bluuebunny/crossref_metadata_2025 huggingface dataset:
Depression associated with dementia with Lewy bodies (DLB) and the effect of somatotherapy
Authors: TAKAHASHI Sho , MIZUKAMI Katsuyoshi , YASUNO Fumihiko , ASADA Takashi
Published: July 2009

Background:  Dementia with Lewy bodies (DLB) is a common type of dementia. It is difficult to make an initial diagnosis of DLB because of a variety of early symptoms, including psychosis‐like and depressive states. In this study, we examined the characteristic depressive symptoms of the prestage of DLB and the efficacy and safety of somatotherapy for depression accompanying DLB.

Methods:  Subjects in the study were 167 consecutive clinical cases aged 50 years or more, hospitalized at Tsukuba University Hospital from December 2002 to September 2007. At the time of admission, patients were diagnosed with certain types of mood disorders according to the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision. For each subject, a series of neuropsychological tests, along with a standard psychiatric and neurological assessment and biological examinations, were conducted. Using the data from these exams, we diagnosed probable and possible DLB according to the criteria for dementia with Lewy bodies established by McKeith et al.

1 We compared patients' depressive symptoms according to the Hamilton Depression Scale, and distinguished between patients with depression associated with DLB and those with other mood disorders.

2 We also examined the efficacy and safety of somatotherapy (electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS)) for patients with drug therapy–resistant depression associated with DLB.

Results: 1 The characteristic symptoms of patients with DLB were classified into two groups: psychotic and non‐psychotic. The former consisted of patients with states such as delusion and agitation, and the latter included patients exhibiting psychomotor retardation, loss of insight and hypochondriasis.

2 Eight DLB patients with therapy‐resistant depression underwent ECT. After ECT, significant improvement was observed, with no remarkable safety hazards. Six patients with drug therapy–resistant DLB underwent TMS. TMS appears to be an effective, safe remedy for this kind of patient.

Conclusions: • A total of 13.8% of patients came to be re‐diagnosed as having DLB as a consequence of a thorough examination after admission.

• Patients with depression associated with DLB were classified into psychotic and non‐psychotic clusters.

• ECT and TMS are effective and safe therapeutic tools for drug therapy–resistant depression observed in DLB patients.
Quantifying tissue level ischemia: Hypoxia response element‐luciferase transfection in a rabbit ear model
Authors: Said Hakim K. , Roy Nakshatra K. , Gurjala Anandev N. , Mustoe Thomas A.
Published: July 2009

Ischemia is a common underlying factor in a number of pathologic conditions ranging from cardiac dysfunction to delayed wound healing. Previous efforts have shown the resulting hypoxia activates the hypoxia inducible factor, a transcription factor with signaling effects through an intranuclear hypoxia response element (HRE). We hypothesized that ischemic conditions should activate these hypoxic signaling pathways in a measurable manner. We tested our hypothesis using variations of an established rabbit ear ischemic wound model and an HRE‐luciferase‐reporter gene construct. This plasmid construct was transfected into the ears of young, female New Zealand White rabbits, harvested at day 7 and processed to yield a reactive solution. Luminometry was used to quantify luciferase expression in each solution as a marker for HRE activation in each wound. Quantitative readings of hypoxic signaling as measured by luminescence yielded profound and statistically significant differences between the various ischemic models. Our results suggest that the biologic systems for hypoxic signaling can be used to detect local ischemia. HRE‐luciferase transfection is an effective tool for quantifying the degree of tissue hypoxia. The caudal ischemic rabbit ear model showed significantly higher levels of hypoxia. Use of a validated model that produces sufficient tissue levels of hypoxia is recommended for meaningful study of ischemic wound healing.
Basic fibroblast growth factor induces down‐regulation of α‐smooth muscle actin and reduction of myofibroblast areas in open skin wounds
Authors: Ishiguro Shigeki , Akasaka Yoshikiyo , Kiguchi Hideko , Suzuki Takeya , Imaizumi Risa , Ishikawa Yukio , Ito Kinji , Ishii Toshiharu
Published: July 2009

To examine the effects of basic fibroblast growth factor (bFGF) on the inhibition of α‐smooth muscle actin (α‐SMA) expression in dermal fibroblasts, we have established two dermal myofibroblastic cell lines positive for α‐SMA (rat myofibroblasts [RMF] and rat myofibroblast‐like [RMFL] cells) and one fibroblastic cell line negative for α‐SMA (rat fibroblasts cells) as a model of fibroblast differentiation. In contrast to the increased expression of α‐SMA in RMF and RMFL cells, irrespective of transforming growth factor‐β1 treatment, bFGF induced a decrease in α‐SMA expression in the myofibroblastic cells and the reduced expression patterns of α‐SMA differed between cells, as demonstrated by Western blot and reverse transcription polymerase chain reaction analyses. Along with the inhibition of α‐SMA expression by bFGF, the RMF and RMFL cells also showed different activated expression of extracellular signal‐regulated kinase 1/2, suggesting the involvement of extracellular signal‐regulated kinase 1/2 activation in the down‐regulation of α‐SMA expression in myofibroblasts. Furthermore, an in vivo study demonstrated that bFGF administration markedly decreases the area that is positive for α‐SMA expression in the treated wounds after day 18. In contrast, bFGF administration significantly increased the number of terminal deoxynucleotidyl transferase (TdT)‐mediated dUTP nick‐end labeling (TUNEL) staining and α‐SMA‐positive cells at days 10 and 14, and reduced the double‐positive cells rapidly after day 18. Collectively, the current investigation identified bFGF as a potent stimulator for the reduction of the myofibroblastic area in vivo, presumably because of its effects on the down‐regulation of α‐SMA expression as well as rapid induction of apoptosis in myofibroblasts.
Assessment of microcirculatory influence on cellular morphology in human burn wound healing using reflectance‐mode‐confocal microscopy
Authors: Altintas Ahmet Ali , Altintas Mehmet Ali , Ipaktchi Kyros , Guggenheim Merlin , Theodorou Pauangiotis , Amini Peymaneh , Spilker Gerald
Published: July 2009

Previous studies have assessed the effects of changes in microcirculation on wound healing; however, the influence of microcirculation on tissue histomorphology remains widely unknown. Reflectance‐mode‐confocal microscopy (RMCM) enables in vivo tissue observation on a cellular level. We present RMCM data evaluating the local microcirculation and assess the influence on histomorphology during burn healing. RMCM was performed in 12 patients (aged; 36.2±14.2 years, maximum‐burn‐extent: 4% total body surface area) at times 12, 36, and 72 hours after a superficial burn. The following parameters were assessed: quantitative blood‐cell‐flow (cbf), epidermal thickness (Emin), basal‐layer thickness (tbl), and granular cell‐size (Agran). Cbf was found to be 54±3.6 cells/minutes (control), increased to 91±3.6 cells/minutes (p<0.05) 12 hours postburn; decreased to 71±6.1 cells/minutes (p<0.05) (36 hours), and to 63±2.3 cells/minutes (p>0.05) 72 hours postburn. Emin was 43.74±3.87 μm (control), increased to 51.67±4.04 μm (p<0.05) 12 hours, decreased to 48.67±3.51 μm (p<0.05) 36 hours, and to 45.33±3.21 μm (p>0.05) at 72 hours postburn. Tbl was 14.17±0.6 μm (control), increased to 16.93±1.15 μm (p<0.05) 12 hours, decreased to 15.93±1.20 μm (p<0.05) 32 hours, and to 15.00±0.85 μm (p>0.05) 72 hours postburn. Agran was 718±56.20 μm2 (control), increased to 901±66.02 μm2 (p<0.05) 12 hours, decreased to 826±56.86 μm2 36 hours, and 766±65.06 μm2 at 72 hours postburn. RMCM enables in vivo observation of wound microcirculation and allows direct assessment of vascular effects on cutaneous histomorphology during the healing course of superficial burns.
Metamorphic P–T conditions and thermal structure of Chinese Continental Scientific Drilling main hole eclogites: Fe–Mg partitioning thermometer vs. Zr‐in‐rutile thermometer
Authors: ZHANG R. Y. , IIZUKA Y. , ERNST W. G. , LIOU J. G. , XU Z.‐Q. , TSUJIMORI T. , LO C.‐H. , JAHN B.‐M.
Published: July 2009

Core rocks recovered from the main hole (5158 m deep) of the Chinese Continental Scientific Drilling (CCSD‐MH) project, southern Sulu UHP terrane, east‐central China, consist of eclogites, various gneisses and minor metaperidotite cumulates; this lithological section underwent subduction‐zone UHP metamorphism. Coesite‐bearing eclogites are mainly present between the depths of 100–2000 m, but below 2000 m, mafic eclogites are rare. Selected elements (Zr, Nb, Cr, Fe, Si, Mg, Al & Ti) in rutile from 39 eclogite cores from 100 to 2774 m, and major elements of minerals from representative eclogites were analysed by electron microprobe. Zirconium and Nb concentrations of rutile cluster ∼100–400 and 200–700 ppm respectively. However, Zr and Nb contents in rutile from strongly retrograded eclogites show larger variations than those of fresh or less retrograded eclogites, implying that somehow fluid infiltration affected rutile chemistry during retrograde metamorphism. Zr contents in rutile inclusions in garnet and omphacite are slightly lower than those of the matrix rutile, suggesting that the rutile inclusions formed before or close to the peak temperature. The P–T conditions of the CCSD‐MH eclogites were estimated by both Fe–Mg exchange and Zr‐in‐rutile thermometers, as well as by the Grt–Cpx–Phn–Ky geothermobarometer. The maximum temperature range of 700–811 °C calculated at 40 kbar using the Zr‐in‐rutile thermometer is comparable with temperature estimates by the Fe–Mg exchange thermometer. The temperature estimates of eclogites in a ∼3000 m thick section define a continuous gradient, and do not show a distinct temperature gap, suggesting that the rocks from 100 to 3000 m depth might belong to a single, large‐scale UHP slab. These data combined with P–T calculations for CCSD‐MH peridotites yield a low geotherm (∼5 °C km−1) for the Triassic subduction zone between the Sino‐Korean and Yangtze cratons; it lies ∼30–35 mW m−2 conductive model geotherm.
From Psychoneurosis to ICHD‐2: An Overview of the State of the Art in Post‐Traumatic Headache
Authors: Gladstone Jonathan
Published: July 2009

Post‐traumatic headache (PTH) is an important public health issue – head injuries are common, headache is the most common sequelae of head injuries, and PTH can be particularly disabling. Fortunately, for most individuals with PTH, the headache gradually dissipates over a period of several days, weeks, or months either spontaneously or aided by non‐pharmacologic and/or pharmacologic management. Regrettably, for a minority of head‐injured individuals, the PTH is intractable and disabling despite aggressive and comprehensive treatment.

Unfortunately, there are many prejudices against individuals with PTH. Frequently, the presence or absence of litigation and/or the mechanism of head injury (sports‐related trauma, slip‐and‐fall injury, motor vehicle accident, or military service‐related injury) biases physicians' views on the legitimacy of the patient's PTH. Accordingly, this review attempts to summarize the state of the art of our understanding of PTH. This clinical review highlights: (a) views on PTH throughout the last few centuries, (b) the ICHD‐2 classification of PTH, (c) the epidemiology of head injuries and PTH, (d) the clinical characteristics of PTH, (e) PTH related postconcussive symptoms, (f) pathophysiology of PTH, (g) evaluation of PTH, and (h) management of PTH.
ABO‐identical versus nonidentical platelet transfusion: a systematic review
Authors: Shehata Nadine , Tinmouth Alan , Naglie Gary , Freedman John , Wilson Kumanan
Published: July 2009

BACKGROUND: The significance of ABO matching for platelet (PLT) transfusion has not been clearly defined. The primary objective of this report is to assess whether ABO‐identical PLT transfusion is associated with improved mortality and/or morbidity for patients with hematologic/oncologic disorders.

STUDY DESIGN AND METHODS: A systematic review to January 2009 was conducted. Data on mortality, morbidity, PLT refractoriness, and PLT increment after transfusion were abstracted.

RESULTS: A total of 100 citations were identified. Nineteen studies were included in the systematic review. A total of 1502 patients from three randomized controlled trials and 16 observational studies were included. Survival, bleeding events, and transfusion reactions were only considered as secondary outcomes in the reports reviewed. The PLT count increment was the primary outcome of several studies and was consistently higher with ABO‐identical PLT transfusion. The largest difference in increment between ABO‐identical and nonidentical PLT transfusion was 4 × 109/L. No consistent benefit in clinical outcomes was noted. Survival was assessed in three reports with conflicting results. Although two studies described bleeding as an outcome, the assessment of hemorrhage was considered inadequate. In six studies, ABO‐nonidentical PLT transfusion was not associated with transfusion reactions, and the results from four studies addressing the impact of ABO‐identical PLT transfusion on PLT and red blood cell utilization were conflicting.

CONCLUSION: ABO‐identical PLT transfusion results in a higher PLT increment. Randomized controlled trials are required to definitely determine the effect of ABO‐identical PLT transfusion on survival, bleeding events, or transfusion reactions.
BLOOD COMPONENTS: Red blood cell hemolysis during blood bank storage: using national quality management data to answer basic scientific questions
Authors: Hess John R. , Sparrow Rosemary L. , Van Der Meer Pieter F. , Acker Jason P. , Cardigan Rebecca A. , Devine Dana V.
Published: July 2009

BACKGROUND: Hemolysis of red blood cells (RBCs) during blood bank storage is the most obvious manifestation of RBC storage system failure. However, its analysis is made difficult because the largest source of interunit difference is donor specific. Availability of data from national blood systems on large numbers of RBC units used for internal quality control (QC) purposes and stored and processed in uniform ways permits statistical analysis.

STUDY DESIGN AND METHODS: Measures of hemolysis during and at the end of storage on randomly selected donor units observed for QC purposes were obtained from four national blood systems. Groups of these measures from units that had undergone similar processing and storage were sorted to create histograms and the histograms were compared statistically.

RESULTS: A total of 14,087 measures were obtained under seven storage conditions, including more than 12,000 measures made in a single country under four closely related conditions. Distributions of percent hemolysis are skewed normal and outliers are random. Additive solutions appear to be equivalent, except that the 42 mmol/L mannitol in AS‐1 reduces hemolysis compared to conventional 30 mmol/L mannitol in saline, adenine, glucose, and mannitol. Increasing storage from 35 to 42 days increased measured hemolysis by 30% and leukoreduction decreased it by 53%.

CONCLUSIONS: Large national data sets provide useful information about the distribution of hemolysis at the end of RBC storage. This information can aid blood storage system development and regulatory science.
Implementing Presidential Policy Agendas Administratively: A View from the Inside
Authors: Barnes A. James
Published: July 2009

Drawing on his experience in a variety of positions over 40 years, the author details a wide range of variables that are involved in implementing presidential policy, including (1) the nature, origin, and validity of the presidential policy agendas and how they are communicated; (2) the background, experience, and relationships of the appointee; (3) the internal agency context; and (4) the larger political and social context. The author concludes that the large number of variables makes it very difficult—if not impossible—to produce a coherent, useful set of guidelines for appointees that will have utility across the board. Rather, implementation often requires individually nuanced responses. At the same time, the author concludes that the documented experiences of appointees in similar circumstances can serve as useful reference points for the future.
Nonprofits as Local Government Service Contractors
Authors: Feiock Richard C. , Jang Hee Soun
Published: July 2009

Despite the growing role that contracts with nonprofits play in local service delivery, only limited attention has been directed to why some cities rely more on nonprofit organizations to produce services or how political institutions influence the role nonprofits play in service delivery. To investigate these issues, the authors present a transaction cost explanation that focuses on how political system characteristics and structures of service markets shape the costs of negotiating, monitoring, and enforcing contracts for local governments. The findings indicate that forms of government, mayoral turnover, racial segregation, and the market of nonprofit producers influence the role of nonprofits in delivering elder services, but decisions to contract exclusively with nonprofits are subject to different influences than decisions to jointly produce service with a nonprofit organization.
Self‐Interest, Ideological/Symbolic Politics, and Citizen Characteristics: A Cross‐National Analysis of Support for Privatization
Authors: Battaglio R. Paul , Legge Jerome S.
Published: July 2009

In this essay, the authors explore attitudes toward government privatization of electric utilities across two sets of nations: developed market economies (DMEs) and transition economies (TEs). They utilize generalized hierarchical linear model to analyze individual attitudes nested within these two groups of polities and discover a wide gap between the DME and TE nations in terms of preferences for privatization, with attitudes in DME nations being far more favorable. Attitudes toward the privatization of electricity are explained by a combination of ideological/symbolic predispositions, self‐interest, and citizen values/characteristics. The most consistent variables in the model are the ideological/symbolic predispositions, while the weakest are citizen characteristics/values. In terms of self‐interest, the analysis indicates that those who work for the public service or a public firm are more likely than others to oppose the privatization of electricity. In contrast to some public administration literature that asserts well‐informed and interested citizens will oppose privatization, the authors find no convincing relationships. Instead, the most educated and politically efficacious citizens, as well as those who have confidence in the way democracy works within their nation, are more prone than others to support privatization of electricity.
The Path Not Taken: Leonard White and the Macrodynamics of Administrative Development
Authors: Roberts Alasdair
Published: July 2009

Leonard White, The Federalists: A Study in Administrative History (New York: Macmillan, 1948).

Leonard White, The Jeffersonians: A Study in Administrative History, 1801–1829 (New York: Macmillan, 1951).

Leonard White, The Jacksonians: A Study in Administrative History, 1829–1861 (New York: Macmillan, 1954).

Leonard White, The Republican Era, 1869–1901: A Study in Administrative History (New York, Macmillan, 1958).

This is a review of four books by Leonard White: The Federalists (1948), The Jeffersonians (1951), The Jacksonians (1954), and The Republican Era (1958). In these books, White develops an approach to the study of administrative development that accounts for a broad range of considerations, including political and economic structure, the organization of the international order, popular culture, the stock of available communication and organizational technologies, and executive talent. White also offers an early argument about the significance of path dependence in institutional evolution. White's approach is largely concerned with the macrodynamics of administrative development. It has been neglected within the field of public administration over the last half century. A literature that builds on White's work would improve the field's ability to explain and anticipate failures in state building and administrative reform.
Higher‐Order Systematic Comoments and Asset Pricing: New Evidence
Authors: Nguyen Duong , Puri Tribhuvan N.
Published: July 2009

We provide evidence supporting Rubinstein's (1973) model that if returns are not normal, measuring risk requires more than just measuring covariance. Higher‐order systematic comoments should be important to risk‐averse investors who are concerned about the extreme outcomes of their investments. Our paper shows that the Fama‐French factors [SMB (return on small stocks less the return on big stocks), HML (return on high book‐to‐market stocks less the return on low book‐to‐market stocks)] as well as the momentum and market liquidity factors can be explained by the higher‐order systematic comoments, and it lends support to the traditional covariance risk‐based theory without having to resort to behavior assumptions.
The Forex Forward Puzzle: The Career Risk Hypothesis
Authors: Liu Fang , Sercu Piet
Published: July 2009

We conjecture that the forward puzzle may reflect career risks. When professional investors observe public danger signals about a currency, they require a premium for holding it. We find evidence of this in Exchange Rate Mechanism rates. As deep discounts do signal danger, we next specify nonlinear variants of the Fama regression to capture this risk. We also decompose the forward premium into a long‐memory trend and short‐term component. We find empirical evidence for a career risk premium; risk is in fact dominant in the trend component while the short‐term component loads more on expectations. All confidence intervals are calculated via Monte Carlo.
Preparticipation Screening and Preparticipation Forms
Authors: CAMPBELL ROBERT M.
Published: July 2009

Published literature supports the fact that many pediatric patients at risk for sudden cardiac death (SCD) will exhibit warning signs and symptoms. The use of comprehensive cardiovascular screening questionnaires and physical examination should help identify these patients at risk. Recognizing that many of the cardiac disorders predisposing to SCD are genetic, the role of careful and extensive family history cannot be overemphasized. While preparticipation screening is primarily directed toward high school and college athletes, the use of cardiovascular screening should also be considered for children of all ages.
Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: HAMILTON ROBERT M.
Published: July 2009

Arrhythmogenic right ventricular cardiomyopathy (ARVC) has evolved from postmortem pathology at to a diagnosable clinical condition, and holds promise for definitive genetic diagnosis. Its prevalence is between 1/1,000 and 1/5,000, with 10% of deaths occurring before age 19 and 50% before age 35. When analyzed against age‐specific norms, the electrocardiography (ECG) and signal‐averaged ECG (SAECG) have moderate sensitivity for ARVC. Endomyocardial biopsy in young individuals with ARVC demonstrates fibrosis more frequently than fatty infiltration, and is convincing for the diagnosis in approximately 1/3 (often in patients who would not otherwise be diagnosed), but has a recognized complication rate of 2%. Newer technologies of magnetic resonance imaging and voltage mapping hold promise but require further assessment in young individuals suspected to have ARVC. Genetic diagnosis of one of several desmosomal mutations is positive in an approximately 50% of suspected patients, and may provide clues to the pathophysiology of the disease. Serial studies of myocardial function, ambulatory electrocardiography, and SAECG parameters may be useful in risk stratification of identified patients, although their applicability to genetically identified asymptomatic individuals has not been studied.
Brugada and Short QT Syndromes
Authors: TRIEDMAN JOHN K.
Published: July 2009

Brugada syndrome and short QT syndrome are among the rarer cardiac channelopathies that may result in sudden cardiac arrest. The genetics and molecular mechanisms of these diseases provide insight into the mechanisms of more common channelopathies, and may dictate special therapeutic approaches with respect to drug therapy and risk stratification.
Implantable Cardioverter Defibrillator Criteria for Primary and Secondary Prevention of Pediatric Sudden Cardiac Death
Authors: BERUL CHARLES I.
Published: July 2009

The implantable cardioverter defibrillator is established as life‐saving in specific adult populations. However, the precise indications and criteria for defibrillator implantation in children are less well defined. This article provides a succinct review of the indications and implantation criteria in pediatric populations at risk for sudden cardiac death, including specific disease substrates such as cardiomyopathies, inherited arrhythmias, and congenital heart disease.
Patient Advocacy: What Is Its Role?
Authors: LARA ALICE ANN , SALBERG LISA
Published: July 2009

While there are significant differences in the delivery of health care throughout the world, there is one constant, the patient. Patients' needs vary greatly on the basis of socioeconomic and geographic issues, expected prognosis, family dynamics, health literacy, and many other factors. In the past 20 years, the role of patient advocacy organizations has added an important new dynamic to patient care. Understanding patient advocacy organizations and how to access their services can be beneficial to clinicians, researchers, and patients. Critical issues are (1) closer collaboration and partnership with physician organizations, like PACES, in order to improve individual patient care and the quality of care that physicians are able to deliver; (b) work with physicians, physician organizations, and advocacy groups to measure the impact of advocacy groups; and (3) increase community‐based participatory research.
Uncontrolled Hemorrhage in Insulin‐dependent Diabetic Rats
Authors: Morley Eric J. , Paladino Lorenzo , Tham Edward , Gantman Miriam , Carrer Alexandra , Yakabov Michael , Kelly Shane , Sinert Richard
Published: July 2009

Objectives: Diabetes mellitus (DM) is a known risk factor for higher morbidity and mortality after trauma. The authors tested the hypothesis that there is a difference in the response to uncontrolled hemorrhage between normal euglycemic rats and insulin‐dependent diabetic rats.

Methods: Thirty‐one adult male Sprague‐Dawley rats were used in this study. Fifteen streptozocin (STZ)‐injected rats became diabetic (DM+) 2 weeks after treatment. Sixteen rats served as nondiabetic controls (DM–). All rats were anesthetized with Althesin and their femoral arteries were catheterized via cutdown, allowing continuous monitoring of vital signs. Sixteen (eight DM–, eight DM+) rats underwent uncontrolled hemorrhage by 75% tail amputation. Fifteen (eight DM–, seven DM+) rats served as nonhemorrhage controls. The mean arterial pressure (MAP), lactate, and cumulative hemorrhage volume per 100 g were measured prehemorrhage and then every 15 minutes posthemorrhage for 2 hours. Data were reported as mean ± standard deviation. Interval data were analyzed by analysis of variance (two tails, α = 0.05).

Results: Prehemorrhage glucose was significantly higher (p < 0.001) in the DM+ (357.9 ± 22.2 mg/dL) versus DM– (125.7 ± 9.7 mg/dL) rats. At baseline, there was no significant difference in weight, MAP, or lactate between DM+ and DM– rats. Body‐weight‐adjusted mean cumulative hemorrhage volume was significantly greater (p < 0.04) in diabetic rats (2.52 ± 0.15 cm3/100 g body weight) than the nondiabetic rats (1.86 ± 0.25 cm3/100 g body weight).

Conclusions: Compared to nondiabetic rats, diabetic rats suffered a greater blood loss after the same uncontrolled vascular injury.
Autophagy inhibition enhances vorinostat‐induced apoptosis via ubiquitinated protein accumulation
Authors: Carew Jennifer S. , Medina Ernest C. , Esquivel II Juan A. , Mahalingam Devalingam , Swords Ronan , Kelly Kevin , Zhang Hui , Huang Peng , Mita Alain C. , Mita Monica M. , Giles Francis J. , Nawrocki Steffan T.
Published: July 2009

Autophagy is an evolutionarily conserved cell survival pathway that enables cells to recoup ATP and other critical biosynthetic molecules during nutrient deprivation or exposure to hypoxia, which are hallmarks of the tumour microenvironment. Autophagy has been implicated as a potential mechanism of resistance to anticancer agents as it can promote cell survival in the face of stress induced by chemotherapeutic agents by breaking down cellular components to generate alternative sources of energy. Disruption of autophagy with chloroquine (CQ) induces the accumulation of ubiquitin‐conjugated proteins in a manner similar to the proteasome inhibitor bortezomib (BZ). However, CQ‐induced protein accumulation occurs at a slower rate and is localized to lysosomes in contrast to BZ, which stimulates rapid buildup of ubiquitinated proteins and aggresome formation in the cytosol. The histone deacetylase (HDAC) inhibitor vorinostat (VOR) blocked BZ‐induced aggresome formation, but promoted CQ‐mediated ubiquitinated protein accumulation. Disruption of autophagy with CQ strongly enhanced VOR‐mediated apoptosis in colon cancer cells. Accordingly, knockdown of the essential autophagy gene Atg7 also sensitized cells to VOR‐induced apoptosis. Knockdown of HDAC6 greatly enhanced BZ‐induced apoptosis, but only marginally sensitized cells to CQ. Subsequent studies determined that the CQ/VOR combination promoted a large increase in superoxide generation that was required for ubiquitinated protein accumulation and cell death. Finally, treatment with the CQ/VOR combination significantly reduced tumour burden and induced apoptosis in a colon cancer xenograft model. Collectively, our results establish that inhibition of autophagy with CQ induces ubiquitinated protein accumulation and VOR potentiates CQ‐mediated aggregate formation, superoxide generation and apoptosis.
Diabetes‐ and angiotensin II‐induced cardiac endoplasmic reticulum stress and cell death: metallothionein protection
Authors: Xu Jiancheng , Wang Guanjun , Wang Yuehui , Liu Qiuju , Xu Wei , Tan Yi , Cai Lu
Published: July 2009

We have shown cardiac protection by metallothionein (MT) in the development of diabetic cardiomyopathy (DCM) via suppression of cardiac cell death in cardiac‐specific MT‐overexpressing transgenic (MT‐TG) mice. The present study was undertaken to define whether diabetes can induce cardiac endoplasmic reticulum (ER) stress and whether MT can prevent cardiac cell death via attenuating ER stress. Diabetes was induced by streptozotocin in both MT‐TG and wild‐type (WT) mice. Two weeks, and 2 and 5 months after diabetes onset, cardiac ER stress was detected by expression of ER chaperones, and apoptosis was detected by CCAAT/enhancer‐binding protein (C/EBP) homologous protein (CHOP) and cleaved caspase‐3 and caspase‐12. Cardiac apoptosis in the WT diabetic mice, but not in MT‐TG diabetic mice, was significantly increased 2 weeks after diabetes onset. In parallel with apoptotic effect, significant up‐regulation of the ER chaperones, including glucose‐regulated protein (GRP)78 and GRP94, cleaved ATF6 and phosporylated eIF2α, in the hearts of WT, but not MT‐TG diabetic mice. Infusion of angiotensin II (Ang II) also significantly induced ER stress and apoptosis in the hearts of WT, but not in MT‐TG mice. Direct administration of chemical ER stress activator tunicamycin significantly increased cardiac cell death only in WT mice. Pre‐treatment with antioxidants completely prevented Ang II‐induced ER stress and apoptosis in the cultured cardiac cells. These results suggest that ER stress exists in the diabetic heart, which may cause the cardiac cell death. MT prevents both diabetes‐ and Ang II‐induced cardiac ER stress and associated cell death most likely via its antioxidant action, which may be responsible for MT's prevention of DCM.
Image‐guided tissue engineering
Authors: Ballyns Jeffrey J. , Bonassar Lawrence J.
Published: July 2009

Introduction

Imaging techniques

Fabrication techniques

Conclusions

Replication of anatomic shape is a significant challenge in developing implants for regenerative medicine. This has lead to significant interest in using medical imaging techniques such as magnetic resonance imaging and computed tomography to design tissue engineered constructs. Implementation of medical imaging and computer aided design in combination with technologies for rapid prototyping of living implants enables the generation of highly reproducible constructs with spatial resolution up to 25 μm. In this paper, we review the medical imaging modalities available and a paradigm for choosing a particular imaging technique. We also present fabrication techniques and methodologies for producing cellular engineered constructs. Finally, we comment on future challenges involved with image guided tissue engineering and efforts to generate engineered constructs ready for implantation.
Cyclin A2 confers cisplatin resistance to endometrial carcinoma cells via up‐regulation of an Akt‐binding protein, periplakin
Authors: Suzuki Akihisa , Horiuchi Akiko , Ashida Takashi , Miyamoto Tsutomu , Kashima Hiroyasu , Nikaido Toshio , Konishi Ikuo , Shiozawa Tanri
Published: July 2009

Although overexpression of cyclin A2 is reportedly an indicator of a poor prognosis of various malignancies including endometrial carcinoma, its molecular mechanism remains undetermined. To address this issue, we examined the effect of cyclin A2 on the development of resistance to chemotherapeutic drugs. The expression of cyclin A2 protein was increased in advanced‐stage and chemotherapy‐refractory stage endometrial carcinomas compared with that in early‐stage tumours. The expression levels of cyclin A2 in endometrial carcinoma cell lines correlated positively with the IC50 for cisplatin. Endometrial carcinoma HHUA cells that overexpressed cyclin A2 showed increased resistance to cisplatin in vitro and in vivo, via the activation of a survival pathway, the inositol‐3 phosphate kinase (PI3K) cascade. The use of a cDNA microarray identified an Akt‐binding protein, periplakin, as a novel target of cyclin A2. The cyclin A2‐induced up‐regulation of periplakin was mediated via direct binding of Sp1 to the promoter that was activated by cyclin A2 along with chromatin remodelling involving CBP/p300, and the siRNA‐mediated silencing of periplakin suppressed the PI3K pathway. These results indicate cyclin A2 to be involved in the acquisition of aggressive behaviour of tumour cells through the activation of PI3K by cyclin A2‐induced periplakin, and to be a promising therapeutic target.
A novel recombinant immunotoxin with the smallest ribosome‐inactivating protein Luffin P1: T‐cell cytotoxicity and prolongation of allograft survival
Authors: Wang Rupeng , Gan Chenjun , Gao Wenda , He Weifeng , Wang Xiaojuan , Peng Yanmeng , Zhuo Junyi , Tan Jianglin , Peng Xu , Wu Jun , Luo Gaoxing
Published: July 2009

In the creation of stable tolerance to MHC‐incompatible allografts, reducing the large mass of donor‐reactive cells via apoptosis is often required. Apoptosis induction by immunotoxins targeting surface molecules specifically presented on donor‐reactive cytopathic T effector (Teff) cells is a promising strategy. Traditionally, the toxin moieties are bacterial exotoxins or plant‐derived ribosome‐inactivating proteins (RIPs) with large molecular size and strong immunogenicity, hence causing the problems of tissue penetration, host immune reaction and quick clearance. We have identified a novel class of small molecule RIPs (<10 kD) from the seeds of the plant Luffa cylindrica. The smallest member of this family, Luffin P1, has a molecular weight of 5226.8 Da, yet possessing a highly potent inhibitory activity on cell‐free protein synthesis with IC50 of 0.88 nM. We now report a recombinant hIL‐2‐Luffin P1 immunotoxin, which strongly inhibited T‐cell proliferation in mixed lymphocyte reaction and ConA response with IC50 of 1.8–10 nM. In vivo, hIL‐2‐Luffin P1 significantly prolonged the survival of major MHC‐mismatched skin and kidney allografts in animal models. Thus, we demonstrate for the first time the efficacy of the smallest immunotoxin that could be further combined with other pharmacological and immunological reagents for synergistic control of pathogenic lymphocytes in immune‐mediated diseases.
Lysyl oxidase interacts with AGE signalling to modulate collagen synthesis in polycystic ovarian tissue
Authors: Papachroni Katerina K. , Piperi Christina , Levidou Georgia , Korkolopoulou Penelope , Pawelczyk Leszek , Diamanti‐Kandarakis Evanthia , Papavassiliou Athanasios G.
Published: July 2009

Connective tissue components – collagen types I, III and IV – surrounding the ovarian follicles undergo drastic changes during ovulation. Abnormal collagen synthesis and increased volume and density of ovarian stroma characterize the polycystic ovary syndrome (PCOS). During the ovulatory process, collagen synthesis is regulated by prolyl hydroxylase and lysyl oxidase (LOX) activity in ovarian follicles. LOX catalyzes collagen and elastin cross‐linking and plays essential role in coordinating the control of ovarian extracellular matrix (ECM) during follicular development. We have recently shown accumulation of advanced glycation end products (AGEs), molecules that stimulate ECM production and abnormal collagen cross‐linking, in ovarian tissue. However, the possible link between LOX and AGEs‐induced signalling in collagen production and stroma formation in ovarian tissue from PCOS remains elusive. The present study investigates the hypothesis of AGE signalling pathway interaction with LOX gene activity in polycystic ovarian (PCO) tissue. We show an increased distribution and co‐localization of LOX, collagen type IV and AGE molecules in the PCO tissue compared to control, as well as augmented expression of AGE signalling mediators/effectors, phospho(p)‐ERK, phospho(p)‐c‐Jun and nuclear factor κB (NF‐κB) in pathological tissue. Moreover, we demonstrate binding of AGE‐induced transcription factors, NF‐κB and activator protein‐1 (AP‐1) on LOX promoter, indicating a possible involvement of AGEs in LOX gene regulation, which may account for the documented increase in LOX mRNA and protein levels compared to control. These findings suggest that deposition of excess collagen in PCO tissue that induces cystogenesis may, in part, be due to AGE‐mediated stimulation of LOX activity.
RNA‐binding proteins implicated in the hypoxic response
Authors: Masuda Kiyoshi , Abdelmohsen Kotb , Gorospe Myriam
Published: July 2009

Introduction

Post‐transcriptional gene regulation by hypoxia

HuR

PTB

Other RBPs implicated in the response to hypoxia

Perspective

In cells responding to low oxygen levels, gene expression patterns are strongly influenced by post‐transcriptional processes. RNA‐binding proteins (RBPs) are pivotal regulators of gene expression in response to numerous stresses, including hypoxia. Here, we review the RBPs that modulate mRNA turnover and translation in response to hypoxic challenge. The RBPs HuR (human antigen R) and PTB (polypyrimidine tract‐binding protein) associate with mRNAs encoding hypoxia‐response proteins such as HIF‐1α and VEGF mRNAs, enhance their expression after hypoxia and play a major role in establishing hypoxic gene expression patterns. Additional RBPs such as iron‐response element‐binding proteins (IRPs), cytoplasmic polyadenylation‐element‐binding proteins (CPEBs) and several heterogeneous nuclear ribonucleoproteins (hnRNPs) also bind to hypoxia‐regulated transcripts and modulate the levels of the encoded proteins. We discuss the efficient regulation of hypoxic gene expression by RBPs and the mounting interest in targeting hypoxia‐regulatory RBPs in diseases with aberrant hypoxic responses.
Influence of heat stress to matrix on bone formation
Authors: Yoshida Keiko , Uoshima Katsumi , Oda Kimimitsu , Maeda Takeyasu
Published: July 2009

Objectives: It is important to know the etiology of implant failure. It has been reported that heat stress during drilling was one of the causes for failure and the threshold was 47°C. However, clinically, we encounter cases in which overheating does not seem to affect osseointegration eventually. The purpose of this study was to assess histologically the spatio‐temporal effect of heat stress on bone formation after overheating the bone matrix.

Material and methods: Rat calvarial bone was heated to 37°C, 43°C, 45°C and 48°C for 15 min by a temperature stimulator. Paraffin sections were prepared 1, 3 and 5 weeks after heating and investigated histologically under light microscopy. Hematoxylin and eosin staining, alkaline phosphatase (ALP), osteopontin (OPN), heat shock protein 27 (Hsp27) and heat shock protein 70 (Hsp70) immunohistochemistry and tartrate‐resistant acid phosphatase (TRAP) enzyme histochemistry were carried out. The area of dead osteocytes was calculated and statistically analyzed. Apoptotic osteocytes were detected by the terminal deoxynucleotidyltransferase‐mediated dUTP nick end‐labeling (TUNEL) method.

Results: Along with the temperature increase, the area of dead osteocytes increased and regeneration of the periosteal membrane was delayed. Hsps‐ and TUNEL‐positive cells were only seen in the 48°C group. Spatio‐temporal changes of TRAP‐ and ALP‐positive cell numbers were observed, while OPN expression was mostly absent. Even after 48°C stimulation, bone formation on the calvarial surface was observed after 5 weeks.

Conclusions: Although there was a temperature‐dependent delay in bone formation after heat stress, the 48°C heat stress did not obstruct bone formation eventually. This delay was probably caused by slow periosteal membrane regeneration.
Surface‐modified zirconia implants: tissue response in rabbits
Authors: Rocchietta Isabella , Fontana Filippo , Addis Alessandro , Schupbach Peter , Simion Massimo
Published: July 2009

Aim: To evaluate the bone tissue response to zirconia implants with three different surface modifications in comparison with the oxidized titanium surface with the goal to optimize osseointegration in terms of strength and speed.

Materials and methods: A total of 18 rabbits with 143 implants were used. One hundred and twenty‐three were threaded zirconia ceramic implants with three different surface topographies and 20 modified titanium oxide implants were controls. Each rabbit received eight implants and sacrificed after 3 weeks. The removal torque test (RTQ) and histology were performed.

Results: Sixteen out of 18 rabbits completed the study with a total of 110 implants. No statistical significance was observed between the chemical modification implants compared with the topographically modified zirconia implant in terms of interfacial shear strength proven by the RTQ applied. No statistical significance was also observed in the bone‐to‐implant contact between the zirconia implants and the control oxidized implants.

Conclusions: The findings suggest that additional specific chemical modifications of the topographically modified zirconia implants do not seem to enhance the bone‐to‐implant contact and appear not to increase the interfacial shear strength.
Cyclosporine A enhances apoptosis in gingival keratinocytes of rats and in OECM1 cells via the mitochondrial pathway
Authors: Tu H.‐P. , Chen Y.‐T. , Chiu H.‐C. , Chin Y.‐T. , Huang S.‐M. , Cheng L.‐C. , Fu E. , Chiang C.‐Y.
Published: July 2009

Background and Objective:  We reported previously that cyclosporine A induces a high level of expression of p21 in rat gingival keratinocytes and in OECM1 cells. In this study, the apoptosis of gingival keratinocytes after treatment with cyclosporine A was evaluated using the same models.

Material and Methods:  Forty Sprague–Dawley rats with right edentulous ridges were assigned into cyclosporine A (30 mg/kg) and control groups. Four weeks later, gingivae were screened for expression of apoptotic genes using microarray analyses and DNA fragmentation. The expression of bcl2‐associated X protein (Bax), apoptosis‐inducing factor (AIF) and Caspase 3 mRNAs, and the expression of Bax, AIF, Caspase 9 and Fas proteins, were analyzed using the reverse transcription–polymerase chain reaction and immunohistochemistry, respectively. Apoptosis in OECM1 cells (keratinocytes of a gingival carcinoma cell line), after treatment with cyclosporine A, was evaluated by 4′,6‐diamidino‐2‐phenylindole (DAPI) staining and flow cytometry, whereas the expression of Bax, AIF, Caspase 3 and 8, Bcl‐2 and Fas proteins were examined using western blotting.

Results:  According to microarray analyses, the expression of certain apoptotic genes was altered in the gingiva of rats who received cyclosporine A, and increased number of DNA fragments were detected. Expression of mRNA or protein for Bax, AIF and Caspase 3 and 9 in the gingivae of rats increased after treatment with cyclosporine A. An increased number of apoptotic bodies and of OECM1 cells in the sub‐G1 phase was observed after treatment with cyclosporine A. Increased expression of AIF, Bax and Caspase 3 protein, but not of bcl‐2, Caspase 8 or Fas protein, was observed in cells after treatment with cyclosporine A.

Conclusion:  Based on the above findings, we suggest that cyclosporine A might enhance the apoptosis of gingival keratinocytes, mainly via the mitochondrial pathway.
Thiopental pharmacokinetics in newborn infants: a case report of overdose
Authors: Norman Elisabeth , Malmqvist Ulf , Westrin Per , Fellman Vineta
Published: July 2009

Thiopental may be used for sedation before intubation in newborn infants. A boy, born at 33 weeks of gestation (gw); birth weight 2435 g, was prescribed thiopental 3 mg/kg before intubation. He developed temporary hypotension and oxygen desaturation, and remained unconscious for longer than expected with a suppressed electroencephalography for 48 h. Serum thiopental concentration was 82, 59, 42 and 32 μmol/L after 20 min and 6, 24 and 68 h respectively. Serum concentrations from five newborn infants at the same time points after intubation with the same thiopental dose were used as reference values, and indicated a 10‐fold overdose in the index case. The cause of the overdose could not be identified. The infant recovered; cerebral magnetic resonance imaging at the age of 42 gw and psychomotor development at 2 years were normal. These results show that thiopental concentrations are variable in neonates and there is a high risk of dosage error as no specific paediatric formulation is available.

Conclusion:  Well‐designed procedures and continuous education are required to prevent errors and adverse events during drug delivery to newborn infants. To develop a safe method of administration for thiopental, an extended pharmacokinetic and pharmacodynamic study in neonates is warranted.