bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotypic correction and long-term expression of factor VIII in hemophilic mice by immunotolerization and nonviral gene transfer using the Sleeping Beauty transposon system
Authors: Ohlfest John R. , Frandsen Joel L. , Fritz Sabine , Lobitz Paul D. , Perkinson Scott G. , Clark Karl J. , Nelsestuen Gary , Key Nigel S. , McIvor R. Scott , Hackett Perry B. , Largaespada David A. 
Published: December 2004

AbstractHemophilia A is a lead candidate for treatment by gene therapy because small increments in the missing secreted protein product, coagulation factor VIII (FVIII), would result in substantial clinical amelioration. Clinically relevant therapy might be achieved by stably delivering a human FVIII cDNA to correct the bleeding disorder. We used the Sleeping Beauty (SB) transposon, delivered as naked plasmid DNA by tail-vein injection, to integrate B-domain–deleted FVIII genes into the chromosomes of hemophilia A mice and correct the phenotype. Since FVIII protein is a neoantigen to these mice, sustaining therapeutic plasma FVIII levels was problematic due to inhibitory antibody production. We circumvented this problem by tolerizing 82% of neonates by a single facial-vein injection of recombinant FVIII within 24 hours of birth (the remaining 18% formed inhibitors). Achievement of high-level (10%-100% of normal) FVIII expression and phenotypic correction required co-injection of an SB transposase-expressing plasmid to facilitate transgene integration in immunotolerized animals. Linker-mediated polymerase chain reaction was used to clone FVIII transposon insertion sites from liver genomic DNA, providing molecular evidence of transposition. Thus, SB provides a nonviral means for sustained FVIII gene delivery in a mouse model of hemophilia A if the immune response is prevented.
Human CD14 is an efficient target for recombinant immunoglobulin vaccine constructs that deliver T cell epitopes
Authors: Tunheim Gro , Schjetne Karoline W , Fredriksen Agnete B , Sandlie Inger , Bogen Bjarne 
Published: December 2004

AbstractIt has been shown in the mouse that recombinant immunoglobulin (Ig) molecules with T cell epitopes inserted into the constant domain (Troybodies) can target antigen-presenting cells (APC) for efficient delivery of T cell epitopes. Here, we have extended the Troybody concept to human applications. Moreover, we show that a receptor of innate immunity, CD14, which is a part of the lipopolysaccharide receptor complex on monocyte APC, is an efficient target. For construction of CD14-specific Troybodies, we used rearranged variable(diversity)joining regions cloned from the 3C10 mouse B cell hybridoma. As a model T cell epitope, amino acids 40–48 of mouse Cκ, presented on human leukocyte antigen-DR4, were inserted into a loop connecting β-strands in CH1 of human γ3. In the presence of monocytes, CD14-specific Troybodies were &gt;100 times as efficient as a nontargeting control antibody (Ab) at stimulating Cκ40–48-specific/DR4-restricted T cells. Presentation was dependent on the conventional processing pathway for presentation on major histocompatibility complex (MHC) class II molecules. Enhanced presentation of the Cκ epitope was most likely a result of increased loading of MHC class II molecules, as the CD14-specific monoclonal Ab 3C10 did not induce maturation of the APC. The results show that CD14, a receptor of innate immunity, may be a promising target of recombinant Ig-based vaccines for elicitation of T cell responses in humans.
Effects of Atorvastatin on the Clearance of Triglyceride-Rich Lipoproteins in Familial Combined Hyperlipidemia
Authors: Castro Cabezas M. , Verseyden C. , Meijssen S. , Jansen H. , Erkelens D. W. 
Published: December 2004

AbstractFamilial combined hyperlipidemia (FCHL) patients have an impaired catabolism of postprandial triglyceride (TG)-rich lipoproteins (TRLs). We investigated whether atorvastatin corrects the delayed clearance of large TRLs in FCHL by evaluating the acute clearance of Intralipid (10%) and TRLs after oral fat-loading tests. Sixteen matched controls were included. Atorvastatin reduced fasting plasma TG (from 3.6 ± 0.4 to 2.5 ± 0.3 mm; mean ± sem) without major effects on fasting apolipoprotein B48 (apoB48) and apoB100 in large TRLs. Atorvastatin significantly reduced fasting intermediate density lipoprotein (Svedberg flotation, 12–20)-apoB100 concentrations. After Intralipid, TG in plasma and TRL showed similar kinetics in FCHL before and after atorvastatin treatment, although compared with controls, the clearance of large TRLs was only significantly slower in untreated FCHL, suggesting an improvement by atorvastatin. Investigated with oral fat-loading tests, the clearance of very low density lipoprotein (Sf20–60)-apoB100 improved by 24%, without major changes in the other fractions. The most striking effects of atorvastatin on postprandial lipemia in FCHL were on hepatic TRL, without major improvements on intestinal TRLs. Fasting plasma TG should be reduced more aggressively in FCHL to overcome the lipolytic disturbance causing delayed clearance of postprandial TRLs.
Preeclampsia and Future Cardiovascular Disease: Potential Role of Altered Angiogenesis and Insulin Resistance
Authors: Wolf Myles , Hubel Carl A. , Lam Chun , Sampson Marybeth , Ecker Jeffrey L. , Ness Roberta B. , Rajakumar Augustine , Daftary Ashi , Shakir Alia S. M. , Seely Ellen W. , Roberts James M. , Sukhatme Vikas P. , Karumanchi S. Ananth , Thadhani Ravi 
Published: December 2004

Abstract
Altered angiogenesis and insulin resistance are associated with preeclampsia and cardiovascular disease (CVD), and women with preeclampsia appear to be at increased risk of future CVD. We hypothesized that these factors are detectable in asymptomatic postpartum women with a history of preeclampsia and may represent pathophysiological mechanisms bridging preeclampsia and future CVD. We measured fasting insulin, glucose, vascular endothelial growth factor, and its circulating inhibitor, soluble fms-like tyrosine kinase (sFlt-1) in 29 normotensive women with a history of preeclampsia and 32 women with prior normotensive pregnancies at 18.0 ± 9.7 months postpartum. The homeostasis model of insulin resistance (HOMAIR) [(insulin [microunits per milliliter] × glucose [millimoles per liter])/22.5] was calculated. Compared with women with normal pregnancies, women with prior preeclampsia had significantly increased levels of sFlt-1 (41.6 ± 6.7 vs. 30.4 ± 10.2; P &lt; 0.01) and median HOMAIR (2.8 vs. 1.9; P = 0.04). Membership in the upper quartile of either sFlt-1 or HOMAIR was associated with prior preeclampsia (odds ratio 5.7; 95% confidence interval 1.7, 20.0; P &lt; 0.01), and all five women in the upper quartiles of both sFlt-1 and HOMAIR had a history of preeclampsia. Women with a history of preeclampsia demonstrate altered expression of angiogenesis-related proteins and increased HOMAIR more than 1 yr postpartum. These factors may contribute to their risk of future CVD.
X-Chromosome Inactivation Patterns and Androgen Receptor Functionality Influence Phenotype and Social Characteristics as Well as Pharmacogenetics of Testosterone Therapy in Klinefelter Patients
Authors: Zitzmann Michael , Depenbusch Marion , Gromoll Jörg , Nieschlag Eberhard 
Published: December 2004

AbstractKlinefelter syndrome is characterized by a vast range of phenotypes related to androgen effects. Testosterone (T) acts via the X-linked androgen receptor gene carrying the CAG repeat (CAGn) polymorphism, the length of which is inversely associated with androgen action and might account for the marked variation in phenotypes. In 77 newly diagnosed and untreated Klinefelter patients with a 47,XXY karyotype we assessed phenotype and social traits in relation to X-weighted biallelic CAGn length using X-chromosome inactivation analysis after digestion of leukocyte DNA with methylation-sensitive HpaII. Forty-eight men were hypogonadal and received T substitution therapy; in these, pharmacogenetic effects were investigated. The shorter CAGn allele was preferentially inactive. CAGn length was positively associated with body height. Bone density and the relation of arm span to body height were inversely related to CAGn length. The presence of long CAGn was predictive for gynecomastia and smaller testes, whereas short CAGn were associated with a stable partnership and professions requiring higher standards of education also when corrected for family background. There was a trend for men with longer CAGn to be diagnosed earlier in life. Under T substitution, men with shorter CAGn exhibited a more profound suppression of LH levels, augmented prostate growth, and higher hemoglobin concentrations. A significant genotype-phenotype association exists in Klinefelter patients: androgen effects on appearance and social characteristics are modulated by the androgen receptor CAGn polymorphism. The effects of T substitution are pharmacogenetically modified. This finding is magnified by preferential inactivation of the more functional short CAGn allele.
Subcortical White Matter Metabolic Changes Remote from Focal Hemorrhagic Lesions Suggest Diffuse Injury after Human Traumatic Brain Injury
Authors: Wu Hsiao-Ming , Huang Sung-Cheng , Hattori Naoya , Glenn Thomas C. , Vespa Paul M. , Hovda David A. , Bergsneider Marvin 
Published: December 2004

Abstract

OBJECTIVE:
We used positron emission tomographic studies to prospectively examine the relationship between glucose and oxidative metabolism in the subcortical white matter (WM) acutely after traumatic brain injury (TBI). The objective was to determine the nature, extent, and degree of metabolic abnormalities in subcortical brain regions remote from hemorrhagic lesions.

METHODS:
Sixteen normal volunteers and 10 TBI patients (Glasgow Coma Scale score, 4–10; age, 17–64 yr; 6 with focal and 4 with diffuse injury) were studied. Each subject underwent dynamic positron emission tomographic studies using [15O]CO, 15O2, [15O]H2O, and fluorodeoxyglucose plus a magnetic resonance imaging scan acutely after TBI. Parametric images of the metabolic rate of oxygen and metabolic rate of glucose were generated, and a molar oxygen-to-glucose utilization ratio was calculated. Data from gray matter and WM remote from hemorrhagic lesions, plus whole brain, were analyzed.

RESULTS:
There was a significant reduction in the subcortical WM oxygen-to-glucose utilization ratio after TBI compared with normal values (3.99 ± 0.77 versus 5.37 ± 1.00; P &lt; 0.01), whereas the mean cortical gray matter and whole-brain values remained unchanged. WM metabolic changes, which were diffuse throughout the hemispheres, were characterized by a reduction in the metabolic rate of oxygen without a concomitant drop in the metabolic rate of glucose.

CONCLUSION:
The extent and degree of subcortical WM metabolic abnormalities after moderate and severe TBI suggest that diffuse WM injury is a general phenomenon after such injuries. This pervasive finding may indicate that the concept of focal traumatic injury, although valid from a computed tomographic imaging standpoint, may be misleading when considering metabolic derangements associated with TBI.
Radiotherapeutic Factors in the Management of Cervical-basal Chordomas and Chondrosarcomas
Authors: Noël Georges , Feuvret Loïc , Ferrand Régis , Boisserie Gilbert , Mazeron Jean-Jacques , Habrand Jean-Louis 
Published: December 2004

Abstract

OBJECTIVE:
To define prognostic factors for local control and survival in 90 consecutive patients treated by fractionated photon and proton radiation for chordoma or chondrosarcoma of the cranial base and upper cervical spine.

METHODS:
Between December 1995 and December 2000, 90 patients (median age, 51.3 yr; range, 10–85 yr; male/female ratio, 3:2) were treated by a combination of high-energy photons and protons. Sixty-four patients had a chordoma, and 26 had a chondrosarcoma. The proton component was delivered by the 201-MeV proton beam of the Centre de Protonthérapie d'Orsay. The median total dose delivered to the gross tumor volume (GTV) was 67 cobalt Gray equivalents (range, 22–70 cobalt Gray equivalents).

RESULTS:
With a median follow-up of 34 months (range, 3–74 mo), treatment of 25 tumors failed locally. The 3-year local control rates were 69.2% (±6.0%) and 91.6% (±8.4%) for chordomas and chondrosarcomas, respectively. According to multivariate analysis, a small tumor volume excluded from the 95% isodose line (P = 0.032; relative risk [RR], 0.098; 95% confidence interval [CI], 0.01–0.81) and a controlled tumor (P = 0.049; RR, 0.19; 95% CI, 0.04–0.99) were independent favorable prognostic factors for overall survival. On multivariate analysis, a high minimum dose (P = 0.02; RR, 2.8; 95% CI, 1.2–6.6), a high tumor control probability (P = 0.02; RR, 3.8; 95% CI, 1.2–12.5), a high dose delivered to 95% of the GTV (P = 0.03; RR, 3.4; 95% CI, 1.15–10.2), a high GTV encompassed by the 90% isodose line (P = 0.01; RR, 3.29; 95% CI, 1.29–8.44), and a small GTV excluded from the 90% isodose line (P = 0.036; RR, 0.4; 95% CI, 0.1–0.9) were independent favorable prognostic factors for local control.

CONCLUSION:
In chordomas and chondrosarcomas of the cranial base and cervical spine treated by surgical resection and then by high-dose photon and proton irradiation, local control is mainly dependent on the quality of radiation, especially dose uniformity within the GTV. Special attention must be paid to minimize underdosed areas because of the close proximity of critical structures and to redefine and possibly escalate dose constraints to tumor targets in future studies in view of the low toxicity observed to date.
Spinal en Plaque Meningiomas: A Contemporary Experience
Authors: Caroli Emanuela , Acqui Michele , Roperto Raffaelino , Ferrante Luigi , D'Andrea Giancarlo 
Published: December 2004

Abstract

OBJECTIVE:
Spinal en plaque meningiomas are rare and challenging lesions because of their tendency to induce spinal arachnoiditis. The surgical treatment of this type of meningioma is more complex than that of classic meningioma.

METHODS:
We report seven cases of spinal en plaque meningiomas and review all the cases reported in the literature accessible to us by a MEDLINE search.

RESULTS:
All patients underwent microsurgery. Complete tumor removal was achieved in three patients. Subtotal removal was performed in four patients. A permanent neurological worsening was observed in one patient.

CONCLUSION:
Spinal meningiomas en plaque bear a prognosis poorer than that of classic meningiomas with regard to the possibility of a definitive surgical cure because recurrence or postoperative arachnoiditis occurs frequently. Total surgical removal should be attempted only when a clear plane of cleavage between tumor and arachnoid exists.
Evaluating the Effect of Decompression Surgery on Cerebrospinal Fluid Flow and Intracranial Compliance in Patients with Chiari Malformation with Magnetic Resonance Imaging Flow Studies
Authors: Sivaramakrishnan Anusha , Alperin Noam , Surapaneni Sushma , Lichtor Terry 
Published: December 2004

Abstract

OBJECTIVE:
To quantify the effect of decompression surgery on craniocervical junction hydrodynamics and on global intracranial compliance (ICC) in patients with Chiari I malformation by use of magnetic resonance measurements of cerebrospinal fluid and blood flow. Studying the effect of decompression surgery may improve our understanding of the pathophysiological characteristics of Chiari I malformation and aid in identifying patients who will benefit from the procedure.

METHODS:
Twelve patients were studied with a 1.5-T magnetic resonance imaging scanner before and after decompression surgery. Cine phase contrast magnetic resonance images were used to quantify maximum cord displacement, maximum systolic cerebrospinal fluid velocity and volumetric flow rate, and overall ICC. ICC was derived by use of a previously reported method that measures small changes in intracranial volume and pressure that occur naturally with each cardiac cycle.

RESULTS:
After surgery, changes were documented both in the local hydrodynamic parameters and in ICC. However, only the change in ICC, an average increase of more than 60%, was statistically significant. Increased ICC, which was associated with improved outcome, was measured in 10 of the 12 patients, no significant change was documented in 1 patient, and decreased ICC was measured in 1 patient whose symptoms persisted after surgery.

CONCLUSION:
An increase in the overall compliance of the intracranial compartment is the most significant and consistent change measured after decompression surgery. Changes in cord displacement, cerebrospinal fluid velocities, and flow in the craniospinal junction were less consistent and less affected by the operation. Thus, ICC may play an important role in the outcome of decompression surgery related to improving symptoms and restoring normal neurological hydrodynamics in patients with Chiari I malformations.
A Call to Define Stereotactic Radiosurgery
Authors: Pollock Bruce E. , Lunsford L Dade 
Published: December 2004

Abstract
STEREOTACTIC RADIOSURGERY IS the single-session, precise delivery of a therapeutically effective radiation dose to an imaging-defined target. Conceived and developed during the past 5 decades, stereotactic radiosurgery has involved significant advances, which have improved patient outcomes and made it a critical component of modern neurosurgical practice and training. In this article, a short history of stereotactic surgery and radiosurgery are presented, and radiosurgery is contrasted to radiation therapy. Adherence to accepted, descriptive terms in defining stereotactic radiosurgery and radiation therapy permits a clear distinction among the results of the different radiation delivery techniques for patients, physicians, and other interested parties.
Toward an Expanded View of Radiosurgery
Authors: Adler John R. , Colombo Federico , Heilbrun M Peter , Winston Ken 
Published: December 2004

Abstract
RADIOSURGERY AND RADIOTHERAPY were originally distinguished on the basis of the manner in which they protected normal tissues from radiation injury. Radiosurgery does so by precise targeting of cross-fired radiation beams to abnormal tissue, with abrupt falloff of radiation doses to surrounding normal tissue. Radiotherapy was historically less concerned with targeting accuracy and anatomic precision; normal tissues were protected by dividing doses into multiple fractions separated by time to allow recovery of normal tissues. By this means, radiotherapy applied radiobiological principles to disrupt dividing cells selectively. Despite the development of computer-based, image-guided frameless technology that eliminates the necessity to perform radiosurgery in a single session, there are some who still insist that radiosurgery be distinguished from radiotherapy on the basis of whether treatment is delivered in a single session. Here, we propose that this definition of radiosurgery is needlessly restrictive and that staging or hypofractionation of radiosurgical treatment permits the limited application of radiobiological principles of radiotherapy to improve radiosurgical treatment. We therefore define radiosurgery as a procedure that involves the active participation of a surgeon and in which spatially accurate and highly conformal doses of radiation are targeted at well-defined structures with an ablative intent.
Multiple Spinal Cavernous Malformations with Atypical Phenotype after Prior Irradiation: Case Report
Authors: Jabbour Pascal , Gault Judith , Murk Steven E. , Awad Issam A. 
Published: December 2004

Abstract

OBJECTIVE AND IMPORTANCE:
This is the first reported case of histologically proven multiple spinal cavernous malformations (CMs) associated with previous irradiation. There are only two cases reported in the literature of solitary spinal CM after irradiation. In addition, the lesions in our patient had an atypical magnetic resonance imaging appearance mimicking intraspinal drop metastasis.

CLINICAL PRESENTATION:
A 33-year-old man had an incidental finding of multiple enhancing intraspinal lesions as revealed by magnetic resonance imaging during staging tests for hepatocellular carcinoma. He had a history of Wilms' tumor at a young age with irradiation to the abdomen and pelvis. His family history included a paternal cousin with multiple cerebral CMs. The diagnosis of spinal drop metastasis was made, and further intervention was undertaken for confirmation.

INTERVENTION:
The patient underwent a lumbar laminectomy with durotomy and excision of two of the lesions. Macroscopic analysis revealed mulberry-like appearance with nerve root involvement, and pathological analysis confirmed the diagnosis of CM. Genetic testing of the patient and his affected cousin was negative for the CCM1 gene.

CONCLUSION:
The occurrence of multiple spinal lesions in the context of known neoplasia indicates a diagnosis of metastasis. Spinal CMs were not suspected preoperatively because of the atypical appearance revealed by magnetic resonance imaging scans, with uniform contrast enhancement and absence of hemosiderin rim. This case report is discussed relative to previous literature regarding radiation-induced CMs and other known causes of the disease.
A GPI-linked carbonic anhydrase expressed in the larval mosquito midgut
Authors: Seron Terri J. , Hill Jennifer , Linser Paul J. 
Published: December 2004

SUMMARYWe have previously described the first cloning and partial characterization of carbonic anhydrase from larval Aedes aegypti mosquitoes. Larval mosquitoes utilize an alkaline digestive environment in the lumen of their anterior midgut, and we have also demonstrated a critical link between alkalization of the gut and carbonic anhydrase(s). In this report we further examine the nature of the previously described carbonic anhydrase and test the hypothesis that its pattern of expression is consistent with a role in gut alkalization. Additionally we take advantage of the recently published genome of the mosquito Anopheles gambiae to assess the complexity of the carbonic anhydrase gene family in these insects. We report here that the previously described carbonic anhydrase from Aedes aegypti is similar to mammalian CA IV in that it is a GPI-linked peripheral membrane protein. In situ hybridization analyses identify multiple locations of carbonic anhydrase expression in the larval mosquito. An antibody prepared against a peptide sequence specific to the Aedes aegypti GPI-linked carbonic anhydrase labels plasma membranes of a number of cell types including neuronal cells and muscles. A previously undescribed subset of gut muscles is specifically identified by carbonic anhydrase immunohistochemistry. Bioinformatic analyses using the Ensembl automatic analysis pipeline show that there are at least 14 carbonic anhydrase genes in the Anopheles gambiae genome, including a homologue to the GPI-linked gene product described herein. Therefore, as in mammals which similarly possess numerous carbonic anhydrase genes, insects require a large family of these genes to handle the complex metabolic pathways influenced by carbonic anhydrases and their substrates.