysiological and genetic methods were used to show that presynaptic GluR5 KARs are involved in the modulation of inhibitory transmission in the SG of spinal slices in vitro. The GluR5 selective agonist, ATPA, facilitated the frequency but not amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) in SG neurons. ATPA increased sIPSC frequency in all neurons with different firing patterns as delayed, tonic, initial and single spike patterns. The frequency of either GABAergic or glycinergic sIPSCs was significantly increased by ATPA. ATPA could also induce inward currents in all SG neurons recorded. The frequency, but not amplitude, of action potential-independent miniature IPSCs (mIPSCs) was also facilitated by ATPA in a concentration-dependent manner. However, the effect of ATPA on the frequency of either sIPSCs or mIPSCs was abolished in GluR5−/− mice. Deletion of the GluR5 subunit gene had no effect on the frequency or amplitude of mIPSCs in SG neurons. However, GluR5 antagonist LY293558 reversibly inhibited sIPSC and mIPSC frequencies in spinal SG neurons. Taken together, these results suggest that GluR5 KARs, which may be located at presynaptic terminals, contribute to the modulation of inhibitory transmission in the SG. GluR5-containing KARs are thus important for spinal sensory transmission/modulation in the spinal cord.
Protocol design and current status of CLIVIT: a randomized controlled multicenter relevance trial comparing clips versus ligatures in thyroid surgery
Authors: Seiler CM , Fröhlich BE , Veit JA , Gazyakan E , Wente MN , Wollermann C , Deckert A , Witte S , Victor N , Buchler MW , Knaebel HP
Published: September 2006

Background

Annually, more than 90000 surgical procedures of the thyroid gland are performed in Germany. Strategies aimed at reducing the duration of the surgical procedure are relevant to patients and the health care system especially in the context of reducing costs. However, new techniques for quick and safe hemostasis have to be tested in clinically relevance randomized controlled trials before a general recommendation can be given. The current standard for occlusion of blood vessels in thyroid surgery is ligatures. Vascular clips may be a safe alternative but have not been investigated in a large RCT.

Methods/design

CLIVIT (Clips versus Ligatures in Thyroid Surgery) is an investigator initiated, multicenter, patient-blinded, two-group parallel relevance randomized controlled trial designed by the Study Center of the German Surgical Society. Patients scheduled for elective resection of at least two third of the gland for benign thyroid disease are eligible for participation. After surgical exploration patients are randomized intraoperatively into either the conventional ligature group, or into the clip group. The primary objective is to test for a relevant reduction in operating time (at least 15 min) when using the clip technique. Since April 2004, 121 of the totally required 420 patients were randomized in five centers.

Discussion

As in all trials the different forms of bias have to be considered, and as in this case, a surgical trial, the role of surgical expertise plays a key role, and will be documented and analyzed separately. This is the first randomized controlled multicenter relevance trial to compare different vessel occlusion techniques in thyroid surgery with adequate power and other detailed information about the design as well as framework. If significant, the results might be generalized and may change the current surgical practice.
Enhanced radiation sensitivity and radiation recall dermatitis (RRD) after hypericin therapy – case report and review of literature
Authors: Putnik Kurt , Stadler Peter , Schäfer Christof , Koelbl Oliver
Published: September 2006

Background

Modern radiotherapy (RT) reduces the side effects at organ at risk. However, skin toxicity is still a major problem in many entities, especially head and neck cancer. Some substances like chemotherapy provide a risk of increased side effects or can induce a "recall phenomenon" imitating acute RT-reactions months after RT. Moreover, some phototoxic drugs seem to enhance side effects of radiotherapy while others do not. We report a case of "radiation recall dermatitis" (RRD) one year after RT as a result of taking hypericin (St. John's wort).

Case report

A 65 year old man with completely resected squamous cell carcinoma of the epiglottis received an adjuvant locoregional RT up to a dose of 64.8 Gy. The patient took hypericin during and months after RT without informing the physician. During radiotherapy the patient developed unusual intensive skin reactions. Five months after RT the skin was completely bland at the first follow up. However, half a year later the patient presented erythema, but only within the area of previously irradiated skin. After local application of a steroid cream the symptoms diminished but returned after the end of steroid therapy. The anamnesis disclosed that the patient took hypericin because of depressive mood. We recommended to discontinue hypericin and the symptoms disappeared afterward.

Conclusion

Several drugs are able to enhance skin toxicity of RT. Furthermore, the effect of RRD is well known especially for chemotherapy agents such as taxans. However, the underlying mechanisms are not known in detail so far. Moreover, it is unknown whether photosensitising drugs can also be considered to increase radiation sensitivity and whether a recall phenomenon is possible. The first report of a hypericin induced RRD and review of the literature are presented. In clinical practise many interactions between drugs and radiotherapy were not noticed and if registered not published. We recommend to ask especially for complementary or alternative drugs because patients tend to conceal such medication as harmless.
TWEAK/Fn14 interaction regulates RANTES production, BMP-2-induced differentiation, and RANKL expression in mouse osteoblastic MC3T3-E1 cells
Authors: Ando Takashi , Ichikawa Jiro , Wako Masanori , Hatsushika Kyosuke , Watanabe Yoshiyuki , Sakuma Michitomo , Tasaka Kachio , Ogawa Hideoki , Hamada Yoshiki , Yagita Hideo , Nakao Atsuhito
Published: September 2006

Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), a member of the TNF family, is a multifunctional cytokine that regulates cell growth, migration, and survival principally through a TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14). However, its physiological roles in bone are largely unknown. We herein report various effects of TWEAK on mouse osteoblastic MC3T3-E1 cells. MC3T3-E1 cells expressed Fn14 and produced RANTES (regulated upon activation, healthy T cell expressed and secreted) upon TWEAK stimulation through PI3K-Akt, but not nuclear factor-κB (NF-κB), pathway. In addition, TWEAK inhibited bone morphogenetic protein (BMP)-2-induced expression of osteoblast differentiation markers such as alkaline phosphatase through mitogen-activated protein kinase (MAPK) Erk pathway. Furthermore, TWEAK upregulated RANKL (receptor activation of NF-κB ligand) expression through MAPK Erk pathway in MC3T3-E1 cells. All these effects of TWEAK on MC3T3-E1 cells were abolished by mouse Fn14-Fc chimera. We also found significant TWEAK mRNA or protein expression in osteoblast – and osteoclast-lineage cell lines or the mouse bone tissue, respectively. Finally, we showed that human osteoblasts expressed Fn14 and induced RANTES and RANKL upon TWEAK stimulation. Collectively, TWEAK/Fn14 interaction regulates RANTES production, BMP-2-induced differentiation, and RANKL expression in MC3T3-E1 cells. TWEAK may thus be a novel cytokine that regulates several aspects of osteoblast function.
The human urinary proteome contains more than 1500 proteins, including a large proportion of membrane proteins
Authors: Adachi Jun , Kumar Chanchal , Zhang Yanling , Olsen Jesper V , Mann Matthias
Published: September 2006

Background

Urine is a desirable material for the diagnosis and classification of diseases because of the convenience of its collection in large amounts; however, all of the urinary proteome catalogs currently being generated have limitations in their depth and confidence of identification. Our laboratory has developed methods for the in-depth characterization of body fluids; these involve a linear ion trap-Fourier transform (LTQ-FT) and a linear ion trap-orbitrap (LTQ-Orbitrap) mass spectrometer. Here we applied these methods to the analysis of the human urinary proteome.

Results

We employed one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis and reverse phase high-performance liquid chromatography for protein separation and fractionation. Fractionated proteins were digested in-gel or in-solution, and digests were analyzed with the LTQ-FT and LTQ-Orbitrap at parts per million accuracy and with two consecutive stages of mass spectrometric fragmentation. We identified 1543 proteins in urine obtained from ten healthy donors, while essentially eliminating false-positive identifications. Surprisingly, nearly half of the annotated proteins were membrane proteins according to Gene Ontology (GO) analysis. Furthermore, extracellular, lysosomal, and plasma membrane proteins were enriched in the urine compared with all GO entries. Plasma membrane proteins are probably present in urine by secretion in exosomes.

Conclusion

Our analysis provides a high-confidence set of proteins present in human urinary proteome and provides a useful reference for comparing datasets obtained using different methodologies. The urinary proteome is unexpectedly complex and may prove useful in biomarker discovery in the future.
The role of cytokines in hepatocellular carcinoma
Authors: Budhu Anuradha , Wang Xin Wei
Published: September 2006

Hepatocellular carcinoma (HCC) is a frequent malignancy worldwide with a high rate of metastasis. The hepatitis B and C viruses are considered major etiological factors associated with the development of HCC, particularly as a result of their induction of chronic inflammation. There is increasing evidence that the inflammatory process is inherently associated with many different cancer types, including HCC. Specifically, this review aims to cover evidence for the potential roles of cytokines, an important component of the immune system, in promoting HCC carcinogenesis and progression. A global summary of cytokine levels, functions, polymorphisms, and therapies with regard to HCC is presented. In particular, the role of proinflammatory Th1 and anti-inflammatory Th2 cytokine imbalances in the microenvironment of HCC patients with metastasis and the possible clinical significance of these findings are addressed. Overall, multiple studies, spanning many decades, have begun to elucidate the important role of cytokines in HCC.
MD-2 expression is not required for cell surface targeting of Toll-like receptor 4 (TLR4)
Authors: Visintin Alberto , Halmen Kristen A , Khan Naseema , Monks Brian G , Golenbock Douglas T , Lien Egil
Published: September 2006

The cell surface receptor complex formed by TLR4 and myeloid differentiation 2 (MD-2) is engaged when cells are exposed to LPS. Recent studies suggested that surface localization of functional mouse TLR4 (mTLR4) depends on the simultaneous expression of MD-2. As we did not observe a similar requirement, we conducted a comparative study of human TLR4 and mTLR4 surface expression in immune cells derived from the MD-2 knockout mouse and LPS-responsive cell lines and in cells that ectopically express TLR4. Our results indicate that in the human and mouse models, neither TLR4 function nor TLR4 surface targeting requires MD-2 coexpression. Accordingly, we report on one human cell line, which constitutively expresses functional TLR4 on the cell surface in the absence of MD-2 expression.
Procedural Sedation in the Community Emergency Department: Initial Results of the ProSCED Registry
Authors: Sacchetti Alfred , Senula Gary , Strickland James , Dubin Reva
Published: September 2006

Objectives

Procedural sedation and analgesia (PSA) has been well profiled in experimental studies in university emergency departments. Extrapolation of these practices into the community hospital setting is not well established. This report describes community hospital practices and outcomes in a multicenter PSA registry.

Methods

The Procedural Sedation in the Community Emergency Department (ProSCED) registry is a prospective observational database composed of consecutive emergency physician–directed procedural sedation cases in community hospitals. Registered procedures described by 15 categorical data fields are collected at the time of the patient encounter and entered into a secure Internet‐housed database.

Results

A total of 1,028 procedural sedations were performed on 980 patients at 14 study sites. The most common specified procedures performed included shoulder relocation (392), hip relocation (102), elbow relocation (70), upper extremity fracture care (69), lower extremity fracture care (66), and facial laceration repair (67). Complications of any description occurred in 42 cases (4.1%), with no patient's disposition changed secondary to a complication. Patients' ages ranged from 1 month to 95 years, with a median age of 31 years. Of procedures attempted, 982 (95.5%) were successfully completed, 21 cases (2.0%) were adequately sedated but unable to have their procedure completed, and 21 cases (2.0%) were believed to be inadequately sedated. Medication use included midazolam in 423 cases (41.1%), propofol in 253 (24.6%), fentanyl in 253 (24.6%), etomidate in 241 (23.4%), and ketamine in 145 (14.1%), as well as several others. Cases using either ketamine or propofol exhibited the fewest complications, while those using fentanyl, hydromorphone, or midazolam demonstrated the highest complication rates.

Conclusions

Community emergency physicians deliver safe and effective PSA over a wide variety of ages and procedures while using a broad selection of agents.
The Effects of Ambulance Diversion: A Comprehensive Review
Authors: Pham Julius Cuong , Patel Ronak , Millin Michael G. , Kirsch Thomas Dean , Chanmugam Arjun
Published: September 2006

Objectives

To review the current literature on the effects of ambulance diversion (AD).

Methods

The authors performed a systematic review of AD and its effects. PubMed, EMBASE, the Cochrane database, societal meeting abstracts, and references from relevant articles were searched. All articles were screened for relevance to AD.

Results

The authors examined 600 citations and reviewed the 107 articles relevant to AD. AD is a common occurrence that is increasing in frequency. AD is associated with periods of emergency department (ED) crowding (Mondays, mid‐afternoon to early evening, influenza season, and when hospitals are at capacity). Interventions that redesign the AD process or that provide additional hospital or ED resources reduce diversion frequency. AD is associated with increased patient transport times and time to thrombolytics but not with mortality. AD is associated with loss of estimated hospital revenues. Short of anecdotal or case reports, no studies measured the effect of AD on ED crowding, morbidity, patient and provider satisfaction, or EMS resource utilization.

Conclusions

Despite its common use, there is a relative paucity of studies on the effects of AD. Further research into these effects should be performed so that we may understand the role of AD in the health system.
Emergency Department Performance Measures and Benchmarking Summit
Authors: Welch Shari , Augustine James , Camargo Carlos A. , Reese Charles
Published: September 2006

The findings are presented of a consensus group created to address the standardization of performance measures for emergency medicine. This group, whose members have affiliations with most major organizations interested in emergency medicine performance, benchmarking and quality improvement, was tasked with standardizing definitions pertinent to emergency department performance measures, creating a set of general and operational measures, developing a comparison system for benchmarking and creating a plan for the dissemination of this information. The formation of this group, the problem statement, and the mission statement for the summit are all described, and the consensus document is presented.
Limited Opportunities for Paramedic Student Endotracheal Intubation Training in the Operating Room
Authors: Johnston Bradford D. , Seitz S. Robert , Wang Henry E.
Published: September 2006

Background Paramedics, who often are the first to provide emergency care to critically ill patients, must be proficient in endotracheal intubation (ETI). Training in the controlled operating room (OR) setting is a common method for learning basic ETI technique.

Objectives To determine the quantity and nature of OR ETI training currently provided to paramedic students.

Methods The authors surveyed directors of paramedic training programs accredited by the Commission on Accreditation of Allied Health Education Programs. An anonymous 12‐question, structured, closed‐response survey instrument was used that requested information regarding the duration and nature of OR training provided to paramedic students. The results were analyzed by using descriptive statistics.

Results From 192 programs, 161 completed surveys were received (response rate, 85%). OR training was used at 156 programs (97%) but generally was limited (median, 17–32 hours per student). Half of the programs provided fewer than 16 OR hours per student. Students attempted a limited number of OR ETI (median, 6–10 ETI). Most respondents (61%) reported competition from other health care students for OR ETI. Other identified hindering factors included the increasing OR use of laryngeal mask airways and physicians' medicolegal concerns. Respondents from 52 (33%) programs reported a recent reduction in OR access, and 56 (36%) programs expected future OR opportunities to decrease.

Conclusions Despite its key role in airway management education, the quantity and nature of OR ETI training that is available to paramedic students is limited in comparison to that available to other ETI providers.
State of Research in High‐consequence Hospital Surge Capacity
Authors: Schultz Carl H. , Koenig Kristi L.
Published: September 2006

High‐consequence surge research involves a systems approach that includes elements such as healthcare facilities, out‐of‐hospital systems, mortuary services, public health, and sheltering. This article focuses on one aspect of this research, hospital surge capacity, and discusses a definition for such capacity, its components, and future considerations. While conceptual definitions of surge capacity exist, evidence‐based practical guidelines for hospitals require enhancement. The Health Resources and Services Administration's (HRSA) definition and benchmarks are extrapolated from those of other countries and rely mainly on trauma data. The most significant part of the HRSA target, the need to care for 500 victims stricken with an infectious disease per one million population in 24 hours, was not developed using a biological model. If HRSA's recommendation is applied to a sample metropolitan area such as Orange County, California, this translates to a goal of expanding hospital capacity by 20%–25% in the first 24 hours. Literature supporting this target is largely consensus based or anecdotal. There are no current objective measures defining hospital surge capacity. The literature identifying the components of surge capacity is fairly consistent and lists them as personnel, supplies and equipment, facilities, and a management system. Studies identifying strategies for hospitals to enhance these components and estimates of how long it will take are lacking. One system for augmenting hospital staff, the Emergency System for Advance Registration of Volunteer Health Professionals, is a consensus‐derived plan that has never been tested. Future challenges include developing strategies to handle the two different types of high‐consequence surge events: 1) a focal, time‐limited event (such as an earthquake) where outside resources exist and can be mobilized to assist those in need and 2) a widespread, prolonged event (such as pandemic influenza) where all resources will be in use and rationing or triage is needed.
Fanconi Anemia a Is a Nucleocytoplasmic Shuttling Molecule Required for Gonadotropin-Releasing Hormone (GnRH) Transduction of the GnRH Receptor
Authors: Larder Rachel , Karali Dimitra , Nelson Nancy , Brown Pamela
Published: September 2006

GnRH binds its cognate G protein-coupled GnRH receptor (GnRHR) located on pituitary gonadotropes and drives expression of gonadotropin hormones. There are two gonadotropin hormones, comprised of a common α- and hormone-specific β-subunit, which are required for gonadal function. Recently we identified that Fanconi anemia a (Fanca), a DNA damage repair gene, is differentially expressed within the LβT2 gonadotrope cell line in response to stimulation with GnRH. FANCA is mutated in more than 60% of cases of Fanconi anemia (FA), a rare genetically heterogeneous autosomal recessive disorder characterized by bone marrow failure, endocrine tissue cancer susceptibility, and infertility. Here we show that induction of FANCA protein is mediated by the GnRHR and that the protein constitutively adopts a nucleocytoplasmic intracellular distribution pattern. Using inhibitors to block nuclear import and export and a GnRHR antagonist, we demonstrated that GnRH induces nuclear accumulation of FANCA and green fluorescent protein (GFP)-FANCA before exporting back to the cytoplasm using the nuclear export receptor CRM1. Using FANCA point mutations that locate GFP-FANCA to the cytoplasm (H1110P) or functionally uncouple GFP-FANCA (Q1128E) from the wild-type nucleocytoplasmic distribution pattern, we demonstrated that wild-type FANCA was required for GnRH-induced activation of gonadotrope cell markers. Cotransfection of H1110P and Q1128E blocked GnRH activation of the αGsu and GnRHR but not the β-subunit gene promoters. We conclude that nucleocytoplasmic shuttling of FANCA is required for GnRH transduction of the αGSU and GnRHR gene promoters and propose that FANCA functions as a GnRH-induced signal transducer.
Androgens Differentially Potentiate Mouse Intestinal Smooth Muscle by Nongenomic Activation of Polyamine Synthesis and Rho Kinase Activation
Authors: González-Montelongo Maria C. , Marín Raquel , Gómez Tomás , Díaz Mario
Published: September 2006

We demonstrate that testosterone and its active metabolite 5α-dihydrotestosterone acutely (∼30 min) potentiate mouse ileal, but not duodenal, muscle activity. Androgens augment the amplitude of spontaneous peak-to-peak oscillations, alter the spontaneous activity frequency spectrum, and increase the amplitude of calcium-induced and carbachol-induced contractions. Concentration-dependence analyses revealed that maximal potentiation (449–910%) occurred at physiological concentrations of androgens (100 pm to 10 nm) with EC50 values in the picomolar range (8–20 pm). Western blot analyses using an antiandrogen receptor (anti-AR) antibody revealed the presence of two different AR proteins migrating at 87 and 110 kDa in ileal, but not duodenal, extracts. Androgen-induced potentiation was prevented by preincubation with AR antagonists flutamide or cyproterone acetate but was unaffected by pretreatment with cycloheximide plus actinomycin D, indicating that potentiation was mediated by ARs via a novel nongenomic mechanism. Androgen effects were mimicked by polyamines putrescine and spermine and were blocked by the ornithine decarboxylase and S-adenosyl-l-methionine decarboxylase inhibitors α-difluoromethylornithine and berenil, respectively. Accordingly, androgens increase α-difluoromethylornithine-sensitive ornithine-decarboxylase- mediated l-ornithine decarboxylation in ileal tissues within the same time course as isometric potentiation. Both putrescine and dihydrotestosterone induced Ca2+ sensitization of ionomycin-permeabilized ileal smooth muscle. Finally, inhibition of the Rho kinase (ROK) pathway with the specific inhibitor Y27632 completely prevented androgen-induced potentiation. In agreement, androgens elicited ROK-induced Ser19 phosphorylation of myosin light chain 2 in ileal muscle. These data indicate that androgens potentiate ileal contractile activity by an AR-dependent nongenomic mechanism involving intracellular polyamine signaling and Ca2+ sensitization via ROK activation.
Aldosterone and the Cardiovascular System: Genomic and Nongenomic Effects
Authors: Funder John W.
Published: September 2006

There is clear evidence for rapid nongenomic effects of aldosterone in the cardiovascular system in addition to its well characterized effects of unidirectional transepithelial sodium transport. Many of these effects are mediated by the classical mineralocorticoid receptors, although others may be exerted independently. Given that mineralocorticoid receptors are largely constitutively occupied but not activated by physiological glucocorticoids, effects of aldosterone administered in vitro or in vivo may or may not equate with true physiological mineralocorticoid roles. In many systems (e.g. blood pressure regulation and cardiac fibrosis), the time course of effects is such that it is not possible, and perhaps not important, to distinguish between rapid nongenomic and classical genomic effects in the context of homeostatic physiology.
RET/PTC Rearrangements and BRAF Mutations in Thyroid Tumorigenesis
Authors: Ciampi Raffaele , Nikiforov Yuri E.
Published: September 2006

Thyroid papillary carcinoma is the most common type of endocrine cancer. It is frequently associated with genetic alterations leading to activation of the MAPK signaling pathway. The two most frequently affected genes, BRAF and RET, are activated by either point mutation or as a result of chromosomal rearrangement. These mutations are tumorigenic in thyroid follicular cells and correlate with specific phonotypical features and biological properties of papillary carcinomas, including tumor aggressiveness and response to radioiodine therapy. Molecular inhibitors that block RET/PTC or BRAF kinase activity have shown substantial therapeutic effects in the experimental systems and are currently being tested in clinical trials.
The Paired Box-8/Peroxisome Proliferator-Activated Receptor-γ Oncogene in Thyroid Tumorigenesis
Authors: Reddi Honey V. , McIver Bryan , Grebe Stefan K. G. , Eberhardt Norman L.
Published: September 2006

The American Cancer Society estimates 30,180 new cases of thyroid cancer in the United States in 2006. Of all thyroid cancers, 15–20% are follicular thyroid carcinoma (FTC), making this the second most common thyroid malignancy (after papillary carcinoma). A proportion of FTC has been found to be associated with a chromosomal translocation, t (2, 3)(q13;p25), which fuses the thyroid-specific transcription factor paired box-8 with the peroxisome proliferator-activated receptor-γ nuclear receptor, a ubiquitously expressed transcription factor. This fusion event causes expression of a paired box-8/peroxisome proliferator-activated receptor-γ fusion protein (PPFP). PPFP is detected in approximately 30% of FTC. In this report we review data on the role of PPFP in FTC, its mechanism of oncogenesis, and PPFP targeting as a strategy in thyroid cancer treatment.
Gene Methylation in Thyroid Tumorigenesis
Authors: Xing Mingzhao
Published: September 2006

Aberrant gene methylation plays an important role in human tumorigenesis, including thyroid tumorigenesis. Many tumor suppressor genes are aberrantly methylated in thyroid cancer, and some even in benign thyroid tumors, suggesting a role of this epigenetic event in early thyroid tumorigenesis. Methylation of some of these genes tends to occur in certain types of thyroid cancer and is related to specific signaling pathways. For example, methylation of PTEN and RASSF1A genes occurs mostly in follicular thyroid cancer, and its tumorigenic role may be related to the phosphatidylinositol 3-kinase/Akt signaling pathway, whereas methylation of genes for tissue inhibitor of metalloproteinase-3, SLC5A8, and death-associated protein kinase occurs in papillary thyroid cancer and is related to the BRAF/MAPK kinase/MAPK pathway. Methylation of thyroid-specific genes, such as those for sodium/iodide symporter and thyroid-stimulating hormone receptor, is also common in thyroid cancer. Although its tumorigenic role is not clear, methylation, and hence silencing, of these thyroid-specific genes is a cause for the failure of clinical radioiodine treatment of thyroid cancer. Unlike gene methylation, histone modifications have been relatively poorly investigated in thyroid tumors. Future studies need to emphasize the mechanistic aspects of these two types of epigenetic alterations to uncover new molecular mechanisms in thyroid tumorigenesis and to provide novel therapeutic targets for thyroid cancer.
Rapid Glucocorticoid Signaling via Membrane-Associated Receptors
Authors: Tasker Jeffrey G. , Di Shi , Malcher-Lopes Renato
Published: September 2006

Glucocorticoids are secreted into the systemic circulation from the adrenal cortex and initiate a broad range of actions throughout the organism that regulate the function of multiple organ systems, including the liver, muscle, the immune system, the pancreas, fat tissue, and the brain. Delayed glucocorticoid effects are mediated by classical steroid mechanisms involving transcriptional regulation. Relatively rapid effects of glucocorticoids also occur that are incompatible with genomic regulation and invoke a noncanonical mode of steroid action. Studies conducted in several labs and on different species suggest that the rapid effects of glucocorticoids are mediated by the activation of one or more membrane-associated receptors. Here, we provide a brief review focused on multiple lines of evidence suggesting that rapid glucocorticoid actions are triggered by, or at least dependent on, membrane-associated G protein-coupled receptors and activation of downstream signaling cascades. We also discuss the possibility that membrane-initiated actions of glucocorticoids may provide an additional mechanism for the regulation of gene transcription.
Pregnancy-Associated Plasma Protein-A Increases Osteoblast Proliferation in Vitro and Bone Formation in Vivo
Authors: Qin Xuezhong , Wergedal Jon E. , Rehage Mark , Tran Kiet , Newton Jacqueline , Lam Paggie , Baylink David J. , Mohan Subburaman
Published: September 2006

Pregnancy-associated plasma protein (PAPP)-A, a protease for IGF binding protein (IGFBP)-2, -4, and -5, may enhance IGF action by increasing its bioavailability. Here we have determined the role and mechanism of action of PAPP-A in the regulation of osteoblast proliferation in vitro and bone metabolism in vivo. Recombinant PAPP-A (100 ng/ml) significantly increased osteoblast proliferation and free IGF-I concentration. These effects were abolished by noncleavable IGFBP-4, suggesting that PAPP-A promotes osteoblast proliferation by increasing IGF bioavailability. To determine whether PAPP-A exerts an anabolic effect on bone in vivo, we developed transgenic mice that overexpress PAPP-A in osteoblasts using the 2.3-kb rat type I collagen promoter. Consistent with the increase in IGFBP-4 proteolysis, free IGF-I concentration was significantly increased in the conditioned medium of cultured osteoblasts derived from transgenic mice compared with the wild-type littermates. Calvarial bone thickness, bone marrow cavity, and skull bone mineral density were significantly increased in transgenic mice. Bone size-related parameters in femur and tibia such as total bone area and periosteal circumference as determined by peripheral quantitated computed tomography and histological analysis were significantly increased in transgenic mice. Bone formation rate and osteoid surface were increased by more than 2-fold, whereas bone resorbing surface was unaffected. These anabolic effects were sustained with aging. These findings provide strong evidence that PAPP-A acts as a potent anabolic factor in the regulation of bone formation. Thus, enhancing IGF bioavailability by PAPP-A can be a powerful strategy in the treatment of certain metabolic diseases such as osteoporosis.