bluuebunny/crossref_metadata_2025 huggingface dataset:
Paroxetine Is an Effective Treatment for Hot Flashes: Results From a Prospective Randomized Clinical Trial
Authors: Stearns Vered , Slack Rebecca , Greep Nancy , Henry-Tilman Ronda , Osborne Michael , Bunnell Craig , Ullmer Lynda , Gallagher Ann , Cullen Jennifer , Gehan Edmund , Hayes Daniel F , Isaacs Claudine
Published: September 2005

Purpose

In an open-label trial we have previously demonstrated that paroxetine reduces hot flashes. We initiated a stratified, randomized, double-blind, cross-over, placebo-controlled trial to investigate the efficacy of paroxetine 10 mg and 20 mg compared to placebo in reducing hot flash frequency and composite score. A secondary objective was to evaluate quality of life (QOL) parameters.

Patients and Methods

Women who suffered at least two hot flashes a day for 1 month or longer were eligible. Women were randomly assigned to 4 weeks of paroxetine 10 mg or 20 mg followed by placebo for 4 weeks, or placebo for 4 weeks followed by paroxetine 10 mg or 20 mg for 4 weeks. Participants completed baseline daily hot flash diaries for one week prior to the start of the study and throughout the study, and QOL questionnaires at baseline, week 5 and week 9.

Results

279 women were screened, and 151 were randomly assigned. Paroxetine 10 mg reduced hot flash frequency and composite score by 40.6% and 45.6%, respectively, compared to 13.7% and 13.7% for placebo (P = .0006 and P = .0008, respectively). Paroxetine 20 mg reduced hot flash frequency and composite score by 51.7% and 56.1%, respectively, compared with 26.6% and 28.8% for placebo (P = .002 and P = .004, respectively). Efficacy was similar between the two doses, but women were less likely to discontinue low-dose paroxetine. Paroxetine 10 mg was associated with a significant improvement in sleep compared with placebo (P = .01).

Conclusion

Paroxetine is an effective treatment for hot flashes in women with or without a prior breast cancer.
Population-Based Analysis of Prognostic Factors and Survival in Familial Melanoma
Authors: Florell Scott R. , Boucher Kenneth M. , Garibotti Gilda , Astle John , Kerber Richard , Mineau Geraldine , Wiggins Charles , Noyes R. Dirk , Tsodikov Alexander , Cannon-Albright Lisa A. , Zone John J. , Samlowski Wolfram E. , Leachman Sancy A.
Published: September 2005

Purpose

Familial melanoma patients are reported to present with thinner melanomas, to be younger at the time of diagnosis, and to have a greater likelihood of developing multiple primary tumors. We sought to determine whether melanomas that occur in a familial setting demonstrate different prognostic and survival statistics relative to sporadic melanoma.

Patients and Methods

This population-based study used the Utah Cancer Registry and Utah Population Database to objectively evaluate prognostic and survival statistics of the familial melanoma population. From 1973 to 1999, there were 7,785 cases of invasive melanoma identified through the Utah Cancer Registry. These were linked to the Utah Population Database, resulting in 2,659 subjects with family-history information from which a familiality score could be calculated. Cases scored in the top ninth percentile were assigned as high familial risk, and the remaining 91% were considered low familial risk.

Results

Multivariate logistic-regression analysis found no association between sex, Breslow depth, Clark level, or survival and the familial status. Age at first diagnosis of invasive melanoma was slightly lower in the high-familial-risk group (57 v 60 years; P = .03). High-familial-risk subjects had more melanomas diagnosed at age 30 or younger (12% v 6%; P < .001). A significant difference in the overall number of individuals with two or more primary malignant melanomas was not detected among the groups (P = .2).

Conclusion

These data suggest that melanomas occurring in the context of an underlying inherited susceptibility do not have a significantly different biologic behavior.
Late Effects of Pelvic Rhabdomyosarcoma and Its Treatment in Female Survivors
Authors: Spunt Sheri L. , Sweeney Teresa A. , Hudson Melissa M. , Billups Catherine A. , Krasin Matthew J. , Hester Allison L.
Published: September 2005

Purpose

To document the spectrum and severity of late effects in female survivors of pelvic rhabdomyosarcoma.

Patients and Methods

We reviewed the demographic, diagnostic, treatment, and outcome data of the 26 females treated for pelvic rhabdomyosarcoma at our institution between March 1962 and December 1996 who survived free of disease for 5 or more years. Adverse effects that occurred 5 or more years after diagnosis were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.

Results

The most common tumor sites were vagina (n = 7), pelvis/retroperitoneum (n = 6), and bladder (n = 4). All patients received chemotherapy (alkylating agent, n = 23; doxorubicin, n = 16); 22 received radiotherapy (median dose, 46 Gy). Median follow-up of the 23 survivors was 20.3 years. Late effects occurred in 24 patients, 23 of whom had grade 3/4 late effects (median grade 3/4 late effects per patient, three; range, zero to 14). Fourteen patients (54%) required surgery for late complications. The 22 patients who had received radiotherapy had a greater median number of late effects per patient than did the remaining four (9.5 v one; P = .002). The median number of late effects per patient was higher in the 12 patients treated during or after 1984 than in the 14 treated earlier (12.5 v 6.5; P = .041).

Conclusion

The burden of late effects in girls treated for pelvic rhabdomyosarcoma is significant and does not seem to be diminishing with advances in treatment. Prospective studies are needed to better assess the impact of these late effects on quality of life and functional outcome, and to refine the treatment approach to pelvic rhabdomyosarcoma.
Impact of Total Lymph Node Count on Staging and Survival After Gastrectomy for Gastric Cancer: Data From a Large US-Population Database
Authors: Smith David D. , Schwarz Rebecca R. , Schwarz Roderich E.
Published: September 2005

Background

Prognosis of potentially curable (M0), completely resected gastric cancer is primarily determined by pathologic T and N staging criteria. The optimal regional dissection extent during gastrectomy for gastric adenocarcinoma continues to be debated.

Methods

A gastric cancer data set was created through structured queries to the Surveillance, Epidemiology, and End Results database (1973 to 1999). Relationships between the number of lymph nodes (LNs) examined and survival were analyzed for the stage subgroups T1/2N0, T1/2N1, T3N0, and T3N1.

Results

In every stage subgroup, overall survival was highly dependent on the number of LNs examined. Multivariate prognostic variables in the T1/2N0M0 subgroup were number of LNs examined, age (for both, P < .0001), race (P = .0004), sex (P = .0006), and tumor size (P = .02). A linear trend for superior survival based on more LNs examined could be confirmed for all four stage subgroups. Baseline model–predicted 5-year survival with only one LN examined was 56% (T1/2N0), 35% (T1/2N1), 29% (T3N0), or 13% (T3N1). For every 10 extra LNs dissected, survival improved by 7.6% (T1/2N0), 5.7% (T1/2N1), 11% (T3N0), or 7% (T3N1). A cut-point analysis yielded the greatest survival difference at 10 LNs examined but continued to detect significantly superior survival differences for cut points at up to 40 LNs, always in favor of more LNs examined.

Conclusion

Although the impact of stage migration versus improved regional disease control cannot be separated on basis of the available information, the data provide support in favor of extended lymphadenectomy during potentially curative gastrectomy for gastric cancer.
Phase III Study of Adjuvant Vaccination With Bec2/Bacille Calmette-Guerin in Responding Patients With Limited-Disease Small-Cell Lung Cancer (European Organisation for Research and Treatment of Cancer 08971-08971B; Silva Study)
Authors: Giaccone Giuseppe , Debruyne Channa , Felip Enriqueta , Chapman Paul B. , Grant Stefan C. , Millward Michael , Thiberville Luc , D'addario Giannicola , Coens Corneel , Rome Lisa S. , Zatloukal Petr , Masso Oriol , Legrand Catherine
Published: September 2005

Purpose

Bec2 is an anti-idiotypic antibody that mimics GD3, a ganglioside that is expressed on the surface of tumor cells and is of neuroectodermal origin. We assessed whether Bec2/bacille Calmette-Guerin (BCG) vaccination prolongs survival in patients with limited-disease small-cell lung cancer (SCLC) after a major response to chemotherapy and chest radiation.

Patients and Methods

Patients were randomly assigned to receive five vaccinations of Bec2 (2.5 mg)/BCG vaccine or follow-up. Vaccination was given over a 10-week period. The sample size was targeted to detect an increase in median survival of 40% after random assignment, and stratification was by performance status, response, and institution. Quality of life was assessed by using the European Organisation for Research and Treatment of Cancer instrument. Humoral response was assessed in patients who received vaccination.

Results

A total of 515 patients were randomly assigned. The primary toxicities of vaccination were transient skin ulcerations and mild flu-like symptoms. There was no improvement in survival, progression-free survival, or quality of life in the vaccination arm. Median survival from randomization was 16.4 and 14.3 months in the observation and vaccination arms (P = .28), respectively. Among vaccinated patients, a trend toward prolonged survival was observed in those (one third) who developed a humoral response (P = .085). Multivariate analysis showed a positive impact on survival by prior treatment with concomitant chemoradiotherapy, prophylactic cranial irradiation, female sex, low lactate dehydrogenase, and normal platelets.

Conclusion

Vaccination with Bec2/BCG has no impact on outcome of patients with limited-disease SCLC responding to combined-modality treatment. Vaccination strategies in SCLC may still be warranted using vaccines that produce a better immunologic response.
Incidence of Late-Relapse Germ Cell Tumor and Outcome to Salvage Chemotherapy
Authors: Ronnen Ellen A. , Kondagunta G. Varuni , Bacik Jennifer , Marion Stephanie , Bajorin Dean F. , Sheinfeld Joel , Bosl George J. , Motzer Robert J.
Published: September 2005

Purpose

To define the incidence, clinical features, and outcome to salvage chemotherapy in patients with late-relapse germ cell tumor (GCT) after a complete response to first-line chemotherapy.

Patients and Methods

Two patient populations were examined. First, retrospective analysis of 246 patients treated on a clinical trial with salvage chemotherapy was performed; 29 patients with late-relapse GCT were identified and evaluated for treatment outcome and survival. Salvage regimens included paclitaxel, ifosfamide, and cisplatin, single agents, or a high-dose chemotherapy program. Second, the incidence of late relapse was assessed by retrospective analysis of 551 patients after a complete response (CR) to first-line chemotherapy.

Results

Twenty-nine patients received salvage chemotherapy on a clinical trial for late relapse GCT. The median survival was 23.9 months. At a median follow-up of 50.6 months, there were nine survivors. The chemotherapy regimens varied, but the only CRs were observed in patients treated with paclitaxel, ifosfamide, and cisplatin. Seven (50%) of 14 patients treated with paclitaxel, ifosfamide, and cisplatin achieved a continuous CR. Among the second population of 551 patients who had previously achieved a CR to a first-line chemotherapy trial, 17 were identified as having a late relapse (3%). The median time to relapse for these 17 patients was 7.8 years.

Conclusion

Late-relapse GCT is uncommon and is associated with a poor prognosis resulting from a high degree of resistance to chemotherapy. Chemotherapy with paclitaxel, ifosfamide, and cisplatin followed by surgery may be effective in patients with late-relapse GCT who are not considered candidates for primary surgery.
Concurrent Hyperfractionated Radiotherapy and Low-Dose Daily Carboplatin/Paclitaxel in Patients With Early-Stage (I/II) Non–Small-Cell Lung Cancer: Long-Term Results of a Phase II Study
Authors: Jeremić Branislav , Milicić Biljana , Acimović Ljubisa , Milisavljević Slobodan
Published: September 2005

Purpose

Feasibility and activity of concurrent hyperfractionated radiotherapy (Hfx RT) and low-dose, daily carboplatin and paclitaxel were investigated in patients with early-stage (I/II) non–small-cell lung cancer in a phase II study.

Patients and Methods

Fifty-six patients started their treatment on day 1 with 30 mg/m2 of paclitaxel. Hfx RT using 1.3 Gy bid to a total dose of 67.6 Gy and concurrent low-dose daily carboplatin 25 mg/m2 and paclitaxel 10 mg/m2, both given Mondays through Fridays during the RT course, started from the second day.

Results

There were 29 complete responses (52%) and 15 partial responses (27%), and 12 patients (21%), experienced stable disease. The median survival time was 35 months, and 3- and 5-year survival rates were 50% and 36%, respectively. The median time to local progression has not been achieved, but 3- and 5-year local progression-free survival rates were 56% and 54%, respectively. The median time to distant metastasis has not been achieved, but 3- and 5- year distant metastasis-free survival rates were 61% and 61%, respectively. The median and 5-year cause-specific survivals were 39 months and 43%, respectively. Acute high-grade (> 3) toxicity was hematologic (22%), esophageal (7%), or bronchopulmonary (7%). No grade 5 toxicity was observed. Late high-grade toxicity was rarely observed (total, 10%).

Conclusion

Hfx RT and concurrent low-dose daily carboplatin/paclitaxel was feasible with low toxicity and effective in patients with stage I/II non–small-cell lung cancer. It should continue to be investigated for this disease.
Functional redundancy of PIN proteins is accompanied by auxin-dependent cross-regulation of PIN expression
Authors: Vieten Anne , Vanneste Steffen , Wiśniewska Justyna , Benková Eva , Benjamins René , Beeckman Tom , Luschnig Christian , Friml Jiří
Published: September 2005

Plant development displays an exceptional plasticity and adaptability that involves the dynamic, asymmetric distribution of the phytohormone auxin. Polar auxin flow, which requires polarly localized transport facilitators of the PIN family, largely contributes to the establishment and maintenance of the auxin gradients. Functionally overlapping action of PIN proteins mediates multiple developmental processes, including embryo formation, organ development and tropisms. Here we show that PIN proteins exhibit synergistic interactions,which involve cross-regulation of PIN gene expression in pin mutants or plants with inhibited auxin transport. Auxin itself positively feeds back on PIN gene expression in a tissue-specific manner through an AUX/IAA-dependent signalling pathway. This regulatory switch is indicative of a mechanism by which the loss of a specific PIN protein is compensated for by auxin-dependent ectopic expression of its homologues. The compensatory properties of the PIN-dependent transport network might enable the stabilization of auxin gradients and potentially contribute to the robustness of plant adaptive development.
Calmodulin and PF6 are components of a complex that localizes to the C1 microtubule of the flagellar central apparatus
Authors: Wargo Matthew J. , Dymek Erin E. , Smith Elizabeth F.
Published: September 2005

Studies of flagellar motility in Chlamydomonas mutants lacking specific central apparatus components have supported the hypothesis that the inherent asymmetry of this structure provides important spatial cues for asymmetric regulation of dynein activity. These studies have also suggested that specific projections associated with the C1 and C2 central tubules make unique contributions to modulating motility; yet, we still do not know the identities of most polypeptides associated with the central tubules. To identify components of the C1a projection, we took an immunoprecipitation approach using antibodies generated against PF6. The pf6 mutant lacks the C1a projection and possesses flagella that only twitch; calcium-induced modulation of dynein activity on specific doublet microtubules is also defective in pf6 axonemes. Our antibodies specifically precipitated five polypeptides in addition to PF6. Using mass spectrometry, we determined the amino acid identities of these five polypeptides. Most notably, the PF6-containing complex includes calmodulin. Using antibodies generated against each precipitated polypeptide, we confirmed that these polypeptides comprise a single complex with PF6, and we identified specific binding partners for each member of the complex. The finding of a calmodulin-containing complex as an asymmetrically assembled component of the central apparatus implicates the central apparatus in calcium modulation of flagellar waveform.
Bves modulates epithelial integrity through an interaction at the tight junction
Authors: Osler Megan E. , Chang Min S. , Bader David M.
Published: September 2005

We first identified Bves (blood vessel/epicardial substance) as a transmembrane protein that localized to the lateral compartment of the epithelial epicardium. Bves traffics to sites of cell-cell contact in cultured epicardial cells and promotes adhesion following transfection into non-adherent fibroblastic L-cells, reminiscent of a cell adhesion molecule. Currently, no function for Bves in relation to epithelial cell adhesion has been identified. We hypothesize that Bves plays a role at cell junctions to establish and/or modulate cell adhesion or cell-cell interactions in epithelial cell types. In this study, we demonstrate that Bves regulates epithelial integrity and that this function may be associated with a role at the tight junction (TJ). We report that Bves localizes with ZO-1 and occludin, markers of the TJ, in polarized epithelial cell lines and in vivo. We find that the behavior of Bves following low Ca2+ challenge or TPA treatment mimics that observed for ZO-1 and is distinct from adherens junction proteins such as E-cadherin. Furthermore, GST pull-down experiments show an interaction between ZO-1 and the intracellular C-terminal tail of Bves. Finally, we demonstrate that Bves modulates tight junction integrity, as indicated by the loss of transepithelial resistance and junction protein localization at the membrane following Bves knock-down in cultured cells. This study is the first to identify a function for Bves in epithelia and supports the hypothesis that Bves contributes to establishment and/or maintenance of epithelial cell integrity.
The adenomatous polyposis coli protein (APC) exists in two distinct soluble complexes with different functions
Authors: Penman George A. , Leung Louie , Näthke Inke S.
Published: September 2005

Mutations resulting in the truncation of the adenomatous polyposis coli (APC) protein are common to most colonic tumours. The APC protein has emerged as a multifunctional protein that contributes to cytoskeletal organisation and is involved in the regulation of β-catenin. Both, changes in transcription due to increases in β-catenin, as well as defects in directed cell migration and cell division contribute to cancer when APC is mutated. Little is known about how separate functions of APC are coordinated. In this study, we identified two distinct soluble protein pools containing APC. We found that one of these pools represents the fully assembled β-catenin-targeting complex. The second pool contained at least two different forms of APC: APC that was bound to partially assembled β-catenin-targeting complexes and APC that could bind microtubules. Consistent with the previously proposed role for glycogen synthase kinase 3β (GSK3β) in modulating the assembly and activity of the β-catenin-targeting complex, formation of the fully assembled complex was reduced by inhibitors of GSK3β. Similarly, tumour cells with truncated APC only contained the partially assembly β-catenin-targeting complex. We also found that highly elevated levels of β-catenin in tumour cells containing wild-type APC correlated with a decrease in the ability of the endogenous APC protein to bind microtubules. Additionally, APC lacking the direct microtubule binding site was more effective at downregulating β-catenin. Together, our data suggest that the interaction of APC with microtubules and the β-catenin-targeting complex are mutually exclusive, and indicate that the distribution of endogenous APC between different pools is dynamic, which allows cells to distribute it as required.
p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling
Authors: Barberis Davide , Casazza Andrea , Sordella Raffaella , Corso Simona , Artigiani Stefania , Settleman Jeff , Comoglio Paolo M. , Tamagnone Luca
Published: September 2005

Plexins are transmembrane receptors for semaphorins, guiding cell migration and axon extension. Plexin activation leads to the disassembly of integrin-based focal adhesive structures and to actin cytoskeleton remodelling and inhibition of cell migration; however, the underlying molecular mechanisms are unclear. We consistently observe a transient decrease of cellular RhoA-GTP levels upon plexin activation in adherent cells. One of the main effectors of RhoA downregulation is p190, a ubiquitously expressed GTPase activating protein (GAP). We show that, in p190-deficient fibroblasts, the typical functional activities mediated by plexins (such as cell collapse and inhibition of integrin-based adhesion) are blocked or greatly impaired. Notably, the functional response can be rescued in these cells by re-expressing exogenous p190, but not a mutant form specifically lacking RhoGAP activity. We furthermore demonstrate that semaphorin function is blocked in epithelial cells, primary endothelial cells and neuroblasts upon treatment with small interfering RNAs that knockdown p190 expression. Finally, we show that p190 transiently associates with plexins, and its RhoGAP activity is increased in response to semaphorin stimulation. We conclude that p190-RhoGAP is crucially involved in semaphorin signalling to the actin cytoskeleton, via interaction with plexins.
A three-amino-acid-long HLA-DRβ cytoplasmic tail is sufficient to overcome ER retention of invariant-chain p35
Authors: Khalil Hayssam , Brunet Alexandre , Thibodeau Jacques
Published: September 2005

The p35 isoform of the human invariant chain (Iip35) contains an N-terminal RXR endoplasmic-reticulum (ER) retention signal that becomes nonfunctional only after assembly with MHC-class-II molecules. We have previously shown that the MHC-class-II β-chain cytoplasmic tail is crucial for the maturation of class-II/Iip35 complexes. In order to shed some light on the molecular determinants involved in shielding the RXR motif, we performed site-directed mutagenesis of the DRβ chain and Ii cytoplasmic domains. Chimeric β chains with irrelevant cytoplasmic tails allowed the efficient transport of Iip35 out of the ER in transiently transfected HEK 293T cells. An alanine scan of the cytoplasmic tail of HLA-DRβ confirmed that no specific motif is required to overcome ER retention. Surprisingly, a β chain with a three-amino-acid-long cytoplasmic tail (Tyr-Phe-Arg) was sufficient to overcome the Iip35 RXR motif. Moreover, replacement of residues F231 and R232 with alanines created a cytoplasmic tail (Tyr-Ala-Ala) that allowed ER egress. Given the limited length of this tail, steric hindrance would only be possible if the Ii ER retention motif was close to the membrane in the first place. However, this is not likely because an Ii molecule with an internal cytoplasmic deletion bringing the RXR motif closer to the membrane is not retained in the ER, even in the absence of class-II molecules. These results suggest that MHC-class-II molecules overcome ER retention and prevent COPI binding to the Iip35 RXR motif through a mechanism distinct from steric hindrance by its β chain.
Yolk granule tethering: a role in cell resealing and identification of several protein components
Authors: McNeil Anna , McNeil Paul L.
Published: September 2005

Homotypic fusion among echinoderm egg yolk granules has previously been reconstituted in vitro, and shown to be a rapid, Ca2+-triggered reaction that can produce extremely large (>10 μm diameter) fusion products. We here show that, prior to Ca2+-triggered fusion, yolk granules in vitro, if isolated in an appropriate buffer, became tethered to one another, forming large aggregates of more than 100 granules. Granule washing with mildly chaotropic salt abolished this tethering reaction, and prevented Ca2+-triggered formation of the large fusion products characteristic of tethered granules. Protein factors present in the wash restored tethering activity and these factors could be substantially enriched by anion exchange chromatography. The enriched fraction behaved under native conditions as a high molecular weight (∼670 kDa), multisubunit complex of at least seven proteins. Monoclonal antibodies directed against this complex of proteins were capable of immunodepleting tethering activity, confirming the role of the complex in granule tethering. These antibodies selectively stained the surface of yolk granules in the intact egg. We therefore propose a new role for tethering: it can promote the formation of large vesicular fusion products, such as those required for successful resealing. We have, moreover, identified several proteins that may be critical to this tethering mechanism.
A rapid, nongenomic pathway facilitates the synaptic transmission induced by retinoic acid at the developing synapse
Authors: Liou Jau-Cheng , Ho Shih-Yin , Shen Meng-Ru , Liao Yi-Ping , Chiu Wen-Tai , Kang Kai-Hsiang
Published: September 2005

We have previously shown that retinoic acid (RA), a factor highly expressed in spinal cord, rapidly and specifically enhances the spontaneous acetylcholine release at developing neuromuscular synapses in Xenopus cell culture, using whole-cell patch-clamp recording. We have now further investigated the underlying mechanisms that are involved in RA-induced facilitation on the frequency of spontaneous synaptic currents (SSCs). Buffering the rise of intracellular Ca2+ with BAPTA-AM hampered the facilitation of SSC frequency induced by RA. The prompt RA-enhanced SSC frequency was not abolished when Ca2+ was eliminated from the culture medium or there was bath application of the pharmacological Ca2+ channel inhibitor Cd2+, indicating that Ca2+ influx through voltage-activated Ca2+ channels are not required. Application of membrane-permeable inhibitors of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] or ryanodine receptors effectively blocked the increase of SSC frequency elicited by RA. Treating cells with either wortmannin or LY294002, two structurally different inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase) and with the phospholipase Cγ (PLCγ) inhibitor U73122, abolished RA-induced facilitation of synaptic transmission. Preincubation of the cultures with pharmacological inhibitors, either genistein, a broad-spectrum tyrosine kinase inhibitor, or PP2, which predominantly inhibits the Src family of nonreceptor tyrosine kinase, completely abolished RA-induced synaptic facilitation. Taken collectively, these results suggest that RA elicits Ca2+ release from Ins(1,4,5)P3 and/or ryanodine-sensitive intracellular Ca2+ stores of the presynaptic nerve terminal. This is done via PLCγ/PI 3-kinase signaling cascades and Src tyrosine kinase activation, leading to an enhancement of spontaneous transmitter release.
Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro
Authors: Ng Chee Ping , Hinz Boris , Swartz Melody A.
Published: September 2005

The differentiation of fibroblasts to contractile myofibroblasts, which is characterized by de novo expression of α-smooth muscle actin (α-SMA), is crucial for wound healing and a hallmark of tissue scarring and fibrosis. These processes often follow inflammatory events, particularly in soft tissues such as skin, lung and liver. Although inflammatory cells and damaged epithelium can release transforming growth factor β1 (TGF-β1), which largely mediates myofibroblast differentiation, the biophysical environment of inflammation and tissue regeneration, namely increased interstitial flow owing to vessel hyperpermeability and/or angiogenesis, may also play a role. We demonstrate that low levels of interstitial (3D) flow induce fibroblast-to-myofibroblast differentiation as well as collagen alignment and fibroblast proliferation, all in the absence of exogenous mediators. These effects were associated with TGF-β1 induction, and could be eliminated with TGF-β1 blocking antibodies. Furthermore, α1β1 integrin was seen to play an important role in the specific response to flow, as its inhibition prevented fibroblast differentiation and subsequent collagen alignment but did not block their ability to contract the gel in a separate floating gel assay. This study suggests that the biophysical environment that often precedes fibrosis, such as swelling, increased microvascular permeability and increased lymphatic drainage – all which involve interstitial fluid flow – may itself play an important role in fibrogenesis.
Ruthenium-catalyzed Reconstructive Synthesis of Functional Organic Molecules via Cleavage of Carbon–Carbon Bonds
Authors: Kondo Teruyuki , Mitsudo Take-aki
Published: September 2005

Characteristic aspects of ruthenium-catalyzed reconstructive synthesis of functional organic molecules via carbon–carbon bond cleavage are discussed. Most of the compounds obtained in this study are hard to be prepared by the simple combination of traditional synthetic methods. These ruthenium-catalyzed reactions require highly qualified tuning of reaction conditions with substrates to attain high yields and selectivities of the products.
Coordination Driving Self-assembly of Gold Nanoparticles and Tetrapyridylporphine into Hollow Spheres
Authors: Shi Naien , Yin Gui , Han Min , Xu Zheng , Fan Xin , Li Hongbian , Hong Jianming
Published: September 2005

We report a facile method for self-assembling Au nanoparticles and tetrapyridylporphine into composite hollow spheres at the water/oil interface driven by coordination interaction between them. The interaction was studied by X-ray photoelectron spectroscopy, FT-IR spectroscopy, UV–vis spectroscopy, and fluorescence spectroscopy.
Anomalous Decrease of the Work Function of a Carbide-modified W(110) Surface Induced by Hydrogen Chemisorption
Authors: Tono Kensuke , Ikeuchi Junichi , Kondoh Hiroshi , Ohta Toshiaki
Published: September 2005

Electronic property of hydrogen adatoms on a carbide-modified W(110) surface, W(110)(15 × 3)R14°-C, was investigated by means of angle-resolved photoelectron spectroscopy. The work function of the surface decreases anomalously with hydrogen exposure. The hydrogen adatom polarizes positively due to bond formation with surface carbon atoms, resulting in the work-function decrease by as large as 1.0 ± 0.1 eV at saturation.
Light-induced Charge Separation in Photosystem I can be Sensitized by an Artificial Fluorescent Dye Covalently Linked to the Photosystem I Complex Surfaces
Authors: Nakamura Akimasa , Mizoguchi Shinji , Yoshida Emi , Kato Yuki , Watanabe Tadashi
Published: September 2005

To expand the spectral window for the light-induced charge separation in photosystem (PS) I of oxygenic photosynthetic organisms artificially, Rhodamine B (RhB) was covalently linked to the solution-exposed surfaces of PS I. By introduction of RhB to PS I, the activity of light-induced charge separation for excitation wavelength at which the light absorption is dominated by RhB increased by about 1.8-fold, showing that RhB covalently attached to PS I can serve as the artificial light-harvesting antenna.
Synthesis of Nonaphenylenes and Dodecaphenylenes Using Electron-transfer Oxidation of Lipshutz Cuprate Intermediates
Authors: Iyoda Masahiko , Rahman Mohammad Jalilur , Matsumoto Aoi , Wu Mo , Kuwatani Yoshiyuki , Nakao Kazumi , Miyake Yoshihiro
Published: September 2005

Nonaphenylene and its hexaalkyl derivatives have been synthesized using electron-transfer oxidation of Lipshutz cuprates with duroquinone. Oxidation of the Lipshutz cuprate derived from dibromo-o-terphenyl in THF produced nonaphenylene in moderate yield, whereas the similar oxidation of the Lipshutz cuprate derived from diiododiethyl-o-terphenyl in ether afforded the corresponding nonaphenylene and dodecaphenylene. Furthermore, oxidation of Lipshutz cuprate derived from diiododibutyl-o-terphenyl only gave the nonaphenylene.
Facilitated Disassembly of Polyplexes Composed of Self-assembling Amphiphilic Polycations Enhances the Gene Transfer Efficacy
Authors: Kitagawa Tatsuya , Iwase Reiko , Ishihara Kazuhiko , Yamaoka Tetsuji , Murakami Akira
Published: September 2005

Amphiphilic polycations, p(DMAPAA-co-MPC-co-SA)s, with various cation contents were designed as novel micelle-like nonviral gene carriers. The carriers led to a higher transgene expression in COS-1 cells three times as high as the case of the linear-type polycations. The enhanced transgene expressions were found to be related to the disassembly of plasmid DNA/carrier polyplexes. It can be concluded that a topological factor of the carriers greatly influences on the gene expression efficiency.
Preparation of Hybrid Organic/Inorganic Luminescent Thin Solid Films with Highly Concentrated Laser-dye Cations
Authors: Sasai Ryo , Itoh Takanori , Iyi Nobuo , Takagi Katsuhiko , Itoh Hideaki
Published: September 2005

To develop solid materials with high luminescence, the preparation of laser-dye rhodamine 6G (R6G)/clay hybrid thin solid films with surfactant molecules as aggregation suppressors was investigated. Dodecyltrimethylammonium cations were found to be very effective for inhibiting dye aggregation in the clay interlayer space. Consequently, this material showed light emission from the R6G monomer.
A Discrete-Time Model for Common Lifetime Inventory Systems
Authors: Lian Zhaotong , Liu Liming , Neuts Marcel F.
Published: September 2005

We consider a discrete-time (s, S) inventory model in which the stored items have a random common lifetime with a discrete phase-type distribution. Demands arrive in batches following a discrete phase-type renewal process. With zero lead time and allowing backlogs, we construct a multidimensional Markov chain to model the inventory-level process. We obtain a closed-form expected cost function. Numerical results demonstrate some properties of optimal ordering policies and cost functions. When compared with the results for the constant lifetime model, the variance of the lifetime significantly affects the system behavior. Thus, the formalism that we create here adds a new dimension to the research in perishable inventory control under uncertainty in lifetime.
Second-Order Lower Bounds on the Expectation of a Convex Function
Authors: Dokov Steftcho P. , Morton David P.
Published: September 2005

We develop a class of lower bounds on the expectation of a convex function. The bounds utilize the first two moments of the underlying random variable, whose support is contained in a bounded interval or hyperrectangle. Our bounds have applications to stochastic programs whose random parameters are known only through limited-moment information. Computational results are presented for two-stage stochastic linear programs.
Note on Multimodularity and L-Convexity
Authors: Murota Kazuo
Published: September 2005

Multimodular functions and L-convex functions have been investigated almost independently, but they are, in fact, equivalent objects that can be related through a unimodular coordinate transformation. Some facts known for L-convex functions can be translated to new results for multimodular functions, and vice versa. In particular, the local optimality condition for global optimality found in the literature of multimodular functions should be rectified, and a discrete separation theorem holds for multimodular functions.
Lex-Optimal Online Multiclass Scheduling with Hard Deadlines
Authors: Hajek Bruce , Seri Pierre
Published: September 2005

Online scheduling of unit-length packets with hard deadlines by a single server in slotted time is considered. First, the throughput optimal scheduling policies are characterized. Then multiclass packets are considered in which each packet has an M-bit class identifier, and a new optimality property called lex-optimality (short for lexicographic optimality) is defined for online scheduling policies. Lex-optimality is a hierarchical sequence of M throughput optimality properties. The lex-optimal policies that do not drop packets early are characterized. Both characterizations involve identification of a “no-regret subset” of the set of packets available for scheduling in a given slot.

A lex-optimal scheduling algorithm is presented with complexity per packet O(MB), where M is the log of the number of priority classes and B is the maximum buffer size. The algorithm requires no more packets to be buffered than any online, throughput optimal scheduling policy. Simulation results are presented that illustrate that lex-optimality combines elements of pure priority and nested priority scheduling.
On the Empirical State-Action Frequencies in Markov Decision Processes Under General Policies
Authors: Mannor Shie , Tsitsiklis John N.
Published: September 2005

We consider the empirical state-action frequencies and the empirical reward in weakly communicating finite-state Markov decision processes under general policies. We define a certain polytope and establish that every element of this polytope is the limit of the empirical frequency vector, under some policy, in a strong sense. Furthermore, we show that the probability of exceeding a given distance between the empirical frequency vector and the polytope decays exponentially with time under every policy. We provide similar results for vector-valued empirical rewards.
A New Complexity Result on Solving the Markov Decision Problem
Authors: Ye Yinyu
Published: September 2005

We present a new complexity result on solving the Markov decision problem (MDP) with n states and a number of actions for each state, a special class of real-number linear programs with the Leontief matrix structure. We prove that when the discount factor θ is strictly less than 1, the problem can be solved in at most O(n1.5(log 1/(1 − θ) + log n)) classical interior-point method iterations and O(n4(log 1/(1 − θ) + log n)) arithmetic operations. Our method is a combinatorial interior-point method related to the work of Ye (1990. A “build-down” scheme for linear programming. Math. Programming 46 61–72) and Vavasis and Ye (1996. A primal-dual interior-point method whose running time depends only on the constraint matrix. Math. Programming 74 79–120). To our knowledge, this is the first strongly polynomial-time algorithm for solving the MDP when the discount factor is a constant less than 1.
Optimizing Antiepileptic Drug Therapy in the Elderly
Authors: Garnett William R
Published: September 2005

OBJECTIVE

To review and evaluate the medical literature concerning antiepileptic drug (AED) therapy in elderly patients.

DATA SOURCES

A MEDLINE search (1982–December 2004) was conducted. Bibliographies of the articles identified were also reviewed, and an Internet search engine was used to identify additional pertinent references.

STUDY SELECTION AND DATA EXTRACTION

Clinical studies and reviews were evaluated, and relevant information was included.

DATA SYNTHESIS

The elderly have the highest incidence of seizures among all age groups. Complex partial seizures are the most common, followed by primary generalized tonic–clonic seizures. An accurate diagnosis may prove difficult because of a low suspicion of epilepsy in the elderly and other diseases that may mimic seizures. Most AEDs are approved for treatment of elderly patients who have partial and tonic–clonic seizures. However, a number of age-related variables should be addressed when selecting an appropriate AED. Age-dependent differences in pharmacokinetics and pharmacodynamics of AEDs must be taken into account. Drug–drug interactions must be considered since elderly people often take multiple medications. The ultimate factor that often determines AED selection is tolerability.

CONCLUSIONS

Numerous factors must be considered in treating elderly patients for seizures, but maximizing the ability of patients to tolerate drug therapy is often the basis for AED selection. Special consideration should be made along several lines, including elderly patients’ cognitive functioning and their tendency to respond to lower AED concentrations.
Duloxetine and Venlafaxine-XR in the Treatment of Major Depressive Disorder: A Meta-Analysis of Randomized Clinical Trials
Authors: Vis Peter MJ , Baardewijk Marc van , Einarson Thomas R
Published: September 2005

BACKGROUND

Duloxetine has joined venlafaxine on the antidepressant market as a second serotonin–norepinephrine reuptake inhibitor. No previous studies have directly compared these drugs.

OBJECTIVE

To compare indirectly the efficacy and safety of extended-release (XR) venlafaxine and duloxetine, the 2 currently available serotonin–norepinephrine reuptake inhibitors (SNRIs) in treating major depressive disorder.

METHODS

Outcomes from published, randomized, placebo-controlled trials reporting on moderately to severely depressed patients (Hamilton Rating Scale for Depression [HAM-D] ≥15 or Montgomery-Åsberg Depression Rating Scale [MADRS] ≥18). A systematic literature search of Cochrane, EMBASE, and MEDLINE (1996–January 2005) was performed. Two independent reviewers judged the trials for acceptance, and last observation carried forward data were extracted. Differences in remission (8-week HAM-D score ≤7 or MADRS ≤10), response (50% decrease on either scale), and dropout rates from lack of efficacy and adverse events were meta-analyzed using a random effects model. Each rate was contrasted with placebo. Sensitivity analyses were performed to examine the robustness of the results.

RESULTS

Data were obtained from 8 trials evaluating 1754 patients for efficacy and 1791 patients for discontinuation/safety. Venlafaxine-XR rates were 17.8% (95% CI 9.0 to 26.5) and 24.4% (95% CI 15.0 to 37.7) greater than those with placebo for remission and response compared with 14.2% (95% CI 8.9 to 26.5) and 18.6% (95% CI 13.0 to 24.2) for duloxetine. Although numerically higher for venlafaxine-XR, no statistically significant differences were found between the drugs; however, both demonstrated overall remission and response rates significantly higher than the rates achieved with placebo (p < 0.001). Reported adverse events were comparable between drugs.

CONCLUSIONS

Venlafaxine-XR tends to have a favorable trend in remission and response rates compared with duloxetine. However, dropout rates and adverse events did not differ. A direct comparison is warranted to confirm this tendency.
Carbamazepine-Induced Hyponatremia: Assessment of Risk Factors
Authors: Kuz Glenn M , Manssourian Alina
Published: September 2005

OBJECTIVE

To report a case of carbamazepine-induced acute hyponatremia resulting in seizures.

CASE SUMMARY

A 44-year-old white woman developed acute hyponatremia and 2 subsequent tonic–clonic seizures after ingesting twice her evening dose of carbamazepine (usual evening dose 600 mg). On admission, her serum sodium level was 122 mEq/L. An infusion of NaCl 0.9% was begun and, within 24 hours, the serum sodium level had returned to her previous level of 136 mEq/L. The woman's preadmission carbamazepine concentration was 8.6 μg/mL, and it was 11.3 μg/mL on admission. Carbamazepine was withheld and, the following day, the concentration was 5.6 μg/mL. The woman had experienced a similar event 6 months earlier when she also took a large dose of carbamazepine.

DISCUSSION

We attributed the acute hyponatremia and seizures to the large increase in dose of carbamazepine in the presence of other risk factors for hyponatremia. Hyponatremia associated with carbamazepine has been well described. The incidence ranges from 1.8% to 40% depending on the patient population studied. Severe hyponatremia in patients treated with monotherapy is uncommon. Several risk factors have been reported to increase the risk of hyponatremia including age >40 years, concomitant use of medications associated with hyponatremia, menstruation, psychiatric condition, surgery, psychogenic polydipsia, and female gender. Treatment is focused on removal of the precipitating factors or discontinuation of carbamazepine therapy. Use of the Naranjo probability scale indicated a highly probable relationship between acute hyponatremia and carbamazepine in our patient.

CONCLUSIONS

Hyponatremia with carbamazepine is well known. The factors associated with increased risk are less understood. An increased awareness of these risks, careful monitoring, and patient education are important in the prevention of neurologic complications.
Vitamin E Supplementation in Cardiovascular Disease and Cancer Prevention: Part 1
Authors: Pham David Q , Plakogiannis Roda
Published: September 2005

OBJECTIVE

To review clinical trials evaluating the safety and efficacy of vitamin E supplementation in cardiovascular disease and cancer prevention.

DATA SOURCES

Using the MeSH search terms alpha-tocopherol, tocopherols, vitamin E, cardiovascular diseases, cancer, malignancy, and clinical trials, a literature review was conducted to identify peer-reviewed articles in MEDLINE (1966–July 2005).

STUDY SELECTION AND DATA EXTRACTION

Published materials including original research, and previous meta-analyses were included. Only English-language articles and trials on vitamin E alone or in combination with other vitamins or minerals were reviewed. Emphasis was placed on prospective, randomized, double-blind, placebo-controlled clinical trials.

DATA SYNTHESIS

Eight clinical studies demonstrated contradicting results regarding the benefits of vitamin E in the prevention of cardiovascular disease and cancer. There is enough evidence from large, well-designed studies to discourage the use of vitamin E in the primary prevention of cardiovascular disease. Secondary prevention requires more adequate clinical trials with selected populations to examine protective effects of vitamin E in cardiovascular disease. The findings of the studies reviewed do not provide evidence that vitamin E may reduce the risk of cancer; thus, at the present time, we do not recommend daily vitamin E intake for cancer prevention is not recommended.

CONCLUSIONS

Available data do not support the supplementation of vitamin E in cardiovascular disease and cancer prevention.
The Use of the Direct Reading Spectrometer with dc Arc Excitation and Total Sample Combustion in the Analysis of High Purity Materials
Authors: Cooper B. S. , Hobbs D. J.
Published: October 2005

When a dc arc is used for trace analysis on a spectrometer, calibration curves with a pronounced toe due to spectral background are found. For analysis of high purity materials it is most important that linear relationships should be established to ultra-trace levels when total impurity content is specified within the ppm level. A solution to this problem is outlined and the linear relationships obtained for copper, bismuth, and cadmium in high purity silver to 0.1 ppm are shown. An electronic circuit is described that enables these background corrections to be made.
A Slide Valve Suitable for Coupling a Gas Chromatograph to a Mass Spectrometer
Authors: Landis William R. , Alford William C. , Perrine Theodore D. , Thomas George M. , Anderson Frank O.
Published: October 2005

A vacuum slide valve is presented in which inlet and outlet tubes are brought in and out of register. The sliding members are housed in a vacuum chamber to minimize leakage of air into the mass spectrometer. To provide suitable lubrication of the sliding members in the ambient hot vacuum, a gold film is employed.