bluuebunny/crossref_metadata_2025 huggingface dataset:
Non‐linear analysis of a collapsed reinforced concrete chimney
Authors: Huang Wei , Gould Phillip L. , Martinez Raul , Johnson Gayle S.
Published: March 2004

During the Ismit (Kocaeli) earthquake of 17 08 1999, a 115 high reinforced concrete chimney or heater stack, located at the Tüpras Refinery, collapsed. The falling debris cut 63 pipes, which contributed to interrupted production for more than 14 months. This stack was designed and constructed according to international standards and is representative of similar structures at refineries throughout the world, including those in earthquake‐prone regions. It was distinguished from similar stacks at the site by a much larger rectangular opening for the flue duct, circumscribing a horizontal arc of about 50°. The opening was located about 1/3 of the height above the base and appeared to be the region of initiation of the collapse.

The investigation is focused on the dynamic response of the stack due to an earthquake motion recorded at a nearby site. In this paper the results of a response spectrum analysis of the Tüpras stack and a generic U.S. stack are summarized. Then, an on‐linear static analysis of the collapsed stack is presented using a demand–collapse comparison. The demand is represented by an acceleration–displacement response spectrum based on the recorded motion as well as some smoothed adaptations typical of design spectra, while the capacities are calculated from pushover curves using a non‐linear reinforced concrete finite element analysis.

Results are presented that show the effects of the hole and the orientation of the motion with respect to the hole. Also higher‐mode contributions to the pushover pattern are considered. The results confirm that the stack could readily fail under the considered earthquake and are also consistent with the debris pattern. Copyright © 2003 JohnWiley & Sons, Ltd.
Cumulative damage‐based inelastic cyclic demand spectrum
Authors: Kunnath S. K. , Chai Y. H.
Published: March 2004

The estimation of cyclic deformation demand resulting from earthquake loads is crucial to the core objective of performance‐based design if the damage and residual capacity of the system following a seismic event needs to be evaluated. A simplified procedure to develop the cyclic demand spectrum for use in preliminary seismic evaluation and design is proposed in this paper. The methodology is based on estimating the number of equivalent cycles at a specified ductility. The cyclic demand spectrum is then determined using well‐established relationships between seismic input energy and dissipated hysteretic energy. An interesting feature of the proposed procedure is the incorporation of a design spectrum into the proposed procedure. It is demonstrated that the force–deformation characteristics of the system, the ductility‐based force‐reduction factor Rμ, and the ground motion characteristics play a significant role in the cyclic demand imposed on a structure during severe earthquakes. Current design philosophy which is primarily based on peak response amplitude considers cyclic degradation only in an implicit manner through detailing requirements based on observed experimental testing. Findings from this study indicate that cumulative effects are important for certain structures, classified in this study by the initial fundamental period, and should be incorporated into the design process. Copyright © 2003 John Wiley & Sons, Ltd.
Potassium attenuates zinc‐induced death of cultured cortical astrocytes
Authors: Sheline Christian T. , Takata Toshihiro , Ying Howard , Canzoniero Lorella M.t. , Yang Aizhen , Yu Shan Ping , Choi Dennis W.
Published: March 2004

Transient global ischemia induces CA1 hippocampal neuronal death without astrocyte death, perhaps mediated in part by the toxic translocation of zinc from presynaptic terminals to postsynaptic neurons. We tested the hypothesis that cellular depolarization, which occurs in the ischemic brain due to increased extracellular potassium and energy failure, might contribute to astrocyte resistance to zinc‐induced death. We previously reported that neurons in mixed cortical neuronal‐astrocyte cultures were more vulnerable to a 5–15‐min exposure to Zn2+ than astrocytes in the same cultures. In the present report, we show that (1) neurons in isolation or in conjunction with astrocytes were 2–3‐fold more sensitive to a 15‐min nondepolarizing Zn2+ exposure than are glia; (2) KCl‐induced depolarization attenuated glial vulnerability to zinc toxicity but potentiated neuronal vulnerability to zinc toxicity; (3) Zn2+‐induced glial death was attenuated by T‐type Ca2+ channel blockade, as well as compounds that increase NAD+ levels; and (4) both astrocytic 65Zn2+ accumulation and the increase in astrocytic [Zn2+]i induced by Zn2+ exposure were also attenuated by depolarization or T‐type Ca2+ channel blockers. Zn2+‐induced cell death in astrocytes was at least in part apoptotic, as caspase‐3 was activated, and the caspase inhibitor Z‐Val‐Ala‐Asp‐fluoromethylketone partially attenuated Zn2+‐induced death. The levels of peak [Zn2+]i achieved in astrocytes during this toxic nondepolarizing Zn2+ exposure (250 nM) were substantially greater than those achieved in neurons (40 nM). In glia, exposure to 400 μM Zn2+ induced a 13‐mV depolarization, which can activate T‐type Ca2+ channels. This Zn2+‐induced astrocyte death, like neuronal death, was attenuated by the addition of pyruvate or niacinamide to the exposure medium. © 2004 Wiley‐Liss, Inc.
Increased expression of two phospholipase D isoforms during experimentally induced hippocampal mossy fiber outgrowth
Authors: Zhang Yan , Huang Ping , Du Guangwei , Kanaho Yasunori , Frohman Michael A. , Tsirka Stella E.
Published: March 2004

Mammalian phospholipase D (PLD), a multifunctional signaling enzyme, has been reported to facilitate neurite outgrowth in cultured neurons. However, two mammalian isoforms have been found, PLD1 and PLD2, and it has not been determined which isoform is involved, or whether this in vitro phenomenon is relevant to neurite extension in vivo. Using confocal microscopy, we demonstrate that the PLDs are expressed by different cell types in the mouse brain: PLD1 by neurons, and PLD2 by astrocytes. Moreover, using a model of experimentally induced hippocampal mossy fiber sprouting, both isoforms were observed to increase dramatically in expression level along tracts of mossy fiber spouting, supporting the proposal that PLD plays a role in this process. Given that the two isoforms undertake unique molecular functions in cultured cells, our findings suggest that in vivo PLD1 and PLD2 may modulate neuronal plasticity via different pathways and cell types. © 2004 Wiley‐Liss, Inc.
Expression profiling in tuberous sclerosis complex (TSC) knockout mouse astrocytes to characterize human TSC brain pathology
Authors: Ess Kevin C. , Uhlmann Erik J. , Li Wen , Li Hongzhen , Declue Jeffrey E. , Crino Peter B. , Gutmann David H.
Published: March 2004

Individuals with tuberous sclerosis complex (TSC) exhibit a variety of neurologic abnormalities, including mental retardation, epilepsy, and autism. Examination of human TSC brains demonstrate dysplastic astrocytes and neurons, areas of abnormal neuronal migration (tubers), and hamartomatous growths, termed subependymal nodules, which can progress to subependymal giant cell astrocytomas (SEGA). Previous studies have suggested that these neuropathologic features may result from abnormal neuroglial cell differentiation. In an effort to provide support for this hypothesis and to identify specific markers of aberrant neuroglial cell differentiation in TSC, we employed gene expression profiling on Tsc1 conditional knockout (Tsc1GFAPCKO) mouse astrocytes. We identified several transcripts implicated in central nervous system development that are differentially expressed in Tsc1−/− astrocytes compared to wild‐type astrocytes. We validated the differential expression of select transcripts on the protein level both in primary cultures of Tsc1−/− astrocytes and in Tsc1GFAPCKO mouse brains. Moreover, we show that these markers are also differentially expressed within cortical tubers, but not in adjacent normal tissue from TSC patient brains. This study provides supportive evidence for a developmental defect in neuroglial cell differentiation relevant to the genesis of TSC nervous system pathology and underscores the utility of mouse modeling for understanding the molecular pathogenesis of human disease. © 2004 Wiley‐Liss, Inc.
Novel metabotropic glutamate receptor negatively coupled to adenylyl cyclase in cultured rat cerebellar astrocytes
Authors: Kanumilli Srinivasan , Toms Nick J. , Roberts Peter J.
Published: March 2004

Several excitatory amino acid ligands were found potently to inhibit forskolin‐stimulated cAMP accumulation in rat cultured cerebellar astrocytes: L‐cysteine sulfinic acid (L‐CSA) = L‐aspartate > L‐glutamate ≥ the glutamate uptake inhibitor, L‐PDC. This property did not reflect activation of conventional glutamate receptors, since the selective ionotropic glutamate receptor agonists NMDA, AMPA, and kainate, as well as several mGlu receptor agonists [(1S,3R)‐ACPD, (S)‐DHPG, DCG‐IV, L‐AP4, L‐quisqualate, and L‐CCG‐I], were without activity. In addition, the mGlu receptor antagonists, L‐AP3, (S)‐4CPG, Eglu, LY341495, (RS)‐CPPG, and (S)‐MCPG failed to reverse 30 μM glutamate‐mediated inhibitory responses. L‐PDC‐mediated inhibition was abolished by the addition of the enzyme glutamate‐pyruvate transaminase. This finding suggests that the effect of L‐PDC is indirect and that it is mediated through endogenously released L‐glutamate. Interestingly, L‐glutamate‐mediated inhibitory responses were resistant to pertussis toxin, suggesting that Gi/Go type G proteins were not involved. However, inhibition of protein kinase C (PKC, either via the selective PKC inhibitor GF109203X or chronic PMA treatment) augmented glutamate‐mediated inhibitory responses. Although mGlu3 receptors (which are negatively coupled to adenylyl cyclase) are expressed in astrocyte populations, in our study Western blot analysis indicated that this receptor type was not expressed in cerebellar astrocytes. We therefore suggest that cerebellar astrocytes express a novel mGlu receptor, which is negatively coupled to adenylyl cyclase, and possesses an atypical pharmacological profile. © 2003 Wiley‐Liss, Inc.
Induction of glial L‐CCR mRNA expression in spinal cord and brain in experimental autoimmune encephalomyelitis
Authors: Brouwer N. , Zuurman M.W. , Wei T. , Ransohoff R.M. , Boddeke H.W.G.M. , Biber K.
Published: March 2004

Chemokines and chemokine receptors are important regulators of leukocyte trafficking and immune response. It is well established that chemokines and their receptors are also expressed in the central nervous system (CNS), where their expression has been associated with various neuroinflammatory diseases, such as multiple sclerosis (MS). One of the most important chemokines involved in MS pathology is CCL2 (previously known as MCP‐1). CCL2, released by glial cells, activates the chemokine receptor CCR2, causing the infiltration of blood monocytes in tissues affected by MS. There is evidence, however, that CCL2 also has local effects on CNS cells, including induction or modulation of cytokine release and synthesis of matrix metalloproteinases, that might contribute to CNS pathology. These effects are most likely independent of CCR2, since CCR2 expression in glial cells is rarely observed. We have recently provided evidence for the presence of an alternative CCL2 receptor in glial cells called L‐CCR and have investigated the expression of L‐CCR mRNA in a murine EAE model. It is shown that L‐CCR mRNA is expressed in infiltrating macrophages during EAE, but not in infiltrating T cells. Prominent expression of L‐CCR mRNA was detected in astrocytes and microglia already at early time points throughout the brain and spinal cord supporting the hypothesis that L‐CCR expression in glial cells is related to CNS inflammation. © 2004 Wiley‐Liss, Inc.
Targeted sensory restoration to the upper aerodigestive tract with physiologic implications
Authors: Urken Mark L.
Published: March 2004

Background.

Sensory restoration through sensate flaps placed into critical areas of the upper aerodigestive tract is an attractive reconstructive goal to achieve optimal post‐therapy function. The question that has remained unanswered is whether sensory recovery takes place through the newly established neural pathway or through ingrowth of sensory nerves from the periphery of the defect.

Methods.

Three patients with squamous cell cancer underwent resection and primary reconstruction of the laryngopharynx with a sensate radial forearm flap. The flaps were designed with a smaller, proximal paddle to serve as a monitor. Reneurotization of the flaps was carried out to the superior laryngeal nerve.

Results.

All three patients were followed for a minimum of 12 months. Each of these patients reported the development of a cough that resulted from stimulation of the external monitor. This phenomenon was easily duplicated by light stimulation of the monitor, which not only produced the cough but was consistently perceived by the patient as arising from inside their throat.

Conclusions.

This series conclusively demonstrates that sensory feedback can be restored in a targeted fashion through neural anastomoses and that a physiologic response that helps in airway protection can be produced through the use of sensate flaps with a strategically selected recipient nerve. © 2004 Wiley Periodicals, Inc. Head Neck 26: 287–293, 2004
Bilateral vocal fold paresis after endoscopic stapling diverticulotomy for zenker's diverticulum
Authors: Thorne Marc , Harris Philip , Marcus Keith , Teknos Theodoros N.
Published: March 2004

Background.

Zenker's diverticulum may be treated with a variety of surgical techniques. Endoscopic methods, specifically endoscopic stapling diverticulotomy, have gained increasing acceptance because of shorter operative times, decreased morbidity, with shorter hospital stays and time to resumption of oral feedings.

Methods and Results.

We report the occurrence of bilateral vocal fold paresis after endoscopic stapling diverticulotomy for Zenker's diverticulum, previously unreported in the literature. This complication likely resulted from traction on the recurrent laryngeal nerves secondary to unfavorable patient anatomy.

Conclusions.

Endoscopic stapling diverticulotomy is a safe and effective treatment method for Zenker's diverticulum and remains our procedure of choice for most patients. However, inability to safely expose the diverticulum endoscopically results in a significant abandonment rate for attempted procedures and may result in significant postoperative complications.© 2004 Wiley Periodicals, Inc. Head Neck 26: 294–297, 2004
Surgical management of maxillectomy defects based on the concept of buttress reconstruction
Authors: Yamamoto Yuhei , Kawashima Kunihiro , Sugihara Tsuneki , Nohira Kunihiko , Furuta Yasushi , Fukuda Satoshi
Published: March 2004

Background.

Few published large series have described a surgical approach to maxillary skeletal reconstruction on the basis of the extent of maxillectomy.

Methods.

We have reviewed a 10‐year experience with 38 consecutive maxillary reconstructions with respect to maxillectomy defects, reconstructive procedures, reconstructed buttresses, and functional and aesthetic outcomes.

Results.

Maxillectomy defects were classified into three categories on the basis of the buttress concept. Buttress reconstruction was most frequently performed in category III maxillary defects (56%), followed by category I (50%) and category II (20%). The vascularized composite autograft included the rectus abdominis myocutaneous free flap combined with costal cartilage, and the latissimus dorsi myocutaneous free flap combined with the V‐shaped scapula is an effective method for reliable reconstruction of both skeletal and soft tissues.

Conclusions.

A critical assessment for skeletal defects and associated soft tissue defects is essential for an adequate approach to solve complex problems in maxillary reconstruction. On the basis of retrospective analysis of this series, a reconstructive algorithm for surgical management of maxillectomy defects is proposed. © 2004 Wiley Periodicals, Inc. Head Neck 26: 247–256, 2004
Comparing cancer patients who enroll in a smoking cessation program at a comprehensive cancer center with those who decline enrollment
Authors: Schnoll Robert A. , Rothman Randi L. , Lerman Caryn , Miller Suzanne M. , Newman Holly , Movsas Benjamin , Sherman Eric , Ridge John A. , Unger Michael , Langer Corey , Goldberg Melvyn , Scott Walter , Cheng Jonathan
Published: March 2004

Background.

Despite the availability of smoking interventions for cancer patients, many eligible patients decline enrollment into such programs. We examined reasons patients provide for declining smoking treatment and compared treatment decliners to enrollees.

Methods.

Eligible cancer patients (N = 231) were offered smoking cessation treatment. During recruitment, demographic, medical (eg, cancer stage), and smoking‐related behavioral (eg, readiness to quit) data were collected, and decliners stated a reason for refusal. Patients who enrolled in the cessation program (N = 109) were compared with those who declined (N = 122) in terms of recruitment data, and reasons for declining were compiled.

Results.

Decliners were significantly more likely to: (1) have head and neck cancer (vs lung cancer); (2) exhibit fewer physical symptoms (eg, shortness of breath); (3) report a lower readiness to quit smoking; (4) indicate no intention to quit smoking; and (5) smoke fewer cigarettes. A preference to quit without professional assistance was the most common reason for declining treatment.

Conclusions.

Our findings highlight important differences between patients who enroll in a smoking cessation program and those who decline and underscore the need for motivational interventions to facilitate enrollment into smoking interventions for cancer patients. © 2004 Wiley Periodicals, Inc. Head Neck 26: 278–286, 2004
Genetically targeted radiotherapy of head and neck squamous cell carcinoma using the sodium‐iodide symporter (NIS)
Authors: Gaut Andrew W. , Niu Gang , Krager Kimberly J. , Graham Michael M. , Trask Douglas K. , Domann Frederick E.
Published: March 2004

Background.

Gene therapy that uses delivery of the sodium‐iodide symporter (NIS) gene followed by radioiodide administration has been proposed as a novel form of radiotherapy for nonthyroidal cancers.

Methods.

In vitro [125I] iodide accumulation and efflux from cells was determined after treatment with an NIS‐expressing adenovirus (Ad‐NIS). A clonogenic survival assay and tumor growth experiment that used athymic mice were used to demonstrate the in vitro and in vivo cytotoxicity of Ad‐NIS treatment and [131I] iodide delivery.

Results.

Head and neck squamous cell carcinoma (HNSCC) cell lines treated with Ad‐NIS exhibit significant amounts of radioiodide accumulation and retention. In vitro HNSCC cell survival was significantly diminished after NIS gene delivery followed by administration of [131I] iodide. Moreover, NIS gene transfer/[131I] iodide administration dramatically attenuated HNSCC tumor formation in athymic mice.

Conclusions.

Our data demonstrate the feasibility of genetically targeted radiotherapy by use of the NIS gene as a possible therapeutic intervention in head and neck cancer. © 2004 Wiley Periodicals, Inc. Head Neck 26: 265–271, 2004
mTHPC‐mediated photodynamic therapy in patients with advanced, incurable head and neck cancer: a multicenter study of 128 patients
Authors: D'Cruz Anil K. , Robinson Martin H. , Biel Merrill A.
Published: March 2004

Background.

The aim of this multicenter study was to assess tumor response, clinical quality‐of‐life benefit, survival, and safety after treatment with mTHPC in patients with recurrent/refractory squamous cell carcinoma of the head and neck unsuccessfully treated or unsuitable for treatment with conventional modalities.

Methods.

One hundred twenty‐eight patients were treated with mTHPC followed, 96 hours later, by illumination of the tumor surface with 652‐nm laser light. Tumor response was assessed with WHO criteria and tumor mass reduction from baseline. Clinical quality‐of‐life benefit was based on the University of Washington Quality‐of‐Life questionnaire.

Results.

By use of WHO criteria, 38% of evaluable patients achieved an overall tumor response, and 16% achieved a complete tumor response. Forty‐three percent of assessable lesions achieved 100% tumor mass reduction, and 58% achieved 50% or greater tumor mass reduction. Fifty‐three percent of evaluable patients experienced significant clinical quality‐of‐life benefit. Subset analyses revealed two subgroups in which significantly better responses were seen in patients with tumors 10 mm or less in depth and patients with fully illuminated lesions. In patients fulfilling both categories, overall tumor response was 54%, complete tumor response was 30%, and 61% demonstrated significant clinical quality‐of‐life benefit. Median survival was significantly better in responders. No major toxicities were detected.

Conclusions.

Patients with advanced cancer of the head and neck, who have exhausted other treatment options, can achieve significant clinical benefit and improvement in quality of life with mTHPC. © 2004 Wiley Periodicals, Inc. Head Neck 26: 232–240, 2004
Postoperative brachytherapy alone and combined postoperative radiotherapy and brachytherapy boost for squamous cell carcinoma of the oral cavity, with positive or close margins
Authors: Lapeyre Michel , Bollet Marc A. , Racadot Severine , Geoffrois Lionnel , Kaminsky Marie‐Christine , Hoffstetter Sylvette , Dolivet Gilles , Toussaint Bruno , Luporsi Elisabeth , Peiffert Didier
Published: March 2004

Background.

Postoperative radiotherapy is necessary for squamous cell carcinoma (SCC) of the oral cavity with positive or close margins. The aim of the study is to define the indications of postoperative brachytherapy (BRT).

Methods.

From 1979 to 1993, 82 patients with positive or close margins had postoperative BRT (58 T1–2, 24 T3–4, 45 mobile tongue, 37 floor of mouth). Forty‐six patients had combined radiotherapy (RT) with a mean dose of 48 Gy, and BRT boost with a mean dose of 24 Gy. Thirty‐six patients had BRT alone with a mean dose of 60 Gy. BRT was performed with interstitial low dose rate Iridium 192.

Results.

Overall survival (OS), cause‐specific survival (CSS), and local control (LC) at 5 years were, respectively, for T1–2/N0N− with BRT, 75%, 85%, and 88%,and with RT‐BRT 70%, 92%, and 92%; for T1–2/N+ with RT‐BRT, 44%, 67%, and 78%; for T3–4/N− with RT‐BRT, 42%, 90%, and 80%; and for T3–4/N+ with RT‐BRT, 22%, 43%, and 57%. Prognostic factors for OS, CSS, and LC were N+ (p ≤ .009), extracapsular spread (ECS+;p ≤ .000001), and T stage for LC only (p = .02). Prognostic factors for complications were a high number of wires with a cutoff at five wires (p = .008), a high dose rate with a cutoff at 0.57 Gy/hr (p = .01), and a high total dose (BRT + RT) with a cutoff at 71 Gy (p = .07).

Conclusions.

BRT alone for SCC T1–2/N0N− is better than RT‐BRT because, with equivalent results, it avoids the adverse events of postoperative RT (xerostomia) and permits the treatment of a second head and neck primary in nonirradiated tissue. The results for the T3–4/N− are acceptable with this approach (ie, RT‐BRT) but may be improved for N+. © 2004 Wiley Periodicals, Inc. Head Neck 26: 216–223, 2004
MELD score as a predictor of pretransplant and posttransplant survival in OPTN/UNOS status 1 patients
Authors: Kremers Walter K. , van IJperen Marrije , Kim Ray W. , Freeman Richard B. , Harper Ann M. , Kamath Patrick S. , Wiesner Russell H.
Published: March 2004

The Model for End-Stage Liver Disease (MELD) score is predictive of survival and is used to prioritize patients with chronic liver disease patients for orthotopic liver transplantation (OLT). The aims of this study are (1) to assess the ability of MELD score at listing to predict pretransplant and posttransplant survival for nonchronic liver disease patients listed with the Organ Procurement and Transplantation Network/ United Network for Organ Sharing (OPTN/UNOS) as Status 1; and (2) to compare survival associated with 4 diagnostic groups within the Status 1 designation. The study population consisted of adult patients listed for OLT at Status 1 in the UNOS national database between November 1, 1999 and March 14, 2002 (N = 720). Events within 30 days of listing were analyzed using Kaplan-Meier and Cox regression methodology. Patients meeting criteria for fulminant hepatic failure without acetaminophen toxicity (FHF-NA, n = 312) had the poorest survival probability while awaiting OLT; this was negatively correlated with MELD score (P = .0001). These patients experienced the greatest survival benefit associated with OLT, with an estimated improvement of survival from about 58% to 91% (P < .0001). Patients listed for primary nonfunction within 7 days of OLT (n = 268) did not show mortality to be related to MELD score (P = .41) and did not show a significant association between survival and OLT (P = .68). In conclusion, liver allocation within the Status 1 designation may need to be further stratified by diagnosis, and MELD score may be useful for prioritizing FHF-NA candidates. (Hepatology 2004;39:764-769.)
Immortalized p19ARF null hepatocytes restore liver injury and generate hepatic progenitors after transplantation
Authors: Mikula Mario , Fuchs Eva , Huber Heidemarie , Beug Hartmut , Schulte-Hermann Rolf , Mikulits Wolfgang
Published: March 2004

Primary hepatocytes are blocked in mitotic activity and well-defined culture conditions only allow the limited expansion of these cells. Various genetic modifications have therefore been employed to establish immortalized hepatic cell lines, but, unfortunately, proper hepatocyte cultures conducting a faithful hepatic gene expression program and lacking malignancy are hardly available. Here we report the immortalization of primary hepatocytes isolated from p19ARF null mice using the rationale that loss of p19ARF lowers growth-suppressive functions of p53 and bypasses cellular senescence without losing genetic stability. The established hepatocytes, called MIM, express liver-specific markers, show a nontumorigenic phenotype, and competence to undergo Fas-mediated apoptosis. Intrasplenic transplantation of GFP-expressing parental MIM cells into Fas-injured livers of SCID mice revealed liver-reconstituting activity. In the regenerated liver, MIM cells localized in small-sized clusters and showed presence in structures comparable to canals of Hering, the site of oval cells. Transplantation of MIM-Bcl-XL cells, which are protected against apoptosis, and successive Fas-induced liver damage, enhanced donor-derived liver repopulation by showing differentiation into cholangiocytes and cells expressing markers characteristic of both fetal hepatocytes and oval cells. In conclusion, these data indicate that long-term cultivated p19ARF null hepatocytes are capable of generating hepatic progenitor cells during liver restoration, and thus represent a highly valuable tool to study the differentiation repertoire of hepatocytes. (Hepatology 2004;39:628-634.)
Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: Results of a randomized trial
Authors: Lindor Keith D. , Kowdley Kris V. , Heathcote Jenny E. , Harrison Edwyn M. , Jorgensen Roberta , Angulo Paul , Lymp James F. , Burgart Lawrence , Colin Patrick
Published: March 2004

No effective medical therapy is available for all patients with nonalcoholic steatohepatitis (NASH). Ursodeoxycholic acid (UDCA) has been suggested to be of benefit based on open label clinical studies. We randomized 166 patients with liver biopsy-proven NASH to receive between 13 and 15 mg/kg/d of UDCA or placebo for 2 years. End points included changes in liver test results and liver histology at 2 years of therapy. The treatment groups were comparable at entry with regard to age, gender, risk factors for NASH, serum liver biochemistries, and baseline liver histology. A total of 126 patients completed 2 years of therapy. Pre- and posttreatment liver biopsies were available in 107 patients for review at the end of the study. UDCA was well tolerated and body weight was stable during the study duration. Serum liver biochemistries were stable or improved in both the UDCA and placebo-treated groups. Changes in the degree of steatosis, necroinflammation, or fibrosis that occurred with therapy were not significantly different between the UDCA and placebo groups. In conclusion, 2 years of therapy with UDCA at a dose of 13 to 15 mg/kg/d, although safe and well tolerated, is not better than placebo for patients with NASH. (Hepatology 2004;39:770-778.)
Is fibrolamellar carcinoma different from hepatocellular carcinoma? A US population-based study
Authors: El-Serag Hashem B. , Davila Jessica A.
Published: March 2004

There have been no population-based studies of the epidemiology and prognosis of patients with fibrolamellar carcinoma (FLC). We conducted a retrospective cohort study using information collected by population-based registries of the Surveillance, Epidemiology, and End Results (SEER) program. The demographic features, stage at diagnosis, and type of therapy, as well as age-adjusted incidence rates and observed and relative survival rates were compared between persons with FLC and those with hepatocellular carcinoma (HCC) diagnosed between 1986 and 1999. A multivariate Cox proportional hazards model was constructed to examine the effect of histology (FLC vs. HCC) on the risk of mortality. There were 68 microscopically confirmed cases of FLC and 7,896 cases of HCC. FLC constituted 0.85% of all cases of primary liver cancer and 13.4% of all cases below the age of 40. Compared to HCC, patients with FLC were more likely to be younger (mean age 39 vs. 65), female (51.5% vs. 26.3%), and white (85.3% vs. 56.9%). A greater proportion of case with FLC had localized disease (41.2% vs. 30.9%), or received potentially curative therapy (resection, transplantation), compared to cases with HCC. The age-adjusted incidence rate for FLC was 0.02 per 100,000; No significant differences in age-adjusted incidence rates were observed by gender or race. The 1- and 5-year observed and relative survival rates were significantly longer in patients with FLC than HCC. The 5-year relative survival rate was 31.8% (95% CI, 20.5%-43.1%) for FLC, compared with 6.8% (95% CI, 6.3 %-7.4 %) for HCC. Adjusting for differences in age, gender, race, stage of disease, receipt of resection or transplantation, and time of diagnosis, FLC was independently associated with a 46% reduction in risk of mortality within 5years compared with HCC. In conclusion, in a population-based study, we observed remarkable differences in the epidemiology and prognosis of FLC compared to HCC. (Hepatology 2004;39:798-803.)
P-selectin suppresses hepatic inflammation and fibrosis in mice by regulating interferon γ and the IL-13 decoy receptor
Authors: Wynn Thomas A. , Hesse Matthias , Sandler Netanya G. , Kaviratne Mallika , Hoffmann Karl F. , Chiaramonte Monica G. , Reiman Rachael , Cheever Allen W. , Sypek Joseph P. , Mentink-Kane Margaret M.
Published: March 2004

The selectin family of cell adhesion molecules is widely thought to promote inflammatory reactions by facilitating leukocyte recruitment. However, it was unexpectedly found that mice with targeted deletion of the P-selectin gene (PsKO mice) developed unpolarized type 1/type 2 cytokine responses and severely aggravated liver pathology following infection with the type 2-promoting pathogen Schistosoma mansoni. In fact, liver fibrosis, which is dependent on interleukin 13 (IL-13), increased by a factor of more than 6, despite simultaneous induction of the antifibrotic cytokine interferon gamma (IFN-γ). Inflammation, as measured by granuloma size, also increased significantly in the absence of P-selectin. When infected PsKO mice were treated with neutralizing anti-IFN-γ monoclonal antibodies, however, granuloma size was restored to wild-type levels; this finding revealed the potent proinflammatory role of IFN-γ when expressed concomitantly with IL-13. Untreated PsKO mice also exhibited a significant (sixfold) reduction in decoy IL-13 receptor (IL-13 receptor alpha-2) expression when compared with infected wild-type animals. It is noteworthy, however, that when decoy receptor activity was restored in PsKO mice by treatment with soluble IL-13 receptor alpha-2-Fc, the exacerbated fibrotic response was completely inhibited. Thus, reduced expression of the decoy IL-13 receptor mediated by the elevated type 1 cytokine response probably accounts for the enhanced activity of IL-13 in PsKO mice and for the resultant increase in collagen deposition. In conclusion, the current study has revealed the critical role of P-selectin in the progression of chronic liver disease caused by schistosome parasites. By suppressing IFN-γ and up-regulating the decoy IL-13 receptor, P-selectin dramatically inhibits the pathologic tissue remodeling that results from chronic type 2 cytokine-mediated inflammation. (Hepatology 2004;39:676-687.)
Recombinant activated factor VII (rFVIIa) as a hemostatic agent in liver disease: A break from convention in need of controlled trials
Authors: Caldwell Stephen H. , Chang Charissa , Macik Gail B.
Published: March 2004

The management of coagulopathy in patients with acute and chronic liver disease has undergone little change in many years despite advances in our understanding of the pathogenesis of this problem. In general, deficiency of clotting factors as a result of poor hepatic synthetic function accounts for most of the coagulopathy. However, other processes such as disseminated intravascular coagulation (DIC), hyperfibrinolysis, dysfibrinogenemia, hemolysis, and a decrease in number or function of platelets may be present and thus add to the complexity of the problem. Coexisting portal hypertension and the associated risks of volume expansion, renal failure, and endothelial dysfunction add even more difficulty to the management of these patients. The clinician's despair is only exacerbated by uncertainty regarding the significance of laboratory indices of coagulation and the lack of agreement between health care providers regarding how to use these indices. Simple, conventional interventions such as vitamin K or plasma administration often produce only limited amelioration, and the latter carries the potential disadvantage of volume overexpansion as well as the risk of infection and transfusion reactions. Into this complex and uncertain clinical situation has arrived the antihemophilic agent recombinant activated factor VII (rFVIIa). Its development has led to a fundamental re-evaluation of the classic understanding of the normal clotting cascade. Moreover, use of this product in liver disease patients is increasing despite the lack of definitive studies or literature to guide therapy. Herein we review the mechanism of action of this agent, report the clinical applications in patients with liver disease, address the limitations and risks associated with the drug, and discuss the issue of its cost-effectiveness. (Hepatology 2004;39:592-598)
The construct of the learning organization: Dimensions, measurement, and validation
Authors: Yang Baiyin , Watkins Karen E. , Marsick Victoria J.
Published: March 2004

This research describes efforts to develop and validate a multidimensional measure of the learning
organization. An instrument was developed based on a critical review of both the conceptualization and practice of
this construct. Supporting validity evidence for the instrument was obtained from several sources, including best
model‐data fit among alternative measurement models, nomological network among dimensions of the learning
organization, and organizational performance outcomes. Acceptable reliability estimates were obtained for the
seven proposed dimensions. Consequently, the instrument, Dimensions of the Learning Organization Questionnaire,
was recommended for use in organizational studies.
Should child labor be eliminated? An HRD perspective
Authors: Budhwani Nadir , Wee Belinda , McLean Gary N.
Published: March 2004

Child labor, especially in developing countries, has been an increasing target for social reformers. Although
there are many suggested solutions for the eradication of child labor, many are simplistic and create more
problems than they cure. Suggested reforms are explored and analyzed. Additional recommendations, especially
from a human resource development perspective, are explored.
Direct injection of immature dendritic cells into irradiated tumor induces efficient antitumor immunity
Authors: Kim Kwang‐Woon , Kim Sun‐Hee , Shin Jin‐Gue , Kim Gui‐Sook , Son Young‐Ok , Park Soon‐Won , Kwon Byung‐Hyun , Kim Dong‐Won , Lee Chang‐Hun , Sol Mee‐Young , Jeong Min‐Ho , Chung Byung‐Seon , Kang Chi‐Dug
Published: March 2004

Although there are several ways to load tumor antigens to DCs, in vitro preparation of tumor antigens and manipulation of DCs are usually required. Therefore, to develop a simple antitumor immunization method, we examined if direct injection of DCs into tumor apoptosed by ionizing IR could induce efficient antitumor immunity. Ionizing IR with 15 Gy induced apoptosis in tumor maximally after 6 hr. Injection of DCs i.t. into IR tumor induced strong cytotoxicity of splenocytes against tumor cells compared to i.t. injection of DCs or ionizing IR of tumor, both of which induced weak cytotoxicity. In an animal study, i.t. injection of DCs into IR tumor induced therapeutic antitumor immunity against a tumor established at a distant site. Moreover, when TNF‐α or LPS was added as a danger/maturation signal to DC suspension before i.t. injection, antitumor immunity was significantly potentiated compared to a group treated with i.t. injection of DCs into IR tumor. Our results suggest that injection of DCs into tumor apoptosed by ionizing IR might be a simple and efficient method of immunization against tumor. © 2004 Wiley‐Liss, Inc.
Explaining gastric cancer survival differences among European countries
Authors: Verdecchia Arduino , Corazziari Isabella , Gatta Gemma , Lisi Daniele , Faivre Jean , Forman David
Published: March 2004

Wide geographic variability in incidence and mortality rates for gastric cancer exists throughout the world despite persistent decreases over several decades. Variability in survival from gastric cancer is also evident and countries with higher incidence rates of gastric cancer show better survival rates than countries with lower incidence. The aim of this study was to identify reasons for the association between incidence and survival and to obtain survival estimates and differences corrected for this variation, thus facilitating further interpretation by clinical factors such as stage and treatment. Relative survival rates for gastric cancer derived from the EUROCARE‐2 database for 47 cancer registries in 17 European countries were analyzed with regression methods to adjust differences by age, sex, period of diagnosis, subsite of the stomach, histologic type and stage at diagnosis. Overall, nearly 60% of the variability in gastric cancer relative survival was explained by differences in these variables. Factors are related to treatment and general management of patients is expected to explain the residual variability in gastric cancer survival between European countries. There is a need to improve completeness and standardization of detailed information collected on gastric cancer patients to allow detailed comparative analyses and interpretation. © 2004 Wiley‐Liss, Inc.
Chemotherapy of glioblastoma in rats using doxorubicin‐loaded nanoparticles
Authors: Steiniger Sebastian C.J. , Kreuter Jörg , Khalansky Alexander S. , Skidan Igor N. , Bobruskin Alexey I. , Smirnova Zoya S. , Severin Sergey E. , Uhl Reiner , Kock Martin , Geiger Kathrin D. , Gelperina Svetlana E.
Published: March 2004

Glioblastomas belong to the most aggressive human cancers with short survival times. Due to the blood‐brain barrier, they are mostly inaccessible to traditional chemotherapy. We have recently shown that doxorubicin bound to polysorbate‐coated nanoparticles crossed the intact blood‐brain barrier, thus reaching therapeutic concentrations in the brain. Here, we investigated the therapeutic potential of this formulation of doxorubicin in vivo using an animal model created by implantation of 101/8 glioblastoma tumor in rat brains. Groups of 5–8 glioblastoma‐bearing rats (total n = 151) were subjected to 3 cycles of 1.5–2.5 mg/kg body weight of doxorubicin in different formulations, including doxorubicin bound to polysorbate‐coated nanoparticles. The animals were analyzed for survival (% median increase of survival time, Kaplan‐Meier). Preliminary histology including immunocytochemistry (glial fibrillary acidic protein, ezrin, proliferation and apoptosis) was also performed. Rats treated with doxorubicin bound to polysorbate‐coated nanoparticles had significantly higher survival times compared with all other groups. Over 20% of the animals in this group showed a long‐term remission. Preliminary histology confirmed lower tumor sizes and lower values for proliferation and apoptosis in this group. All groups of animals treated with polysorbate‐containing formulations also had a slight inflammatory reaction to the tumor. There was no indication of neurotoxicity. Additionally, binding to nanoparticles may reduce the systemic toxicity of doxorubicin. This study showed that therapy with doxorubicin bound to nanoparticles offers a therapeutic potential for the treatment of human glioblastoma. © 2004 Wiley‐Liss, Inc.
Expression mapping at 12p12‐13 in advanced prostate carcinoma
Authors: Kibel Adam S. , Huagen John , Guo Chan , Isaacs William B. , Yan Yan , Pienta Kenneth J. , Goodfellow Paul J.
Published: March 2004

We have previously mapped a putative prostate cancer tumor‐suppressor gene to a 1–2 Mb region of 12p12‐13. Initial work to identify the tumor suppressor at this locus focused on candidates previously implicated in malignancy; however, mutational and methylation analyses failed to identify significant genomic events. An alternative approach is to use expression analysis to prioritize the genes within the region of interest. This experimental design is based on the hypothesis that tumor‐suppressor genes demonstrate decreased expression in tumors compared to normals. Herein, we narrow the region of interest using deletion mapping data and employ expression analysis to prioritize the genes in the minimal deleted region. Highly informative polymorphic markers spanning our region were used to assess for loss of heterozygosity in 99 tumor and normal DNA pairs. The minimal region of deletion was determined to be approximately 500 kb bounded by D12S391 and A002Q26. Publically available databases place 7 genes within this minimal deletion region. An additional 3 genes lie just outside this minimal deletion region and could possibly be inactivated by deletion of promoter, 3′‐untranslated region sequences or alternative splice variants. Relative levels of expression of these 10 candidate genes were determined in 6 normal prostates, 5 local prostate tumors, 9 prostate lymph node metastases, 6 prostate cancer cell lines and 12 prostate cancer xenografts using quantitative RT‐PCR. DUSP16, FLJ10298 and BCLG were significantly downregulated in both clinical tumors and cultured prostate cancer tissue, indicating that one or all may be critical to initiation or progression of prostate carcinoma. © 2004 Wiley‐Liss, Inc.
A vitamin E analogue suppresses malignant mesothelioma in a preclinical model: A future drug against a fatal neoplastic disease?
Authors: Tomasetti Marco , Gellert Nina , Procopio Antonio , Neuzil Jiri
Published: March 2004

Malignant mesothelioma is a fatal type of neoplasia of the pleura and the peritoneum with currently no known cure. Therefore, discovery of an efficient antimesothelioma drug with low deleterious side effects is desirable. Here, we studied in vivo the effect of α‐tocopheryl succinate, a semisynthetic vitamin E analogue with proapoptotic and anticancer activity and selectivity for malignant cells, on experimental peritoneal mesothelioma using immunocompromised mice. Compared to untreated animals, the agent increased their survival >3‐fold. Our finding warrants further testing of vitamin E analogues as potential antimesothelioma drugs. © 2004 Wiley‐Liss, Inc.
Effect of hydroxyapatite/tricalcium‐phosphate coating on osseointegration of plasma‐sprayed titanium alloy implants
Authors: Stewart Matthew , Welter Jean F. , Goldberg Victor M.
Published: March 2004

This study determined the effects of a plasma‐sprayed hydroxyapatite/tricalcium phosphate (HA/TCP) coating on osseointegration of plasma‐sprayed titanium alloy implants in a lapine, distal femoral intramedullary model. The effects of the HA/TCP coating were assessed at 1, 3, and 6 months after implant placement. The HA/TCP coating significantly increased new bone apposition onto the implant surfaces at all time points. The ceramic coating also stimulated intramedullary bone formation at the middle and distal levels of the implants. Fluorescent bone labeling indicated that new bone formation occurred primarily during the first 3 months after implantation, with comparatively little activity detected in the latter stages of the study. There was no associated increase in pullout strength at either 3 or 6 months; however, post‐pullout evaluation of the implants indicated that the HA/TCP coating itself was not the primary site of construct failure. Rather, failure was most commonly observed through the periprosthetic osseous struts that bridged the medullary cavity. The demonstrated osteoconductive activity of HA/TCP coating on plasma‐sprayed titanium alloy implant surfaces may have considerable clinical relevance to early host–implant interactions, by accelerating the establishment of a stable prosthesis–bone interface. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 69A: 1–10, 2004
Biocompatibility of a xenogenic elastin‐based biomaterial in a murine implantation model: The role of aluminum chloride pretreatment
Authors: Hinds Monica T. , Courtman David W. , Goodell Teresa , Kwong Mason , Brant‐Zawadzki Halina , Burke Allen , Fox Bernard A. , Gregory Kenton W.
Published: March 2004

We have investigated the long‐term effect of aluminum chloride (AlCl3) treatment on the calcification and inflammatory reaction of a porcine elastin‐derived biomaterial (PEB) in a novel subdermal adult mouse model. Untreated PEB disks and PEB treated with AlCl3 were implanted subdermally in BALB/c mice for 30, 60, and 180 days. The calcification of the elastin disks was examined with histological analysis and atomic absorption analysis of calcium content. The inflammatory reaction was evaluated both with histological analysis of explants and by an enzyme‐linked immunosorbent assay of the serum in each mouse to determine the production of antielastin antibodies. Robust calcification was evident in all untreated PEBs with calcium levels of 107.1 ± 11.8, 151.4 ± 14.4, and 227.2 ± 23.8 μg/mg for 30, 60, and 180 days, respectively. AlCl3 treatment only temporarily prevented the calcification of the elastin disks for 30 days. By 60 and 180 days, the AlCl3‐treated materials had significant calcification with 88.7 ± 17.4 and 105.3 ± 27.0 μg/mg calcium, respectively. The inflammatory reaction was moderate for both types of implants. The AlCl3‐treated implants displayed significantly more macrophage and lymphocyte infiltration at 180 days after implantation, and a trend to higher humoral responses at 30 and 60 days when compared with untreated PEBs. We conclude that PEBs extensively calcify in the adult mice model. AlCl3 treatment of elastin enhances the long‐term immunological response to xenogenic elastin implants and merely delays the onset of calcification. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 69A: 55–64, 2004