bluuebunny/crossref_metadata_2025 huggingface dataset:
Downstream Competition, Bargaining, and Welfare
Authors: Symeonidis George
Published: January 2008

I analyze the effects of downstream competition when there is bargaining between downstream firms and upstream agents (firms or unions). When bargaining is over a uniform input price, a decrease in the intensity of competition (or a merger) between downstream firms may raise consumer surplus and overall welfare. When bargaining is over a two‐part tariff, a decrease in the intensity of competition reduces downstream profits and upstream utility and raises consumer surplus and overall welfare. Standard welfare results of oligopoly theory can be reversed: less competition can be unprofitable for firms and/or beneficial for consumers and society as a whole.
Bicortical Implant Insertion in Caudal Cervical Spondylomyelopathy: A Computed Tomography Simulation in Affected Doberman Pinschers
Authors: CORLAZZOLI DANIELE
Published: January 2008

Objective— To evaluate the safety of the angle of insertion of bicortical implants in Doberman Pinschers affected by caudal cervical spondylomyelopathy (CCSM) using simulation on computed tomography (CT) images.

Animals— Doberman Pinschers (n=9) with dynamic spinal compression attributed to CCSM.

Methods— Dogs had CT evaluation of the cervical vertebral column. Digital images were used to evaluate the safety of bicortical implant insertion from the midline at 30, 35, and 40° inclination by drawing a line simulating implant position. Correct surgical positioning of dogs was evaluated by measuring the degree of rotation of the spine along the longitudinal axis.

Results— Insertion of an implant at 30, 35, and 40° inclination was considered safe in 42%, 59%, and 67% of selected sites. Rotation of the spine from 9° counter clockwise to 10° clockwise along the longitudinal axis occurred in 53% of the areas considered.

Conclusions— These results suggest that bicortical implants in the caudal cervical area in Doberman Pinschers affected by CCSM carry a high risk of vertebral canal and intervertebral foramina violation.

Clinical Relevance— Bicortical implants inserted at 30 and 35° in the caudal cervical area in Doberman Pinschers affected by CCSM carry a high risk of vertebral canal and intervertebral foramina violation. CT planning for individual dogs can facilitate selection of the appropriate insertion plane and vertebral column rotation needs to be considered in surgical planning.
Sparing Effect of a Low Dose of Intrathecal Morphine on Fentanyl Requirements During Spinal Surgery: A Preliminary Clinical Investigation in Dogs
Authors: NOVELLO LORENZO , CORLETTO FEDERICO , RABOZZI ROBERTO , PLATT SIMON R.
Published: January 2008

Objective—To evaluate the effect of preoperative intrathecal administration of a low dose of morphine on intraoperative fentanyl requirements in dogs undergoing cervical and thoracolumbar spinal surgery.

Study Design—Prospective randomized clinical study.

Animals—Dogs (n=18) matched by surgical procedure administered intrathecal morphine (MG) or no‐treatment (control group, CG).

Methods—After premedication with romifidine (4 μg/kg, intravenously) and induction with propofol, anesthesia was maintained with sevoflurane in oxygen. Intrathecal morphine 0.03 (0.023–0.034) mg/kg was administered at lumbar level 41 (25–65) minutes before surgery in MG. Ketamine (0.5 mg/kg) was administered hourly, starting before incision. Fentanyl infusion (1.2 and 4.2 μg/kg/h in MG and CG, respectively) was administered after a loading dose (5 and 10 μg/kg in MG and CG, respectively), and boluses were given if an increase >20% in heart rate and arterial blood pressure was observed. Total amount of fentanyl administered was recorded, to calculate hourly requirements and predict plasma concentration using a computer simulation.

Results—Hourly fentanyl consumption and predicted plasma concentrations at the time of response to surgery were significantly lower in MG compared with CG.

Conclusions—Preoperative administration of a low dose of intrathecal morphine has a sparing effect on intraoperative fentanyl requirements.

Clinical Relevance—Preoperative intrathecal administration of a low dose of morphine at the lumbar level represented a safe and effective mean of providing intraoperative analgesia in dogs undergoing cervical and thoracolumbar spinal surgery.
Surgical Correction of Wry Nose in Four Horses
Authors: SCHUMACHER JIM , BRINK PALLE , EASLEY JACK , POLLOCK PATRICK
Published: January 2008

Objective— To describe surgical techniques used for correction of congenital nasal deviation (wry nose) in horses (wry nose) and to report outcome.

Study Design— Retrospective study.

Animals— Horses (n=4), 5–17 months old with wry nose.

Methods— Nasal deviation was corrected by transecting the premaxillae/maxillae and nasal bones at their site of maximum curvature and realigning and stabilizing the bones in a more normal alignment using internal fixation. The nasal septum was removed during the same anesthetic period.

Results— For each horse, physical appearance was improved and respiratory stridor eliminated.

Conclusions— Wry nose can be corrected by transecting the premaxillae/maxillae and nasal bones and stabilizing the transected bones in a more normal alignment; the nasal septum can be removed concurrently.

Clinical Relevance— Surgical correction of wry nose may provide a good functional and cosmetic outcome.
Prospective Evaluation of Techniques for Differentiating Shoulder Pathology As a Source of Forelimb Lameness in Medium and Large Breed Dogs
Authors: COGAR STEVEN M. , COOK CRISTI R. , CURRY STEPHEN L. , GRANDIS ANNAMARIA , COOK JAMES L.
Published: January 2008

Objective— To assess lameness evaluation, shoulder abduction angles, radiography, and ultrasonography for determining presence, location, and severity of forelimb pathology.

Study Design— Prospective cohort study.

Animals— Dogs ≥20 kg (n=30).

Methods— Each dog was assigned lameness scores. Shoulder abduction angles were determined. Radiographs of shoulders and elbows were subjectively graded for pathology. One investigator unaware of dog history (lameness, radiographic findings) performed ultrasonographic assessment of shoulders with subjective grading of pathology. Another investigator unaware of dog history (lameness, radiographic, ultrasonographic findings) performed arthroscopic assessment of shoulders with subjective grading of pathology. Elbows were disarticulated and evaluated for gross pathology. Histologic pathology scoring of shoulder tissues was performed. Data were compared for differences among groups, sensitivities, specificities, positive and negative predictive values, and positive and negative likelihood ratios were calculated.

Results— Twenty‐seven forelimbs were considered clinically normal, 26 had shoulder pathology, 5 had elbow pathology, and 2 had pathology of both the shoulder and elbow. Dogs with shoulder pathology were twice as likely to be lame compared with dogs with elbow pathology. Limbs with medial shoulder instability had significantly higher abduction angles than normal limbs and those with elbow pathology. Radiographs were clinically useful for diagnosing elbow, but not shoulder, pathology. Ultrasonography was clinically useful for diagnosing shoulder pathology other than instability. Abduction angles, ultrasonographic evaluation, and arthroscopic assessments had strong, significant correlations with reference standards.

Conclusions— Clinically relevant diagnostic techniques yielded characteristic, repeatable differences in objective and subjective assessments for distinguishing presence, location, and severity of forelimb lameness in dogs.

Clinical Relevance— The diagnostic approach to forelimb lameness in dogs should include shoulder pathology as a differential with multiple assessments used to determine the clinical cause of lameness.
A Technique for Internal Fixation of Scapulohumeral Luxation Using Scapulohumeral Tension Sutures in Three Alpacas and One Miniature Steer
Authors: WATTS ASHLEE E. , FORTIER LISA A. , NIXON ALAN J. , DUCHARME NORM G.
Published: January 2008

Objective—To report a technique for open reduction and internal fixation of scapulohumeral joint luxation in large animals, and outcome.

Study Design—Clinical case reports.

Animals—Mature alpacas (n=3) and immature miniature steer (1).

Methods—Shoulder joint luxation was diagnosed by physical examination and confirmed by radiography. Open reduction was performed with internal fixation using lateral tension band sutures.

Results—Animals maintained shoulder joint reduction and were sound with radiographically normal shoulder joints (n=2) and normal range of motion without appreciable gait abnormalities (4) at follow‐up 8–36 months later.

Conclusions—In contrast to previous reports of open reduction with internal fixation of shoulder joint luxation in large animals, open reduction and use of lateral scapulohumeral tension sutures resulted in functionally normal shoulder joints.

Clinical Relevance—Stabilization of the shoulder joint with lateral scapulohumeral tension sutures after open reduction is effective, technically simple, and should be considered in large animal species weighing <100 kg.
Sympathoexcitation Increases the QT/RR Slope in Healthy Men: Differential Effects of Hypoxia, Dobutamine, and Phenylephrine
Authors: XHAËT OLIVIER , ARGACHA JEAN‐FRANCOIS , PATHAK ATUL , GUJIC MARKO , HOUSSIERE ANNE , NAJEM BOUTAÏNA , DEGAUTE JEAN‐PAUL , VAN DE BORNE PHILIPPE
Published: January 2008

Introduction: Dynamic ventricular repolarization assessed by QT/RR slopes studies the effects of modifications in cardiac repolarization independently of variations in RR interval (RR). The effects of changes in sympathetic and vagal activity on the QT/RR slope are controversial. We tested the hypothesis that sympathoexcitation is an important determinant of the QT/RR slope.

Methods and Results: We compared the effects of a reflex sympathetic activation in response to hypoxia, to the direct effects of the infusion of the beta‐adrenergic agent dobutamine, on the QTa (apex) and QTe (end)/RR slopes. Dobutamine was titrated to obtain similar increases in cardiac output than with hypoxia. Cardiac vagal activity was estimated by rMSSD and pNN50. In a second group of healthy subjects, we assessed the effect of a reflex cardiac vagal activation in response to phenylephrine infusion on the same variables. We observed a similar increase in QTa and QTe slopes during hypoxia and dobutamine (both P < 0.017 vs. normoxia), despite divergent changes in cardiac vagal activity, as rMSSD and pNN50 decreased with hypoxia compared to normoxia (P < 0.001) but increased during dobutamine infusion compared to hypoxia (P < 0.017). In contrast, these slopes did not change during the rises in rMSSD and pNN50 elicited by phenylephrine (P > 0.7).

Conclusion: Beta‐adrenergic stimulation induces comparable increases in the QT/RR slopes than hypoxia, but in the presence of a larger cardiac vagal activity. Vagal cardiac activation by phenylephrine does not change the QT slopes. This reveals that the sympathetic system is an important determinant of QT/RR dynamicity in healthy men.
Abciximab‐Induced Thrombocytopenia: Management of Bleeding in the Setting of Recent Coronary Stents
Authors: NOWAKOWSKI KRIS , ROGERS JAMES , NELSON GREGORY , GUNALINGAM BRENDAN
Published: January 2008

This case report and subsequent literature review describes the management difficulties in a patient who developed abciximab‐induced thrombocytopenia and gastrointestinal bleeding. Abciximab was used to treat the no‐reflow phenomenon, which occurred during insertion of three sequential Taxus coronary artery stents. Resuscitation of this bleeding patient with fluids, blood, and platelet transfusion, and the cessation of antiplatelet agents, was complicated by acute stent thrombosis. We discuss the risk factors for stent thrombosis and discuss abciximab‐induced thrombocytopenia, looking at its incidence, pathophysiology, differential diagnosis, investigation, course, management, preventative strategies, and prognostic implications.
A Randomized Trial of 5 versus 7 French Guiding Catheters for Transfemoral Percutaneous Coronary Stent Implantation
Authors: BÜCHLER JORGE R. , RIBEIRO EXPEDITO E. , FALCÃO JOÃO L. , MARTINEZ EULÓGIO E. , BÜCHLER RICA D. , FERES FAUSTO , MAIELO JOSÉ R. , HADDAD NAGIB , RAMIRES JOSÉ F. , ELLIS STEPHEN G.
Published: January 2008

Comparative studies between 5 French guiding catheter and others of larger size using the transfemoral approach to coronary stenting have not been described. Coronary stent implantation was performed in 90 patients in a randomized trial. The primary end‐point was to compare the incidence of successful uncomplicated stent implantation per lesion with the 5F and 7F guiding catheters. Patients were excluded for excessive vessel tortuosity or anticipated need for equipment not fitting through a 5 catheter. Baseline characteristics and the use of direct stenting did not differ between the two groups. The primary success rate was 97.8% per patient in both groups and 98% per lesion in the 5 French and 97.9% in the 7 French. Guiding catheter change was necessary in 1 patient in each group to successfully complete the procedure in both groups. The amount of contrast used was 63 ± 27.3 mL in the 5 French and 76 ± 25 mL in the 7 French groups (P < 0.05). Vascular complications and blood transfusions occurred somewhat more frequently in the 7 French group (P = 0.058). The manual compression time after sheath removal was 5.1 ± 2.0 min and 8.0 ± 4.3 min, respectively, in the 5 and 7 French groups (P < 0.01). In conclusion, the 5 French guiding catheters showed a similar success rate with coronary stenting when compared to the 7 French, but the amount of contrast used and manual compression time after sheath removal, as well as the rate of vascular and bleeding complications, were reduced in the 5 French group.

(J Interven Cardiol 2007;**:1–6)
Migraine Headache Relief after Percutaneous Transcatheter Closure of Interatrial Communications
Authors: DUBIEL MARK , BRUCH LEONHARD , SCHMEHL INGO , LIEBNER MATTHIAS , WINKELMANN ANNE , STRETZ ANNA , GRAD MARC OLIVER , KLEBER FRANZ XAVER
Published: January 2008

Background: Migraine headache (MHA) is present in 12% of adults, but has been reported to have a higher prevalence in patients with presumed paradoxical embolism and patent foramen ovale. PFO closure in these patients has been reported to improve migraine, but follow‐up periods in previous studies have been relatively short and concomitant medical therapy as well as placebo effects might have influenced the results. This study investigated the long term course of MHA in a large cohort of patients after closure of PFO well beyond the initial phase of concomitant antiplatelet medication.

Methods: 191 consecutive patients with presumed paradoxical embolism underwent percutaneous transcatheter closure of patent interatrial communications for prevention of recurrent thromboembolism. We report the course of MHA before and after closure.

Results: Before the procedure, MHA was present in 24% of patients. At a mean follow‐up of 38 months (range 6 to 82) after the procedure MHA had disappeared completely in 24% of patients, and in another 63% symptoms had improved. At a mean duration of follow‐up of 38 months a significant reduction (p < 0.000) of number, intensity, duration of episodes, and in the number of accompanying symptoms during an MHA episode was found.

Conclusions: Percutaneous transcatheter closure of patent interatrial communications results in significant amelioration of MHA in 87% of patients (complete resolution in 24% and significant improvement in symptoms in 63%). Ongoing randomized trials and larger epidemiologic surveys need to further elucidate the role of device therapy for MHA.
Management of Multivessel Coronary Disease after ST Elevation Myocardial Infarction Treated by Primary Angioplasty
Authors: RIGATTIERI STEFANO , BIONDI‐ZOCCAI GIUSEPPE , SILVESTRI PASQUALE , RUSSO CRISTIAN DI , MUSTO CARMINE , FERRAIUOLO GIUSEPPE , LOSCHIAVO PAOLO
Published: January 2008

Background: Optimal treatment strategy of patients with ST elevation myocardial infarction (STEMI) and multivessel coronary artery disease (CAD) undergoing primary angioplasty is still unclear. Percutaneous coronary intervention (PCI) of non‐culprit vessels simultaneously or soon after primary angioplasty is feasible and safe, but available data failed to consistently show a benefit in long‐term clinical outcomes.

Methods: We retrospectively compared in‐hospital and long‐term outcomes for patients with STEMI and multivessel CAD treated by primary angioplasty with (Group 1, n=64) or without (Group 2, n=46) early, staged PCI of other angiographically significant coronary lesions. In‐hospital major adverse cardiovascular events (MACE) were defined as a composite of death, periprocedural myocardial infarction after staged, elective PCI, stroke, stent thrombosis, major bleeding, and vascular complications. MACE at follow‐up were defined as a composite of death, stroke, stent thrombosis, any coronary revascularization, and re‐hospitalization for acute coronary syndrome.

Results: Group 1 patients underwent staged PCI 5.9 ± 3.5 days after primary angioplasty. The mean length of follow‐up was 13 months (392 ± 236 days). The incidence of in‐hospital MACE was 20.3% in Group 1 and 10.8% in Group 2 (P=0.186); the incidence of out of hospital MACE was 9.3% in Group 1 and 23.9% in Group 2 (P=0.037). In Group 1 in‐hospital MACE were driven by periprocedural myocardial infarction after the elective procedure, which occurred in 15.6% of patients.

Conclusions: Our data show that multivessel, staged PCI in STEMI patients is associated with a low incidence of adverse events at follow‐up but with a higher incidence of in‐hospital MACE, mainly driven by periprocedural myocardial infarction during the elective procedure.
Contrast‐Induced Nephropathy
Authors: BARTORELLI ANTONIO L. , MARENZI GIANCARLO
Published: January 2008

Radiological procedures utilizing intravascular iodinated contrast media are being widely applied for both diagnostic and therapeutic purposes and represent one of the main causes of contrast‐induced nephropathy (CIN) and hospital‐acquired renal failure. Due to the lack of any effective treatment, prevention of this iatrogenic disease, which is associated with significant in‐hospital and long‐term morbidity and mortality and increased costs, is the key strategy. However, prevention of CIN continues to elude clinicians and is a major concern during percutaneous coronary interventions (PCI), as patients undergoing these procedures often have multiple comorbidities. The purpose of this article is to examine the pathophysiology, risk factors, and clinical course of CIN, as well as the most recent studies dealing with its prevention and potential therapeutic interventions, especially during PCI.
Dilatation and Stenting of the Fontan Pathway: Impact of the Stenosis Treatment on Chronic Ascites
Authors: OVROUTSKI STANISLAV , EWERT PETER , ALEXI‐MESKISHVILI VLADIMIR , PETERS BJORN , HETZER ROLAND , BERGER FELIX
Published: January 2008

Objective: Low pulmonary artery pressure (PAP) and unobstructed flow in the pulmonary arteries (PA) and the systemic veins are the most important factors for optimal long‐term Fontan hemodynamics. We retrospectively analyzed the impact of transcatheter interventions for treatment of stenoses in the Fontan pathway to optimize the circulation, with special attention to chronic ascites.

Patients and Design: Sixty‐three of a total of 112 patients underwent heart catheterization 4.6 (1.0–11.4) years after Fontan operation. The median age of the patients at the end of follow‐up was 11 (3.1–45) years. Patients were divided into two groups, one with chronic ascites and one without. The impact of elevated PAP and of morphologic stenoses in the Fontan pathway for the development of chronic ascites was analyzed.

Results: Ascites was observed in 11 patients; 5 of them had stenosis in the Fontan pathway (P = 0.010). High PAP of 15 mmHg or more (n = 13) was correlated positively with the development of ascites (5 of 13, P = 0.040). Twenty interventions for removal of stenosis in the Fontan pathway were performed in 14 patients. We observed temporary relief of ascites in all and complete resolution of ascites after alleviation of the stenosis in 2 patients with PAP <12 mmHg.

Conclusion: Transcatheter treatment of stenosis can effectively improve the hemodynamics in Fontan circulation, even in patients without measurable pressure gradient. In those with low PAP, it may lead to the disappearance of chronic ascites.
Fenestrated Occluders for Treatment of ASD in Elderly Patients with Pulmonary Hypertension and/or Right Heart Failure
Authors: BRUCH LEONHARD , WINKELMANN ANNE , SONNTAG STEFFEN , SCHERF FRANZISKA , RUX SASCHA , GRAD MARC O. , KLEBER FRANZ X.
Published: January 2008

Atrial septal defect (ASD) occlusion in adult patients with advanced age and left or right heart diastolic or systolic heart failure and in patients with pulmonary arterial hypertension bears a considerable risk of deterioration of heart failure. Therefore, we conducted this feasibility trial in 15 ASD patients with pulmonary hypertension and/or right heart failure using a fenestrated Amplatzer septal occluder (AGA Medical Corporation, Golden Valley, MN), allowing an overflow of blood in both directions in case of univentricular diastolic or systolic heart failure. In all patients, the device could be implanted without complications. All symptomatic patients showed an improvement in the New York Heart Association (NYHA) class, and no right or left heart decompensation occurred. On echocardiography, right ventricular end diastolic dimension (RVEDD) and pulmonary artery pressure (PAP) decreased significantly, whereas left ventricular end diastolic dimension (LVEDD) increased. Our series of 15 patients with fenestrated ASD occlusion shows that high‐risk ASD occlusion can safely be accomplished with excellent clinical results and without complications by a fenestrated occluder.
Cryptosporidium fayeri n. sp. (Apicomplexa: Cryptosporidiidae) from the Red Kangaroo (Macropus rufus)
Authors: RYAN UNA M. , POWER MICHELLE , XIAO LIHUA
Published: January 2008

ABSTRACT. The morphology and infectivity of the oocysts of a new species of Cryptosporidium from the faeces of the red kangaroo (Macropus rufus) are described. Oocysts are structurally indistinguishable from those of Cryptosporidium parvum. Oocysts of the new species are passed fully sporulated, lack sporocysts, and measure 4.5–5.1 μm (mean=4.9) × 3.8–5.0 μm (mean=4.3 μm) with a length to width ratio 1.02:1.18 (mean 1.14) (n=50). Oocysts were not infectious for neonate ARC Swiss mice. Multi‐locus analysis of numerous unlinked loci demonstrated this species to be distinct (90.64%–97.88% similarity) from C. parvum. Based on biological and molecular data, this Cryptosporidium infecting marsupials is proposed to be a new species Cryptosporidium fayeri n. sp.
Monopsony as a metaphor for the emerging post‐union labour market
Authors: ERICKSON Christopher L. , MITCHELL Daniel J.B.
Published: January 2008

How can employers worldwide be experiencing increasingly severe labour shortages in the face of globalization? Why don't wages rise in expanding economies? This article argues that declining union power has allowed employers to take the upper hand, setting pay and other conditions of employment as they would in a monopsonistic labour market. Rejecting the perfect competition model matching supply to demand, the authors argue that, far from being a pedagogical curiosity, monopsony's imbalance in bargaining power is widespread. Employee voice needs to be restored to counter the undesirable consequences of strong macroeconomic performance, such as wage inequality and reduced worker rights.
A review of instruments developed to measure outcomes for carers of people with mental health problems
Authors: Harvey K. , Catty J. , Langman A. , Winfield H. , Clement S. , Burns E. , White S. , Burns T.
Published: January 2008

Objective:  Community‐based care for mental disorders places considerable burden on families and carers. Measuring their experiences has become a priority, but there is no consensus on appropriate instruments. We aimed to review instruments carers consider relevant to their needs and assess evidence for their use.

Method:  A literature search was conducted for outcome measures used with mental health carers. Identified instruments were assessed for their relevance to the outcomes identified by carers and their psychometric properties.

Results:  Three hundred and ninety two published articles referring to 241 outcome measures were identified, 64 of which were eligible for review (used in three or more studies). Twenty‐six instruments had good psychometric properties; they measured (i) carers’ well‐being, (ii) the experience of caregiving and (iii) carers’ needs for professional support.

Conclusion:  Measures exist which have been used to assess the most salient aspects of carer outcome in mental health. All require further work to establish their psychometric properties fully.
Expression of cathepsin D and galectin 3 in tubular carcinomas of the breast
Authors: FERNANDEZ‐AGUILAR SERGIO , NOËL JEAN‐CHRISTOPHE
Published: January 2008

Tubular carcinoma (TC) is a distinctive type of grade I (G1) ductal carcinoma with particularly favourable outcome and low rate of axillary metastases. To the best of our knowledge, few data are available in the literature concerning the expression of molecules mediating intercellular and cell‐matrix interactions in TC. We examined with immunohistochemical methods the expression of galectin 3 and cathepsin D in 17 TC and in 33, 31 and 28 ductal carcinomas of G1, grade II (G2) and grade III (G3), respectively. Results were compared using Chi‐square test. Galectin 3 expression was higher in TC than in G1 carcinomas (p<0.05). The pattern of immunostaining was also different with a focal cytoplasmic apical reinforcement in TC. However, cathepsin D stromal and epithelial expression was similar in TC and G1 cases (p>0.05), and lower than in G2 and G3 patients at a stromal level. The higher expression of galectin 3 in TC and its focal staining (apical) pattern suggests that within the group of G1 carcinomas, galectin 3 expression varies according to histological type, and may correlate with prognosis and metastatic potential. We also suggest that cathepsin D could not be involved in neoplastic progression and metastasis in low‐grade (G1) ductal breast carcinomas.
Expression of the cell‐cell adhesion molecule β‐catenin in colorectal carcinomas and their metastases
Authors: BUHMEIDA A. , ELZAGHEID A. , ÅLGARS A. , COLLAN Y. , SYRJÄNEN K. , PYRHÖNEN S.
Published: January 2008

To study the dynamic events leading to impaired cell‐cell adhesion upon transition to the invasive phenotype of colorectal cancer (CRC), we examined three distinct β‐catenin expression patterns (membranous, cytoplasmic, and nuclear) in the paired samples of the primary tumours (P) and their metastatic lesions (M). β‐catenin expression was detected by immunohistochemistry (IHC) in 33 pairs of the primary CRC and their metastases. In a pair‐wise (P‐M) comparison, the membranous index (MI) was significantly different between P and M (p=0.036, Wilcoxon Signed‐Ranks test), while cytoplasmic index (CI) and nuclear index (NI) values did not significantly deviate between P and M. MI in primary tumours was inversely related to the patient's age (p=0.04) and tumour grade (p=0.03), while patients with low MI in M had a high rate of metastasis at diagnosis (p=0.06). CI in P was lower in patients with LN involvement (p=0.02) and in advanced tumour stage (p=0.002). Tumours of the ascending colon had the highest CI in their M (p=0.04). Interestingly, high MI of the M lesions was a significant predictor of favourable overall survival (OS) in univariate (Kaplan‐Meier) survival analysis (p=0.035). In conclusion, significant aberrations in β‐catenin expression probably take place in CRC cells during the development of metastatic phenotype, but a change from membrane expression to cytoplamic and/or nuclear expression is not a prerequisite for metastasis in all cases.
Aberrant methylation in promoter regions of cyclin‐dependent kinase inhibitor genes in adenoid cystic carcinoma of the salivary gland
Authors: DAA TSUTOMU , KASHIMA KENJI , KONDO YOSHIYUKI , YADA NAOMI , SUZUKI MASASHI , YOKOYAMA SHIGEO
Published: January 2008

Adenoid cystic carcinoma (ACC) is a common malignant neoplasm of the salivary gland. The mechanism underlying ACC carcinogenesis is not fully elucidated, although data on associated genetic alterations are accumulating. Cyclin‐dependent kinase inhibitors (CKIs) act as tumor suppressors in various cancers, and aberrant methylation in the CKI gene promoter region has been linked to gene silencing and downregulation of expression. The present study investigated methylation of CKI genes, p15, p18, p19, p21, and p27, in 34 cases of ACC. We found frequent and plural methylations of these genes in most cases (68.8% in p15, 90.3% in p18, 78.8% in p19, 92.3% in p21, and 26.5% in p27). Cell cycle disruption induced by these epigenetic aberrations might be important in the tumorigenesis of ACC.
Evaluation of clinical, laboratory, and therapeutic features of 145 tularemia cases: the role of quinolones in oropharyngeal tularemia
Authors: MERIC MELIHA , WILLKE AYSE , FINKE ERNST‐JURGEN , GRUNOW ROLAND , SAYAN MURAT , ERDOGAN SARPER , GEDIKOGLU SUNA
Published: January 2008

Tularemia outbreaks have occurred in various regions of Turkey in recent years. In this study, clinical (145 patients) and laboratory (97 patients) features of patients with oropharyngeal tularemia were evaluated during the tularemia outbreak in the district of Gölcük in Kocaeli, Turkey. We analyzed the risk factors for therapeutic failure and prolonged recovery time, and compared the efficacy of three antibiotic groups, namely aminoglycoside, tetracycline and quinolone. The most common physical sign and laboratory findings in patients were lymphadenopathy (LAP) and increased erythrocyte sedimentation rate, respectively. Treatment failure was observed in 55 of the 145 (38%) patients during one‐year follow‐up and the most successful results were obtained in the quinolone group. It was determined that antimicrobial therapy initiated 14 days after onset of symptoms was a statistically significiant risk factor, reducing the success rate (p=0.0001, OR=13.10, 95% CI=5.69–30.15) and prolonging the recovery period (p=0.001, OR=3.23, 95% CI=1.63–6.40) in oropharyngeal tularemia cases. These results suggest that antimicrobial treatment should be started early, and quinolones such as moxifloxacin and ciprofloxacin seem to be new alternatives in the treatment of oropharyngeal tularemia.
High numbers of human skin cancers express MMP2 and several integrin genes
Authors: Orimoto Adriana Mari , Neto Cyro Festa , Pimentel Eugênio R. A. , Sanches José A. , Sotto Mirian Nacagami , Akaishi Eduardo , Ruiz Itamar R. G.
Published: January 2008

Background:  Basal cell carcinomas (BCC), squamous cell carcinomas (SCC) and cutaneous malignant melanoma (MM) are solid skin cancers derived from different cell types, with different ability to metastasize. Several subtypes of integrins and matrix metalloproteinases (MMP) have been related to malignization and metastasis processes. This work aimed at a quantitative evaluation of skin cancers expressing eight integrins and MMP2 genes.

Methods:  Expression of integrins and MMP2 genes was evaluated on fresh tumor biopsies from BCC, SCC and MM, and respective controls, by the reverse transcriptase polychain reaction (RT‐PCR) technique.

Results:  More than 90% tumors expressed α6a, β1, β3 and β6 (non‐melanoma), and α5a, α6a and MMP2 (MM). Up to 100% controls also expressed β1 and β3. The results were significant for α6a in BCC (p = 0.026), α6b in SCC (p = 0.035), α2a in BCC (p = 0.003), β5 and β6 in BCC (p = 0.005). MMP2 was expressed in 100% MM (p = 0.0004).

Conclusion:  Integrin subunits α2a and α6a would be interesting targets for BCC anti‐tumor therapy, as well as α6b in case of SCC. The elevated number of BCC expressing α2 and α6, and of MM expressing αv and MMP2, corroborate literature data.
A Picky Eater: Exploring the Mechanisms of Selective Autophagy in Human Pathologies
Authors: Van Der Vaart Aniek , Mari Muriel , Reggiori Fulvio
Published: January 2008

Autophagy is a catabolic process conserved among all eukaryotes essential for the cellular and organismal homeostasis. One of the principal roles of this pathway is to maintain an accurate balance between synthesis, degradation and subsequent recycling of cellular components. Under certain conditions, however, cells are also able to modulate autophagy and specifically remove a number of structures that are potentially harmful. Aberrant protein aggregates, damaged organelles or pathogens can be selectively incorporated into large double‐membrane vesicles called autophagosomes to be delivered into lysosomes for destruction. This ability to eliminate specific structures is exploited by the cells in several physiological processes as well as in multiple pathological situations, making autophagy a precious multitask cellular degradative pathway. In this review, we will first examine what is known about the basic mechanisms of autophagy and then discuss in a second part the nature of the cargoes that are selectively sequestered into autophagosomes, what provides the specificity and the possible implications of selective types of autophagy in human pathologies.
The Tail that Wags the Dog: The Globular Tail Domain Defines the Function of Myosin V/XI
Authors: Li Jian‐Feng , Nebenführ Andreas
Published: January 2008

Actin‐based organelle movements are driven by the related multifunctional myosin motors of class V in animals and fungi and class XI in plants. The versatility of these motors depends critically on their C‐terminal globular tail domain that allows them to bind to a broad variety of cargo molecules. Regulation of this motor–cargo attachment is frequently employed to modulate organelle movement. While the overall structure of the cargo‐binding globular tail appears to be conserved between myosin V and XI, it has become apparent that the motor–cargo interactions differ widely even within a single organism and involve protein complexes with different architecture and completely unrelated protein domains. At the same time, indirect evidence suggests that adaptor or receptor dimerization could facilitate efficient myosin capture. Comparison of myosin V and XI across the large evolutionary distance between animals and plants will likely reveal more fundamental insights into these important motors.
Structure of Vps26B and Mapping of its Interaction with the Retromer Protein Complex
Authors: Collins Brett M. , Norwood Suzanne J. , Kerr Markus C. , Mahony Donna , Seaman Matthew N. J. , Teasdale Rohan D. , Owen David J.
Published: January 2008

Retromer is a heteromeric protein complex with important roles in endosomal membrane trafficking, most notably in the retrograde transport of lysosomal hydrolase receptors from endosomes to the Golgi. The core of retromer is composed of three subunits vacuolar protein sorting (Vps)35, Vps26 and Vps29, and in mammals, there are two paralogues of the medium subunit Vps26A and Vps26B. We find that both Vps26A and Vps26B bind to Vps35/Vps29 with nanomolar affinity and compete for a single‐binding site to define distinct retromer complexes in vitro and in vivo. We have determined the crystal structure of mouse Vps26B and compare this structure with that of Vps26A. Vps26 proteins have a striking similarity to the arrestin family of proteins that regulate the signalling and endocytosis of G‐protein‐coupled receptors, although we observe that surface residues involved in arrestin function are not conserved in Vps26. Using structure‐based mutagenesis, we show that both Vps26A and Vps26B are incorporated into retromer complexes through binding of Vps35 to a highly conserved surface patch within the C‐terminal subdomain and that this interaction is required for endosomal recruitment of the proteins.
Imaging of Lipid Biosynthesis: How a Neutral Lipid Enters Lipid Droplets
Authors: Kuerschner Lars , Moessinger Christine , Thiele Christoph
Published: January 2008

The biosynthesis and storage of triglyceride (TG) is an important cellular process conserved from yeast to man. Most mammalian cells accumulate TG in lipid droplets, most prominent in adipocytes, which are specialized to store large amounts of the TG over long periods. In this study, we followed TG biosynthesis and targeting by fluorescence imaging in living 3T3‐L1 adipocytes and COS7 fibroblasts. Key findings were (i) not only TG but also its direct metabolic precursor diacylglycerol, DG, accumulates on lipid droplets; (ii) the essential enzyme diacylglycerol acyltransferase 2 associates specifically with lipid droplets where it catalyzes the conversion of DG to TG and (iii) individual lipid droplets within one cell acquire TG at very different rates, suggesting unequal access to the biosynthetic machinery. We conclude that at least part of TG biosynthesis takes place in the immediate vicinity of lipid droplets. In vitro assays on purified lipid droplets show that this fraction of the biosynthetic TG is directly inserted into the growing droplet.
Distinct Motifs of Neuropeptide Y Receptors Differentially Regulate Trafficking and Desensitization
Authors: Ouedraogo Moussa , Lecat Sandra , Rochdi Moulay Driss , Hachet‐Haas Muriel , Matthes Hans , Gicquiaux Hervé , Verrier Sophie , Gaire Mireille , Glasser Nicole , Mély Yves , Takeda Kenneth , Bouvier Michel , Galzi Jean‐Luc , Bucher Bernard
Published: January 2008

Activated human neuropeptide Y Y1receptors rapidly desensitize and internalize through clathrin‐coated pits and recycle from early and recycling endosomes, unlike Y2receptors that neither internalize nor desensitize. To identify motifs implicated in Y1receptor desensitization and trafficking, mutants with varying C‐terminal truncations or a substituted Y2C‐terminus were constructed. Point mutations of key putative residues were made in a C‐terminal conserved motif [φ‐H‐(S/T)‐(E/D)‐V‐(S/T)‐X‐T] that we have identified and in the second intracellular i2 loop. Receptors were analyzed by functional assays, spectrofluorimetric measurements on living cells, flow cytometry, confocal imaging and bioluminescence resonance energy transfer assays for β‐arrestin activation and adaptor protein (AP‐2) complex recruitment. Inhibitory GTP‐binding protein‐dependent signaling of Y1receptors to adenylyl cyclase and desensitization was unaffected by C‐terminal truncations or mutations, while C‐terminal deletion mutants of 42 and 61 amino acids no longer internalized. Substitutions of Thr357, Asp358, Ser360 and Thr362 by Ala in the C‐terminus abolished both internalization and β‐arrestin activation but not desensitization. A Pro145 substitution by His in an i2 consensus motif reported to mediate phosphorylation‐independent recruitment of β‐arrestins affected neither desensitization, internalization or recycling kinetics of activated Y1receptors nor β‐arrestin activation. Interestingly, combining Pro145 substitution by His and C‐terminal substitutions significantly attenuates Y1desensitization. In the Y2receptor, replacement of His155 with Pro at this position in the i2 loop motif promotes agonist‐mediated desensitization, β‐arrestin activation, internalization and recycling. Overall, our results indicate that β‐arrestin‐mediated desensitization and internalization of Y1and Y2receptors are differentially regulated by the C‐terminal motif and the i2 loop consensus motif.
RACK1 Regulates the Cell Surface Expression of the G Protein‐Coupled Receptor for Thromboxane A2
Authors: Parent Audrey , Laroche Geneviève , Hamelin Émilie , Parent Jean‐Luc
Published: January 2008

We used the yeast two‐hybrid system to screen for proteins that interact with the C‐terminus of the β isoform of the thromboxane A2 receptor (TPβ). This screen identified receptor for activated C‐kinase 1 (RACK1) as a new TPβ‐interacting protein. Here, we show that RACK1 directly binds to the C‐terminus and the first intracellular loop of TPβ. The TPβ–RACK1 association was further confirmed by co‐immunoprecipitation studies in HEK293 cells and was not modulated by stimulation of the receptor. We observed that cell surface expression of TPβ was increased when RACK1 was overexpressed, while it was inhibited when endogenous RACK1 expression was knocked down by small interfering RNA. Confocal microscopy confirmed the impaired cell surface expression of TPβ and suggested that the receptors remained predominantly localized in the endoplasmic reticulum (ER) in RACK1‐depleted cells. Confocal microscopy also revealed that a transient TPβ–RACK1 association takes place in the ER. The effect of RACK1 on receptor trafficking to the cell surface appears to be selective to some G protein‐coupled receptors (GPCRs) because inhibition of RACK1 expression also affected cell surface targeting of the angiotensin II type 1 receptor and CXCR4 but not of β2‐adrenergic and prostanoid DP receptors. Our data demonstrate for the first time a direct interaction between RACK1 and a GPCR and identify a novel role for RACK1 in the regulation of the transport of a membrane receptor from the ER to the cell surface.
Lack of a Vacuolar Sorting Receptor Leads to Non‐Specific Missorting of Soluble Vacuolar Proteins in Arabidopsis Seeds
Authors: Craddock Christian P. , Hunter Paul R. , Szakacs Erika , Hinz Giselbert , Robinson David G. , Frigerio Lorenzo
Published: January 2008

The plant vacuolar sorting receptor (VSR) binds proteins carrying vacuolar sorting signals (VSS) of the ‘sequence‐specific’ type (ssVSS) but not the C‐terminal, hydrophobic sorting signals (ctVSS). Seeds of Arabidopsis mutants lacking the major VSR isoform, AtVSR1, secrete a proportion of the proteins destined to storage vacuoles. The sorting signals for these proteins are not well defined, but they do not seem to be of the ssVSS type. Here, we tested whether absence of VSR1 in seeds leads to secretion of reporter proteins carrying ssVSS but not ctVSS. Our results show that reporters carrying either ssVSS or ctVSS are equally secreted in the absence of VSR1. We discuss our findings in relation to the current model for vacuolar sorting.
Evidence for CALM in Directing VAMP2 Trafficking
Authors: Harel Asaff , Wu Fangbai , Mattson Mark P. , Morris Christa M. , Yao Pamela J.
Published: January 2008

Clathrin assembly lymphoid myeloid leukemia protein (CALM) is a clathrin assembly protein with a domain structure similar to the neuron‐specific assembly protein AP180. We have previously found that CALM is expressed in neurons and present in synapses. We now report that CALM has a neuron‐related function: it facilitates the endocytosis of the synaptic vesicle protein VAMP2 from the plasma membrane. Overexpression of CALM leads to the reduction of cell surface VAMP2, whereas knockdown of CALM by RNA interference results in the accumulation of surface VAMP2. The AP180 N‐terminal homology (ANTH) domain of CALM is required for its effect on VAMP2 trafficking, and the ANTH domain itself acts as a dominant‐negative mutant. Thus, our results reveal a role for CALM in directing VAMP2 trafficking during endocytosis.
The Itinerary of Autophagosomes: From Peripheral Formation to Kiss‐and‐Run Fusion with Lysosomes
Authors: Jahreiss Luca , Menzies Fiona M. , Rubinsztein David C.
Published: January 2008

Macroautophagy, a constitutive process in higher eukaryotic cells, mediates degradation of many long‐lived proteins and organelles. The actual events occurring during the process in the dynamic system of a living cell have never been thoroughly investigated. We aimed to develop a live‐cell assay in which to follow the complete itinerary of an autophagosome. Our experiments show that autophagosomes are formed randomly in peripheral regions of the cell. They then move bidirectionally along microtubules, accumulating at the microtubule‐organizing centre, in a similar way to lysosomes. Their centripetal movement is dependent on the motor protein dynein and is important for their fusion with lysosomes. Initially, autophagosomes dock on to lysosomes, independent of lysosomal acidification. Two kinds of fusion then occur: complete fusions, creating a hybrid organelle, or more often kiss‐and‐run fusions, i.e. transfer of some content while still maintaining two separate vesicles. Surprisingly, the autophagolysosomal compartment seems to be more long lived than expected. Our study documents many aspects of autophagosome behaviour, adding to our understanding of the mechanism and control of autophagy. Indeed, although the formation of autophagosomes is completely different from any other vesicular structures, their later itinerary appears to be very similar to those of other trafficking pathways.
The Lysophospholipid Acyltransferase Antagonist CI‐976 Inhibits a Late Step in COPII Vesicle Budding
Authors: Brown William J. , Plutner Helen , Drecktrah Daniel , Judson Bret L. , Balch William E.
Published: January 2008

The mechanism of coat protein (COP)II vesicle fission from the endoplasmic reticulum (ER) remains unclear. Lysophospholipid acyltransferases (LPATs) catalyze the conversion of various lysophospholipids to phospholipids, a process that can promote spontaneous changes in membrane curvature. Here, we show that 2,2‐methyl‐N‐(2,4,6,‐trimethoxyphenyl)dodecanamide (CI‐976), a potent LPAT inhibitor, reversibly inhibited export from the ER in vivo and the formation of COPII vesicles in vitro. Moreover, CI‐976 caused the rapid and reversible accumulation of cargo at ER exit sites (ERESs) containing the COPII coat components Sec23/24 and Sec13/31 and a marked enhancement of Sar1p‐mediated tubule formation from ERESs, suggesting that CI‐976 inhibits the fission of assembled COPII budding elements. These results identify a small molecule inhibitor of a very late step in COPII vesicle formation, consistent with fission inhibition, and demonstrate that this step is likely facilitated by an ER‐associated LPAT.
Protein Trafficking insideToxoplasma gondii
Authors: Sheiner Lilach , Soldati‐Favre Dominique
Published: January 2008

The accurate targeting of proteins to their final destination is an essential process in all living cells. Apicomplexans are obligate intracellular protozoan parasites that possess a compartmental organization similar to that of free‐living eukaryotes but can be viewed as professional secretory cells. Establishment of parasitism involves the sequential secretion from highly specialized secretory organelles, including micronemes, rhoptries and dense granules. Additionally, apicomplexans harbor a tubular mitochondrion, a nonphotosynthetic plastid organelle termed the apicoplast, acidocalcisomes and an elaborated inner membrane complex composed of flattened membrane cisternae that are derived from the secretory pathway. Given the multitude of destinations both inside and outside the parasite, the endoplasmic reticulum/Golgi of the apicomplexans constitutes one of the most busy roads intersections in eukaryotic traffic.