bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Pregnancy on Survival in Women With Cutaneous Malignant Melanoma
Authors: Lens Marko B. , Rosdahl Inger , Ahlbom Anders , Farahmand Bahman Y. , Synnerstad Ingrid , Boeryd Bernt , Newton Bishop Julia A.
Published: October 2004

Purpose

An adverse influence of pregnancy on the risk of death in women with cutaneous melanoma was suggested historically by anecdotal reports. Previous studies included small numbers of women observed for short periods.

Methods

Using data from the Swedish National and Regional Registries, we performed a retrospective cohort study of all Swedish women who were diagnosed with cutaneous melanoma during their reproductive period, from January 1, 1958, to December 31, 1999. The relationship between pregnancy status at the diagnosis of melanoma and overall survival was examined in multivariable proportional-hazards models.

Results

The cohort comprised 185 women (3.3%) diagnosed with melanoma during pregnancy and 5,348 (96.7%) women of the same childbearing age diagnosed with melanoma while not pregnant. There was no statistically significant difference in overall survival between pregnant and nonpregnant groups (log-rank χ21[r] = 0.84, P = .361). Pregnancy status at the time of diagnosis of melanoma was not related to survival in a multivariable Cox model in the 2,101 women (hazard ratio for death in the pregnant group was 1.08; 95% CI, 0.60 to 1.93). In the multivariable analysis, pregnancy status after diagnosis of melanoma was not a significant predictor of survival (hazard ratio for death in women who had pregnancy subsequent to the diagnosis of melanoma was 0.58; 95% CI, 0.32 to 1.05).

Conclusion

The survival of pregnant women with melanoma is not worse than the survival of nonpregnant women with melanoma. Pregnancy subsequent to the diagnosis of primary melanoma was not associated with an increased risk of death.
Quality of Life of Postmenopausal Women in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Adjuvant Breast Cancer Trial
Authors: Fallowfield Lesley , Cella David , Cuzick Jack , Francis Stephen , Locker Gershon , Howell Anthony
Published: October 2004

Purpose

To determine the quality of life (QoL) of women participating in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Adjuvant Breast Cancer Trial during the first 2 years of treatment.

Patients and Methods

A total of 1,021 women were enrolled onto the QoL subprotocol. All had completed primary treatment (surgery ± radiotherapy ± chemotherapy) and were to receive 5 years of adjuvant treatment with anastrozole (n = 335), tamoxifen (n = 347), or a combination (n = 339) of both. Patients completed the Functional Assessment of Cancer Therapy-Breast (FACT–B) plus endocrine subscale (ES) at baseline and 3, 6, 12, 18, and 24 months, or until disease recurrence. The primary end point was the FACT–B Trial Outcome Index (TOI). The secondary end point was the ES total score. Analyses of individual endocrine symptoms were also explored.

Results

Questionnaire completion approximated 85% of assessments available for analysis. Overall QoL for all groups improved from baseline during the 2-year period. There were no significant differences in TOI or ES scores across treatment groups. Endocrine symptoms increased between baseline and 3 months for all groups and stabilized thereafter. There were some small differences in side effect profiles. Compared with patients receiving tamoxifen only, patients receiving anastrozole only reported significantly fewer cold sweats and vaginal discharge, yet more vaginal dryness, painful intercourse, and loss of sexual interest.

Conclusion

Two years of treatment with anastrozole, tamoxifen, or the combination had a similar overall QoL impact, showing gradual improvement over time. Endocrine-related symptoms for all three arms worsened initially and recovered partially during 2 years. The different symptoms experienced may assist in decision making about treatment and supportive care needs.
Phase II Study of Fenretinide (NSC 374551) in Adults With Recurrent Malignant Gliomas: A North American Brain Tumor Consortium Study
Authors: Puduvalli Vinay K. , Yung W.K. Alfred , Hess Kenneth R. , Kuhn John G. , Groves Morris D. , Levin Victor A. , Zwiebel James , Chang Susan M. , Cloughesy Timothy F. , Junck Larry , Wen Patrick , Lieberman Frank , Conrad Charles A. , Gilbert Mark R. , Meyers Christina A. , Liu Vivien , Mehta Minesh P. , Nicholas M. Kelly , Prados Michael
Published: October 2004

Purpose

Fenretinide induces apoptosis in malignant gliomas in vitro. This two-stage phase II trial was conducted to determine the efficacy of fenretinide in adults with recurrent malignant gliomas.

Patients and Methods

Twenty-two patients with anaplastic gliomas (AG) and 23 patients with glioblastoma (GBM) whose tumors had recurred after radiotherapy and no more than two chemotherapy regimens were enrolled. Fenretinide was given orally on days 1 to 7 and 22 to 28 in 6-week cycles in doses of 600 or 900 mg/m2bid.

Results

Six of 21 (29%) patients in the AG arm and two of 23 (9%) patients in the GBM arm had stable disease at 6 months. One patient with AG treated at 900 mg/m2bid dosage had a partial radiologic response. Median progression-free survival (PFS) was 6 weeks for the AG arm and 6 weeks for the GBM arm. PFS at 6 months was 10% for the AG arm and 0% for the GBM arm. Grade 1 or 2 fatigue, dryness of skin, anemia, and hypoalbuminemia were the most frequent toxicities reported. The trial was closed after the first stage because of the inadequate activity at the fenretinide doses used. The first-administration mean plasma Cmaxfor fenretinide was 832 ± 360 ng/mL at the 600 mg/m2bid dosage and 1,213 ± 261 ng/mL at the 900 mg/m2bid dosage.

Conclusion

Fenretinide was inactive against recurrent malignant gliomas at the dosage used in this trial. However, additional studies using higher doses of the agent are warranted based on the tolerability of the agent and the potential for activity of a higher fenretinide dosage, as suggested in this trial.
Cancer Consultation Preparation Package: Changing Patients but Not Physicians Is Not Enough
Authors: Butow Phyllis , Devine Rhonda , Boyer Michael , Pendlebury Susan , Jackson Michael , Tattersall Martin H.N.
Published: October 2004

Purpose

This study evaluated a cancer consultation preparation package (CCPP) designed to facilitate patient involvement in the oncology consultation.

Patients and Methods

A total of 164 cancer patients (67% response rate) were randomly assigned to receive the CCPP or a control booklet at least 48 hours before their first oncology appointment. The CCPP included a question prompt sheet, booklets on clinical decision making and patient rights, and an introduction to the clinic. The control booklet contained only the introduction to the clinic. Physicians were blinded to which intervention patients received. Patients completed questionnaires immediately after the consultation and 1 month later. Consultations were audiotaped, transcribed verbatim, and coded.

Results

All but one patient read the information. Before the consultation, intervention patients were significantly more anxious than were controls (mean, 42 v 38; P = .04); however anxiety was equivalent at follow-up. The CCPP was reported as being significantly more useful to family members than the control booklet (P = .004). Patients receiving the intervention asked significantly more questions (11 v seven questions; P = .005), tended to interrupt the physician more (1.01 v 0.71 interruptions; P = .08), and challenged information significantly more often (twice v once; P = .05). Patients receiving the CCPP were less likely to achieve their preferred decision making style (22%) than were controls (35%; P = .06).

Conclusion

This CCPP influences patients' consultation behavior and does not increase anxiety in the long-term. However, this intervention, without physician endorsement, reduced the percentage of patients whose preferred involvement in decision making was achieved.
Where Infants Look Determines How They See: Eye Movements and Object Perception Performance in 3‐Month‐Olds
Authors: Johnson Scott P. , Slemmer Jonathan A. , Amso Dima
Published: October 2004

A fundamental question of perceptual development concerns how infants come to perceive partly hidden objects as unified across a spatial gap imposed by an occluder. Much is known about the time course of development of perceptual completion during the first several months after birth, as well as some of the visual information that supports unity perception in infants. The goal of this investigation was to examine the inputs to this process. We recorded eye movements in 3‐month‐old infants as they participated in a standard object unity task and found systematic differences in scanning patterns between those infants whose post‐habituation preferences were indicative of unity perception versus those infants who did not perceive unity. Perceivers, relative to nonperceivers, scanned more reliably in the vicinity of the visible rod parts and scanned more frequently across the range of rod motion. These results suggest that emerging object concepts are tied closely to available visual information in the environment, and the process of information pickup.
Developmental Changes in Visual Scanning of Dynamic Faces and Abstract Stimuli in Infants: A Longitudinal Study
Authors: Hunnius Sabine , Geuze Reint H.
Published: October 2004

The characteristics of scanning patterns between the ages of 6 and 26 weeks were investigated through repeated assessments of 10 infants. Eye movements were recorded using a corneal‐reflection system while the infants looked at 2 dynamic stimuli: the naturally moving face of their mother and an abstract stimulus. Results indicated that the way infants scanned these stimuli stabilized only after 18 weeks, which is slightly later than the ages reported in the literature on infants' scanning of static stimuli. This effect was especially prominent for the abstract stimulus. From the 14‐week session on, infants adapted their scanning behavior to the stimulus characteristics. When scanning the video of their mother's face, infants directed their gaze at the mouth and eye region most often. Even at the youngest age, there was no indication of an edge effect.
Advances in Relating Eye Movements and Cognition
Authors: Hayhoe Mary M.
Published: October 2004

Measurement of eye movements is a powerful tool for investigating perceptual and cognitive function in both infants and adults. Straightforwardly, eye movements provide a multifaceted measure of performance. For example, the location of fixations, their duration, time of occurrence, and accuracy all are potentially revealing and often allow stronger inferences than measures such as percentage correct or reaction time. Another advantage is that eye movements are an implicit measure of performance and do not necessarily involve conscious processes. Indeed, they are often a more revealing measure than conscious report (Hayhoe, Bensinger, & Ballard, 1998). Although the mere presence of gaze at a particular location in the visual field does not reveal the variety of brain computations that might be operating at that moment, the experimental context within which the fixation occurs often provides critical information that allows powerful inferences. The articles in this thematic collection are excellent examples of this.
Toddlers' Reactions to the Distress of Familiar Peers: The Importance of Context
Authors: Demetriou Helen , Hay Dale F.
Published: October 2004

Reactions to peers' distress were recorded for 52 toddlers (hosts), 18 to 36 months old, who were observed playing with familiar peers in their own homes during 2 sessions, 6 months apart. Four contextual factors were explored: the host's responsibility for the guest's distress, similarity between the toddler and the distressed peer, relative familiarity of the peer, and the toddler's experience with peers and siblings. Hosts responded more positively to distress they had caused than to distress they witnessed. Negative reactions were most likely to be shown when hosts themselves had caused the distress of a guest of the same sex. Hosts were less likely to respond either positively or negatively if they had known their guests all their lives. Toddlers who had older siblings were more likely than other hosts to respond negatively to guests' distress.
You are what you Wear: An Interactive Demonstration of the Self-Fulfilling Prophecy
Authors: Hebl Michelle R. , King Eden B.
Published: October 2004

This article presents evidence in support of an interactive classroom activity that demonstrates the self-fulfilling prophecy. After a brief description of the topic, 5 volunteers from an introductory psychology course of 81 students blindly donned one of several labeled hats (i.e., intelligent, attractive, good leader, annoying, lazy). The instructor told volunteers to treat each other in accordance with the labels while they completed a series of group tasks. During the task, volunteers acted in accordance with their label, thereby confirming the self-fulfilling prophecy. Findings indicated that the demonstration does elicit the self-fulfilling prophecy and that students' understanding of this phenomenon improves. Furthermore, students overwhelmingly reported that this demonstration was interesting and enjoyable and recommended its use in future classes.
A pharmacokinetic and pharmacodynamic study of desmopressin: evaluating sex differences and the effect of pre-treatment with piroxicam, and further validation of an indirect response model
Authors: Odeberg Johanna Mercke , Callréus Torbjörn , Lundin Stefan , Roth E Bodil , Höglund Peter
Published: October 2004

Desmopressin is a synthetic vasopressin analogue mainly used in treatment of diabetes insipidus and nocturia. Studies in rats have revealed a sex difference in the response to a vasopressin infusion, which was diminished after treatment with an NSAID. This study was performed in man to investigate the influence of sex and concomitant treatment of piroxicam on the pharmacokinetics and dynamics of desmopressin, and to validate a previously described indirect response model. Eight healthy males and eight healthy females participated in the trial, which was conducted in a pharmacokinetic (PK) part followed by a pharmacodynamic (PD) part. Desmopressin was administered intravenously as a single dose (PK = dose 2 μg, PD = dose 0.2 μg). Piroxicam was administered to achieve steady state. The pharmacokinetic parameters of desmopressin were estimated and calculated by means of two-compartmental analysis. In the dynamic part a study design based on an oral hydration model was used. Parameters for urine flow and urine osmolality were estimated. Individual estimates of the pharmacokinetic parameters served as input to the indirect response model that subsequently was fitted to urine osmolality data. The pharmacokinetics of desmopressin after a fixed bolus injection was neither influenced by piroxicam nor sex of the subject. The pharmacodynamics of desmopressin showed a sex difference where females exhibited a more pronounced antidiuretic effect than males, which was statistically significant when the effects were submaximal (>4.5 h after dose). The sex differences were diminished after pre-treatment with piroxicam, indicating a prostaglandin PGE2-mediated mechanism. The indirect response model was confirmed, although the modelling could not distinguish a sex difference, indicating a limitation of this model compared with traditional descriptive statistics.
The combination of modified antioxidant enzymes for anti-thrombotic protection of the vascular wall: the significance of covalent connection of superoxide dismutase and catalase activities
Authors: Maksimenko Alexander V , Golubykh Vladimir L , Tischenko Elena G
Published: October 2004

Vascular wall protection can be achieved by preventive attachment to the vascular wall of antioxidants and elimination/neutralization of toxic products after their disproportioning. For this purpose we have prepared covalent conjugates between the vascular wall glycosaminglycan chondroitin sulfate (CHS) and the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). The following conjugates were obtained: SOD-CHS, CAT-CHS and SOD-CHS-CAT. Their anti-thrombotic activity was comparedin a rat model of arterial thrombosis by measuring the time of occlusion emergence and thrombus mass. It is noteworthy that the effectiveness of single bolus injections of SOD-CHS/CAT-CHS mixture was much lower than that of the bienzymic SOD-CHS-CAT conjugate. The conjugate SOD-CHS-CAT proved to be anti-thrombotically effective in doses two orders of magnitude lower than the native biocatalysts and an order of magnitude lower than SOD-CHS and CAT-CHS derivatives. For effective anti-thrombotic protection in oxidative conditions it is important to maintain the stable connection of SOD and CAT activity on the vascular wall and the large size of these conjugates. Covalent conjugate SOD-CHS-CAT is the best prospect for pharmaceutical development.
Red marine alga Bryothamnion triquetrum lectin induces endothelium-dependent relaxation of the rat aorta via release of nitric oxide
Authors: Lima Ricardo F , Criddle David N , Souza Emmanuel P , Sampaio Alexandre H , Nascimento Kyria S , Cavada Benildo S , Assreuy Ana Maria S
Published: October 2004

We have investigated the vascular relaxant effects of the lectin from a red marine alga Bryothamnion triquetrum (BTL), in particular, the endothelial-dependency and the participation of a specific glycoprotein-binding site. BTL (1–100 μg mL−1) was applied to rat isolated aortic rings, with or without endothelium, tonically precontracted with phenylephrine (0.1 μm). Endothelium-dependent relaxation was assessed in the presence of indometacin (10 μm), l-nitro arginine methyl ester (L-NAME, 100 μm) and tetraethylammonium (TEA, 500 μm). For the involvement of the glycoprotein-binding site, BTL was assayed in presence of mucin (300 μg mL−1) or N-acetyl d-glucosamine (GlcNAc; 300 μg mL−1), a specific and non-specific lectin-binding sugar, respectively. BTL fully and concentration dependently relaxed preparations that possessed an intact endothelium (IC50 (concn producing 50% contraction) = 12.1 ± 1.6 μg mL−1), whereas no significant relaxation was observed in endothelial-denuded tissue. L-NAME, but not indometacin or TEA, completely inhibited the lectin relaxation, suggesting the involvement of nitric oxide (NO). The lectin in association with mucin, but not with GlcNAc, inhibited BTL-induced relaxation, implicating the involvement of the lectin binding site. Our data suggest that the relaxant effect of the red marine alga Bryothamnion triquetrum lectin on isolated aorta occurs via interaction with a specific lectin-binding site on the endothelium, resulting in a release of NO.
Induction of apoptosis in human breast adenocarcinoma MCF-7 cells by prodelphinidin B-2 3,3′-di-O-gallate from Myrica rubra via Fas-mediated pathway
Authors: Kuo Po-Lin , Hsu Ya-Ling , Lin Ta-Chen , Lin Liang-Tzung , Lin Chun-Ching
Published: October 2004

Myrica rubra Sieb et Zucc. (Myricaceae) is well known as a rich source of tannins. Prodelphinidin B-2 3,3′-di-O-gallate (PB233′OG) is a proanthocyanidin gallate that has been reported to exhibit anti-oxidant and antiviral activity. In this study, we evaluated the anti-proliferative activity of PB233′OG isolated from the bark of M. rubra in human breast adenocarcinoma MCF-7 cells. To identity the anti-cancer mechanism of PB233′OG, we assayed its effect on apoptosis, cell cycle distribution, and levels of p53, p21/WAF1, Fas/APO-1 receptor and Fas ligand. The results showed that PB233′OG induced apoptosis of MCF-7 cells without mediation of p53 and p21/WAF1. We suggest that Fas/Fas ligand apoptotic system is the main pathway of PB233′OG-mediated apoptosis of MCF-7 cells. Our study reports here for the first time that the activity of the Fas/Fas ligand apoptotic system may participate in the anti-proliferative activity of PB233′OG in MCF-7 cells.
Microsphere-liposome complexes protect adenoviral vectors from neutralising antibody without losses in transfection efficiency, in-vitro
Authors: Steel Jason C , Cavanagh Heather M A , Burton Mark A , Kalle Wouter H J
Published: October 2004

Adenoviral vectors have been commonly used in gene therapy protocols but the success of their use is often limited by the induction of host immunity to the vector. Following exposure to the adenoviral vector, adenoviral-specific neutralising antibodies are produced, which limits further administration. This study examines the effectiveness of a novel combination of microspheres and liposomes for the shielding of adenovirus from neutralising antibodies in an in-vitro setting. We show that liposomes are effective in the protection of adenovirus from neutralising antibody and that the conjugation of these complexes to microspheres augments the level of protection. This study further reveals that previously neutralised adenovirus may still be transported into the cell via liposome-cell interactions and is still capable of expressing its genes, making this vector an effective tool for circumvention of the humoral immune response. We also looked at possible side effects of using the complexes, namely increases in cytotoxicity and reductions in transfection efficiency. Our results showed that varying the liposome:adenovirus ratio can reduce the cytotoxicity of the vector as well as increase the transfection efficiency. In addition, in cell lines that are adenoviral competent, transfection efficiencies on par with uncomplexed adenoviral vectors were achievable with the combination vector.
Investigation into the mast cell stabilizing activity of nature-identical and synthetic indanones
Authors: Frankish Neil , Farrell Ronan , Sheridan Helen
Published: October 2004

As part of an ongoing search for novel molecules with therapeutic potential we examined the mediator release inhibition activity of a number of indanones and their derivatives. The aldol condensation product 18 was approximately twice as potent as disodium cromoglycate as an inhibitor of compound 48/80-stimulated histamine release from rat peritoneal mast cells. The activity of this class of dimeric indanone compound is significantly higher than controls and may represent a new class of mast cell stabilizing agents. Compound 18 has been selected for further biological evaluation of its mast cell stabilization profile.
Corni fructus as the major herb of Die-Huang-Wan for lowering plasma glucose in Wistar rats
Authors: Liou Shorong-Shii , Liu I-Min , Hsu Sheng-Fa , Cheng Juei-Tang
Published: October 2004

Die-Huang-Wan is a mixture of six herbs used to lower plasma glucose by increasing insulin secretion in normal rats. Die-Huang-Wan contains the herbs dioscorea (Dioscoreae rhizoma), cornus (Corni fructus), alisma (Rhizoma alismatis), holelen (Poria), rehmannia (Rehmanniae radix) and tree peony bark (Moutan radicis cortex). The present study was designed to clarify the major herb contributing to the plasma glucose-lowering action of Die-Huang-Wan in rats. A decrease in plasma glucose was not observed in Wistar rats treated with the cornus-deleted formula of Die-Huang-Wan; however, the action was retained in the other herb-deleted formulas containing cornus. In normal rats, the decrease in plasma glucose and increase in plasma insulin concentrations were dependent on the dose of cornus and were similar to those produced by Die-Huang-Wan. Treatment of Wistar rats with each of the other five herbs separately did not result in a decrease in plasma glucose. Moreover, the increase in plasma insulin or reduction in plasma glucose resulting from cornus treatment was blocked by atropine or 4-diphenylacetoxy-N-methylpiperidine methiodide mustard, indicating mediation of muscarinic M3 receptors similar to that caused by Die-Huang-Wan. These results suggest that cornus is the major contributor to the plasma glucose-lowering action in Die-Huang-Wan in normal rats.
Role of the carboxylic group in the antispasmodic and vasorelaxant action displayed by kaurenoic acid
Authors: Ambrosio Sergio R , Tirapelli Carlos R , Coutinho Silvia T , de Oliveira Dionéia C R , de Oliveira Ana M , Da Costa Fernando B
Published: October 2004

The present work describes the investigation of the role of the carboxylic group in the structure-activity relationship of the diterpene ent-kaur-16-en-19-oic acid (kaurenoic acid, KA) in inhibiting rat aorta contraction. For this purpose the methylation of the C-19 carboxyl group of KA was carried out. The effects of the obtained ent-methyl-kaur-16-en-19-oate (KAMe) were compared with those induced by KA. Vascular reactivity experiments showed that KA (50 and 100 μm) concentration-dependently inhibited KCl-induced contraction in both endothelium-intact and denuded rat aortic rings. On the other hand, KAMe attenuated KCl-induced contraction at 100 μm, but not at 50 μm. KA also reduced CaCl2-induced contraction in Ca2+-free solution containing KCl (30 mM). Again, KAMe produced a less accentuated reduction in CaCl2-induced contraction than that induced by the acid KA. KAMe (1–450 μm) concentration-dependently relaxed KCl-pre-contracted rings (percentages of relaxation 82.57±1.65 and 70.55±4.71, respectively) with denuded endothelium. Similarly, the relaxation induced by KA on phenylephrine (Phe)-pre-contracted rings (73.06±3.68%) was more pronounced than that found for KAMe (53.68±4.75%). Pre-incubation of denuded rings for different periods with KA and KAMe showed that the equilibrium periods required by each compound to achieve its maximal inhibitory response on KCl-induced contraction are different. Collectively, our results provide functional evidence that methylation of the C-19 carboxyl group of KA reduces but does not abolish the antispasmodic activity displayed by KA. Additionally, we showed that the equilibrium period is a critical step for the inhibitory effect displayed by kaurane-type diterpenes.
Hepatoprotective activity of Terminalia catappa L. leaves and its two triterpenoids
Authors: Gao Jing , Tang Xinhui , Dou Huan , Fan Yimei , Zhao Xiaoning , Xu Qiang
Published: October 2004

The aim of this study was to evaluate the effect of the chloroform extract of Terminalia catappa L. leaves (TCCE) on carbon tetrachloride (CCI4)-induced acute liver damage and D-galactosamine (D-GaIN)-induced hepatocyte injury. Moreover, the effects of ursolic acid and asiatic acid, two isolated components of TCCE, on mitochondria and free radicals were investigated to determine the mechanism underlying the action of TCCE on hepatotoxicity. In the acute hepatic damage test, remarkable rises in the activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (5.7- and 2.0-fold) induced by CCI4 were reversed and significant morphological changes were lessened with pre-treatment with 50 and 100 mg kg−1 TCCE. In the hepatocyte injury experiment, the increases in ALT and AST levels (1.9- and 2.1-fold) in the medium of primary cultured hepatocytes induced by D-GaIN were blocked by pre-treatment with 0.05, 0.1, 0.5 gL−1 TCCE. In addition, Ca2+-induced mitochondrial swelling was dose-dependently inhibited by 50–500 μm ursolic acid and asiatic acid. Both ursolic acid and asiatic acid, at concentrations ranging from 50 to 500 μm, showed dose-dependent superoxide anion and hydroxyl radical scavenging activity. It can be concluded that TCCE has hepatoprotective activity and the mechanism is related to protection of liver mitochondria and the scavenging action on free radicals.
Griseofulvin micronization and dissolution rate improvement by supercritical assisted atomization
Authors: Reverchon E , Porta G Della , Spada A , Antonacci A
Published: October 2004

Supercritical assisted atomization (SAA) was used to micronize griseofulvin (GF), selected as a model compound, to verify the performance of this innovative process. SAA is based on the solubilization of supercritical carbon dioxide in a liquid solution containing the drug. The ternary mixture is then sprayed through a nozzle and microparticles are formed as a consequence of the enhanced atomization. Precipitation temperature and drug concentration in the liquid solution were studied to evaluate their influence on morphology and size of precipitated particles. A good particle size control was obtained and GF spherical particles with mean diameters ranging from 0.5 to 2.5 μm were produced with a narrow particle size distribution. Processed GF was characterized by high-performance liquid chromatography-UV/vis, headspace-gas chromatography-flame ionization detection, differential scanning calorimetry, BET and X-ray analyses. No drug degradation was observed and a solvent residue (acetone) less than 800 ppm was measured. GF microparticles showed good stability and surface areas ranging from about 4 to 6 m2 g−1; moreover, the micronized drug retained the crystalline habit. GF capsules were formulated with starch and used to compare the dissolution rate of SAA-processed and conventional jet-milled drug. A faster dissolution and a better reproducibility of the dissolution profile were observed for SAA-processed GF.
Metabolism of the dihydropyridine calcium channel blockers mebudipine and dibudipine by isolated rat hepatocytes
Authors: Bohlooli S , Mahmoudian M , Skellern G G , Grant M H , Tettey J N A
Published: October 2004

The prototype 1,4-dihydropyridine (1,4-DHP) nifedipine, indicated for the management of hypertension and angina pectoris, has drawbacks of rapid onset of vasodilating action and a short half-life. Several newer analogues have been designed to offset these problems and these include mebudipine and dibudipine. These analogues contain t-butyl substituents that have been selected to alter the fast metabolism without altering pharmacological activity. In this study, the metabolism of mebudipine and dibudipine by isolated rat hepatocytes has been investigated. These compounds were extensively metabolized in 2 h by oxidative pathways, analogous to those known for nifedipine, and by O-glucuronidation after hydroxylation of the t-butyl substituents. The in-vitro half-lives of mebudipine (22 ± 7.1 min) and dibudipine (40 ± 9.8 min) were significantly longer than that of nifedipine (5.5 ± 1.1 min), which was investigated in parallel in this study. These newer 1,4-DHPs address the problem of the short half-life of nifedipine and have potential for further development in view of their comparable potency to nifedipine.
In-vitro vasodilatory activity of the hexanic extract of leaves and stems from Piper truncatum Vell. in rats
Authors: Raimundo Juliana Montani , de Almeida Roberta Ramos , Velozo Leosvaldo Salazar Marques , Kaplan Maria Auxiliadora Coelho , Gattass Cerli Rocha , Zapata-Sudo Gisele
Published: October 2004

Several plants from the Brazilian Tropical Forest are used in folk medicine for treatment of hypertension and asthma. In this study, we investigated the effects of hexanic extracts of leaves (HLE) and stems (HSE) from Piper truncatum on the contractility of cardiac, vascular and tracheal smooth muscles. Twitches of cardiac muscles obtained with electrical stimulation were recorded before and after exposure to increasing concentrations of hexanic extracts. HLE and HSE respectively reduced significantly the amplitude of twitches to 57.05 ± 11.63 and 61.58 ±5.70% of control in the presence of 100 μg mL−1. Contractile response to a single concentration of adrenaline (epinephrine) was measured before and after exposure of rat aorta rings to HLE and HSE. Both extracts inhibited aorta contraction in a concentration-dependent manner. The concentration of 50% inhibitory effect (IC50) was 32.3 ± 13.8 and 47.0 ± 23.8 μg mL−1 for HLE and HSE, respectively, in aorta with intact endothelium. HLE and HSE also reduced the acetylcholine-precontracted trachea in a concentration-dependent manner with maximal effect observed at 250 and 350 μg mL−1, respectively. Vasodilatation and trachea relaxation induced by HLE and HSE could explain the use of Piper extracts to reduce blood pressure and bronchospasm.
Fenestration of the Lamina Terminalis as a Valuable Adjunct in Aneurysm Surgery
Authors: Andaluz Norberto , Zuccarello Mario
Published: October 2004

OBJECTIVE:

Hydrocephalus, vasospasm, and frontobasal injury are common complications after aneurysmal subarachnoid hemorrhage (SAH) from anterior communicating artery aneurysms. Previous studies have suggested that fenestration of the lamina terminalis (FLT) during surgery may be associated with reduced rates of shunt-dependent hydrocephalus and vasospasm. We report 106 patients affected by anterior communicating artery aneurysms and Fisher Grade 3 aneurysmal SAH and the affect of FLT on shunt-dependent hydrocephalus, vasospasm, and frontobasal injury.

METHODS:

During a 3-year period, 53 patients underwent FLT and 53 did not. We prospectively evaluated admission and discharge clinical grades, hydrocephalus at admission, occurrence of clinical vasospasm, need for interventional vasospasm therapy, frontobasal hypodensity incidence, and permanent ventriculoperitoneal shunting requirement. Follow-up ranged from 3 to 35 months (mean, 17.9 mo).

RESULTS:

Shunting incidence after aneurysmal SAH with hydrocephalus was 4.25% in patients who underwent FLT and 13.9% in patients who did not (P< 0.001). Clinical cerebral vasospasm occurred in 29.6% of patients who underwent FLT and in 54.7% of patients who did not (P< 0.001). Frontobasal hypodensity was identified postoperatively in 0% of patients who underwent FLT and in 5% of patients who did not. Good outcome was reported in 69.81% of patients who underwent FLT and in 33.96% of patients who did not (P< 0.001). Poor outcome was associated with higher Hunt and Hess grades, need for ventricular drainage, elevated intracranial pressure, and multiple interventional vasospasm therapies. No complications were linked to FLT.

CONCLUSION:

FLT was associated with statistically significant decreases in shunting rates, incidence of vasospasm, and better outcomes. We recommend its routine use in patients with Fisher Grade 3 anterior communicating artery aneurysmal SAH.
Anatomy of the Anterior Temporal Lobe and the Frontotemporal Region Demonstrated by Fiber Dissection
Authors: Peuskens Diedrik , van Loon Johannes , Van Calenbergh Frank , van den Bergh Raymond , Goffin Jan , Plets Christian
Published: October 2004

OBJECTIVE:

The white matter structure of the anterior temporal lobe and the frontotemporal region is complex and not well appreciated from the available neurosurgical literature. The fiber dissection method is an excellent means of attaining a thorough knowledge of the three-dimensional structure of the white matter tracts. This study was performed to demonstrate the usefulness of the dissection technique in understanding the white matter anatomy and the effects of current surgical approaches on the subcortical structure of the region.

METHODS:

Seventeen brain specimens obtained at routine autopsy were dissected by use of Klingler's fiber dissection technique after preparation by fixation and freezing. The dissections were performed with an operating microscope and followed a stepwise pattern of progressive white matter dissection.

RESULTS:

The dissection is described in an orderly fashion showing the white matter tracts of the anterior temporal lobe and the frontotemporal region. An insight is gained into the three-dimensional course of the anterior loop of the optic radiation, the temporal stem, the anterior commissure, and the ansa peduncularis.

CONCLUSION:

The anterior temporal lobe and the frontotemporal region contain several important white matter tracts that can be uniquely understood by performing a white matter dissection of the region. Surgical procedures on the anterior temporal lobe differ substantially as to their repercussions on the subcortical white matter tract anatomy, as shown by the findings in this study.
Temporary Balloon Occlusion of the Cavernous Carotid Artery for Removal of an Orbital and Intracranial Foreign Body: Case Report
Authors: Cunningham Edwin J. , Albani Barbara , Masaryk Thomas J. , Rasmussen Peter A.
Published: October 2004

OBJECTIVE AND IMPORTANCE:

We describe the first reported use of temporary balloon occlusion of the cavernous internal carotid artery for controlled removal of a foreign object from the cavernous sinus. This endovascular approach may be an alternative to craniotomy in highly selected cases.

CLINICAL PRESENTATION:

A 34-year-old incarcerated male attempted suicide by stabbing the earpiece of his glasses through his right orbit into the intracranial compartment. He presented with complete ophthalmoplegia. The earpiece traversed the cavernous sinus, penetrating its posterior wall to enter the perimesencephalic cistern and cerebellum. Angiography demonstrated a small direct carotid-cavernous fistula.

INTERVENTION:

Removal of the foreign body was performed under general anesthesia in the angiography suite with the operating room on standby. Nondetachable and detachable balloons were inflated in the cavernous carotid artery to provide vascular control while the foreign body was withdrawn from the cranium at the orbit. Follow-up angiographic runs with the balloons deflated revealed minimal arteriovenous shunting, which disappeared on subsequent studies. The balloons were removed. The patient remained neurologically stable with his baseline right ophthalmoplegia and V1–V2 hemianesthesia. At the 6-week follow-up, the patient remained clinically stable with no evidence of carotid-cavernous fistula or interval abscess formation.

CONCLUSION:

Endovascular temporary balloon occlusion of the cavernous carotid artery provides immediate control of the vessel (with an option of permanent carotid sacrifice), allowing removal of a foreign body without craniotomy in appropriate cases.
Linear Accelerator Radiosurgery in the Treatment of Brain Metastases
Authors: Ulm Arthur J. , Friedman William A. , Bova Frank J. , Bradshaw Patrick , Amdur Robert J. , Mendenhall William M.
Published: October 2004

OBJECTIVE:

To review a 12-year experience treating metastatic brain disease with linear accelerator-based stereotactic radiosurgery (SRS).

METHODS:

We performed a retrospective analysis of all patients treated between 1989 and 2001 with linear accelerator radiosurgery for brain metastases. Patients were followed up both clinically and with imaging studies to document local control, regional control, and survival. Demographic data, dosing parameters, number of lesions, histology, history of whole-brain radiation therapy, and other factors were obtained prospectively. Cox proportional-hazards regression with multivariate and univariate analysis was performed with Stata 8.0 software.

RESULTS:

A total of 383 patients received SRS for brain metastases during the study interval. Median survival was 9 months. Patients with tumor-type melanoma or multiple metastatic lesions had decreased survival. Actuarial 1-year local control was 75%. Differences in regional control rates were not statistically significant between patients treated with SRS and whole-brain radiation therapy versus SRS alone.

CONCLUSION:

Radiosurgery is an effective and safe method for treating selected patients with brain metastases.
Preoperative Localization of the Carotid Bifurcation for Carotid Endarterectomy Using Magnetic Resonance Angiography without Tomography: Technical Note
Authors: Weaver Kyle D. , Huang Judy , Tamargo Rafael J. , Bernard Estrada J.
Published: October 2004

OBJECTIVE:

Carotid endarterectomy without angiography is becoming increasingly common. Magnetic resonance imaging accurately demonstrates vascular anatomy and the degree of stenosis but may not localize the cervical carotid bifurcation for incision planning without tomography. We report a method for preoperative localization of the bifurcation using the relatively constant axial coplanar relationship between the horizontal petrous (C2) segment of the internal carotid artery and the external auditory canal (EAC).

METHODS:

The vertical distance between the midpoint of the C2 segment and the cervical carotid bifurcation was measured on magnetic resonance angiography images in five patients. Before surgery, a transverse incision was planned the same distance below the EAC. After exposure, the distance from the EAC to the bifurcation was measured with calipers. The distances from the anterior, posterior, superior, and inferior wound margins during retraction were also measured.

RESULTS:

The mean vertical distance between the C2 segment and the bifurcation was 7.2 cm on preoperative imaging and 7.6 cm between the EAC and bifurcation using intraoperative measurement (difference, 0.4 cm). The average distances between the midportion of the bifurcation and the wound margins after retractor placement were 2.9, 2.4, 2.8, and 3.5 cm for anterior, posterior, superior, and inferior measurements, respectively.

CONCLUSION:

The C2 segment-cervical carotid bifurcation distance may be used to estimate accurately the vertical distance from the EAC to the bifurcation. When coupled with a transverse incision for carotid endarterectomy, the use of this preoperative measurement produces a target well centered within the operative field.
NCR-1 and NCR-2, theC. eleganshomologs of the human Niemann-Pick type C1 disease protein, function upstream of DAF-9 in the dauer formation pathways
Authors: Li Jie , Brown Gemma , Ailion Michael , Lee Samuel , Thomas James H.
Published: October 2004

Mutations in the human NPC1 gene cause most cases of Niemann-Pick type C(NP-C) disease, a fatal autosomal recessive neurodegenerative disorder. NPC1 is implicated in intracellular trafficking of cholesterol and glycolipids, but its exact function remains unclear. The C. elegans genome contains two homologs of NPC1, ncr-1 and ncr-2, and an ncr-2;ncr-1 double deletion mutant forms dauer larvae constitutively (Daf-c). We have analyzed the phenotypes of ncr single and double mutants in detail, and determined the ncr gene expression patterns. We find that the ncr genes function in a hormonal branch of the dauer formation pathway upstream of daf-9 and daf-12, which encode a cytochrome P450 enzyme and a nuclear hormone receptor, respectively. ncr-1 is expressed broadly in tissues with high levels of cholesterol, whereas expression of ncr-2 is restricted to a few cells. Both Ncr genes are expressed in the XXX cells, which are implicated in regulating dauer formation via the daf-9 pathway. Only the ncr-1 mutant is hypersensitive to cholesterol deprivation and to progesterone, an inhibitor of intracellular cholesterol trafficking. Our results support the hypothesis that ncr-1 and ncr-2 are involved in intracellular cholesterol processing in C. elegans, and that a sterol-signaling defect is responsible for the Daf-c phenotype of the ncr-2; ncr-1 mutant.
Embryonic signaling centers expressing BMP, WNT and FGF proteins interact to pattern the cerebral cortex
Authors: Shimogori Tomomi , Banuchi Victoria , Ng Hanyann Y. , Strauss Jonathan B. , Grove Elizabeth A.
Published: October 2004

Recent findings implicate embryonic signaling centers in patterning the mammalian cerebral cortex. We used mouse in utero electroporation and mutant analysis to test whether cortical signaling sources interact to regulate one another. We identified interactions between the cortical hem, rich in Wingless-Int (WNT) proteins and bone morphogenetic proteins (BMPs), and an anterior telencephalic source of fibroblast growth factors (FGFs).

Expanding the FGF8 domain suppressed Wnt2b, Wnt3a and Wnt5a expression in the hem. Next to the hem, the hippocampus was shrunken, consistent with its dependence for growth on a hem-derived WNT signal. Maintenance of hem WNT signaling and hippocampal development thus require a constraint on the FGF8 source, which is likely to be supplied by BMP activity. When endogenous BMP signaling is inhibited by noggin, robust Fgf8 expression appears ectopically in the cortical primordium.

Abnormal signaling centers were further investigated in mice lacking the transcription factor EMX2, in which FGF8 activity is increased, WNT expression reduced, and the hippocampus defective. Suggesting that these defects are causally related, sequestering FGF8 in Emx2 homozygous mutants substantially recovered WNT expression in the hem and partially rescued hippocampal development.

Because noggin can induce Fgf8 expression, we examined noggin and BMP signaling in the Emx2 mutant. As the telencephalic vesicle closed, Nog expression was expanded and BMP activity reduced,potentially leading to FGF8 upregulation. Our findings point to a cross-regulation of BMP, FGF, and WNT signaling in the early telencephalon,integrated by EMX2, and required for normal cortical development.
Differing strategies for the establishment and maintenance ofteashirtandhomothoraxrepression in theDrosophilawing
Authors: Zirin Jonathan D. , Mann Richard S.
Published: October 2004

Secreted signaling molecules such as Wingless (Wg) and Decapentaplegic(Dpp) organize positional information along the proximodistal (PD) axis of the Drosophila wing imaginal disc. Responding cells activate different downstream targets depending on the combination and level of these signals and other factors present at the time of signal transduction. Two such factors, teashirt (tsh) and homothorax (hth), are initially co-expressed throughout the entire wing disc, but are later repressed in distal cells, permitting the subsequent elaboration of distal fates. Control of tsh and hth repression is, therefore,crucial for wing development, and plays a role in shaping and sizing the adult appendage. Although both Wg and Dpp participate in this control, their specific contributions remain unclear. In this report, we analyze tshand hthregulation in the wing disc, and show that Wg and Dpp act independently as the primary signals for the repression of tsh and hth, respectively. In cells that receive low levels of Dpp, hth repression also requires Vestigial (Vg). Furthermore, although Dpp is required continuously for hth repression throughout development, Wg is only required for the initiation of tshrepression. Instead, the maintenance of tsh repression requires Polycomb group (PcG) mediated gene silencing, which is dispensable for hth repression. Thus, despite their overall similar expression patterns, tsh and hth repression in the wing disc is controlled by two very different mechanisms.
The p150-Glued Ssm4p regulates microtubular dynamics and nuclear movement in fission yeast
Authors: Niccoli Teresa , Yamashita Akira , Nurse Paul , Yamamoto Masayuki
Published: October 2004

During vegetative growth of the fission yeast Schizosaccharomyces pombe, microtubules nucleate from multiple microtubule organising centres (MTOCs) close to the nucleus, polymerising until they reach the end of the cell and then shrinking back to the cell centre. In response to mating pheromone, S. pombe undergoes a morphological switch from a vegetative to a shmooing growth pattern. The switch in growth mode is paralleled by a switch in microtubular dynamics. Microtubules nucleate mostly from a single MTOC and pull on the ends of the cell to move the nucleus back and forth. This movement continues after cellular and nuclear fusion in the zygote and is important to ensure correct chromosome pairing, recombination and segregation during meiosis. Here we show that Ssm4p, a p150-Glued protein, is induced specifically in response to pheromone and is required for this nuclear movement. Ssm4p is associated with the cytoplasmic dynein complex and together with the CLIP-170 homologue Tip1p regulates dynein heavy chain localisation. We also show that Ssm4p collaborates with Tip1p in establishing the shmooing microtubular array.