bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence Against a Perihemorrhagic Penumbra Provided by Perfusion Computed Tomography
Authors: Herweh Christian , Jüttler Eric , Schellinger Peter D. , Klotz Ernst , Jenetzky Ekkehart , Orakcioglu Berk , Sartor Klaus , Schramm Peter
Published: September 2007

Background and Purpose—

Several recent studies analyzing perfusion changes in acute intracerebral hemorrhage fed the debate whether there is secondary ischemic tissue damage in the vicinity of intracerebral hemorrhage. We used perfusion CT to address this question.

Methods—

We examined 36 patients between 2001 and 2002 with acute intracerebral hemorrhage (within 24 hours after symptom onset). A subgroup of 8 patients was examined serially on day 1, between days 2 and 4, and after day 5. Nonenhanced CT images and maps of cerebral blood flow, cerebral blood volume, and time to peak were evaluated by region of interest analysis.

Results—

In comparison to the contralateral hemisphere, perfusion values were clearly reduced around the hematoma (relative values: cerebral blood flow 0.51, cerebral blood volume 0.62, time to peak 1.7 seconds). There was no difference in size between the area of reduced perfusion and the area of edema (5.17 versus 5.75 cm
2
, respectively) surrounding the hematoma. At time point 2, the edema grew significantly.

Conclusions—

In accordance with previous studies, we found reduced perfusion as well as edema surrounding acute intracerebral hemorrhage. Regarding ischemic tissue damage, we did not detect an initial mismatch between the perfusion deficit and the edema and therefore could not identify any tissue at risk of ischemia. We therefore interpret the reduced perfusion as a secondary phenomenon, ie, reduced oxygen demand of tissue damaged by pressure and clot components, not as the cause of any tissue damage associated with acute intracerebral hemorrhage.
Antiedema Therapy in Ischemic Stroke
Authors: Bardutzky Juergen , Schwab Stefan
Published: September 2007

Life-threatening, space-occupying brain edema occurs in up to 10% of patients with supratentorial infarcts and is traditionally associated with a high mortality rate of up to 80%. Management of these patients is currently being changed to an earlier and more aggressive treatment regimen. Early surgical decompression has recently been proven effective to reduce mortality and increase the number of patients with a favorable outcome in randomized controlled trials and is now the “antiedema” therapy of first choice for patients with large middle cerebral artery infarction aged 60 years or younger. Several medical treatment strategies have been proposed to control brain edema and reduce intracranial pressure, including different osmotherapeutics, hyperventilation, tromethamine, hypothermia, and barbiturate coma. None of these treatments is supported by level 1 evidence of efficacy in clinical trials, and some of them may even be detrimental. Preliminary results on hypothermia for space-occupying hemispheric infarction are encouraging, but far from definitive.
Transcutaneous Electrical Nerve Stimulation Combined With Task-Related Training Improves Lower Limb Functions in Subjects With Chronic Stroke
Authors: Ng Shamay S.M. , Hui-Chan Christina W.Y.
Published: September 2007

Background and Purpose—Previous studies have shown that repeated sensory inputs could enhance brain plasticity and cortical motor output. The purpose of this study was to investigate whether combining electrically induced sensory inputs through transcutaneous electrical nerve stimulation (TENS) with task-related training (TRT) in a home-based program would augment voluntary motor output in chronic stroke survivors better than either treatment alone or no treatment.

Methods—Eighty-eight patients with stroke were assigned randomly to receive a home-based program of (1) TENS, (2) TENS+TRT, (3) placebo TENS+TRT, or (4) no treatment (control) 5 days a week for 4 weeks. Outcome measurements included Composite Spasticity Scale, peak torques generated during maximum isometric voluntary contraction of ankle dorsiflexors and plantarflexors, and gait velocity recorded at baseline, after 2 and 4 weeks of treatment, and 4 weeks after treatment ended.

Results—When compared with TENS, the combined TENS+TRT group showed significantly greater improvement in ankle dorsiflexion torque at follow-up and in ankle plantarflexion torque at week 2 and follow-up (P<0.01). When compared with placebo+TRT, the TENS+TRT group produced earlier and greater reduction of plantarflexor spasticity and improvement in ankle dorsiflexion torque at week 2 (P<0.01). When compared with all 3 groups, the TENS+TRT group showed significantly greater improvement in gait velocity (P<0.01).

Conclusions—In patients with chronic stroke, 20 sessions of a combined TENS+TRT home-based program decreased plantarflexor spasticity, improved dorsiflexor and plantarflexor strength, and increased gait velocity significantly more than TENS alone, placebo+TRT, or no treatment. Such improvements can even be maintained 4 weeks after treatment ended.
Selective Serotonin Reuptake Inhibitors and Risk of Hemorrhagic Stroke
Authors: Kharofa Jordan , Sekar Padmini , Haverbusch Mary , Moomaw Charles , Flaherty Matthew , Kissela Brett , Broderick Joseph , Woo Daniel
Published: September 2007

Background and Purpose—

Selective serotonin reuptake inhibitors (SSRI) are widely prescribed. Several reports have observed an increased bleeding risk associated with SSRI use, which is hypothesized to be secondary to their antiplatelet effect.

Methods—

We tested the hypothesis that SSRIs increase the risk for or potentiate the risk of hemorrhagic stroke associated with antiplatelets and anticoagulants.

Results—

In multivariate analysis, we found no increased risk associated with SSRI use for intracerebral hemorrhage (odds ratio=1.1, 95% CI: 0.7 to 1.8;
P
=0.63) or subarachnoid hemorrhage (odds ratio=0.6, 95% CI: 0.4 to 1.0;
P
=0.054). In addition, potentiation of risk with warfarin or antiplatelets was not observed.

Conclusions—

Further studies with larger populations would be needed to exclude a small increase in intracranial hemorrhage risk with SSRI use.
The New History of World War I and What It Means for International Relations Theory
Authors: Lieber Keir A.
Published: September 2007

World War I looms large in international relations theory. The core concepts of defensive realism—the security dilemma, spiral model, and offense-defense balance—were largely inspired by this single historical case, and evidence from the war is frequently used to test explanations built on those concepts. The new historiography of World War I, however, challenges many of the long-held assumptions about the origins of the conflict. Newly available evidence strongly suggests that German leaders went to war in 1914 with eyes wide open. They provoked a war to achieve their goal of dominating the European continent, and did so aware that the coming conflict would almost certainly be long and bloody. Germany's leaders did not go to war with a bold operational blueprint for quick victory embodied in the Schlieffen Plan; they did not misjudge the nature of modern war; and they did not lose control of events on the eve of the conflict and attack out of fear that Germany's enemies would move first. In light of the new history, international relations scholars should reexamine their empirical understandings of this conflict, as well as their theoretical presuppositions about the causes of war.
Dead Center: The Demise of Liberal Internationalism in the United States
Authors: Kupchan Charles A. , Trubowitz Peter L.
Published: September 2007

According to mainstream opinion, the George W. Bush administration's assertive unilateralism represents a temporary departure from the traditional foreign policy of the United States, one that will be rectified by a change of personnel in the White House in 2009. This interpretation of recent trends in U.S. policy is illusory. The Bush administration's foreign policy, far from representing an aberration, marks the end of an era; it is a symptom, as much as a cause, of the unraveling of the liberal internationalist compact that guided the United States for more than half a century. The geopolitical and domestic conditions that gave rise to liberal internationalism have disappeared, eroding its bipartisan political foundations. In today's partisan landscape, the challenge is devising a grand strategy that not only meets the country's geopolitical needs but also is politically sustainable. A strategy that is as judicious and selective as it is purposeful offers the best hope for moving the United States toward a more stable and solvent political equilibrium.
The Variational Assimilation Method for the Retrieval of Humidity Profiles with the Wind-Profiling Radar
Authors: Furumoto Jun-ichi , Imura Shingo , Tsuda Toshitaka , Seko Hiromu , Tsuyuki Tadashi , Saito Kazuo
Published: September 2007

Recently, a humidity estimation technique was developed by using the turbulence echo characteristics detected with a wind-profiling radar. This study is concerned with improvement of the retrieval algorithm for delineating a humidity profile from the refractive index gradient (M) inferred from the echo power. To achieve a more precise estimate of humidity, a one-dimensional variational method is adopted. Because the radar data provide only the absolute value of M, its sign must be determined in the retrieval. A statistical probability for the sign of M [Pr(z)] is introduced to the cost function of the variational method to determine the optimum result with reduced calculation cost. GPS-derived integrated water vapor (IWV) was assimilated together with the radar-derived |M| for constraining the signs of |M| to agree with the radar-derived IWV and the GPS-derived IWV. Humidity profiles were retrieved from the Middle and Upper Atmosphere (MU) radar–Radio Acoustic Sounding System (RASS) data for July–August 1999 using the first guess calculated from the time interpolation of radiosonde results. The |M| profiles from the MU radar–RASS were assimilated at 21 height layers between 1.5 and 7.5 km. A genetic algorithm is employed to find the global optimum. The humidity profiles are retrieved with the same vertical resolution as that of the observation values. The precision of the retrieval result using the new method is superior to that of the conventional method. The difference between the analysis and simultaneous radiosonde results was related to a large error in the first guess. The sensitivity of the analysis result to the shape of the Pr(z) profile was investigated, and the result appears to be insensitive to the profile of Pr(z). The improvement over the conventional method is especially evident for the case of a large error in the first guess.
General Matrix Inversion Technique for the Calibration of Electric Field Sensor Arrays on Aircraft Platforms
Authors: Mach D. M. , Koshak W. J.
Published: September 2007

A matrix calibration procedure has been developed that uniquely relates the electric fields measured at the aircraft with the external vector electric field and net aircraft charge. The calibration method can be generalized to any reasonable combination of electric field measurements and aircraft. A calibration matrix is determined for each aircraft that represents the individual instrument responses to the external electric field. The aircraft geometry and configuration of field mills (FMs) uniquely define the matrix. The matrix can then be inverted to determine the external electric field and net aircraft charge from the FM outputs. A distinct advantage of the method is that if one or more FMs need to be eliminated or deemphasized (e.g., due to a malfunction), it is a simple matter to reinvert the matrix without the malfunctioning FMs. To demonstrate the calibration technique, data are presented from several aircraft programs (ER-2, DC-8, Altus, and Citation).
Pediatric Hospitalist Comanagement of Surgical Patients: Challenges and Opportunities
Authors: Rappaport David I. , Pressel David M.
Published: September 2007

Hospitalists are increasingly providing comanagement of surgical patients. Limited data published regarding hospitalist comanagement of adult surgical patients have suggested that these partnerships may help improve outcomes and limit resource usage. Pediatric surgical comanagement programs at community hospitals will face different clinical challenges than those at tertiary referral pediatric centers. Pediatric hospitalists providing surgical comanagement must also address specific administrative issues including program structure, communication, staffing, and finances.
The Cost and Safety of Multidose Use of Palivizumab Vials
Authors: Gooding Julie , Millage Aaron , Rye Anna-Kathryn , Lacroix Robin
Published: September 2007

Palivizumab is an antirespiratory syncytial virus humanized murine monoclonal antibody that has been shown to reduce the frequency of hospitalization rates of preterm infants infected with respiratory syncytial virus. The United States Food and Drug Administration has approved palivizumab for single-vial dosage; however, if multidose use of single-use vials is proven safe, significant cost savings for respiratory syncytial virus prophylaxis would result. A total of 446 palivizumab vials administered to patients during the respiratory syncytial virus seasons of 2004-2006 were examined for bacterial contamination. One single-use vial showed growth of multiple organisms, and all multidose-use vials were culture negative. The cost benefits of multidose palivizumab vials netted a potential average savings of $37 410 per year in this institution. This study suggests that multidose distribution is a possible solution for cost savings with no increased risk to patients. Secondary to the low incidence of complications, the safety of this practice will require a larger study.
Hemodynamic Interaction Between a Daily Dosed Phosphodiesterase 5 Inhibitor, Tadalafil, and the α‐Adrenergic Blockers, Doxazosin and Tamsulosin, in Middle‐Aged Healthy Male Subjects
Authors: Guillaume Michel , Lonsdale Finnuala , Darstein Christelle , Jimenez Maria C. , Mitchell Malcolm I.
Published: September 2007

The hemodynamic interaction between tadalafil (5 mg/d) and doxazosin or tamsulosin was investigated in 2 randomized, double‐blind, crossover phase 1 studies. Healthy men (n = 45) received tadalafil or placebo for 28 days and increasing doses of doxazosin (1, 2, and 4 mg/d) for the last 21 days of treatment. In the second study, participants (n = 39) received tadalafil or placebo for 14 days and tamsulosin (0.4 mg/d) for the last 7 days of treatment. Similar mean maximum postbaseline changes in standing systolic blood pressure were observed in subjects given tadalafil or placebo with 4 mg of doxazosin (−0.5 mm Hg; 95% confidence interval, −4 to 3.1 mm Hg) or with tamsulosin (0.9 mm Hg; 95% confidence interval, −1.4 to 3.2 mm Hg). Standing systolic blood pressure less than 85 mm Hg (blood pressure outlier) occurred in 1 subject treated with 4 mg of doxazosin plus tadalafil but was not reported in subjects treated with tamsulosin and tadalafil. Three subjects experienced moderate hypotensive events lasting less than 2 hours, 2 with syncope (after tadalafil alone or with 4 mg of doxazosin) and 1 without (after 4 mg of doxazosin with placebo). The incidence of hypotension was low in healthy men given increasing doses of doxazosin with chronically dosed tadalafil or placebo. Administration of tadalafil with tamsulosin was well tolerated in healthy men.
Socioeconomic Disparities in Voluntary Organization Involvement Among Older Adults
Authors: Fengyan Tang
Published: September 2007

This study examines the relationship between volunteer socioeconomic status (SES) and voluntary organization involvement among older adults. Using longitudinal data from the Americans' Changing Lives surveys, this study assesses the effects of education and income on the type and scope of voluntary organization involvement. Multiple imputation and generalized estimating equations methods are used in the data analysis. The results indicate that more highly educated, older adults are more likely than their less-educated counterparts to volunteer in all five types of organizations (i.e., religious, educational, political, senior citizen, and others), volunteer in a wider range of organizations, and devote more hours. However, income makes little significant difference in organizational volunteering. Voluntary organizations are advised to facilitate older adults from diverse socioeconomic backgrounds in taking volunteer roles. Innovative recruitment programs are needed to tap the resource for volunteering that elders from all SES groups represent.
Fluorapatite-monazite relationships in granulite-facies metapelites, Schwarzwald, southwest Germany
Authors: Harlov D. E. , Marschall H. R. , Hanel M.
Published: September 2007

Fluorapatite grains with monazite inclusions and/or rim grains are described in two of four samples from a set of granulite-facies metapelites collected from the Variscan Schwarzwald, southern Germany. Fluorapatite in all four samples appears to have experienced some dissolution in the partial granitic melt formed during granulite-facies metamorphism. Monazite inclusions and rim grains are highly deficient in Th and are presumed to have formed from fluorapatite in association with partial melting during granulite-facies metamorphism. Monazite inclusions range from very small (<1 μm) and very numerous to small (1–2 μm), sometimes elongated, and less numerous; both types are evenly distributed throughout the fluorapatite grain interior. Monazite rim grains tend to be 1–10 μm. The formation of monazite inclusions is proposed to be due to dissolution-reprecipitation of the fluorapatite by the aqueous fluids inherent in the granitic melt. We propose that an increase in inclusion size coupled with a decrease in inclusion number is due to Ostwald ripening (interfacial energy reduction), which is greatly facilitated by the presence of an interconnected, fluid-filled porosity in the metasomatized fluorapatite. We further propose that monazite rim grains formed principally during partial dissolution of the fluorapatite in the granitic melt and to a lesser extent by partial dissolutionreprecipitation of the fluorapatite grain rim area allowing for the partial removal of (Y+REE). We conclude that fluorapatite, with monazite inclusions and rim grains, experienced partial dissolution in a H2O-rich peraluminous granitic melt compared to fluorapatite with monazite rim grains and no inclusions which reacted with a similar, relatively less H2O-rich melt. In contrast, monazite-free fluorapatite experienced partial dissolution in a comparatively H2O-poor, subaluminous, possibly peralkaline melt.
Long-term outcome following hematopoietic stem-cell transplantation in Wiskott-Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Group for Blood and Marrow Transplantation
Authors: Ozsahin Hulya , Cavazzana-Calvo Marina , Notarangelo Luigi D. , Schulz Ansgar , Thrasher Adrian J. , Mazzolari Evelina , Slatter Mary A. , Le Deist Francoise , Blanche Stephane , Veys Paul , Fasth Anders , Bredius Robbert , Sedlacek Petr , Wulffraat Nico , Ortega Juan , Heilmann Carsten , O'Meara Anne , Wachowiak Jacek , Kalwak Krzysztof , Matthes-Martin Susanne , Gungor Tayfun , Ikinciogullari Aydan , Landais Paul , Cant Andrew J. , Friedrich Wilhelm , Fischer Alain
Published: September 2007

Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency with microthrombocytopenia, eczema, recurrent infections, autoimmune disorders, and malignancies that are life-threatening in the majority of patients. In this long-term, retrospective, multicenter study, we analyzed events that occurred in 96 WAS patients who received transplants between 1979 and 2001 who survived at least 2 years following hematopoietic stem-cell transplantation (HSCT). Events included chronic graft-versus-host disease (cGVHD), autoimmunity, infections, and sequelae of before or after HSCT complications. Three patients (3%) died 2.1 to 21 years following HSCT. Overall 7-year event-free survival rate was 75%. It was lower in recipients of mismatched related donors, also in relation with an older age at HSCT and disease severity. The most striking finding was the observation of cGVHD-independent autoimmunity in 20% of patients strongly associated with a mixed/split chimerism status (P < .001), suggesting that residual-host lymphocytes can mediate autoimmune disease despite the coexistence of donor lymphocytes. Infectious complications (6%) related to splenectomy were also significant and may warrant a more restrictive approach to performing splenectomy in WAS patients. Overall, this study provides the basis for a prospective, standardized, and more in-depth detailed analysis of chimerism and events in long-term follow-up of WAS patients who receive transplants to design better-adapted therapeutic strategies.
Roles of general adult psychiatrists in follow-up clinics
Authors: Mehta Sunil , Salvaji Abhijeetha , Abed Riadh
Published: September 2007

Aims and Method

Core features of New Ways of Working include concentrating on service users with complex needs, acting in a consultative role and carrying out interventions that are timely rather than routine. In this service-mapping exercise a retrospective analysis of 150 case notes was performed to evaluate clinical activity in general adult out-patient clinics and to attempt to measure the complexity of the workload.

Results

Analysis of care programme approach (CPA) level revealed that 40% of patients were not on CPA and 16% of patients were on enhanced CPA. Only a third of the sample had a non-medical care coordinator. Absolutely no changes were made to the management plan in around half of the sample. A minority of patients needed to be seen acutely, within a month, or had their appointment brought forward.

Clinical Implications

Current out-patient activity of consultant teams does not appear to be consistent with New Ways of Working. Psychiatrists will be required to reflect on their roles in out-patient clinics to avoid ‘routine’ appointments and to use their time more efficiently.
Violence against psychiatrists by patients: survey in a London mental health trust
Authors: Dhumad Saleh , Wijeratne Anusha , Treasaden Ian
Published: September 2007

Aims and Method

A survey was undertaken to investigate assaults of psychiatrists by patients in a 12-month period. Surveys were sent to 199 psychiatrists representing all sub-specialties and grades in a London mental health trust.

Results

There were 129 returned responses (response rate 64.8%). In the 12-month study period, 12.4% of all psychiatrists and 32.4% of senior house officers were assaulted. None received or took up offers of formal, as opposed to informal, psychological support. Most assaults occurred on a psychiatric ward. Vulnerability to assaults was not influenced by courses on prevention and management of violence or by the attitudes of psychiatrists to violence by psychiatric patients.

Clinical Implications

Senior house officers are most vulnerable to assaults. Greater attention may need to be given to psychiatric wards where most assaults occurred. Trusts should ensure that those assaulted are identified and offered support.
Before and after: introduction of the Mental Health (Care and Treatment) (Scotland) Act 2003
Authors: Smith Helen , White Tom
Published: September 2007

Aims and Method

The aim of the study was to assess the impact of the introduction of new mental health legislation in October 2005 on general adult psychiatry admissions. Patients were included in the study if they were admitted to Murray Royal Hospital, Perth from December 2004 to July 2005 and December 2005 to July 2006.

Results

Fewer patients were detained but they were more likely to progress to longer-term detentions. Overall detained patients remained in hospital for shorter periods.

Clinical Implications

The change in de novo detention procedures reduced the number of de novo detentions. The new power to enforce medication in the community may have contributed to the reduced length of detention in hospital.
Measurement of In Vivo BCR-ABL Kinase Inhibition to Monitor Imatinib-Induced Target Blockade and Predict Response in Chronic Myeloid Leukemia
Authors: White Deborah , Saunders Verity , Grigg Andrew , Arthur Chris , Filshie Robin , Leahy Michael F. , Lynch Kevin , To L. Bik , Hughes Timothy
Published: September 2007

Purpose

Intrinsic sensitivity to imatinib, based on measurement of inhibitory concentration 50% for imatinib, is variable in untreated patients with chronic myeloid leukemia (CML). This suggests that patient-tailored dosing may be more rational than a fixed dose for all. Dose optimization potentially could be based on accurate measurement of the level of BCR-ABL kinase inhibition achieved in vivo.

Patients and Methods

In vivo kinase inhibition was measured by calculating the reduction in protein (p) -Crkl level in mononuclear blood cells taken from 49 CML patients at weekly intervals after imatinib therapy was commenced.

Results

Greater than 50% inhibition (> 50% reduction in p-Crkl from baseline) was achieved by 21% of patients by days 7 to 14 (and maintained in all patients on days 21 to 28) and an additional 24% of patients achieved more than 50% inhibition by days 21 to 28. Thus, overall 45% of patients achieved more than 50% inhibition. All of these patients achieved major molecular responses by 24 months compared with 56% of the patients who failed to achieve 50% kinase inhibition (P < .001). Patients with less than 50% kinase inhibition were also more likely to have suboptimal responses.

Conclusion

In vivo BCR-ABL kinase inhibition can be assessed in the first month of imatinib therapy and may provide a valuable guide to optimization of dosage. The extent of BCR-ABL kinase inhibition is an excellent predictor of cytogenetic and molecular response. These observations suggest that dose adjustment based on in vivo measurements of drug-induced target inhibition could be applied in settings beyond imatinib and may be a more effective approach than using one dose for all patients in targeted anticancer therapy.
Treatment-Specific Risks of Second Malignancies and Cardiovascular Disease in 5-Year Survivors of Testicular Cancer
Authors: van den Belt-Dusebout Alexandra W. , de Wit Ronald , Gietema Jourik A. , Horenblas Simon , Louwman Marieke W.J. , Ribot Jacques G. , Hoekstra Harald J. , Ouwens Gabey M. , Aleman Berthe M.P. , van Leeuwen Flora E.
Published: September 2007

Purpose

To compare radiotherapy and chemotherapy effects on long-term risks of second malignant neoplasms (SMNs) and cardiovascular diseases (CVDs) in testicular cancer (TC) survivors.

Patients and Methods

In our nationwide cohort comprising 2,707 5-year TC survivors, incidences of SMNs and CVDs were compared with general-population rates by calculating standardized incidence ratios (SIRs) and absolute excess risks (AERs). Treatment effects on risks of SMN and CVD were quantified in multivariable Cox regression and competing risks analyses.

Results

After a median follow-up time of 17.6 years, 270 TC survivors developed SMNs. The SIR of SMN overall was 1.7 (95% CI, 1.5 to 1.9), with an AER of 32.3 excess occurrences per 10,000 person-years. SMN risk was 2.6-fold (95% CI, 1.7- to 4.0-fold) increased after subdiaphragmatic radiotherapy and 2.1-fold (95% CI, 1.4- to 3.1-fold) increased after chemotherapy, compared with surgery only. Subdiaphragmatic radiotherapy increased the risk of a major late complication (SMN or CVD) 1.8-fold (95% CI, 1.3- to 2.4-fold), chemotherapy increased the risk of a major late complication 1.9-fold (95% CI, 1.4- to 2.5-fold), and smoking increased the risk of a major late complication 1.7-fold (95% CI, 1.4- to 2.1-fold), compared with surgery only. The median survival time was 1.4 years after SMN and 4.7 years after CVD.

Conclusion

Radiotherapy and chemotherapy increased the risk of developing SMN or CVD to a similar extent as smoking. Subdiaphragmatic radiotherapy strongly increases the risk of SMNs but not of CVD, whereas chemotherapy increases the risks of both SMNs and CVDs. Prolonged follow-up after chemotherapy is needed to reliably compare the late complications of radiotherapy and chemotherapy after 20 years.
Global Histone Modifications Predict Prognosis of Resected Non–Small-Cell Lung Cancer
Authors: Barlési Fabrice , Giaccone Giuseppe , Gallegos-Ruiz Marielle I. , Loundou Anderson , Span Simone W. , Lefesvre Pierre , Kruyt Frank A.E. , Rodriguez Jose Antonio
Published: September 2007

Purpose

Epigenetic modifications may contribute to the development and progression of cancer. We investigated whether epigenetic changes involving multiple histones influence prognosis of non–small-cell lung cancer (NSCLC) patients.

Patients and Methods

We used immunohistochemistry to assess histone 3 lysine 4 dimethylation (H3K4diMe), and acetylation of histone 2A lysine 5 (H2AK5Ac), histone 2B lysine 12, histone 3 lysine 9 (H3K9Ac), and histone 4 lysine 8 in resected tumor samples of 138 NSCLC patients. Data were analyzed using a recursive partitioning analysis (RPA).

Results

The RPA classified the patients into seven distinct prognostic groups based on TNM stage (first node), histology, and histone modifications: H3K4diMe (< or ≥ 85% tumor cells), H3K9Ac (< or ≥ 68% tumor cells), and H2AK5Ac (< or ≥ 5% tumor cells). The seven groups were associated with significantly different disease-free (P < .0001) and overall survival (P < .0001). Interestingly, the four groups determined by stage I patients (below the first node) displayed dramatic differences in survival (median, 10 months in adenocarcinoma patients with H3K9Ac ≥ 68% v 147 months in nonadenocarcinoma patients with H3K4diMe ≥ 85%). A Cox model retained age and RPA groups as the sole independent factors significantly influencing overall survival.

Conclusion

The prognostic influence of epigenetic changes involving multiple histones, in particular H2A and H3, is greater in early NSCLC, and evaluation of these changes may help in selecting early-stage NSCLC patients for adjuvant treatment. Our observations provide a rationale for the use of a combination of standard chemotherapy with drugs interacting with histone modifications, such as histone deacetylase inhibitors.
Obesity-Induced Inflammation in White Adipose Tissue Is Attenuated by Loss of Melanocortin-3 Receptor Signaling
Authors: Ellacott Kate L. J. , Murphy Jonathan G. , Marks Daniel L. , Cone Roger D.
Published: September 2007

Metabolic syndrome, a complex of highly debilitating disorders that includes insulin resistance, hypertension, and dyslipidemia, is associated with the development of obesity in humans as well as rodent models. White adipose tissue (WAT) inflammation, caused in part by macrophage infiltration, and fat accumulation in the liver are both linked to development of the metabolic syndrome. Despite large increases in body fat, melanocortin 3-receptor (MC3-R)-deficient mice do not get fatty liver disease or severe insulin resistance. This is in contrast to obese melanocortin 4-receptor (MC4-R)-deficient mice and diet-induced obese (DIO) mice, which show increased adiposity, fatty liver disease, and insulin resistance. We hypothesized that defects in the inflammatory response to obesity may underlie the protection from metabolic syndrome seen in MC3-R null mice. MC4-R mice fed a chow diet show increased proinflammatory gene expression and macrophage infiltration in WAT, as do wild-type (WT) DIO mice. In contrast, MC3-R-deficient mice fed a normal chow diet show neither of these inflammatory changes, despite their elevated adiposity and a comparable degree of adipocyte hypertrophy to the MC4-R null and DIO mice. Furthermore, even when challenged with high-fat chow for 4 wk, a period of time shown to induce an inflammatory response in WAT of WT animals, MC3-R nulls showed an attenuated up-regulation in both monocyte chemoattractant protein-1 (MCP-1) and TNFα mRNA in WAT compared with WT high-fat-fed animals.
Tamoxifen Neuroprotection in Cerebral Ischemia Involves Attenuation of Kinase Activation and Superoxide Production and Potentiation of Mitochondrial Superoxide Dismutase
Authors: Wakade Chandramohan , Khan Mohammad M. , De Sevilla Liesl M. , Zhang Quan-Guang , Mahesh Virendra B. , Brann Darrell W.
Published: September 2007

The purpose of this study was to enhance our understanding of the mechanisms of neuronal death after focal cerebral ischemia and the neuroprotective effects of tamoxifen (TMX). The phosphorylation state of 31 protein kinases/signaling proteins and superoxide anion (O2−) production in the contralateral and ipsilateral cortex was measured after permanent middle cerebral artery occlusion (pMCAO) in ovariectomized rats treated with placebo or TMX. The study revealed that pMCAO modulated the phosphorylation of a number of kinases/proteins in the penumbra at 2 h after pMCAO. Of significant interest, phospho-ERK1/2 (pERK1/2) was elevated significantly after pMCAO. TMX attenuated the elevation of pERK1/2, an effect correlated with reduced infarct size. In situ detection of O2− production showed a significant elevation at 1–2 h after pMCAO in the ischemic cortex with enhanced oxidative damage detected at 24 h. ERK activation may be downstream of free radicals, a suggestion supported by the findings that cells positive for O2− had high pERK activation and that a superoxide dismutase (SOD) mimetic, tempol, significantly attenuated pERK activation after MCAO. TMX treatment significantly reduced the MCAO-induced elevation of O2− production, oxidative damage, and proapoptotic caspase-3 activation. Additionally, pMCAO induced a significant reduction in the levels of manganese SOD (MnSOD), which scavenge O2−, an effect largely prevented by TMX treatment, thus providing a potential mechanistic basis for the antioxidant effects of TMX. As a whole, these studies suggest that TMX neuroprotection may be achieved via an antioxidant mechanism that involves enhancement of primarily MnSOD levels, with a corresponding reduction of O2− production, and downstream kinase and caspase-3 activation.
Minireview: The Neuroendocrinology of the Suprachiasmatic Nucleus as a Conductor of Body Time in Mammals
Authors: Karatsoreos Ilia N. , Silver Rae
Published: September 2007

Circadian rhythms in physiology and behavior are regulated by a master clock resident in the suprachiasmatic nucleus (SCN) of the hypothalamus, and dysfunctions in the circadian system can lead to serious health effects. This paper reviews the organization of the SCN as the brain clock, how it regulates gonadal hormone secretion, and how androgens modulate aspects of circadian behavior known to be regulated by the SCN. We show that androgen receptors are restricted to a core SCN region that receives photic input as well as afferents from arousal systems in the brain. We suggest that androgens modulate circadian behavior directly via actions on the SCN and that both androgens and estrogens modulate circadian rhythms through an indirect route, by affecting overall activity and arousal levels. Thus, this system has multiple levels of regulation; the SCN regulates circadian rhythms in gonadal hormone secretion, and hormones feed back to influence SCN functions.
Cellular and Subcellular Evidence for Neuronal Interaction between the Chemokine Stromal Cell-Derived Factor-1/CXCL 12 and Vasopressin: Regulation in the Hypothalamo-Neurohypophysial System of the Brattleboro Rats
Authors: Callewaere Céline , Fernette Brigitte , Raison Danièle , Mechighel Patricia , Burlet Arlette , Calas André , Kitabgi Patrick , Parsadaniantz Stéphane Mélik , Rostène William
Published: September 2007

We previously described a colocalization between arginine vasopressin (AVP) and the chemokine stromal cell-derived factor-1α (SDF-1) in the magnocellular neurons of both the hypothalamic supraoptic and paraventricular nucleus as well as the posterior pituitary. SDF-1 physiologically affects the electrophysiological properties of AVP neurons and consequently AVP release. In the present study, we confirm by confocal and electron microscopy that AVP and SDF-1 have a similar cellular distribution inside the neuronal cell and can be found in dense core vesicles in the nerve terminals in the posterior pituitary. Because the Brattleboro rats represent a good model of AVP deficiency, we tested in these animals the fate of SDF-1 and its receptor CXCR4. We identified by immunohistochemistry that both SDF-1 and CXCR4 immunoreactivity were strongly decreased in Brattleboro rats and were strictly correlated with the expression of AVP protein in supraoptic nucleus, paraventricular nucleus, and the posterior pituitary. We observed by real-time PCR an increase in SDF-1 mRNA in both heterozygous and homozygous rats. The effect on the SDF-1/CXCR4 system was not linked to peripheral modifications of kidney water balance because it could not be restored by chronic infusion of deamino-8D-ariginine-vasopressin, an AVP V2-receptor agonist. These original data further suggest that SDF-1 may play an essential role in the regulation of water balance.
Nuclear Receptor TLX Regulates Cell Cycle Progression in Neural Stem Cells of the Developing Brain
Authors: Li Wenwu , Sun Guoqiang , Yang Su , Qu Qiuhao , Nakashima Kinichi , Shi Yanhong
Published: September 2007

TLX is an orphan nuclear receptor that is expressed exclusively in vertebrate forebrains. Although TLX is known to be expressed in embryonic brains, the mechanism by which it influences neural development remains largely unknown. We show here that TLX is expressed specifically in periventricular neural stem cells in embryonic brains. Significant thinning of neocortex was observed in embryonic d 14.5 TLX-null brains with reduced nestin labeling and decreased cell proliferation in the germinal zone. Cell cycle analysis revealed both prolonged cell cycles and increased cell cycle exit in TLX-null embryonic brains. Increased expression of a cyclin-dependent kinase inhibitor p21 and decreased expression of cyclin D1 provide a molecular basis for the deficiency of cell cycle progression in embryonic brains of TLX-null mice. Furthermore, transient knockdown of TLX by in utero electroporation led to precocious cell cycle exit and differentiation of neural stem cells followed by outward migration. Together these results indicate that TLX plays an important role in neural development by regulating cell cycle progression and exit of neural stem cells in the developing brain.
Prediction of human pharmacokinetics—gut-wall metabolism
Authors: Fagerholm Urban
Published: September 2007

Intestinal mucosal cells operate with different metabolic and transport activity, and not all of them are involved in drug absorption and metabolism. The fraction of these cells involved is dependent on the absorption characteristics of compounds and is difficult to predict (it is probably small). The cells also appear comparably impermeable. This shows a limited applicability of microsome intrinsic clearance (CLint)-data for prediction of gut-wall metabolism, and the difficulty to predict the gut-wall CL (CLGW) and extraction ratio (EGW). The objectives of this review were to evaluate determinants and methods for prediction of first-pass and systemic EGW and CLGW in man, and if required and possible, develop new simple prediction methodology. Animal gut-wall metabolism data do not appear reliable for scaling to man. In general, the systemic CLGW is low compared with the hepatic CL. For a moderately extracted CYP3A4-substrate with high permeability, midazolam, the gut-wall/hepatic CL-ratio is only 1/35. This suggests (as a general rule) that systemic CLGW can be neglected when predicting the total CL. First-pass EGW could be of importance, especially for substrates of CYP3A4 and conjugating enzymes. For several reasons, including those presented above and that blood flow based models are not applicable in the absorptive direction, it seems poorly predicted with available methodology. Prediction errors are large (several-fold on average; maximum-15-fold). A new simple first-pass EGW-prediction method that compensates for regional and local differences in absorption and metabolic activity has been developed. It has been based on human cell in-vitro CLint and fractional absorption from the small intestine for reference (including verapamil) and test substances, and in-vivo first-pass EGW-data for reference substances. First-pass EGW-values for CYP3A4-substrates with various degrees of gastrointestinal uptake and CLint and a CYP2D6-substrate were well-predicted (negligible errors). More high quality in-vitro CLint- and in-vivo EGW-data are required for further validation of the method.
In-vitro controlled release of doxorubicin from silica xerogels
Authors: Prokopowicz Magdalena
Published: September 2007

This study aimed at the development of a novel silica xerogel matrix as a delivery tool for an anti-cancer drug. Doxorubicin was incorporated as a hydrochloride salt during hydrolysis and polycondensation of tetraethylorthosilicate (TEOS) in the sol-gel process. The effect of sol-gel synthesis parameters (drug concentration, size of the device and lyophilizing process) on the release rate of the drug were investigated. In addition, dissolution rate, as well as weight loss of silica xerogel, was evaluated. In general, both the lyophilizing process of xerogels and the increase in size of non-lyophilizing device significantly decrease both the rate of drug release and the rate of dissolution of matrix. The overall release process was found to be governed by diffusion control and simultaneous zero-order dissolution of the xerogel.
Is bicarbonate buffer suitable as a dissolution medium?
Authors: Boni Julia Elisabeth , Brickl Rolf Stefan , Dressman Jennifer
Published: September 2007

The objectives of this study were to compare two methods for the preparation of bicarbonate buffer, and to compare media prepared with bicarbonate buffer with commonly used biorelevant and pharmacopoeial media in terms of their suitability for dissolution testing. The various media were compared with regard to ease of preparation, robustness and reproducibility of composition. The dissolution of three formulations of a typical Biopharmaceutical Classification System Class II drug (BIXX) was compared in bicarbonate buffer, standard phosphate buffer, a biorelevant buffer (fasted-state simulating intestinal fluid, FaSSIF) and a modified FaSSIF prepared with bicarbonate buffer. The bicarbonate buffer used for dissolution testing was produced by supplying carbon dioxide to a saline solution (0.9% NaCl, to which 12 or 42 mmol NaOH had been added). The bicarbonate buffer had to be prepared in-situ, which proved to be time-consuming, and the pH stability of the bicarbonate buffer could only be maintained under constant CO2 supply. To minimize the mechanical stress caused by inflow and evaporation of gas, the carbon dioxide was supplied above the medium during the dissolution test. Despite taking these measures, use of bicarbonate buffer led to less reproducible dissolution results than the phosphate buffers commonly used to prepare compendial media and FaSSIF, with coefficient of variance values 1.5- to 5-times higher in bicarbonate buffer. It was concluded that although a bicarbonate buffer system would be physiologically relevant for the fasted state in the small intestine, its suitability for dissolution testing is restricted by lack of practicability and poor reproducibility of results.
3-[(aryl)(4-fluorobenzyloxy)methyl]piperidine derivatives: high-affinity ligands for the serotonin transporter
Authors: Nencetti Susanna , Demontis Gian Carlo , Mazzoni Maria Rosa , Betti Laura , Banti Irene , Rossello Armando , Lapucci Annalina
Published: September 2007

The structural requirements for high-affinity binding at the serotonin transporter (SERT) have been investigated through the preparation of some 3-[(aryl)(4-fluorobenzyloxy)methyl]piperidine derivatives. The affinity of synthesised piperidinic compounds (1–4) at the SERT was evaluated by displacement of [3H]-paroxetine binding. Derived inhibition constant (Ki) values were in the same order of magnitude as that of fluoxetine, ranging between 2 and 400 nm. To better define the profiles of these compounds as potential antidepressants, binding affinity for 5-HT1A receptors and α2-adrenoceptors was also investigated by competition experiments using [3H]8-hydroxy-2-(dipropylamino)tetralin ([3H]8-OH-DPAT) and [3H]rauwolscine as radiolabelled ligands, respectively. Inhibition data indicate that compounds 1–4 possess a very weak affinity for these receptors. The high affinity of compound 1 for SERT indicates that it is worth investigating further.
Rapid fabrication of metal-coated composite stereolithography parts
Authors: Zhou Z , Li D , Zeng J , Zhang Z
Published: September 2007

In this paper, the rapid fabrication method based on stereolithography (SL) and electrochemical deposition is described in detail and mechanical test results of composite nickel-coated SL parts are presented. Coatings of electrodeposited nickel on SL prototypes result in increases in Young's modulus, UTS, flexural modulus, and strength. Electrodeposited nickel coating has dramatically improved the overall strength and stiffness of SL parts. The adhesive strength of the roughened SL resin-nickel interface is higher than the original. In particular, the influence of the surface roughness on adhesive strength between SL and metal is investigated. Moreover, this paper has presented an application of a structural electrodeposited nickel coating over SL parts to make a functional airfoil model with a complex internal structure and sufficient mechanical strength and stiffness.
Misfire-misfuel classification using support vector machines
Authors: Gani E , Manzie C
Published: September 2007

This paper proposes the use of support vector machines to perform classification between different types of missed combustion event in a six-cylinder engine. On-board diagnostics regulations require the detection of missed combustion events, which is possible through interpretation of crankshaft speed information. However, current approaches provide no information on the actual cause of the event, in particular whether it was caused by a misfuel (absence of fuel) or a misfire (absence of spark) event. Whilst the impact on the environment and emission treatment systems due to misfuel is minimal, misfire events are detrimental to both. Consequently information regarding the causes of missing combustion events potentially allows the development of unique recovery strategies particular to the source of the problem. In this paper, an approach is proposed that will provide the potential for, firstly, detection of a missing combustion event and, secondly, real-time classification of the event into either misfuel or misfire events using feedback from a heated universal exhaust gas oxygen sensor. In order to evaluate the potential of such a system in an engine control unit, a computational complexity measure is also presented.
A method for vibration absorber tuning based on baseline frequency response functions
Authors: Liu C Q , Chang C C
Published: September 2007

This paper presents explicit expressions for new frequency response functions (FRFs) of a primary system when a vibration absorber is attached to it. The new FRF is expressed in terms of the baseline (‘old’) FRFs of the primary system and the physical parameters (the mass, stiffness, and damping) of the vibration absorber. The baseline FRF of the primary system can be obtained by either analytical or experimental methods. This approach allows engineers and designers to evaluate a number of alternative vibration absorbers before these absorbers are physically implemented on the structure. Therefore a considerable amount of time and effort for engineers and designers can be saved. Several examples are provided to illustrate the use of the method.