bluuebunny/crossref_metadata_2025 huggingface dataset:
Elusive equilibrium: the challenge of interpreting receptor pharmacology using calcium assays
Authors: Charlton Steven J , Vauquelin Georges
Published: May 2010

Calcium is a key intracellular signal that controls manifold cellular processes over a wide temporal range. The development of calcium‐sensitive fluorescent dyes and proteins revolutionized our ability to visualize this important second messenger and its complex signalling characteristics. The subsequent advent of high throughput plate‐based fluorescence readers has resulted in the calcium assay becoming the most widely utilized assay system for the characterization of novel receptor ligands. In this review we discuss common approaches to calcium assays, paying particular attention to the potential issues associated with interpretation of receptor pharmacology using this system. Topics covered include dye saturation and forced‐coupling of receptors to the calcium pathway, but special consideration is given to the influence of non‐equilibrium conditions in this rapid signalling system. Modelling the calcium transient in a kinetic mode allows the influence of ligand kinetics, receptor reserve and read time to be explored. This demonstrates that observed ligand pharmacology at very early time points can be quite different to that determined after longer incubations, even resulting in reversal of agonist potency orders that may be misinterpreted as agonist biased signalling. It also shows that estimates of antagonist affinity, whether by Schild analysis or inhibition curves, are similarly affected by hemi‐equilibrium conditions. Finally we end with a discussion on practical approaches to accurately estimate the affinity of insurmountable antagonists using calcium assays.

LINKED ARTICLESThis article is part of a themed section on Analytical Receptor Pharmacology in Drug Discovery. To view the other articles in this section visithttp://dx.doi.org/10.1111/bph.2010.161.issue‐6
Neural injury following stroke: are Toll‐like receptors the link between the immune system and the CNS?
Authors: Downes Catherine E , Crack Peter J
Published: May 2010

The CNS can exhibit features of inflammation in response to injury, infection or disease, whereby resident cells generate inflammatory mediators, including cytokines, prostaglandins, free radicals and complement, chemokines and adhesion molecules that recruit immune cells, and activate glia and microglia. Cerebral ischaemia triggers acute inflammation, which exacerbates primary brain damage. The regulation of inflammation after stroke is multifaceted and comprises vascular effects, distinct cellular responses, apoptosis and chemotaxis. There are many cell types that are affected including neurons, astrocytes, microglia and endothelial cells, all responding to the resultant neuroinflammation in different ways. Over the past 20 years, researchers examining brain tissue at various time intervals after stroke observed the presence of inflammatory cells, neutrophils and monocytes at the site of injury, as well as the activation of endogenous glia and microglia. This review examines the involvement of these cells in the progression of neural injury and proposes that the Toll‐like receptors (TLRs) are likely to be an integral component in the communication between the CNS and the periphery. This receptor system is the archetypal pathogen sensing receptor system and its presence and signalling in the brain following neural injury suggests a more diverse role. We propose that the TLR system presents excellent pharmacological targets for the design of a new generation of therapeutic agents to modulate the inflammation that accompanies neural injury.
Cost‐effectiveness of Endoscopic Surveillance for Gastric Intestinal Metaplasia
Authors: Hassan Cesare , Zullo Angelo , Di Giulio Emilio , Annibale Bruno , Lahner Edith , De Francesco Vincenzo , Ierardi Enzo
Published: May 2010

Background:  Patients with intestinal metaplasia (IM) are at increased risk for gastric cancer. Endoscopic surveillance has been shown to anticipate cancer diagnosis in an earlier stage. Cost‐effectiveness of endoscopic surveillance in IM patients is unknown. To assess the efficacy and cost‐effectiveness of an yearly endoscopic surveillance in patients with IM.

Methods:  A decision analysis model was constructed in order to compare a strategy of performing an EGD every year for a 10‐year period (surveillance strategy) following a new diagnosis of IM to a policy of nonsurveillance in a simulated cohort of 10,000 American patients. A 1.8% 10‐year cumulative incidence of gastric cancer in IM patients was estimated from the literature. Endoscopic surveillance was simulated to downstage the detected cancers by 58–84%. Costs of EGD and cancer care were estimated from Medicare reimbursement data. The main outcome measurement was the incremental cost‐effectiveness ratio.

Results:  The number of EGDs required to detect one cancer and to prevent one gastric cancer‐related death in the surveillance arm were 556 and 3738, respectively. The incremental cost‐effectiveness ratio of endoscopic surveillance as compared to a nonsurveillance policy was $72,519 per life‐year gained (5–95% percentiles Monte Carlo analysis: $54,843–$98,853). At sensitivity analysis, cancer incidence and the rate of downstaging were the most important variables.

Conclusions:  According to our simulation, the relatively high risk of cancer in patients with IM and the substantial efficacy of endoscopic surveillance in reducing cancer‐related mortality would support the cost‐effectiveness of an endoscopic surveillance program in patients with IM. Further research is needed before implementing it in the clinical practice.
Time Trends of Helicobacter pylori Resistance to Antibiotics in Children Living in Vienna, Austria
Authors: Vécsei Andreas , Kipet Andrea , Innerhofer Albina , Graf Ulrike , Binder Christa , Gizci Heidemarie , Hammer Karin , Bruckdorfer Andrea , Huber Wolf‐Dietrich , Hirschl Alexander M. , Makristathis Athanasios
Published: May 2010

Background:  Increase of antibiotic resistance is a worldwide problem. Within the 4 years before the turn of the millennium Helicobacter pylori strains isolated in children living in Vienna, Austria, showed a primary clarithromycin and metronidazole resistance of 20% and 16%, respectively. The aim of this retrospective follow‐up survey was to assess the further development and current antimicrobial resistance status.

Methods:  Children having undergone upper endoscopy between March 2002 and March 2008 at the same two co‐operating pediatric gastroenterology units which had also been collaborating on the prior assessment were included. H. pylori infection was diagnosed by rapid urease test, histology, and culture. If the latter was positive, susceptibility testing to amoxicillin, clarithromycin and metronidazole by E‐test followed. From March 2004 onwards, susceptibility to levofloxacin, tetracycline and rifampin was additionally assessed.

Results:  Out of 897 children, 153 had a proven infection with H. pylori and no history of prior eradication treatment. Their median age was 11.5 years (range 0.5–20.9 years). Primary resistance to clarithromycin and metronidazole were 34% and 22.9%, respectively; dual resistance was found in 9.8% of the strains; 0.9% was resistant to tetracycline and rifampin, respectively. No case of amoxicillin resistance was detected. The only independent risk factor for clarithromycin resistance turned out to be the origin of a child from Austrian parents.

Conclusions:  In the last decade, the rate of primary resistance of H. pylori to clarithromycin continued to rise. No significant change was found regarding primary resistance to metronidazole or dual resistance to metronidazole and clarithromycin, respectively.
Development of Immunoreagents for Diagnostics of CagA‐Positive Helicobacter pylori Infections
Authors: Klimovich Alexander V. , Samoylovich Marina P. , Gryazeva Irina V. , Terekhina Lidiya A. , Suvorov Alexander N. , Klimovich Vladimir B.
Published: May 2010

Background:  Helicobacter pylori strains expressing cytotoxic CagA protein are more likely to provoke severe gastric mucosal pathology and cause adenocarcinoma development than that lacking CagA. Determination of the CagA‐status of a pathogen, therefore, is regarded as informative approach in H. pylori infection diagnostics and disease risk prediction.

Materials and Methods:  Molecular cloning, recombinant protein expression in Escherichia coli, affinity chromatography, electrophoresis and commonly used techniques of hybridoma production and screening were used as well as different immunosorbent assays and Western blot procedures.

Results:  Four overlapping N‐terminally His6‐tagged recombinant fragments of CagA that covered the entire CagA sequence were produced and purified. An ELISA for specific anti‐CagA serum antibodies detection was developed and evaluated. Utilizing recombinant fragments, the first set of monoclonal antibodies against CagA‐antigen was produced and characterized. Three antibodies recognized distinct linear epitopes inside conserved regions of the cytotoxin whereas the epitope of the forth antibody was mapped in the variable area of CagA. The monoclonal antibodies allowed discriminating CagA‐positive and CagA‐negative H. pylori strains by means of Western blot and immunosorbent assays.

Conclusions:  The use of recombinant protein technology allowed obtaining pure CagA antigen, thus providing new perspectives for development of immunodiagnostic reagents. The set of monoclonal antibodies is a valuable tool for determination of CagA‐status of H. pylori infection and for the investigation of cytotoxin molecule as well.
Profile of Expression of Helicobacter pyloriγ‐Glutamyltranspeptidase
Authors: Wachino Jun‐Ichi , Shibayama Keigo , Suzuki Satowa , Yamane Kunikazu , Mori Shigetarou , Arakawa Yoshichika
Published: May 2010

Background:  Helicobacter pylori produces γ‐glutamyltranspeptidase (GGT), a potential virulence factor involved in induction of host cell apoptosis. Regulation of the production of this protein is not known.

Methods:  The transcription start sites were determined by primer extension analysis. Transcription level of the GGT gene was examined by measuring the mRNA by RT‐PCR and expression level of GGT protein was examined by Western blot analysis under different conditions.

Results:  Two transcription start sites were identified; thymine at 78‐bp upstream and adenine at 79‐bp upstream from the ATG codon of the GGT gene. There was a possible ‐10 consensus promoter sequence (ATTAAT), but no apparent ‐35 consensus sequence was found. The transcription of the mRNA and the expression of the protein were at almost constant level during the course of culture. The mRNA level increased by exposure to low pH; however, the actual protein expression level remained almost constant. Addition of glutamine or glutamate did not affect the mRNA level and the protein expression level to a remarkable degree, nor did co‐culture with AGS cells affect the GGT activity level.

Conclusion:  It was suggested that H. pylori GGT is constitutively expressed under various conditions.
Endoscopic Tests for the Diagnosis of Helicobacter pylori Infection in Children: Validation of Rapid Urease Test
Authors: Roma‐Giannikou Eleftheria , Roubani Alkaterini , Sgouras Dionyssios N. , Panayiotou Joanna , Van‐Vliet Catherine , Polyzos Alexandros , Roka Kleoniki , Daikos George
Published: May 2010

Background:  Rapid urease test (CLO‐test) is an inexpensive and quick method for diagnosis of Helicobacter pylori infection with controversial results in children. We evaluated the performance of CLO‐test in relation to endoscopic and histological findings in children with H. pylori infection.

Materials and methods:  We studied the medical records of children with H. pylori infection who were diagnosed between 1989 and 2009. Noninfected children were used as controls. H. pylori infection was defined by positive culture or by two other positive tests (histology and CLO‐test, or urea breath test when a single test was positive). All children had histology together with CLO‐test. Tissue culture was performed whenever possible.

Results:  Five hundred thirty infected children (10.4 ± 3.0 years) and 1060 controls (7.3 ± 4.4 years) were studied. Sensitivity of CLO‐test was 83.4% (95% CI, 79.9–86.3%), of culture 84.6% (95% CI, 78.7–89.1%), of histology 93.2% (95% CI, 90.7–95.1%), and specificity 99% (95% CI, 98.2–99.4%), 100%, and 100% respectively. CLO‐test positivity was correlated with higher bacterial density (p < .001), activity (p < .001) and severity of gastritis (p < .01), older age (p < .01), and the presence of antral nodularity (p < .001). When CLO‐test was positive, the concordance with histology and culture was high (95.5 and 89.2% respectively), whereas low concordance was observed when CLO‐test was negative (17.05 and 45.83% respectively).

Conclusions:  CLO‐test had lower sensitivity and comparable specificity with histology. Both tests should be performed concurrently to accurately diagnose H. pylori infection in children.
High Efficacy of 14‐Day Triple Therapy‐Based, Bismuth‐Containing Quadruple Therapy for Initial Helicobacter pylori Eradication
Authors: Sun Qinjuan , Liang Xiao , Zheng Qing , Liu Wenzhong , Xiao Shudong , Gu Weiqi , Lu Hong
Published: May 2010

Background:  The success rate of currently recommended 7‐day triple therapy with a PPI plus amoxicillin and clarithromycin has fallen into the unacceptable range. It is urgent to look for a new strategy to treat the infection of Helicobacter pylori.

Aims:  To observe the efficacy of triple therapy‐based, bismuth‐containing quadruple therapy for H. pylori treatment.

Methods:  A total of 160 patients with functional dyspepsia who were Hp+ were randomly assigned into two groups. Regimen: Omeprazole 20 mg, Amoxicillin 1.0 g, Clarithromycin 500 mg and Bismuth Potassium Citrate 220 mg, twice a day. Eighty patients received 7‐day quadruple therapy and 80 patients received the same therapy for 14 days. Six weeks after treatment, H. pylori eradication was assessed by 13C‐urea breath test. Minimal inhibitory concentrations of metronidazole, clarithromycin and amoxicillin of clinical isolates were determined by the twofold agar dilution method.

Results:  Fourteen‐day therapy led to a significant increase of H. pylori eradication success when compared to 7‐day therapy in the intention‐to‐treat analysis (93.7 vs 80.0%; p = .01), and the per‐protocol analysis (97.4 vs 82.0%; p = .0016). The H. pylori resistance rates to metronidazole, clarithromycin and amoxicillin were 42.1, 18.0 and 0%. Fourteen‐day therapy was significantly more effective in patients with clarithromycin‐resistant strains. Incidences of adverse events were comparable.

Conclusions:  Addition bismuth and prolonging treatment duration can overcome H. pylori resistance to clarithromycin and decrease the bacterial load. Fourteen‐day triple therapy‐based, bismuth‐containing quadruple therapy achieved ITT success rate 93% and could be recommended as the first line eradication regimen.
Implantable Imaging System for Visual Prosthesis
Authors: Zhou Chuanqing , Tao Chen , Chai Xinyu , Sun Yong , Ren Qiushi
Published: May 2010

In order to propose a method of intraocular imaging system for the visual prosthesis, an implantable microcamera was developed and evaluated in vivo. The microcamera was specially developed and shaped to fit the rabbit's lens capsule and encapsulated with the biocompatible silicone. To evaluate the feasibility of this novel approach, the custom‐built device was implanted following the surgical extraction of rabbit's lens. And clinical examinations were performed 1 day, 3 days, 1 week, 2 week, and 1 month postoperatively, including slit‐lamp examination, intraocular pressure, wound status, anterior chamber depth, the presence of the iris fibrosi of neovascularization, and the position of the implant. Real‐time imaging was performed in vivo 1 month after the operation, and the acquired images were processed with the software and hardware that were specially developed for generating the stimulating pulses. Short‐term results showed the novel approach is promising.
The Influence of Cannulation Technique on Blood Flow to the Brain in Rats Undergoing Cardiopulmonary Bypass: A Cautionary “Tail”
Authors: Gourlay Terence , Modine Thomas
Published: May 2010

Recently, there has been an increase in the use of rat models of cardiopulmonary bypass (CPB) for research purposes. Much of this work has focused on cerebral injury associated with CPB. Many of these studies employ a peripheral cannulation approach, often utilizing the caudal artery and internal or external jugular vein. The aim of the present study was to establish whether there is any alteration in blood flow to the brain associated with the use of different cannulation routes. Twenty‐four adult male Sprague Dawley rats were allocated to one of three study groups: Group 1—caudal artery return, Group 2—open‐chest aortic return, and Group 3—nonbypass control group. Colored microspheres were injected into all animals at four time points (postinduction, initiation of bypass, midbypass, and end bypass). After the termination of each experiment, the brains were excised, the tissue was digested, the microspheres were harvested, and the global blood flow to the brain was assessed using the reference flow method. There was a significant reduction in blood flow to the brain between both bypass groups and the control group. Additionally, cerebral blood flow was significantly lower in the caudal return group than in the aortic return group. There is a significant drop in blood flow to the brain associated with the initiation and continuation of CPB when compared to non‐CPB controls. These results also confirm a considerable cerebral hypoperfusion associated with the peripheral cannulation technique, and suggest that peripheral bypass may exaggerate the influence CPB has on cerebral injury. This technique must therefore be employed with caution.
In Vivo Evaluation of Zirconia Ceramic in the DexAide Right Ventricular Assist Device Journal Bearing
Authors: Saeed Diyar , Shalli Shanaz , Fumoto Hideyuki , Ootaki Yoshio , Horai Tetsuya , Anzai Tomohiro , Zahr Roula , Horvath David J. , Massiello Alex L. , Chen Ji‐Feng , Dessoffy Raymond , Catanese Jacquelyn , Benefit Stephen , Golding Leonard A.R. , Fukamachi Kiyotaka
Published: May 2010

Zirconia is a ceramic with material properties ideal for journal bearing applications. The purpose of this study was to evaluate the use of zirconium oxide (zirconia) as a blood journal bearing material in the DexAide right ventricular assist device. Zirconia ceramic was used instead of titanium to manufacture the DexAide stator housing without changing the stator geometry or the remaining pump hardware components. Pump hydraulic performance, journal bearing reliability, biocompatibility, and motor efficiency data of the zirconia stator were evaluated in six chronic bovine experiments for 14–91 days and compared with data from chronic experiments using the titanium stator. Pump performance data including average in vivo pump flows and speeds using a zirconia stator showed no statistically significant difference to the average values for 16 prior titanium stator in vivo studies, with the exception of a 19% reduction in power consumption. Indices of hemolysis were comparable for both stator types. Results of coagulation assays and platelet aggregation tests for the zirconia stator implants showed no device‐induced increase in platelet activation. Postexplant evaluation of the zirconia journal bearing surfaces showed no biologic deposition in any of the implants. In conclusion, zirconia ceramic can be used as a hemocompatible material to improve motor efficiency while maintaining hydraulic performance in a blood journal bearing application.
Long‐Term Evaluation of Myoblast Seeded Patches Implanted on Infarcted Rat Hearts
Authors: Giraud Marie‐Noëlle , Flueckiger Remy , Cook Stéphane , Ayuni Erick , Siepe Matthias , Carrel Thierry , Tevaearai Hendrik
Published: May 2010

Cell transplantation presents great potential for treatment of patients with severe heart failure. However, its clinical application was revealed to be more challenging than initially expected in experimental studies. Further investigations need to be undertaken to define the optimal treatment conditions. We previously reported on the epicardial implantation of a bio‐engineered construct of skeletal myoblast‐seeded polyurethane and its preventive effect on progression toward heart failure. In the present study, we present a long‐term evaluation of this functional outcome. Left anterior descending coronary ligation was performed in female Lewis rats. Two weeks later, animals were treated with either epicardial implantation of biograft, acellular scaffold, sham operation, or direct intramyocardial skeletal myoblast injection. Functional assessments were performed with serial echocardiographies every 3 months and end point left ventricle pressure was assessed. Hearts were then harvested for histological examinations. Myocardial infarction induced a slow and progressive reduction in fractional shortening after 3 months. Progression toward heart failure was significantly prevented for up to 6 months after injection of myoblasts and for up to 9 months following biograft implantation. Nevertheless, this effect vanished after 12 months, with immunohistological examinations revealing an absence of the transplanted myoblasts within the scaffold. We demonstrated that tissue therapy is superior to cell therapy for stabilization of heart function. However, beneficial effects are transient.
Risk for Contrast Nephropathy in Patients Undergoing Coronarography
Authors: Manna Gaetano La , Pancaldi Leonardo Goffredo , Capecchi Alessandro , Maska Edlira , Comai Giorgia , Cappuccilli Maria L. , Carretta Elisa , Lombardi Alessandro , Colì Luigi , Stefoni Sergio
Published: May 2010

Among the causes of in‐hospital acute renal failure, contrast‐induced nephropathy ranks third in prevalence. Although it represents a condition of renal impairment with spontaneous recovery, contrast nephropathy should always be considered, because it prolongs hospitalization and it may become a severe complication requiring dialysis. The purposes of this study are: (i) to determine if the application of the most effective contrast‐induced nephropathy prevention strategies in the Cardiology Intensive Care Unit can prove to be successful in reducing nephropathy risk; and (ii) to identify which of the involved risk factors persist after the preventive treatment. We examined the patients who had a coronarography at the Bentivoglio hospital from April 2007 to April 2008 who required at least 3 days of permanence in hospital due to the presence of potential risk factors; 136 out of 784 patients were included. Among the selected patients, 21 (15.44%) developed a renal impairment compatible with contrast‐induced nephropathy. The risk factors that seemed to display the best correlation with risk of contrast nephropathy were advanced age and an ventricular failure (ejection fraction <40%); however, the critical condition did not appear to be due to a single risk factor, but it resulted from the association of more contextual risk factors. Particularly, the concomitant presence of ventricular failure, anemia, diabetes, previous myocardial infarction and advanced age (>70 years) determined a threefold increased risk of contrast nephropathy. Our data suggest that the development of contrast nephropathy following coronarography is associated with worse renal function during hospitalization and at discharge.
Identification of Abnormal Neuromagnetic Signatures in the Motor Cortex of Adolescent Migraine
Authors: Wang Xiaoshan , Xiang Jing , Wang Yingying , Pardos Maria , Meng Lu , Huo Xiaolin , Korostenskaja Milena , Powers Scott W. , Kabbouche Marielle A. , Hershey Andrew D.
Published: May 2010

(Headache 2010;50:1005‐1016)

Objective.— To investigate the functional abnormalities of the motor cortices in children with migraine using magnetoencephalography (MEG) and a finger‐tapping task.

Background.— Cortical hyperexcitability has been reported in adults with migraine using MEG. Many children with migraine report difficulty with motor functioning. There is no report on motor‐evoked magnetic activation in children with migraine using MEG and the latest signal processing methods.

Methods.— Ten children with migraine (all female, 9 right‐handed and 1 left‐handed, aged 13‐17 years) and 10 age‐ and gender‐matched healthy children were studied with a 275‐channel MEG system. After hearing a unilateral, randomly presented sound cue (500 Hz, 30 milliseconds square tone), each subject immediately performed a brisk index finger tapping with either the right or the left index finger. The auditory stimuli consisted of 200 trials of square tone, 100 trials per ear, randomly distributed. The latency and amplitude of neuromagnetic responses were analyzed with averaged waveforms. Neuromagnetic sources were estimated using synthetic aperture magnetometry (SAM). SAM images were normalized for each participant for group comparison.

Results.— In comparison with healthy children, children with migraine had prolonged latency of motor‐evoked magnetic response in the right hemispheres during left finger movement (62.33 ± 34.55 milliseconds vs 34.9 ± 17.29 milliseconds, P < .05). In addition, children with migraine had stronger activation in the motor cortex during right finger movement (8097.46 ± 5168.99 vs 4697.54 ± 3194.74, P < .05).

Conclusions.— The results suggest that there are neurophysiological changes in the motor cortices of children with migraine that can be measured with neuromagnetic imaging techniques. The findings expand the ability to study the cerebral mechanisms of migraine using MEG and may facilitate the development of new therapeutic strategies in migraine treatment via alterations in cortical excitability.
Peripheral Nerve Blocks and Trigger Point Injections in Headache Management – A Systematic Review and Suggestions for Future Research
Authors: Ashkenazi Avi , Blumenfeld Andrew , Napchan Uri , Narouze Samer , Grosberg Brian , Nett Robert , DePalma Traci , Rosenthal Barbara , Tepper Stewart , Lipton Richard B.
Published: May 2010

(Headache2010;50:943‐952)

Interventional procedures such as peripheral nerve blocks (PNBs) and trigger point injections (TPIs) have long been used in the treatment of various headache disorders. There are, however, little data on their efficacy for the treatment of specific headache syndromes. Moreover, there is no widely accepted agreement among headache specialists as to the optimal technique of injection, type, and doses of the local anesthetics used, and injection regimens. The role of corticosteroids in this setting is also debated. We performed a PubMed search of the literature to find studies on PNBs and TPIs for headache treatment. We classified the abstracted studies based on the procedure performed and the treated condition. We found few controlled studies on the efficacy of PNBs for headaches, and virtually none on the use of TPIs for this indication. The most widely examined procedure in this setting was greater occipital nerve block, with the majority of studies being small and non‐controlled. The techniques, as well as the type and doses of local anesthetics used for nerve blockade, varied greatly among studies. The specific conditions treated also varied, and included both primary (eg, migraine, cluster headache) and secondary (eg, cervicogenic, posttraumatic) headache disorders. Trigeminal (eg, supraorbital) nerve blocks were used in few studies. Results were generally positive, but should be taken with reservation given the methodological limitations of the available studies. The procedures were generally well tolerated. Evidently, there is a need to perform more rigorous clinical trials to clarify the role of PNBs and TPIs in the management of various headache disorders, and to aim at standardizing the techniques used for the various procedures in this setting.
Headache in Thrombotic Thrombocytopenic Purpura: Two Cases With Pathophysiological Considerations
Authors: Bezov David , Lipton Richard B. , Podoltsev Nikolai , Zhao Chi G. , Ashina Sait
Published: May 2010

Headache is one of the most common neurological symptoms reported by patients with thrombotic thrombocytopenic purpura (TTP). Reports of headache characteristics in patients with TTP are rare. We report 2 cases of headache in a setting of TTP and review previous reports. Headache in TTP can have features in common with both migraine and tension‐type headache. Although the pathophysiology of headache in TTP is not certain, platelet aggregation and activation may play a key role.
Biospecimen repositories: are blood donors willing to participate?
Authors: Scott Erik A. , Schlumpf Karen S. , Mathew Sunitha M. , Mast Alan E. , Busch Michael P. , Gottschall Jerome L. ,   for the National Heart, Lung, and Blood Institute Retrovirus Epidemiology Donor Study‐II (REDS‐II)
Published: May 2010

BACKGROUND: Sponsored by the National Heart, Lung, and Blood Institute, the Retrovirus Epidemiology Donor Studies (REDS‐I/‐II) have conducted epidemiologic, laboratory, and survey research on volunteer blood donors. Some studies request additional permission to store biospecimens for future studies. The representativeness and applicability of studies performed using repositories may be reduced by low participation rates.

STUDY DESIGN AND METHODS: Demographics from subjects consenting to participate in the 2007 REDS‐II Leukocyte Antibodies Prevalence Study (LAPS) repository were compared to “study‐only” subjects. Data from the 1998 REDS‐I survey of donor opinion regarding storage and use of biospecimens were also explored.

RESULTS: Overall, 91% of LAPS subjects agreed to participate in the repository. Odds of repository participation were lower among African American and Hispanic donors, 35‐ to 44‐year‐olds, donors who had not completed high school, and donors from one geographic location, regardless of other variables. Survey data from 1998 revealed that 97% of respondents approved of long‐term storage of biospecimens, although only 87% indicated that they would personally participate. Many respondents would require notification or their permission be obtained before participation. Minority respondents would require permission or notification more often and were less certain they would personally participate in a repository.

CONCLUSION: Blood donors are quite willing to participate in biospecimen repositories. Regional differences and lower odds of participation in the minority blood donor population may result in a reduced number of biospecimens available for study and a decreased ability to definitely answer specific research questions in these populations.
Blood component preferences of transfusion services supporting infant transfusions: a University HealthSystem Consortium benchmarking study
Authors: Fung Mark K. , Roseff Susan D. , Vermoch Kathleen L.
Published: May 2010

BACKGROUND:The extent of acceptability of red blood cells (RBCs) containing additive solutions (ASs) for low‐volume neonatal transfusions among hospitals is unknown. Also unknown is whether hospitals have policies that address the risk of hyperkalemia associated with prolonged storage either with or without irradiation for neonatal transfusions.

STUDY DESIGN AND METHODS:A benchmarking survey of University HealthSystem Consortium members included questions regarding the acceptability of RBC units containing ASs for low‐volume neonatal transfusions, policies addressing the length of RBC storage in AS, and policies regarding storage periods after irradiation.

RESULTS:Twenty‐eight of 47 respondents (60%) accept the use of at least one AS (AS‐1, AS‐3, or AS‐5). Twenty‐one (45%) accept the use of all three ASs for neonatal transfusions. Thirty‐seven of 45 respondents (82%) do not have a policy requiring washing of RBCs used for low‐volume transfusions beyond a specified number of days of storage or days after irradiation.

CONCLUSIONS:Although the majority of institutions will use ASs, a significant number of institutions will not. The reasons for these policies were not elicited. Most respondents did not have a policy requiring washing beyond a specified number of days of storage or days after irradiation. Since RBCs stored for prolonged periods of time after irradiation have increased plasma potassium, it is important to develop policies to prevent clinically significant posttransfusion hyperkalemia in at‐risk patients when RBCs are irradiated and not used immediately. More work still needs to be done to resolve these fundamental precepts of neonatal transfusion.
Blood wastage reduction using Lean Sigma methodology
Authors: Heitmiller Eugenie S. , Hill Richard B. , Marshall Christi E. , Parsons Barbara J. , Berkow Lauren C. , Barrasso Christine A. , Zink Elizabeth K. , Ness Paul M.
Published: May 2010

BACKGROUND: Red blood cell (RBC) product wastage in hospitals is reported to range from 0.1% to 6.7%. Wastage at our institution averaged 4.4% of 63,000 issued RBC products. Data indicated that approximately 87% of wasted RBC units were either individual units that were out of blood bank for more than 30 minutes (dispensed but not administered) or units packed in transport containers that had temperature indicators affixed to each unit. We hypothesized that Lean Sigma methodology could be used to reduce RBC wastage by 50%.

STUDY DESIGN AND METHODS: An interdisciplinary hospital team (transfusion medicine, nursing, and anesthesiology) used Lean Sigma methodology as a tool to reduce RBC product wastage, with a focus on container wastage, which was determined to yield the largest impact. Using the five‐part Lean Sigma process—define, measure, analyze, improve, and control—the team collected baseline wastage data, identified major factors affecting RBC product wastage, and implemented interventions to reduce amount of wastage.

RESULTS: Factors identified as contributors to RBC wastage most amenable to improvement were lack of awareness and training of staff ordering and handling RBC products, management of temperature‐validated containers, inconsistent interpretation of RBC temperature indicators, and need for accountability when ordering blood products. Overall RBC product wastage decreased from 4.4% to a sustained rate of less than 2%. This reduction decreased the number of RBC units wasted by approximately 4300 per year, savings approximately $800,000 over the 4‐year period of the study.

CONCLUSIONS: Lean Sigma methodology was an effective tool for reducing RBC wastage in a large academic hospital.
Effects of storage duration and volume on the quality of leukoreduced apheresis‐derived platelets: implications for pediatric transfusion medicine
Authors: Winkler Anne M. , Sheppard Chelsea A. , Culler Elizabeth E. , Myers Robert L. , Duncan Alexander , Castillejo Marta‐Inés , Hillyer Christopher D. , Josephson Cassandra D.
Published: May 2010

BACKGROUND: Platelet (PLT) storage adversely affects PLT structure and function in vitro and is associated with decreased PLT recovery and function in vivo. In pediatric transfusion medicine, it is not uncommon for small residual volumes to remain in parent units after aliquot preparation of leukoreduced apheresis‐derived PLTs (LR‐ADP). However, limited data exist regarding the impact of storage on residual small‐volume LR‐ADP.

STUDY DESIGN AND METHODS: Standard metabolic testing was performed on residual volumes of LR‐ADP after aliquot removal and PLT aggregometry using a dual agonist of ADP and collagen was performed on stored, small‐volume aliquots (10‐80 mL) created from an in vitro model of PLT storage.

RESULTS: Seventy‐seven LR‐ADP underwent metabolic (n = 67) or metabolic and aggregation (n = 10) studies. All products maintained a pH value of more than 6.89 throughout storage. Lactate and pCO2 increased proportionally with longer storage time. Regardless of acceptable metabolism during storage, aggregation in 10‐ to 20‐mL aliquots was impaired by Day 4 and aliquots less than 40 mL demonstrated the most dramatic decrease in aggregation from baseline.

CONCLUSIONS: Despite maintenance of acceptable metabolic conditions, residual volumes of LR‐ADP develop impaired aggregation in vitro that may adversely affect PLT survival and function in vivo. At volumes below 40 mL, LR‐ADP revealed reduced aggregation. As a result, it is recommended to monitor and record volumes of LR‐ADP used for pediatric transfusion. Moreover, once LR‐ADP attain a volume of 50 mL or less on Day 4 or Day 5 of storage, consider discarding these products until their in vivo efficacy can be studied.
Obtaining of CD34+ cells from healthy blood donors: development of a rapid and efficient procedure using leukoreduction filters
Authors: Peytour Yann , Guitart Amélie , Villacreces Arnaud , Chevaleyre Jean , Lacombe Francis , Ivanovic Zoran , Praloran Vincent
Published: May 2010

BACKGROUND: Human CD34+ cells are mandatory to study many aspects of human hematopoiesis. Their low frequency in blood or marrow and ethical reasons limit their obtainment in large quantities. Leukoreduction filters (LRFs) are discarded after preparation of red blood cells. The CD34+ cell concentration in healthy donor blood is low (1 × 103‐4 × 103/mL), but their number trapped in one LRF after filtration of 400 to 450 mL of blood is high (0.4 × 106‐1.6 × 106).

STUDY DESIGN AND METHODS: To develop a procedure allowing obtainment of purified CD34+ cells from LRFs with a good yield, white blood cell (WBC) recoveries after a 500‐mL continuous or after sequential elution (50‐ or 20‐mL fractions) were compared. Different WBC and mononuclear cell (MNC) centrifugation methods were tested to minimize their PLT contamination before the CD34+ cell immunomagnetic selection. Cell functionality was finally analyzed under various culture conditions.

RESULTS: The 20‐mL back‐flushing of LRFs allowed the most efficient WBC recovery. The next steps (110 × g centrifugation, MNC separation on Ficoll, and washes) resulted in a cell suspension in which the lymphocyte recovery was approximately 76 ± 10% and the PLT contamination below 1.6%. After immunomagnetic selection, 4 × 105 to 6 × 105 cells containing approximately 85% of functional CD34+ cells were obtained.

CONCLUSION: This procedure allows the easy, rapid (<5 hr), and efficient preparation of large quantities of CD34+ cells having functional activities similar to those of CD34+ cells from other sources. Therefore, easily available and virally safe, LRFs represent an important and regular WBC source to work with human CD34+ cells, but also with other WBC types.
Networking as a Barrier to Entry and the Competitive Supply of Venture Capital
Authors: HOCHBERG YAEL V. , LJUNGQVIST ALEXANDER , LU YANG
Published: May 2010

We examine whether strong networks among incumbent venture capitalists (VCs) in local markets help restrict entry by outside VCs, thus improving incumbents' bargaining power over entrepreneurs. More densely networked markets experience less entry, with a one‐standard deviation increase in network ties among incumbents reducing entry by approximately one‐third. Entrants with established ties to target‐market incumbents appear able to overcome this barrier to entry; in turn, incumbents react strategically to an increased threat of entry by freezing out any incumbents who facilitate entry into their market. Incumbents appear to benefit from reduced entry by paying lower prices for their deals.
Human Capital, Bankruptcy, and Capital Structure
Authors: BERK JONATHAN B. , STANTON RICHARD , ZECHNER JOSEF
Published: May 2010

We derive the optimal labor contract for a levered firm in an economy with perfectly competitive capital and labor markets. Employees become entrenched under this contract and so face large human costs of bankruptcy. The firm's optimal capital structure therefore depends on the trade‐off between these human costs and the tax benefits of debt. Optimal debt levels consistent with those observed in practice emerge without relying on frictions such as moral hazard or asymmetric information. Consistent with empirical evidence, persistent idiosyncratic differences in leverage across firms also result. In addition, wages should have explanatory power for firm leverage.
Stapled Finance
Authors: POVEL PAUL , SINGH RAJDEEP
Published: May 2010

“Stapled finance” is a loan commitment arranged by a seller in an M&A setting. Whoever wins the bidding contest has the option (not the obligation) to accept this loan commitment. We show that stapled finance increases bidding competition by subsidizing weak bidders, who raise their bids and thereby the price that strong bidders (who are more likely to win) must pay. The lender expects not to break even and must be compensated for offering the loan. This reduces but does not eliminate the seller's benefit. It also implies that stapled finance loans will show poorer performance than other buyout loans.
Cash Holdings and Corporate Diversification
Authors: DUCHIN RAN
Published: May 2010

This paper studies the relation between corporate liquidity and diversification. The key finding is that multidivision firms hold significantly less cash than stand‐alone firms because they are diversified in their investment opportunities. Lower cross‐divisional correlations in investment opportunity and higher correlations between investment opportunity and cash flow correspond to lower cash holdings, even after controlling for cash flow volatility. The effects are strongest in financially constrained firms and in well‐governed firms, and correspond to efficient fund transfers from low‐ to high‐productivity divisions. Taken together, these results bring forth an efficient link between diversification and corporate liquidity.
A Gap‐Filling Theory of Corporate Debt Maturity Choice
Authors: GREENWOOD ROBIN , HANSON SAMUEL , STEIN JEREMY C.
Published: May 2010

We argue that time variation in the maturity of corporate debt arises because firms behave as macro liquidity providers, absorbing the supply shocks associated with changes in the maturity structure of government debt. We document that when the government funds itself with more short‐term debt, firms fill the resulting gap by issuing more long‐term debt, and vice versa. This type of liquidity provision is undertaken more aggressively: (1) when the ratio of government debt to total debt is higher and (2) by firms with stronger balance sheets. Our theory sheds new light on market timing phenomena in corporate finance more generally.
The Political Economy of Financial Regulation: Evidence from U.S. State Usury Laws in the 19th Century
Authors: BENMELECH EFRAIM , MOSKOWITZ TOBIAS J.
Published: May 2010

Financial regulation was as hotly debated a political issue in the 19th century as it is today. We study the political economy of state usury laws in 19th century America. Exploiting the wide variation in regulation, enforcement, and economic conditions across states and time, we find that usury laws when binding reduce credit and economic activity, especially for smaller firms. We examine the motives of regulation and find that usury laws coincide with other economic and political policies favoring wealthy political incumbents, particularly when they have more voting power. The evidence suggests financial regulation is driven by private interests capturing rents from others rather than public interests protecting the underserved.
Risk and the Corporate Structure of Banks
Authors: DELL'ARICCIA GIOVANNI , MARQUEZ ROBERT
Published: May 2010

We identify different sources of risk as important determinants of banks' corporate structures when expanding into new markets. Subsidiary‐based corporate structures benefit from greater protection against economic risk because of affiliate‐level limited liability, but are more exposed to the risk of capital expropriation than are branches. Thus, branch‐based structures are preferred to subsidiary‐based structures when expropriation risk is high relative to economic risk, and vice versa. Greater cross‐country risk correlation and more accurate pricing of risk by investors reduce the differences between the two structures. Furthermore, a bank's corporate structure affects its risk taking and affiliate size.
Financial Strength and Product Market Behavior: The Real Effects of Corporate Cash Holdings
Authors: FRESARD LAURENT
Published: May 2010

This paper shows that large cash reserves lead to systematic future market share gains at the expense of industry rivals. Using shifts in import tariffs to identify exogenous intensification of competition, difference‐in‐difference estimations support the causal impact of cash on product market performance. Moreover, the analysis reveals that the “competitive” effect of cash is markedly distinct from the strategic effect of debt on product market outcomes. This effect is stronger when rivals face tighter financing constraints and when the number of interactions between competitors is large. Overall, the results suggest that cash policy encompasses a substantial strategic dimension.
Executive Compensation and the Maturity Structure of Corporate Debt
Authors: BROCKMAN PAUL , MARTIN XIUMIN , UNLU EMRE
Published: May 2010

Executive compensation influences managerial risk preferences through executives' portfolio sensitivities to changes in stock prices (delta) and stock return volatility (vega). Large deltas discourage managerial risk‐taking, while large vegas encourage risk‐taking. Theory suggests that short‐maturity debt mitigates agency costs of debt by constraining managerial risk preferences. We posit and find evidence of a negative (positive) relation between CEO portfolio deltas (vegas) and short‐maturity debt. We also find that short‐maturity debt mitigates the influence of vega‐ and delta‐related incentives on bond yields. Overall, our empirical evidence shows that short‐term debt mitigates agency costs of debt arising from compensation risk.
Capital Structure as a Strategic Variable: Evidence from Collective Bargaining
Authors: MATSA DAVID A.
Published: May 2010

I analyze the strategic use of debt financing to improve a firm's bargaining position with an important supplier—organized labor. Because maintaining high levels of corporate liquidity can encourage workers to raise their wage demands, a firm with external finance constraints has an incentive to use the cash flow demands of debt service to improve its bargaining position with workers. Using both firm‐level collective bargaining coverage and state changes in labor laws to identify changes in union bargaining power, I show that strategic incentives from union bargaining appear to have a substantial impact on corporate financing decisions.
Learning Times for Large Lexicons Through Cross‐Situational Learning
Authors: Blythe Richard A. , Smith Kenny , Smith Andrew D. M.
Published: May 2010

Cross‐situational learning is a mechanism for learning the meaning of words across multiple exposures, despite exposure‐by‐exposure uncertainty as to a word's true meaning. Doubts have been expressed regarding the plausibility of cross‐situational learning as a mechanism for learning human‐scale lexicons in reasonable timescales under the levels of referential uncertainty likely to confront real word learners. We demonstrate mathematically that cross‐situational learning facilitates the acquisition of large vocabularies despite significant levels of referential uncertainty at each exposure, and we provide estimates of lexicon learning times for several cross‐situational learning strategies. This model suggests that cross‐situational word learning cannot be ruled out on the basis that it predicts unreasonably long lexicon learning times. More generally, these results indicate that there is no necessary link between the ability to learn individual words rapidly and the capacity to acquire a large lexicon.