bluuebunny/crossref_metadata_2025 huggingface dataset:
From R&D to Innovation and Economic Growth in the EU
Authors: Bilbao‐Osorio Beñat , Rodríguez‐Pose Andrés
Published: October 2004

ABSTRACT  Over the last two decades many European governments have pursued ambitious research and development (R&D) policies with the aim of fostering innovation and economic growth in peripheral regions of Europe. The question is whether these policies are paying off. Arguments such as the need to reach a minimum threshold of research, the existence of important distance decay effects in the diffusion of technological spillovers, the presence of increasing returns to scale in R&D investments, or the unavailability of the necessary socio‐economic conditions in these regions to generate innovation seem to cast doubts about the possible returns of these sort of policies. This paper addresses this question. A two‐step analysis is used in order to first identify the impact of R&D investment of the private, public, and higher education sectors on innovation (measured as the number of patent applications per million population). The influence of innovation and innovation growth on economic growth is then addressed. The results indicate that R&D investment, as a whole, and higher education R&D investment in peripheral regions of the EU, in particular, are positively associated with innovation. The existence and strength of this association are, however, contingent upon region‐specific socio‐economic characteristics, which affect the capacity of each region to transform R&D investment into innovation and, eventually, innovation into economic growth.
Spatial Structure and Taxonomy of Decomposition in Shift‐Share Analysis
Authors: Nazara Suahasil , Hewings Geoffrey J.D.
Published: October 2004

ABSTRACT  The goal of this paper is twofold. The first goal is to incorporate spatial structure within shift‐share analysis, to take into account interregional interaction in the decomposition analysis. Secondly, this paper develops a taxonomy of regional growth rate decompositions. A taxonomy of the spatial structure is presented; it comprises twenty alternative decomposition structures, including the original standard shift‐share analysis as well as six alternative structures outlined in the taxonomy for non‐spatial structures.
Effect of different time intervals on the viscosity of batter and on the sensory qualities of puras (pancakes) prepared using chhana and paneer whey
Authors: JINDAL A R , SHOREE M , SHUKLA F C
Published: October 2004

The viscosity of pura (pancakes) batter samples prepared with bovine, buffalo and mixed wheys (80 : 20 whey to water) was measured at different time intervals at a temperature of 25 ± 2°C using a Brookfield viscometer (LVT 98534). The viscosity of sweet pura batter samples increased after 1 h, remained constant for another 2 h and then decreased, whereas the viscosity of salty pura batter samples increased from freshly prepared batter to 1 h and then remained constant. Sensory evaluation of both sweet and salty puras at different time intervals from batter preparation was also carried out. The overall acceptability scores for sweet puras prepared using bovine milk chhana whey, buffalo milk paneer whey and mixed milk chhana whey and stored for up to 4 h at 25 ± 2°C and for 24 h at 4–5°C were not significantly different, and the same conclusion applied to salty puras made from bovine milk chhana whey. It was concluded that sweet and salty pura batters can be prepared from any chhana or paneer whey.
Evolution of a crustal‐scale transpressive shear zone in the Albany–Fraser Orogen, SW Australia: 1. P–T conditions of Mesoproterozoic metamorphism in the Coramup Gneiss
Authors: Bodorkos S. , Clark D. J.
Published: October 2004

The Albany–Fraser Orogen in southwestern Australia preserves an important thermo‐tectonic record of Australo‐Antarctic cratonic assembly during the Mesoproterozoic. New petrologic and thermobarometric data from the Coramup Gneiss (a 10 km wide zone of high strain rocks within the NE‐trending eastern Albany–Fraser Orogen) indicate at least two high‐grade metamorphic events during 1345–1140 Ma convergence and amalgamation of the West Australian and Mawson cratons. The first event (M1) involved c. 1300 Ma granulite facies metamorphism of the Coramup Gneiss (M1a: 800–850 °C, 5–7 kbar), followed by burial and recrystallization under high‐P conditions (M1b: 800–850 °C, c. 10 kbar) prior to high‐T decompression (M1c: 700–800 °C, 7–8 kbar) and the 1290–1280 Ma emplacement of Recherche Granite sills. The second event (M2) entailed high‐T, low‐P metamorphism within dextral D2 shear zones (M2a: 750–800 °C, 5–6 kbar), followed by fluid‐present amphibolite facies M2b retrogression. Subsequent sinistral D3 mylonites and pseudotachylites are considered contemporaneous with similar structures in the adjacent Nornalup Complex that postdate the c. 1140 Ma Esperance Granite. Our petrological and thermobarometric data permit two end‐member P–T‐time relationships between M1 and M2: (1) a single post‐M1b event involving continuous M1b–M1c–M2a–M2b cooling and decompression, and (2) a two‐stage post‐M1b evolution involving M1c metamorphism during the waning stages of an event unrelated causally or temporally to subsequent M2a metamorphism and D2 deformation. In a companion paper, new structural and U–Pb SHRIMP zircon data are presented to support a two‐stage P–T evolution for the Coramup Gneiss, with M1 and M2, respectively, reflecting thermo‐tectonic activity during Stage I (1345–1260 Ma) and Stage II (1215–1140 Ma) of the Albany–Fraser Orogeny.
Evolution of a crustal‐scale transpressive shear zone in the Albany–Fraser Orogen, SW Australia: 2. Tectonic history of the Coramup Gneiss and a kinematic framework for Mesoproterozoic collision of the West Australian and Mawson cratons
Authors: Bodorkos S. , Clark D. J.
Published: October 2004

Within the Albany–Fraser Orogen of southwestern Australia, the Coramup Gneiss is a NE–SW trending zone of high‐strain rocks that preserves a detailed record of orogenesis related to Mesoproterozoic convergence of the West Australian and Mawson cratons. New structural, metamorphic and U–Pb SHRIMP zircon age data establish that the Coramup Gneiss underwent high‐grade tectonism during both Stage I (c. 1290 Ma) and Stage II (c. 1170 Ma) of the Albany–Fraser Orogeny. Stage I commenced with c. 1300 Ma high‐T, low‐P M1a metamorphism during extension, and the formation of small‐scale ptygmatic folds within a subhorizontal S1a gneissosity. High‐P M1b metamorphism at c. 1290 Ma was accompanied by the transposition and shearing of S1a into a composite, shallow SE‐dipping S1b foliation, and the development of tight recumbent F1b folds with S1‐parallel axial surfaces and asymmetries indicating NW‐directed thrusting. The preservation of a similar P–T–time record in the Fraser Complex (NE of the Coramup Gneiss) is consistent with large‐scale, NW‐directed Stage I thrusting of the Mawson Craton margin over the south‐eastern edge of the West Australian Craton. Stage II tectonism in the western Coramup Gneiss involved high‐T, low‐P M2a metamorphism and the formation of subvertical SE‐dipping D2 shear zones, shallow SW‐plunging L2 mineral stretching lineations, and NW‐verging F2 folds with S2‐parallel axial surfaces. A synkinematic pegmatite dyke emplaced into a D2 shear zone yielded a U–Pb SHRIMP zircon age of 1168 ± 12 Ma. Kinematic indicators suggest a combination of pure shear flattening perpendicular to S2, and dextral simple shear. However, contemporaneous structures elsewhere in the Albany–Fraser Orogen are consistent with continued NW–SE convergence at craton‐scale during Stage II, and oblique compression in the Coramup Gneiss is attributed to the arcuate geometry of the orogen‐scale deformation front.
Mechanical and Structural Properties of a Novel Hybrid Heart Valve Scaffold for Tissue Engineering
Authors: Grabow Niels , Schmohl Kathleen , Khosravi Amir , Philipp Mark , Scharfschwerdt Michael , Graf Bernhard , Stamm Christof , Haubold Axel , Schmitz Klaus‐Peter , Steinhoff Gustav
Published: October 2004

Abstract:  Hybrid heart valve scaffolds were fabricated from decellularized porcine aortic heart valve matrices and enhanced with bioresorbable polymers using different protocols: (i) dip coating of lyophilized decellularized matrices, and (ii) impregnation of wet decellularized matrices. The following polymers were evaluated: poly(4‐hydroxybutyrate) and poly(3‐hydroxybutyrate‐co4‐hydroxybutyrate). Tensile tests were conducted to assess the biomechanical behavior of valve leaflet strips. Suture retention strength was evaluated for the adjacent conduit. A pulse duplicator system was used for functional testing of the valves under physiological systemic load conditions. The properties of the hybrid structures were compared with native, decellularized, and glutaraldehyde‐fixed specimens. Mechanisms of the polymer impregnation process were studied with IR spectroscopy, fluorescent microscopic imaging, and SEM. Altogether this study demonstrates the feasibility and improved biomechanical function of a novel hybrid heart valve scaffold for an application in tissue engineering.
Two Multiarticulated Hydraulic Hand Prostheses
Authors: Pylatiuk Christian , Schulz Stefan , Kargov Artem , Bretthauer Georg
Published: October 2004

Abstract: Purpose: Consumers want new prosthetic hand designs that have increased functionality, better cosmetic appearance, and lower weight. Methods: New lightweight hands that fulfill these demands can be designed by integrating a hydraulic system with small fluidic actuators at the digit joints. Results: Two different designs of lightweight experimental prosthetic hand are presented. The weight of the first hand is reduced by 50% compared to a conventional prosthetic hand, whereas the functionality of the second hand is increased by additional prehension types. Optionally, a tactile feedback system can be integrated. Due to multiple articulated digits and flexible materials, both hands are able to conform to the shape of an object held. This significantly reduces the necessary grip force and results in stable holding of an object. For a natural appearance, the hands are covered with a cosmetic silicone rubber glove.
Effect of Temporary Catheter and Late Referral on Hospitalization and Mortality During the First Year of Hemodialysis Treatment
Authors: Gonçalves Elsa A.P. , Andreoli Maria Claudia C. , Watanabe Renato , Freitas Maria Cecilia S. , Pedrosa Alessandra C. , Manfredi Silvia R. , Draibe Sérgio A. , Cendoroglo Miguel , Canziani Maria Eugenia F.
Published: October 2004

Abstract:  Late referral (LR) to dialysis therapy has been associated with poor outcomes in people with end‐stage renal disease. This had been ascribed to the frequent use of temporary vascular catheters (TVCs) in LR patients. The effects of LR and TVC on the outcomes of an incident hemodialysis population (n = 101) were investigated. There was a higher incidence of vascular access infection, longer period of hospitalization, and lower survival in TVC and LR groups, compared with arteriovenous fistula and early referral (ER) groups, respectively. Late referral patients had higher number of hospitalizations than ER patients. In univariate analysis, LR (hazard ratio [HR] 10.8, P = 0.02) and albumin (HR 0.23, P < 0.0001) were associated with mortality. Late referral and body mass index were associated with the increased risk of hospitalization in univariate analysis. In multivariate analysis, LR was the only risk factor associated with hospitalization (HR 3.51, P = 0.002). In conclusion, LR was associated with increased risk of mortality and increased risk of hospitalization independently of the presence of a TVC.
Relation Between Vertical Orientation and Stability of Acetabular Component in the Dysplastic Hip Simulated by Nonlinear Three‐dimensional Finite Element Method
Authors: Oki Hisashi , Ando Masao , Omori Hironori , Okumura Yasuhiro , Negoro Kohei , Uchida Kenzo , Baba Hisatoshi
Published: October 2004

Abstract:  In acetabular dysplasia, more vertical orientation of the acetabular component is often used to minimize the superolateral bone grafting. This study was designed to determine the effects of vertical orientation of the cup on the stability and polyethylene wear of the acetabular component in uncemented total hip arthroplasty (THA). Three‐dimensional finite element models of the hemipelvis with dysplastic acetabulum were developed. Metal‐backed hemispherical cups were placed in the true acetabulum with abduction angles of 35, 45, 55, and 65 degrees. It was found that more vertical orientation of the cup was associated with larger relative motion of the metal shell between the acetabulum and metal shell. Furthermore, tilting and torsional shear stresses in the model of the cup abduction angle of 65 degrees were found to be 1.7 times larger than that in the model with 35 degrees at the bone–metal shell interface. More vertically oriented cups caused larger contact stresses at the articulating surfaces of the polyethylene liners. The results suggest that the abduction angle of the acetabular component significantly influences cup loosening and polyethylene wear in  THA.
Fast Three‐dimensional Numerical Hemolysis Approximation
Authors: Garon André , Farinas Marie‐Isabelle
Published: October 2004

Abstract:  The in vivo implantation of a mechanical device contributes to hemodynamic disturbances, which are responsible for damage to the membranes of red blood cells that in turn can lead to their rupture (hemolysis). It is important to ascertain at the design stage of such mechanical devices that they are innocuous to blood. Because there is no in vivo hemolysis index, we concentrated our efforts on the in vitro hemolysis index of the American Society for Testing and Material (ASTM) standard. We present in this work a framework for minimizing medical device‐induced hemolysis by the development of a numerical method for predicting hemolysis similar to that used in in vitro experiments. The method is based on a novel interpretation of the Giersiepen‐Wurzinger blood damage correlation that replaces the computation of blood damage  along the streamline by a volume integration of a damage function over the computational domain. We assess  the  behavior  and  accuracy  of  this  methodology  with  3D examples.
What Constitutes Normal Hemoglobin Concentration in Community‐Dwelling Disabled Older Women?
Authors: Chaves Paulo H. M. , Xue Qian‐Li , Guralnik Jack M. , Ferrucci Luigi , Volpato Stefano , Fried Linda P.
Published: October 2004

Objectives:To examine the associations between hemoglobin (Hb) concentration and (1) 5‐year all‐cause mortality and (2) serum erythropoietin (EPO), as the basis for the identification of data‐driven thresholds, and to assess the clinical relevance of mildly low Hb.

Design:Prospective study.

Setting:Population based.

Participants:Community‐dwelling women aged 65 and older with moderate‐to‐severe disability—Women's Health and Aging Study I, Baltimore, Maryland, 1992–2000.

Methods:Proportional hazards regression was used to model the relationship between baseline Hb (available for 686 subjects) and time to death. A generalized linear model was used to assess the cross‐sectional association between Hb and EPO in 641 subjects.

Results:A curvilinear slope of steady mortality decrease up to the Hb threshold of 13.9 g/dL was observed. Hb of 11 g/dL was independently associated with greater mortality than the World Health Organization (WHO) low‐normal cutoff of Hb of 12 g/dL (hazard ratio (HR)=1.2, 95% confidence interval (CI)=1.1–1.4), whereas Hb of 14 g/dL was linked to 24% lower mortality (HR=0.76, 95% CI=0.63–0.92), after comprehensive adjustment for major health status and disease‐burden indicators. A curvilinear, statistically significant slope of steady EPO decrease with increasing Hb up to the threshold of 14.3 g/dL was consistently observed.

Conclusion:The meaningfully lower mortality risk with higher Hb levels provides empirical evidence against the notion that Hb currently perceived as mildly low is clinically benign. Furthermore, the mortality risk gradient observed even within the WHO normal Hb range suggests that Hb levels higher than what is currently recommended might offer clinical advantage. The relationship between Hb and EPO provided supporting physiological evidence for this hypothesis.
Safety and Efficacy of Risedronate in Reducing Fracture Risk in Osteoporotic Women Aged 80 and Older: Implications for the Use of Antiresorptive Agents in the Old and Oldest Old
Authors: Boonen Steven , McClung Michael R. , Eastell Richard , El‐Hajj Fuleihan Ghada , Barton Ian P. , Delmas Pierre
Published: October 2004

Objectives: To determine the efficacy of risedronate in reducing vertebral fracture risk in women aged 80 and older with osteoporosis.

Design: Pooled analysis of data from three randomized, double‐blind, controlled, 3‐year‐fracture‐endpoint trials conducted from November 1993 to April 1998: Hip Intervention Program (HIP), Vertebral Efficacy with Risedronate Therapy—Multinational (VERT‐MN), and VERT‐North America (NA).

Setting: Office‐based practices, research centers, and osteoporosis clinics in Europe, North America, and Australia.

Participants: Osteoporotic (femoral neck bone mineral density T‐score < −2.5 standard deviations or at least one prevalent vertebral fracture) women aged 80 and older.

Intervention: Patients received placebo (n=688) or risedronate 5 mg/d (n=704) for up to 3 years. All patients received 1,000 mg/d calcium and, if baseline levels were low, up to 500 IU/d vitamin D.

Measurements: Cumulative incidence of new vertebral fractures.

Results: After 1 year, the risk of new vertebral fractures in the risedronate group was 81% lower than with placebo (95% confidence interval=60–91%; P<.001). The number of women who needed to be treated to prevent one new vertebral fracture after 1 year was 12. This early onset of efficacy was consistent across the clinical programs, and antifracture efficacy was confirmed over 3 years. Risedronate was well tolerated, with a safety profile comparable with that of placebo.

Conclusion: These findings provide the first evidence that, even in the very old, reducing bone resorption rate remains an effective treatment strategy for osteoporosis. Because each therapeutic agent used for the treatment of osteoporosis may have unique characteristics, the observations made in this study should not be assumed to apply to other bisphosphonates.
Cognitive Impairment in Chronic Kidney Disease
Authors: Kurella Manjula , Chertow Glenn M. , Luan Jennifer , Yaffe Kristine
Published: October 2004

Objectives: To assess the prevalence of cognitive impairment in persons with chronic kidney disease (CKD) and its relation to the severity of CKD.

Design: Cross‐sectional study.

Setting: University‐affiliated ambulatory nephrology and dialysis practices.

Participants: Eighty subjects with CKD Stages III and IV not requiring dialysis (CKD) and 80 subjects with CKD Stage V on hemodialysis (end‐stage renal disease (ESRD)) with a mean age±standard deviation of 62.5±14.3.

Measurements: Three standardized cognitive tests, the Modified Mini‐Mental State Examination (3MS), Trailmaking Test B (Trails B), and California Verbal Learning Trial (CVLT). Glomerular filtration rate was estimated in subjects with CKD using the six‐variable Modification of Diet in Renal Disease equation.

Results: There was a graded relation between cognitive function and severity of CKD. Mean scores on the 3MS, Trails B, and CVLT immediate and delayed recall were significantly worse for subjects with ESRD than for subjects with CKD or published norms (P<.001 for all comparisons). Scores on the Trails B (P<.001) and CVLT immediate (P=.01) and delayed (P<.001) recall were significantly worse for subjects with CKD not requiring dialysis than for published norms. In addition, the fraction of subjects with impairment on the 3MS and Trails B increased with decreasing kidney function.

Conclusion: Cognitive impairment is associated with the severity of kidney disease. Further studies are needed to determine the reasons for cognitive impairment in subjects with CKD and ESRD.
Pharmacotherapy of Pain in Depressed Older Adults
Authors: Unützer Jürgen , Ferrell Bruce , Lin Elizabeth H. B. , Marmon Tonya
Published: October 2004

Objectives: To examine pharmacotherapy for pain in a sample of 1,801 depressed older primary care patients.

Design: Cross‐sectional survey data collected from 1999 to 2001.

Setting: Eighteen primary care clinics belonging to eight healthcare organizations in five states.

Participants: One thousand eight hundred one patients aged 60 and older who met diagnostic criteria for major depression or dysthymia.

Measurements: Diagnoses or treatment for chronic pain, functional impairment from pain, and use of over‐the‐counter and prescription analgesic medications.

Results: One thousand four hundred sixteen (79%) participants reported functional impairment from pain in the previous month, and 1,024 (57%) reported a diagnosis of or treatment for chronic pain in the previous 3 years. Fifty‐one percent of those with recent functional impairment from pain reported any analgesic use, ranging from 31% to 75% across the participating healthcare organizations. Opioid analgesic use varied from 5% to 34%. Predictors of analgesic use included a history of chronic pain or arthritis and the degree of functional impairment from pain in the previous month. Differences in analgesic use across participating organizations remained significant after adjusting for clinical and demographic covariates.

Conclusion: Most depressed older adults in the sample reported recent functional impairment from pain and a history of chronic pain, but almost half of those with functional impairment from pain did not report using analgesic medications. Participating organizations varied substantially in their use of analgesics, suggesting that there is room to improve the quality of pain management in depressed older adults.
How Should Clinicians Describe Hospice to Patients and Families?
Authors: Casarett David J. , Crowley Roxane L. , Hirschman Karen B.
Published: October 2004

Objectives: To describe hospice enrollment from the perspective of bereaved family members and to identify information about hospice that would encourage patients and families to enroll sooner.

Design: Cross‐sectional interviews.

Setting: Three Medicare‐certified hospice organizations.

Participants: One hundred family members of 100 patients who died in hospice.

Measurements: Semistructured interviews assessed prior knowledge of hospice, patients' and physicians' involvement in the enrollment process, features of hospice that motivated enrollment, and features that patients and families wished they had learned about sooner.

Results: Almost all family members (n=92) and patients (n=71) knew about hospice before the patient's illness. Almost half the patients (n=44) were not involved at all in the hospice enrollment decision. The patient's physician (n=51) or the patient or family (n=34) initiated most hospice discussions, but patients and families usually obtained information about hospice from a hospice representative (n=75) rather than from the patient's physician (n=22). Family members identified several kinds of information about hospice that were particularly helpful in deciding whether to enroll and described several aspects of hospice that they wished they had known about sooner.

Conclusion: Many patients and families learn about hospice from someone other than the patient's physician, and most learn about valuable hospice features and services only after enrollment. By providing more information about hospice earlier in the illness course, clinicians may be able to facilitate more‐informed and more‐timely decisions about hospice enrollment.
Operationalizing a Frailty Index from a Standardized Comprehensive Geriatric Assessment
Authors: Jones David M. , Song Xiaowei , Rockwood Kenneth
Published: October 2004

Objectives: To construct and validate a frailty index (FI) that is clinically sensible and practical for geriatricians by basing it on a routinely used comprehensive geriatric assessment (CGA) instrument.

Design:  Secondary analysis of a 3‐month randomized, controlled trial of a specialized mobile geriatric assessment team.

Setting: Rural Nova Scotia. Participants were seen in their homes.

Participants: Frail older adults, of whom 92 were in the intervention group and 77 in the control group.

Measurements: A standard CGA form that accounts for impairment, disability, and comorbidity burden was scored and summed as a frailty index (FI‐CGA). The FI‐GCA was stratified to describe three levels of frailty. Patients were followed for up to 12 months to determine how well the index predicted adverse outcomes (institutionalization or mortality, whichever came first).

Results: The three levels of frailty were mild (FI‐CGA 0–7), moderate (FI‐CGA 7–13), and severe (FI‐CGA>13). Demographic and social traits were similar across groups, but greater frailty was associated with worse function (r=0.55) and mental status (r=0.33). Those with moderate and severe frailty had a greater risk of adverse outcomes than those with mild frailty (unadjusted hazard ratio=1.9 and 5.5, respectively). There was no difference between frailty groups in mean 3‐month goal‐attainment scaling scores. Intrarater reliability was 0.95.

Conclusion: The FI‐CGA is a valid, reliable, and sensible clinical measure of frailty that permits risk stratification of future adverse outcomes.
A McLeod phenotype detected by random screening for K:‐4 [Kp(b–)] blood donors in Brazil
Authors: Wendel Silvano , Fontão‐Wendel Rita , Levi José Eduardo , Aravechia Maria Giselda , Bordokan Roberta F.S. , Russo David , Haddad Monica Santoro
Published: October 2004

BACKGROUND:  The red blood cells of the McLeod phenotype have weak expression of Kell System antigens due to no expression of XK protein.

STUDY DESIGN AND METHODS:  One blood donor reacted as K:‐4 [Kp(b–)] during a screening assay. Subsequent serologic studies demonstrated weak expression of K:4 and all other high‐incidence Kell system antigens tested; however, no expression of Kx antigen was observed.

RESULTS:  One apparently healthy blood donor demonstrated low expression of K:2, K:4, K:5, K:7, K:14, K:22, and no Kx antigen in his red blood cells. His brother and mother showed the same weak expression, and his father showed normal expression of antigens tested. Flow cytometry studies confirmed the mother's status as a McLeod carrier female. Genotyping determined the presence of KEL2 and KEL4 alleles in mother and siblings. Southern blot with an exon‐1 probe showed fragments shorter than predicted for the siblings and the mother, suggesting a deletion. Polymerase chain reaction with primers spanning exon 1 and flanking regions displayed a similar pattern. Deoxyribonucleic acid sequence allowed the precise characterization of a deletion of 392 bp, beginning at the 5′ of the coding region up to nucleotide 201 of exon 1, which putatively abrogates the production of XK protein.

CONCLUSION:  Two brothers with McLeod phenotype in a Brazilian blood‐donor population were identified. The molecular basis for this phenotype is a 392‐bp deletion spanning from 5′ of the coding region to exon 1 of the XK gene, never described before.
Severe hemolysis resulting from D incompatibility in a case of ABO‐identical liver transplant
Authors: Fung Mark K. , Sheikh Hina , Eghtesad Bijan , Lopez‐Plaza Ileana
Published: October 2004

BACKGROUND:  Hemolysis due to D incompatibility in the setting of liver transplantation is less frequent than that associated with ABO incompatibility, but can represent an equally adverse event. Approximately 10 percent of ABO‐compatible liver transplants involve a D– donor and a D+ recipient.

CASE REPORT:  A case of severe D incompatibility resulting from liver transplantation in a 50‐year‐old O Rh+ man with end‐stage liver disease who received an O Rh– liver allograft is reported. A declining hemoglobin level complicated the patient's postoperative course with laboratory evidence of anti‐D–mediated hemolysis. Investigations revealed that the transplanted liver was from a female O Rh– donor with detectable antibodies against D, C, and K. The severity of the hemolytic anemia was such that the patient required two separate red blood cell (RBC) exchanges and intermittent RBC transfusions over the course of almost a year. In addition to the use of RBCs negative for D, C, and K, the patient underwent a variety of B‐cell suppressive therapies including glucocorticosteroids, mycophenolate mofetil, and rituximab. A normalization of hemoglobin levels and a decrease in serum bilirubin did not occur until after a splenectomy on postoperative Day 321.

CONCLUSION:  This represents the sixth and most severe case reported of hemolysis resulting from D incompatibility in liver transplantation. When unexpected serologic findings are identified in a transplant recipient, obtaining more information on the donor may help guide transfusion support.
Molecular and serologic tracing of a transfusion‐transmitted hepatitis A virus
Authors: Gowland Peter , Fontana Stefano , Niederhauser Christoph , Taleghani Behrouz Mansouri
Published: October 2004

BACKGROUND:  The transmission of hepatitis A virus (HAV) via blood transfusion has not been evidenced by molecular tracing so far.

CASE REPORT:  A 33‐year‐old asymptomatic female volunteer made a whole‐blood donation. Thirteen days later an acute HAV infection was diagnosed. Retrospectively, a high viral load was measured by quantitative reverse transcription polymerase chain reaction (RT‐PCR) in the quarantine fresh‐frozen plasma (1.4 × 106 geq/mL), whereas immunoglobulin M (IgM) and G (IgG)/IgM anti‐HAV were not detectable and the alanine aminotransferase levels not elevated. The red blood cells have just been transfused on Day 14. The 63‐year‐old male recipient already was HAV seropositive. He did not develop clinical symptoms of HAV and anti‐HAV IgM was not detected. Seventy‐five days later, a 25‐fold increase in the anti‐HAV IgG/IgM titer was observed. Demonstrable HAV ribonucleic acid (RNA) in the recipient by means of RT‐PCR on Day 6, but not on Days 1 and 75, suggests that a transient reinfection did occur. Analyzed sequences of the HAV RNA in the donor and recipient were identical.

CONCLUSION:  For the first time, transfusion‐transmitted HAV was evidenced by molecular and serologic tracing. The transmitted HAV can survive and replicate for a limited period despite the presence of anti‐HAV IgG.
The use of recombinant activated factor VII in three patients with central nervous system hemorrhages associated with factor VII deficiency
Authors: Huang Weei‐Yuarn , Kruskall Margot S. , Bauer Kenneth A. , Uhl Lynne , Shaz Beth H.
Published: October 2004

BACKGROUND:  Recombinant activated factor VII (rFVIIa) is being tested to improve hemostasis in a variety of bleeding disorders. Clinical indications and efficacy are still being evaluated for this product.

CASE REPORT:  Over a 17‐month period, rFVIIa was used to treat central nervous system hemorrhage in three patients who were found to have isolated FVII deficiency (21%, 40%, 27%). Patient A fell 30 feet, Patient B suffered a motor vehicle accident, and Patient C had a spinal cord hematoma. None of the patients had a history of bleeding diathesis. All three patients received rFVIIa after failing initial treatment with fresh‐frozen plasma.

RESULTS:  Patient A was treated with 11 doses (initial dose 95 µg/kg; subsequent doses 8‐38 µg/kg) over 10 days; Patient B received 13 doses (45‐60 µg/kg) over 13 days; and Patient C received 5 doses (12‐24 µg/kg) over 4 days. The prothrombin time corrected from 16.2 ± 1.8 (mean ± SD) to 11.2 ± 1.6 seconds after infusion of rFVIIa, but returned to pretreatment level in 14 ± 4 hours. At the cessation of therapy, all patients showed neurologic improvement. No complications related to the infusion of rFVIIa occurred.

CONCLUSION:   The use of rFVIIa may be of value both for its general effect on hemostasis, and specifically in the setting where there is a documented reduction in FVII. Doses lower than those used in patients with FVIII inhibitors appear to be effective in the setting of central nervous sytem hemorrhage.
Skin aging and sex hormones in women – clinical perspectives for intervention by hormone replacement therapy
Authors: Sator Paul‐G. , Schmidt Jolanta B. , Rabe Thomas , Zouboulis Christos C.
Published: October 2004

Abstract:  The skin, the largest organ of the body, is the organ in which changes associated with aging are most visible. The skin is a target organ for various hormones, and sex steroids have a profound influence on the aging process. A decrease in sex steroids thus induces a reduction of those skin functions that are under hormonal control. Keratinocytes, Langerhans' cells, melanocytes, sebaceous glands, collagen content and the synthesis of hyaluronic acid, for example, are under hormonal influence. Topical application of estrogens has a positive effect on skin aging parameters, whilst numerous studies have also shown the positive influence of systemic hormone replacement therapy on skin aging. As an alternative treatment, phytohormones may be administered, with the structural similarity to 17β‐estradiol explaining their estrogen‐like effects. However, isoflavonoids exhibit an inferior biological potency to synthetic estrogens. Although a large number of publications have documented the effects of sex hormones on the aging process, it is obvious that hormone replacement should not be administered as an independent treatment for skin aging.
Genetically Engineered Animals in Drug Discovery and Development: A Maturing Resource for Toxicologic Research
Authors: Bolon Brad
Published: October 2004

Abstract: Genetically engineered mice that either over‐express a foreign gene (transgenic) or in which the activity of a specific gene has been removed (“knock‐out”) or replaced (“knock‐in”) will be used increasingly to investigate molecular mechanisms of disease, to evaluate innovative therapeutic targets, and to screen novel agents for efficacy and/or toxicity. Recent innovations of relevance to toxicologic researchers include the construction of genetically engineered mice with (1) multiple engineered genes, (2) mutations that can be induced at specific sites and times throughout life, and (3) the substitution of human genes for their mouse counterparts (“humanized” mice) to allow in vivo investigation of xenobiotic toxicity. Contemporary applications of genetically engineered mice in toxicology include basic mechanistic research exploiting newly engineered mouse lines as well as applied screening for genotoxicity and carcinogenicity using commercially available animals. Many caveats must be considered when interpreting genetically engineered mice‐derived toxicity data, the chief of which will be the extent to which the model's phenotype has been fully characterized, the type and incidence of background lesions for the given mouse strain and engineered gene, and the possibility of misinterpreting the presence or absence of a phenotype due to compensatory physiologic processes that mask the outcome produced by the engineering event. Toxicity data acquired using genetically engineered mice currently supplements and in time likely will supplant those gathered using the present “gold standard” bioassays, as genetically engineered mice typically develop more lesions after a shorter latency period than do age‐ and strain‐matched, wild‐type mice.
Cholecystokinin‐8‐Induced Hypoplasia of the Rat Pancreas: Influence of Nitric Oxide on Cell Proliferation and Programmed Cell Death
Authors: Trulsson Lena M. , Gasslander Thomas , Svanvik Joar
Published: October 2004

Abstract: The background of cholecystokinin‐8 (CCK‐8)‐induced hypoplasia in the pancreas is not known. In order to increase our understanding we studied the roles of nitric oxide and NF‐κB in rats. CCK‐8 was injected for 4 days, in a mode known to cause hypoplasia, and the nitric oxide formation was either decreased by means of Nω‐nitro‐L‐arginine (L‐NNA) or increased by S‐nitroso‐N‐acetylpencillamine (SNAP). The activation of NF‐κB was quantified by ELISA detection, apoptosis with caspase‐3 and histone‐associated DNA‐fragmentation and mitotic activity in the acinar, centroacinar and ductal cells were visualized by the incorporation of [3H]‐thymidine. Pancreatic histology and weight as well as protein‐ and DNA contents were also studied. Intermittent CCK injections reduced pancreatic weight, protein and DNA contents and increased apoptosis, acinar cell proliferation and nuclear factor κB (NF‐κB) activation. It also caused vacuolisation of acinar cells. The inhibition of endogenous nitric oxide formation by L‐NNA further increased apoptosis and NF‐κB activation but blocked the increased proliferation and vacuolisation of acinar cells. The DNA content was not further reduced. SNAP given together with CCK‐8 increased apoptosis and other pathways of cell death, raised proliferation of acinar cells and strongly reduced the DNA content in the pancreas. Histological examination showed no inflammation in any group. We conclude that during CCK‐8‐induced pancreatic hypoplasia, endogenously formed nitric oxide suppresses apoptosis but increases cell death along non‐apoptotic pathways and stimulates regeneration of acinar cells. Exogenous nitric oxide enhances the acinar cell turnover by increasing both apoptotic and non‐apoptotic cell death and cell renewal. In this situation NF‐κB activation seems not to inhibit apoptosis nor promote cell proliferation.
High triacylglycerol turnover rate in human skeletal muscle
Authors: Sacchetti Massimo , Saltin Bengt , Olsen David B. , Van Hall Gerrit
Published: October 2004

In the present study we investigated the relationship between plasma fatty acids (FA) and intramuscular triacylglycerol (IMTAG) kinetics of healthy volunteers. With this aim [U‐13C]‐palmitate was infused for 10 h and FA kinetics determined across the leg. In addition, the rate of FA incorporation into IMTAG in vastus lateralis muscle was determined during two consecutive 4‐h periods (2–6 h and 6–10 h). Fifty to sixty per cent of the FA taken up from the circulation were esterified into IMTAG, whereas 32 and 42% were oxidized between 2–6 and 6–10 h, respectively. IMTAG fractional synthesis rate was 3.4 ± 0.8% h−1 and did not change between the two 4‐ h periods, despite an increase in arterial FA concentration (34%, P < 0.01). IMTAG concentration was also unchanged, implying that the IMTAG fractional synthesis rate was balanced by an equal rate of breakdown. FA oxidation increased over time, which could be due to the observed decline in plasma insulin concentration (−74%, P < 0.01). In conclusion, a substantial fraction of the fatty acids entering skeletal muscle in post‐absorptive healthy individuals is esterified into IMTAG, due to its high turnover rate (29 h pool−1). An increase in FA level, as a consequence of short‐term fasting, does not seem to increase IMTAG synthesis rate and pool size.
Transmural expression of transient outward potassium current subunits in normal and failing canine and human hearts
Authors: Zicha Stephen , Xiao Ling , Stafford Sara , Cha Tae Joon , Han Wei , Varro Andras , Nattel Stanley
Published: October 2004

The transient outward current (Ito), an important contributor to transmural electrophysiological heterogeneity, is significantly remodelled in congestive heart failure (CHF). The molecular bases of transmural Ito gradients and CHF‐dependent ionic remodelling are incompletely understood. To elucidate these issues, we studied mRNA and protein expression of Kv4.3 and KChIP2, the principal alpha and beta subunits believed to form Ito, in epicardial and endocardial tissues and in isolated cardiomyocytes from control dogs and dogs with CHF induced by 240 beats min−1 ventricular tachypacing. CHF decreased Ito density in both epicardium and endocardium (by 73 and 55% at +60 mV, respectively), without a significant change in relative current density (endocardium/epicardium 0.11 control, 0.17 CHF). There were transmural gradients in mRNA expression of both Kv4.3 (endocardium/epicardium ratio 0.3 under control conditions) and KChIP2 (endocardium/epicardium ratio 0.2 control), which remained in the presence of CHF (Kv4.3 endocardium/epicardium ratio 0.4; KChIP2 0.4). There were qualitatively similar protein expression gradients in human and canine cardiac tissues and isolated canine cardiomyocytes; however, the KChIP2 gradient was only detectable with a highly selective monoclonal antibody and closely approximated the Ito density gradient. Kv4.3 mRNA expression was reduced by CHF, but KChIP2 mRNA was not significantly changed. CHF decreased Kv4.3 protein expression in canine cardiac tissues and cardiomyocytes, as well as in terminally failing human heart tissue samples, but KChIP2 protein was not down‐regulated in any of the corresponding sample sets. We conclude that both Kv4.3 and KChIP2 may contribute to epicardial–endocardial gradients in Ito, and that Ito down‐regulation in human and canine CHF appears due primarily to changes in Kv4.3.
The ‘window’ T‐type calcium current in brain dynamics of different behavioural states
Authors: Crunelli Vincenzo , Tóth Tibor I. , Cope David W. , Blethyn Kate , Hughes Stuart W.
Published: October 2004

All three forms of recombinant low voltage‐activated T‐type Ca2+ channels (Cav3.1, Cav3.2 and Cav3.3) exhibit a small, though clearly evident, window T‐type Ca2+ current (ITwindow) which is also present in native channels from different neuronal types. In thalamocortical (TC) and nucleus reticularis thalami (NRT) neurones, and possibly in neocortical cells, an ITwindow‐mediated bistability is the key cellular mechanism underlying the expression of the slow (< 1 Hz) sleep oscillation, one of the fundamental EEG rhythms of non‐REM sleep. As the ITwindow‐mediated bistability may also represent one of the cellular mechanisms underlying the expression of high frequency burst firing in awake conditions, ITwindow is of critical importance in neuronal population dynamics associated with different behavioural states.
The lipid‐activated two‐pore domain K+ channel TREK‐1 is resistant to hypoxia: implication for ischaemic neuroprotection
Authors: Buckler K. J. , Honoré E.
Published: October 2004

TREK‐1 is a member of the two‐pore domain potassium (K2P) channel family that is mechano‐, heat, pH, voltage and lipid sensitive. It is highly expressed in the central nervous system and probably encodes one of the previously described arachidonic acid‐activated K+ channels. Polyunsaturated fatty acids and lysophospholipids protect the brain against global ischaemia. Since both lipids are openers of TREK‐1, it has been suggested that this K2P channel is directly involved in neuroprotection. Recently, however, this view has been challenged by a report claiming that TREK‐1 and its activation by arachidonic acid is inhibited by hypoxia. In the present study, we demonstrate that the bubbling of saline with gases results in the loss of arachidonic acid from solution. Using experimental conditions which obviate this experimental artefact we demonstrate that TREK‐1 is resistant to hypoxia and is strongly activated by arachidonic acid even at low PO2 (< 4 Torr). Furthermore, hypoxia fails to affect basal as well as 2,4,6‐trinitrophenol‐ and acid‐stimulated TREK‐1 currents. These data are supportive for a possible role of TREK‐1 in ischaemic neuroprotection and in cell signalling via arachidonic acid.
Earth Tides Can Trigger Shallow Thrust Fault Earthquakes
Authors: Cochran Elizabeth S. , Vidale John E. , Tanaka Sachiko
Published: October 2004

We show a correlation between the occurrence of shallow thrust earthquakes and the occurrence of the strongest tides. The rate of earthquakes varies from the background rate by a factor of 3 with the tidal stress. The highest correlation is found when we assume a coefficient of friction of μ = 0.4 for the crust, although we see good correlation for μ between 0.2 and 0.6. Our results quantify the effect of applied stress on earthquake triggering, a key factor in understanding earthquake nucleation and cascades whereby one earthquake triggers others.
Passive Immunization of Neonatal Mice againstPneumocystis cariniif. sp.murisEnhances Control of Infection without Stimulating Inflammation
Authors: Empey Kerry M. , Hollifield Melissa , Schuer Kevin , Gigliotti Francis , Garvy Beth A.
Published: October 2004

Pneumocystis cariniiis an opportunistic fungal pathogen that causes life-threatening pneumonia in immunocompromised individuals. Infants appear to be particularly susceptible to infection withPneumocystis. We have previously shown that there is a significant delay in clearance of the organisms from the lungs of neonatal mice compared to adults. Since alveolar macrophages are the effector cells responsible for killing and clearance ofPneumocystis, we have examined alveolar macrophage activity in neonatal mice. We found that alveolar macrophage activation is delayed about 1 week inPneumocystis-infected neonates compared to adults. Opsonization of the organism byPneumocystis-specific antibody resulted in increased clearance of the organism in neonatal mice; however, there was decreased expression of activation markers on neonatal alveolar macrophages and reduced levels of cytokines associated with macrophage activation. Mice born to immunized dams had significant amounts ofPneumocystis-specific immunoglobulin G in their lungs and serum at day 7 postinfection, whereas mice born to naïve dams had merely detectable levels. This difference correlated with enhancedPneumocystisclearance in mice born to immunized dams. The increase in specific antibody, however, did not result in significant inflammation in the lungs, as no differences in numbers of activated CD4+cells were observed. Furthermore, there was no difference in cytokine or chemokine concentrations in the lungs of pups born to immune compared to naïve dams. These findings indicate that specific antibody plays an important role inPneumocystisclearance from lungs of infected neonates; moreover, this process occurs without inducing inflammation in the lungs.
Expression of Type IV Pili by
Moraxella catarrhalis
Is Essential for Natural Competence and Is Affected by Iron Limitation
Authors: Luke Nicole R. , Howlett Amy J. , Shao Jianqiang , Campagnari Anthony A.
Published: October 2004

Type IV pili, filamentous surface appendages primarily composed of a single protein subunit termed pilin, play a crucial role in the initiation of disease by a wide range of pathogenic bacteria. Although previous electron microscopic studies suggested that pili might be present on the surface of
Moraxella catarrhalis
isolates, detailed molecular and phenotypic analyses of these structures have not been reported to date. We identified and cloned the
M. catarrhalis
genes encoding PilA, the major pilin subunit, PilQ, the outer membrane secretin through which the pilus filament is extruded, and PilT, the NTPase that mediates pilin disassembly and retraction. To initiate investigation of the role of this surface organelle in pathogenesis, isogenic
pilA
,
pilT
, and
pilQ
mutants were constructed in
M. catarrhalis
strain 7169. Comparative analyses of the wild-type 7169 strain and three isogenic
pil
mutants demonstrated that
M. catarrhalis
expresses type IV pili that are essential for natural genetic transformation. Our studies suggest type IV pilus production by
M. catarrhalis
is constitutive and ubiquitous, although pilin expression was demonstrated to be iron responsive and Fur regulated. These data indicate that additional studies aimed at elucidating the prevalence and role of type IV pili in the pathogenesis and host response to
M. catarrhalis
infections are warranted.