bluuebunny/crossref_metadata_2025 huggingface dataset:
A yeast 2‐hybrid analysis of human GTP cyclohydrolase I protein interactions
Authors: Swick Lance , Kapatos Gregory
Published: April 2006

The yeast 2‐hybrid system was used to identify protein domains involved in the oligomerization of human guanosine 5′‐triphosphate (GTP) Cyclohydrolase I (GCH1) and the interaction of GCH1 with its regulatory partner, GCH1 feedback regulatory protein (GFRP). When interpreted within the structural framework derived from crystallography, our results indicate that the GCH1 N‐terminal α‐helices are not the only domains involved in the formation of dimers from monomers and also suggest an important role for the C‐terminal α‐helix in the assembly of dimers to form decamers. Moreover, a previously unknown role of the extended N‐terminal α–helix in the interaction of GCH1 and GFRP was revealed. To discover novel GCH1 protein binding partners, we used the yeast 2‐hybrid system to screen a human brain library with GCH1 N‐terminal amino acids 1–96 as prey. This protruding extension of GCH1 contains two canonical Type‐I Src homology‐3 (SH3) ligand domains located within amino acids 1–42. Our screen yielded seven unique clones that were subsequently shown to require amino acids 1–42 for binding to GCH1. The interaction of one of these clones, Activator of Heat Shock 90 kDa Protein (Aha1), with GCH1 was validated by glutathione‐s‐transferase (GST) pull‐down assay. Although the physiological relevance of the Aha1–GCH1 interaction requires further study, Aha1 may recruit GCH1 into the endothelial nitric oxide synthase/heat shock protein (eNOS/Hsp90) complex to support changes in endothelial nitric oxide production through the local synthesis of BH4.
Cannabinoid modulation of electrically evoked pH and oxygen transients in the nucleus accumbens of awake rats
Authors: Cheer Joseph F. , Wassum Kate M. , Wightman R. Mark
Published: April 2006

Cannabinoid receptors have been implicated in the regulation of blood flow in the cerebral vasculature. Because the nucleus accumbens (NAc) shows high levels of central cannabinoid receptor 1 (CB1) expression we examined the effects of cannabinoids on the local transient alkaline shifts and increases in extracellular oxygen induced by electrical stimulation of the medial forebrain bundle (MFB) in conscious animals. These changes result from increases in cerebral blood flow (CBF) and metabolism in the NAc that are evoked by the stimulation. Oxygen and pH changes were monitored using fast‐scan cyclic voltammetry at carbon‐fiber microelectrodes in the NAc of freely moving rats. Administration of the cannabinoid receptor agonist WIN55,212‐2 potently inhibited extracellular oxygen and pH changes, an effect that was reversed and prevented by pre‐treatment with the CB1receptor antagonists SR141716A and AM251. The effects on pH following WIN55,212‐2 were similar to those following nimodipine, a recognized vasodilator. When AM251 was injected alone, the amplitude of electrically evoked pH shifts was unaffected. Administration of AM404 and VDM11, endocannabinoid transport inhibitors, partially inhibited pH transients in a CB1receptor‐dependent manner. The present findings suggest that CB1receptor activation modulates changes in two well‐established indices of local blood flow and metabolism resulting from electrically evoked activation of ascending fibers. Although endogenous cannabinoid tone alone is not sufficient to modify these responses, uptake blockade demonstrates that the system has the potential to exert CB1‐specific effects similar to those of full agonists.
Non‐steroidal anti‐inflammatory drug‐related hepatic damage in France and Spain: analysis from national spontaneous reporting systems
Authors: Lapeyre‐Mestre Maryse , De Castro Ana Maria Rueda , Bareille Marie‐Pierre , Pozo Javier Garcia del , Requejo Ana Alvarez , Arias Louis Martin , Montastruc Jean‐Louis , Carvajal Alfonso
Published: April 2006

Several non‐steroidal anti‐inflammatory drugs (NSAIDs) have been associated with liver damage. The aim of this study was to compare proportions of hepatic adverse drug reaction reports associated with NSAIDs in France and Spain. Information from the Spanish and French pharmacovigilance databases were used from 1982 to 2001. To assess the risk of liver injury, the case/non‐case methodology was applied, ‘cases’ being reports of liver damage and ‘non‐cases’ or controls, all other reports. Exposure was considered as the presence of at least one NSAID. Liver injury risk was estimated for each drug in the two databases by calculation of reporting odds ratio in cases and non‐cases, with its 95% confidence interval. Out of 62 456 reports from the Spanish database, 2114 (3.38%) were identified as liver injuries, whereas there were 27 372 liver injuries out of 200 046 (13.68%) in the French database. In Spain, there was a significant association between liver injuries and droxicam, sulindac, and nimesulide. The risk was also slightly above 1 for aceclofenac. In France, the risk was very high with clometacin, followed by sulindac, and was slightly above 1 for naproxen, diclofenac, piroxicam, and tenoxicam. This study shows that some NSAIDs are associated with reports of hepatic injuries when compared with other drugs, and most of those have been withdrawn from the market for this reason. However, the frequency of drug‐related hepatic injuries reported differed in the French and Spanish databases, and some drugs did not show the same risk level in the two countries. These discrepancies could be explained in part not only by reporting rates, but also by difference in drug use patterns and/or by genetic or environmental factors.
Bringing States Back In
Authors: Hindess Barry
Published: April 2006

There is little of value to be said about the concept of power as such. The term itself is best seen as invoking the ‘total structure of actions brought to bear’ by some on the actions of others. What is of interest, then, is not power as such but rather the special cases in which relatively stable configurations of power can be identified. Lukes' focus on domination obscures the significance of other configurations. One is the political power of the state, which Lukes simply takes for granted, focusing instead on the question of who has control over its use. Another, which overlaps with political power but is not reducible to it, is government of the state. The system of states is the site of a third major limitation in PRV‘s discussion, which is the point of the plural, states, in my title. Neither the American debate to which PRV made an influential late contribution nor Lukes' expanded discussion have much to say about the role of these configurations of power in the world today. A view of power that simply ignores them may be radical in certain respects but it is blinkered in others.
Haloperidol in the Acute Treatment of Migraine: A Randomized, Double‐Blind, Placebo‐Controlled Study
Authors: Honkaniemi Jari , Liimatainen Suvi , Rainesalo Sirpa , Sulavuori Sari
Published: April 2006

Objective.—To assess the efficacy and safety of IV haloperidol in treatment of acute migraine headache in a double‐blind, randomized, placebo‐controlled study design.

Background.—Neuroleptics are mainly used as antiemetics in acute migraine. In a previous open trial haloperidol was effective in relieving migraine pain.

Design.—Patients were randomized into 2 groups receiving intravenously either 5 mg haloperidol in 500 mL of normal saline or 500 mL of normal saline alone. Pain was assessed by visual analogue scale (VAS) before and 1 to 3 hours after the infusion. If the patient felt no relief in pain intensity 1 to 3 hours after the infusion and had received placebo, he/she then received haloperidol infusion as an open trial. The open trial also included 7 patients who refused from the placebo‐controlled trial. About 1 month after the infusion the patients were contacted by telephone and interviewed about the side effects of the treatment.

Results.—Forty patients were enrolled into the double‐blind, placebo‐controlled study. Before the infusion the VAS values were 7.7 in the haloperidol and 7.2 in the placebo group. After the infusion the VAS values were 2.2 in the haloperidol and 6.3 in the placebo group (P < .0001). Significant pain relief was achieved in 80% of the patients treated with haloperidol, whereas only 3 patients (15%) responded to placebo (P < .0001). Seventeen patients treated with placebo without response together with 7 patients who refused from the placebo‐controlled study participated in the open trial. In this group VAS declined from 6.7 to 2.4 and 79% of these patients felt significant pain relief. The most common side effects caused by haloperidol were sedation and akathisia, the latter being more troublesome. These effects were very common in patients participating in the double‐blind (80%) and open (88%) trials. Sixteen percent of the patients considered the side effects intolerable and would not like the migraine attacks to be treated with haloperidol in the future. Three patients (7%) returned to the emergency ward because of a relapse.

Conclusions.—This study shows that IV haloperidol is very effective in relieving migraine‐associated pain. Because the majority of the patients had taken other medication without response, haloperidol appears to be an effective rescue medication even when other types of treatment have failed. Relapses are rare, but side effects are common, limiting the use of haloperidol in some patients.
Migraine Care Among Different Ethnicities: Do Disparities Exist?
Authors: Nicholson Robert A. , Rooney Megan , Vo Kelly , O'Laughlin Erinn , Gordon Melanie
Published: April 2006

Objective.—Evaluate whether, in a primary care setting, Caucasians (C) and African Americans (AA) with moderately to severely disabling migraines differed in regards to: utilizing the health‐care system for migraine care, migraine diagnosis and treatment, level of mistrust in the health‐care system, perceived communication with their physician, and perceived migraine triggers.

Background.—Research has documented ethnic disparities in pain management. However, almost no research has been published concerning potential disparities in utilization, diagnosis, and/or treatment of migraine. It is also important to consider whether ethnic differences exist for trust and communication between patients and physicians, as these are essential when diagnosing and treating migraine.

Methods.—Adult patients with headache (n = 313) were recruited from primary care waiting rooms. Of these, 131 (AA = 77; C = 54) had migraine, moderate to severe headache‐related disability, and provided socioeconomic status (SES) data. Participants completed measures of migraine disability (MIDAS), migraine health‐care utilization, diagnosis and treatment history, mistrust of the medical community, patient–physician communication (PPC), and migraine triggers. Analysis of covariance (controlling for SES and recruitment site), chi‐square, and Pearson product moment correlations were conducted.

Results.—African Americans were less likely to utilize the health‐care setting for migraine treatment (AA = 46% vs. C = 72%, P < .001), to have been given a headache diagnosis (AA = 47% vs. C = 70%, P < .001), and to have been prescribed acute migraine medication (AA = 14% vs. C = 37%, P < .001). Migraine diagnosis was low for both groups, and <15% of all participants had been prescribed a migraine‐specific medication or a migraine preventive medication despite suffering moderate to severe levels of migraine disability. African Americans had less trust in the medical community (P < .001, η2= 0.26) and less positive PPC (P < .001, η2= 0.11). Also, the lower the trust and communication, the less likely they were to have ever seen (or currently be seeing) a doctor for migraine care or to have been prescribed medication.

Conclusions.—Migraine utilization, diagnosis, and treatment were low for both groups. However, this was especially true for African Americans, who also reported lower levels of trust and communication with doctors relative to Caucasians. The findings highlight the need for improved physician and patient education about migraine diagnosis and treatment, the importance of cultural variation in pain presentation, and the importance of communication when diagnosing and treating migraine.
The Perceived Intent of Potentially Offensive Sexual Behaviors Among Adolescents
Authors: Lacasse Anne , Mendelson Morton J.
Published: April 2006

Individual differences may partly explain how students react to potentially offensive sexual behaviors from peers. This study focused on situational and personal characteristics that may make such behaviors more or less upsetting. Six hundred and thirty two Quebecois high‐school students in Grades 8–11 completed questionnaires regarding their experience with potentially offensive sexual behaviors. Behaviors experienced at the hand of a close friend were less upsetting than those experienced at the hand of other peers. Compared with high self‐esteem peers, students with lower self‐esteem were more upset by such behaviors and were more likely to perceive the perpetrator's intent as unacceptable. In addition to sex of target, self‐esteem, and relationship with the perpetrator, the attribution of unacceptable intent to the perpetrator predicted upset ratings.
A fatal case of enoxaparin induced skin necrosis and thrombophilia
Authors: Nadir Yona , Mazor Yoav , Reuven Bergman , Sarig Galit , Brenner Benjamin , Krivoy Norberto
Published: April 2006

Abstract:  Skin necrosis caused by heparins is a rare complication. We report a case of a 71‐yr‐old white woman who developed painful diffuse skin lesions, most probably related to enoxaparin treatment. Other causes of skin necrosis, including heparin induced thrombocytopenia, disseminated intravascular coagulation, protein C/protein S deficiencies, anti‐phospholipid antibodies, and vitamin K deficiency were less likely in this case. The concomitant combined thrombophilia possibly aggravated the patient's clinical presentation.
Chemotherapy‐related infections in patients with multiple myeloma: associations with mannan‐binding lectin genotypes
Authors: Mølle Ingolf , Steffensen Rudi , Thiel Steffen , Peterslund Niels A.
Published: April 2006

Abstract:  Objectives: To study a possible association between mannan‐binding lectin genotypes and severe infections in patients with multiple myeloma receiving moderate strength induction chemotherapy. Methods: Chemotherapy‐related infections were identified retrospectively using clinical records and database files. Mannan‐binding lectin genotypes were identified with polymerase chain reaction on stored samples of stem cells or formalin‐fixed paraffin‐embedded bone marrow biopsies. Results: We included 138 myeloma patients. In five patients, data were incomplete, and 133 patients were analysed. Eighty‐eight patients were homozygous for wild‐type MBL2 (AA) and forty‐five patients were heterozygous or homozygous for variant genotypes (AO/OO). A total of 390 chemotherapy cycles were reviewed. Common Toxicity Criteria grades 3 and 4 infections in general were seen in relation to 104 cycles and were not more common in patient with variant MBL2 (P = 0.90). Septicaemia was seen after 10% of chemotherapy cycles in AA patients vs. 15% in AO/OO patients (P = 0.15). In multi‐variate analyses, we found indication of a reduced risk of septicaemia in AA patients [OR 0.27 (0.08–0.90), P = 0.03], after first chemotherapy cycle, but reduction of the risk including all cycles was not significant. A similar trend was seen for grades 3 and 4 infections in general. Conclusions: During induction chemotherapy in patients with multiple myeloma, a general protective effect of wild‐type MBL2 against chemotherapy‐related infections was not apparent in this study. However, we found indications of a reduced occurrence of septicaemia in patients with wild‐type compared with variant MBL2. Further studies in larger cohorts of patients are relevant.
No effect of eccentric training on jumper's knee in volleyball players during the competitive season: a randomized clinical trial
Authors: Visnes H. , Hoksrud A. , Cook J. , Bahr R.
Published: April 2006

BACKGROUND: The effect of surgery on patellar tendinopathy (jumper's knee) is questionable, and conservative treatment protocols have not been properly documented.

PURPOSE: The aim of this study was to investigate the effect of a newly developed eccentric training program for patellar tendinopathy in volleyball players during the competitive season.

STUDY DESIGN: Randomized clinical trial.

METHODS: Patients were recruited from male and female elite volleyball teams in Norway, and the diagnosis was based on clinical examination alone. Of 51 players diagnosed with patellar tendinopathy, 29 could be included in the study. The training group (n=13) performed squats on a 25° decline board as a home exercise program (3 × 15 repetitions twice daily) for a 12‐week intervention period during the final half of the competitive season. The eccentric (downward) component was done on the affected leg. The control group (n=16) trained as usual. The primary outcome was a symptom‐based questionnaire developed specifically for patellar tendinopathy (Victorian Institute of Sport Assessment score), and patients were followed up before and after the intervention period, as well as after 6 and 30 weeks. All subjects self‐recorded training to document their activity level (eccentric training, volleyball training, matches, other training).

RESULTS: There was no change in Victorian Institute of Sport Assessment score during the intervention period in the training (pre, 71.1±11.3; post, 70.2±15.4) or control group (pre, 76.4±12.1; post, 75.4±16.7), nor was there any change during the follow‐up period at 6 weeks or 6 months. The training group completed 8.2±4.6 weekly sessions of eccentric training during the intervention period (59% of the recommended volume), and there was no difference between groups in training or competition load.

CONCLUSION: There was no effect on knee function from a 12‐week program with eccentric training among a group of volleyball players with patellar tendinopathy who continued to train and compete during the treatment period. Whether the training would be effective if the patients did not participate in sports activity is not known.
The guanine nucleotide exchange factor RasGRF1 directly binds microtubules via DHPH2‐mediated interaction
Authors: Forlani Greta , Baldassa Simona , Lavagni Paola , Sturani Emmapaola , Zippel Renata
Published: April 2006

RasGRF is a family of guanine nucleotide exchange factors with dual specificity for both Ras and Rac GTPases. In this study, using mouse brain extracts, we show that both RasGRF1 and RasGRF2 interact with microtubules in an in vitro microtubule assembly system and this binding is very tight. To characterize this association, recombinant purified proteins containing different regions of RasGRF1 were tested for their ability to bind microtubules preassembled from pure tubulin. Only the DHPH2 tandem directly associates with microtubules, whereas the isolated DH or PH2 domains do not, indicating that the entire DHPH2 region is required for this association. The interaction occurs with high affinity (Kd≈ 2 µm) and with a stoichiometry, at saturating conditions, of one DHPH2 molecule for two tubulin dimers. Competition experiments support the hypothesis that the DHPH2 module is largely responsible for RasGRF1–microtubule interaction. In vivo colocalization of RasGRF1 and microtubules was also observed by fluorescence confocal microscopy in nonneuronal cells after stimulation with an oxidative stress agent and in highly differentiated neuron‐like cells. Identification of microtubules as new binding partners of RasGRF1 may help to elucidate the signaling network in which RasGRF1 is involved.
Acute compartment syndrome complicating an intramuscular haemangiosarcoma in a dog
Authors: Radke H. , Spreng D. , Sigrist N. , Lang J. , Bornand V. , Schawalder P.
Published: April 2006

Acute compartment syndrome in dogs is a rare complication of muscle trauma, but it has not been previously reported as a consequence of neoplasia in dogs. This case report describes the occurrence of a compartment syndrome of the femoral compartment in an 11‐year‐old, male, mixed‐breed dog caused by acute bleeding of an intramuscular haemangiosarcoma. The compartment syndrome was relieved by immediate fasciotomy. The dog was euthanased following acute recurrence of clinical signs seven weeks after surgery.
A Model for Condensate Retention on Plain-Fin Heat Exchangers
Authors: ElSherbini A. I. , Jacobi A. M.
Published: April 2006

A model has been developed for predicting the amount of condensate retained as drops on the air-side of heat exchangers operating under dehumidifying conditions. For a coil with a given surface wettability, characterized by the advancing contact angle, the maximum diameter for a retained drop is obtained from a balance between gravitational and surface tension forces. A logarithmic function is used to describe the size-distribution of drops on fins, based on the fraction of fin-area covered by liquid. The volumes of individual drops are calculated by a geometric method for approximating the three-dimensional shapes of drops on vertical and inclined surfaces. The total volume of condensate accumulated on a coil is then found by multiplying the size-distribution and volume functions and integrating over all drop diameters. The model is successful in predicting measurements by other researchers of the mass of condensate retained on plain-fin heat exchangers. The critical fin spacing to avoid the formation of condensate bridges is also predicted.
An In Situ Experimental Method for the Development and Validation of Slat-Type Blind Models in Cooling Load Calculations
Authors: Chantrasrisalai Chanvit , Fisher Daniel E.
Published: April 2006

An in situ experimental procedure suitable for the development and validation of slat-type blind models used in building cooling load calculations is presented. Unique requirements of the experimental facility are presented, and measured data from the facility are compared with existing experimentally validated models. The experimental uncertainty associated with the measured solar transmittance is shown to be less than ±0.05, well within the range of accuracy required for the development of cooling load calculation procedures. The new procedure was used to validate the fenestration model in EnergyPlus, a heat balance based cooling load and energy calculation program.
A Real Options Methodology for Evaluating Risk and Opportunity of Natural Ventilation
Authors: Greden Lara V. , Glicksman Leon R. , Lopez-Betanzos Gabriel
Published: April 2006

The variable, uncertain nature of climate imposes risk in using solar and building technologies, such as natural ventilation (NV). To maximize the potential benefit from NV while reducing risk, a building could be designed for NV along with the “real option” to install mechanical cooling in the future, if needed. Traditional evaluation procedures use expected values, which fail to acknowledge the value of uncertainty when system performance is a nonlinear function of the uncertain variable. A real options methodology is proposed to evaluate the flexible building design under climate uncertainty. A building energy simulation is used to obtain probability distributions of the cost savings of the option-based NV strategy and of the time when (if) the mechanical cooling system is installed. A simplified stochastic temperature generator is used, and it may be used to evaluate real options for other technologies sensitive to future climate. The results of a real options analysis provide information to project investors on (a) the likelihood of exercising the option, and (b) the improved financial value of the technology when implemented with a flexible strategy.
Calcium Carbonate Formation on Cross-Linked Polyethylene (PEX) and Polypropylene Random Copolymer (PP-r)
Authors: Sanft Patricia , Francis Lorraine F. , Davidson Jane H.
Published: April 2006

The accumulation of calcium carbonate (referred to as scale) on the surface of cross-linked polyethylene and polypropylene random copolymer tubes is compared to that on copper. Water with total calcium and carbonate concentration of 3×10−3M and a pH of approximately 9.1, yielding a supersaturation of 7.8, was pumped through the tubes at a velocity of 0.07m∕s for 2.5, 5, and 7.5h. Flow was laminar with Reynolds numbers of <1000. Sections of the tubes were analyzed at the designated time points to determine the extent of scaling. Results include scanning electron microscope images of the tube surfaces before and after exposure to the supersaturated water and chemical analysis to determine the mass of calcium carbonate per unit surface area. Measured scaling rates of the two polymer tubes are similar to that of copper.
Expression of KLF5 is a Prognostic Factor for Disease-Free Survival and Overall Survival in Patients with Breast Cancer
Authors: Tong Dan , Czerwenka Klaus , Heinze Georg , Ryffel Martin , Schuster Eva , Witt Armin , Leodolter Sepp , Zeillinger Robert
Published: April 2006

Purpose: Kruppel-like factor (KLF5) is a cell growth mediator in various epithelial cells. Higher KLF5 increases cell growth rate and leads to transformed phenotypes. Because tumor cell proliferation is tightly associated with tumor progression, and consequently, with survival of cancer patients, we wanted to examine the prognostic value of KLF5 gene expression for patients with breast cancer.

Experimental Design: The gene expression levels of KLF5, ER, PR, HER2, and MKI67 were quantified in the tumor tissues of 90 patients with breast cancer and correlated with disease-free survival and overall survival of the patients. The correlations of gene expression between KLF5 and ER, PR, HER2, and MKI67 were analyzed. In addition, KLF5 expression was also compared with clinical data and age of patients.

Results: Statistically significant correlations were found between gene expression of KLF5 and both disease-free survival (univariate analysis) and overall survival (univariate and multivariate analysis). Patients with higher KLF5 expression had shorter disease-free survival and overall survival time, whereas patients with lower KLF5 expression had better survival. Moreover, KLF5 was also found to be positively correlated with HER2 and MKI67, and negatively correlated with age of the patients at diagnosis.

Conclusion: The gene expression of KLF5 is directly correlated with cell proliferation in vivo and is a prognostic factor for patients with breast cancer. Patients with higher KLF5 expression have shorter disease-free survival and overall survival than patients with lower KLF5 expression. In addition, KLF5 has higher expression in patients ages ≤50 years old than in patients >50 years old.
Systemic Antitumor Effect of Intratumoral Injection of Dendritic Cells in Combination with Local Photodynamic Therapy
Authors: Saji Hisashi , Song Wenru , Furumoto Katsuyoshi , Kato Harubumi , Engleman Edgar G.
Published: April 2006

Purpose: Photodynamic therapy (PDT), which is used clinically for the palliative treatment of cancer, induces local tumor cell death but has no effect on tumors in untreated sites. The purpose of this study was to determine if local PDT followed by intratumoral injection of naïve dendritic cells (IT-DC) induces systemic antitumor immunity that can inhibit the growth of untreated as well as PDT + IT-DC–treated tumors.

Experimental Design: BALB/c or C57Bl/6 mice were injected s.c. with CT26 colorectal carcinoma cells and B16 melanoma cells, respectively, and following 10 to 12 days of tumor growth, the tumors were treated with PDT alone or PDT followed by IT-DC or IT-PBS. In other studies, tumors were established simultaneously in both lower flanks or in one flank and in the lungs, but only one flank was treated.

Results: Whereas neither PDT nor IT-DC alone was effective, PDT + IT-DC eradicated both CT26 and B16 tumors in a significant proportion of animals and prolonged the survival of mice of which the tumors were not cured. The spleens of mice treated with PDT + IT-DC contained tumor-specific cytotoxic and IFN-γ-secreting T cells whereas the spleens of control groups did not. Moreover, adoptive transfer of splenocytes from successfully treated CT26 tumor-free mice protected naïve animals from a subsequent challenge with CT26, and this was mediated mainly by CD8 T cells. Most importantly, PDT plus IT-DC administered to one tumor site led to tumor regression at distant sites, including multiple lung metastases.

Conclusions: PDT + IT-DC induces potent systemic antitumor immunity in mice and should be evaluated in the treatment of human cancer.
A Combination of Molecular Markers Accurately Detects Lymph Node Metastasis in Non–Small Cell Lung Cancer Patients
Authors: Xi Liqiang , Coello Michael C. , Litle Virginia R. , Raja Siva , Gooding William E. , Yousem Samuel A. , El-Hefnawy Talal , Landreneau Rodney J. , Luketich James D. , Godfrey Tony E.
Published: April 2006

Occult lymph node metastasis (micrometastasis) is a good prognostic indicator in non–small cell lung cancer (NSCLC) and could be used to direct adjuvant chemotherapy in stage I patients. This study was designed to evaluate molecular markers for detection of occult lymph node metastasis in NSCLC, define the best marker or marker combination to distinguish positive from benign lymph nodes, and evaluate these markers in lymph nodes from pathologically node-negative (pN0) NSCLC patients. Potential markers were identified through literature and database searches and all markers were analyzed by quantitative reverse transcription-PCR in a primary screen of six NSCLC specimens and 10 benign nodes. Selected markers were further evaluated on 21 primary NSCLC specimens, 21 positive nodes, and 21 benign nodes, and the best individual markers and combinations were identified. A combination of three markers was further validated on an independent set of 32 benign lymph nodes, 38 histologically positive lymph nodes, and 462 lymph nodes from 68 pN0 NSCLC patients. Forty-two markers were evaluated in the primary screen and eight promising markers were selected for further analysis. A combination of three markers (SFTPB, TACSTD1, and PVA) was identified that provided perfect classification of benign and positive nodes in all sample sets. PVA and SFTPB are particularly powerful in tumors of squamous and adenocarcinoma histologies, respectively, whereas TACSTD1 is a good general marker for NSCLC metastasis. The combination of these genes identified 32 of 462 (7%) lymph nodes from 20 of 68 (29%) patients as potentially positive for occult metastasis. Long-term follow-up will determine the clinical relevance of these findings.
Roles of Nitric Oxide Synthase Inhibition and Vascular Endothelial Growth Factor Receptor-2 Inhibition on Vascular Morphology and Function in anIn vivoModel of Pancreatic Cancer
Authors: Camp E. Ramsay , Yang Anthony , Liu Wenbiao , Fan Fan , Somcio Ray , Hicklin Daniel J. , Ellis Lee M.
Published: April 2006

Purpose: Both nitric oxide (NO) and vascular endothelial growth factor (VEGF) mediate tumor vascular function. Because these molecules regulate one another's expression, we hypothesized that NO synthase (NOS) inhibition produces effects comparable to those of anti-VEGF therapy on human pancreatic cancer xenografts.

Experimental Design: L3.6pl human pancreatic cancer cells were s.c. implanted in nude mice. On day 6, mice were randomized to receive (a) PBS (control), (b) DC101 [VEGF receptor 2 (VEGFR-2) antibody] by i.p. injection, (c) N-nitro-l-arginine (NNLA; NOS inhibitor) in the drinking water, or (d) both DC101 and NNLA. Mice were killed on day 20.

Results: DC101 and NNLA as single agents inhibited tumor growth by ∼50% to 60% (P < 0.008 for both). Furthermore, combined therapy inhibited mean tumor growth by 89% (P < 0.008). Combined inhibition of VEGFR-2 and NOS also decreased mean vessel counts by 65% (P < 0.03) and vessel area by 80% versus controls (P < 0.001). In contrast to DC101 where vessel diameter was similar to control, NNLA decreased mean vessel diameter by 42% (P < 0.001). NNLA also led to a 54% (P < 0.03) decrease in tumor uptake of the perfusion marker Hoechst 33342 versus controls whereas DC101 decreased Hoechst 33342 staining by 43% (P < 0.03). The combination of inhibitors decreased perfusion by 73% (P < 0.03).

Conclusions: Although VEGFR-2 can mediate NOS activity, the combination of VEGFR-2 and NOS inhibition significantly increased the antivascular effect over single agent therapy. The addition of NOS inhibition led to an even further alteration of tumor vessel morphology and vascular perfusion compared with VEGFR-2 blockade, suggesting that NO and VEGFR-2 have distinct but complementary effects on the tumor vasculature.
Efficacy of the Kinase Inhibitor SU11248 against Gastrointestinal Stromal Tumor Mutants Refractory to Imatinib Mesylate
Authors: Prenen Hans , Cools Jan , Mentens Nicole , Folens Cedric , Sciot Raf , Schöffski Patrick , Van Oosterom Allan , Marynen Peter , Debiec-Rychter Maria
Published: April 2006

Purpose: The majority of gastrointestinal stromal tumors harbor mutations in the receptor tyrosine kinases KIT or platelet-derived growth factor receptor A (PDGFRA), and respond to treatment with the tyrosine kinase inhibitor imatinib. Some tumors, however, show primary resistance to imatinib treatment, and most others become resistant during treatment. The most common mechanism of imatinib resistance involves specific mutations in the kinase domains of KIT or PDGFRA. We tested the activity of SU11248, an orally active small-molecule tyrosine kinase inhibitor, to inhibit important imatinib-resistant KIT and PDGFRA mutants.

Experimental Design: Primary imatinib-resistant tumor cells and cell lines expressing clinically identified imatinib-resistant KIT-V654A, KIT-T670I, or PDGFRA-D842V mutant isoforms were evaluated for sensitivity to SU11248 by Western immunoblotting and proliferation assays. Three patients with the KIT-V654A mutation were treated with SU11248.

Results: Based on ex vivo assays, SU11248 potently inhibits KIT kinase activity of V654A and T670I mutants and suppresses proliferation of the cells expressing these mutations. Sensitivity of KIT-V654A and KIT-T670I mutants to SU11248 was confirmed using cell lines expressing these mutants. In contrast, SU11248 did not potently inhibit the PDGFRA-D842V mutant. In agreement with these results, two of the three imatinib-resistant patients with the KIT-V654A mutation responded to SU11248 treatment.

Conclusions: These studies suggest that SU11248 may be a useful therapeutic agent to treat gastrointestinal stromal tumors harboring the imatinib-resistant KIT-V654A or KIT-T670I mutations, but it has no effect on the activity of the PDGFRA-D842V mutant. Specific kinase inhibitors should be designed to inhibit the constitutive activating PDGFRA mutation at codon 842.
High-Resolution Mapping of Tumor Redox Status by Magnetic Resonance Imaging Using Nitroxides as Redox-Sensitive Contrast Agents
Authors: Matsumoto Ken-ichiro , Hyodo Fuminori , Matsumoto Atsuko , Koretsky Alan P. , Sowers Anastasia L. , Mitchell James B. , Krishna Murali C.
Published: April 2006

Purpose: There is considerable research directed toward the identification and development of functional contrast agents for medical imaging that superimpose tissue biochemical/molecular information with anatomical structures. Nitroxide radicals were identified as in vivo radioprotectors. Being paramagnetic, they can provide image contrast in magnetic resonance imaging (MRI) and electron paramagnetic resonance imaging (EPRI). The present study sought to determine the efficacy of nitroxide radioprotectors as functional image contrast agents.

Experimental Design: Nitroxide radioprotectors, which act as contrast agents, were tested by EPRI and MRI to provide tissue redox status information noninvasively.

Results: Phantom studies showed that the nitroxide, 3-carbamoyl-PROXYL (3CP), undergoes time-dependent reduction to the corresponding diamagnetic hydroxylamine only in the presence of reducing agents. The reduction rates of 3CP obtained by EPRI and MRI were in agreement suggesting the feasibility of using MRI to monitor nitroxide levels in tissues. The levels of 3CP were examined by EPRI and MRI for differences in reduction between muscle and tumor (squamous cell carcinoma) implanted in the hind leg of C3H mice simultaneously. In vivo experiments showed a T1-dependent image intensity enhancement afforded by 3CP which decreased in a time-dependent manner. Reduction of 3CP was found to be the dominant mechanism of contrast loss. The tumor regions exhibited a faster decay rate of the nitroxide compared to muscle (0.097 min-1 versus 0.067 min-1, respectively).

Conclusions: This study shows that MRI can be successfully used to co-register tissue redox status along with anatomic images, thus providing potentially valuable biochemical information from the region of interest.
Spatial Forecasts of Maximum Hail Size Using Prognostic Model Soundings and HAILCAST
Authors: Brimelow Julian C. , Reuter Gerhard W. , Goodson Ron , Krauss Terrence W.
Published: April 2006

Forecasting the occurrence of hail and the maximum hail size is a challenging problem. This paper investigates the feasibility of producing maps of the forecast maximum hail size over the Canadian prairies using 12-h prognostic soundings from an operational NWP model as input for a numerical hail growth model. Specifically, the Global Environmental Multiscale model run by the Canadian Meteorological Center is used to provide the initial data for the HAILCAST model on a 0.5° × 0.5° grid. Maps depicting maximum hail size for the Canadian prairies are generated for 0000 UTC for each day from 1 June to 31 August 2000. The forecast hail-size maps are compared with radar-derived vertically integrated liquid data over southern Alberta and surface hail reports. Verification statistics suggest that the forecast technique is skillful at identifying the occurrence of a hail day versus no-hail day up to 12 h in advance. The technique is also skillful at predicting the main threat areas. The maximum diameter of the hailstones is generally forecast quite accurately when compared with surface observations. However, the technique displays limited skill when forecasting the distribution of hail on a small spatial scale.
Pharmacokinetics of Buspirone in Autistic Children
Authors: Edwards David J. , Chugani Diane C. , Chugani Harry T. , Chehab Jamal , Malian Monica , Aranda Jacob V.
Published: April 2006

Buspirone is used to treat generalized anxiety disorder in children and may be useful in developmental disorders in which brain serotonin synthesis is altered. Autistic children (13 boys, 7 girls) were given a single oral dose of 2.5 mg (2–3 years) or 5.0 mg (4–6 years). Blood was collected for 8 hours, and plasma was assayed for buspirone and its metabolite 1‐pyrimidinylpiperazine (1‐PP). The peak concentration of buspirone averaged 1141 ± 748 pg/mL with a time to maximum concentration of 0.8 hours. Half‐life was 1.6 ± 0.3 hours. Peak concentrations of 1‐PP were 4.5‐fold higher than for buspirone. Girls had higher peak concentrations (1876 vs 746 pg/mL) for buspirone and a lower peak 1‐PP/buspirone concentration ratio. These results suggest that buspirone is rapidly absorbed and eliminated in young children with extensive metabolism to 1‐PP. Plasma concentrations with 2.5‐ to 5.0‐mg doses were similar to those observed in older children receiving 7.5‐ to 15‐mg doses.
Tibiofemoral Contact Mechanics after Serial Medial Meniscectomies in the Human Cadaveric Knee
Authors: Lee Stephen J. , Aadalen Kirk J. , Malaviya Prasanna , Lorenz Eric P. , Hayden Jennifer K. , Farr Jack , Kang Richard W. , Cole Brian J.
Published: April 2006

Background

There is no consensus regarding the extent of meniscectomy leading to deleterious effects on tibiofemoral contact mechanics.

Hypothesis

The meniscus aids in optimizing tibiofemoral contact mechanics, increasing contact area, and decreasing contact stress.

Study Design

Controlled laboratory study.

Methods

Twelve fresh-frozen human cadaveric knees each underwent 15 separate testing conditions—5 serial 20-mm posterior medial meniscectomy conditions (intact, 50% radial width, 75% radial width, segmental, and total meniscectomy) at 3 flexion angles (0°, 30°, and 60°)—under an 1800-N axial load. Tekscan sensors were used to measure total force and medial force, contact area, mean contact stress, and peak contact stress.

Results

All posterior medial meniscectomy conditions resulted in significantly decreased contact areas and increased mean and peak contact stresses compared with the intact state (P < .05). The changes in contact mechanics after segmental and total posterior medial meniscectomies were not statistically different (P > .05). Incremental changes in contact area and mean contact stress increased as more peripheral portions of the medial meniscus were removed, whereas peak contact stresses exhibited similar incremental changes throughout all meniscectomy conditions.

Conclusions

The meniscus is a crucial load-bearing structure, optimizing contact area and minimizing contact stress. Loss of hoop tension (ie, segmental meniscectomy) is equivalent to total meniscectomy in load-bearing terms. The peripheral portion of the medial meniscus provides a greater contribution to increasing contact areas and decreasing mean contact stresses than does the central portion, whereas peak contact stresses increase proportionally to the amount of meniscus removed.

Clinical Relevance

Because the degree of meniscectomy leading to clinically significant outcomes is unknown, a prudent strategy is to preserve the greatest amount of meniscus possible.
Meniscal Allograft Transplantation in the Sheep Knee
Authors: Kelly Bryan T. , Potter Hollis G. , Deng Xiang-Hua , Pearle Andrew D. , Turner A. Simon , Warren Russell F. , Rodeo Scott A.
Published: April 2006

Background

Early protection of articular cartilage, before degenerative changes appear on radiographs, should result in better long-term results, but scientific evidence regarding the effectiveness of meniscal transplantation is lacking.

Purpose

To assess the chondroprotective effects of a new meniscal allograft transplantation animal model and evaluate a magnetic resonance imaging parameter, T2 mapping, in articular cartilage after meniscectomy and meniscal transplantation.

Study Design

Controlled laboratory study.

Methods

Forty-five skeletally mature sheep were placed into 3 surgical groups lateral meniscectomy (n = 24), meniscal allograft transplant (n = 17), and sham (n = 4). Animals were sacrificed at 2, 4, or 12 months. Cartilage was assessed by gross inspection, magnetic resonance imaging, T2 mapping, biomechanical testing, and semiquantitative histologic analysis.

Results

There were no differences between the sham operation and nonoperated control limbs. Compared with control limbs, meniscectomy resulted in significant increases in cartilage degeneration by all objective criteria (P < .01). Compared with meniscectomy, meniscal allograft transplantation resulted in significant decreases in cartilage degeneration (P < .02). There were significant correlations between T2-mapping data and all other traditional outcomes measures (P < .05, r2 = 0.37-0.67). Compared with the nonoperated control limbs, allograft transplants demonstrated no significant differences at 2 months in any category, except magnetic resonance imaging data. By 4 months, nonoperated control limbs demonstrated significantly less wear compared to allograft limbs in all categories except modified Mankin scores.

Conclusion

This model demonstrated significant chondroprotection compared with meniscectomy but demonstrated more cartilage wear at 4 months compared to control limbs. A high degree of allograft cell viability and vascular ingrowth was seen in allograft explants. T2 mapping may provide an accurate noninvasive measure of early cartilage degeneration after meniscectomy, as well as cartilage protection after meniscal allograft transplantation.

Clinical Relevance

This study establishes a reliable animal model for meniscal allograft transplantation and provides evidence for the utility of T2 mapping at clinically relevant magnetic resonance imaging field strengths for evaluation of early cartilage degeneration.
Being the Next of Kin of an Adult Person With Muscular Dystrophy
Authors: Boström Katrin , Ahlström Gerd , Sunvisson Helena
Published: April 2006

A chronic disorder affects all members of the family in various ways. The aim of this study is to elucidate the next of kin's ( N= 36) experiences when an adult family member has muscular dystrophy. The relationships were partner (36%, n= 14), parent (18%, n= 7), child (21%, n= 8), sibling (15%, n= 6), and other relative (3%, n= 1). Latent content analysis is employed and involves an interpretation of the interviewtext. The results showthe meaning of being close to a person with muscular dystrophy through the themes that emerged: exposure of the family; the span between obligation and love; being vigilant, protective, and supportive; and striving for an ordinary life. This study reveals a need for healthcare staff to understand the next of kin's narrated meaning of changes when a family member has a progressive disease.
Establishing common ground in community-based arts in health
Authors: White Mike
Published: April 2006

This article originates in current research into community-based arts in health. Arts in health is now a diverse field of practice, and community-based arts in health interventions have extended the work beyond healthcare settings into public health. Examples of this work can now be found internationally in different health systems and cultural contexts. The paper argues that researchers need to understand the processes through which community-based arts in health projects evolve, and how they work holistically in their attempt to produce therapeutic and social benefits for both individuals and communities, and to connect with a cultural base in healthcare services themselves. A development model that might be adapted to assist in analysing this is the World Health Organisation Quality of Life Index (WHOQOL). Issues raised in the paper around community engagement, healthy choice and self-esteem are then illustrated in case examples of community-based arts in health practice in South Africa and England; namely the Dram Aide and Siyazama projects in Kwa Zulu-Natal, and Looking Well Healthy Living Centre in North Yorkshire. In South Africa there are arts and media projects attempting to raise awareness about HIV/AIDS through mass messaging, but they also recognize that they lack models of longer-term community engagement. Looking Well by contrast addresses health issues identified by the community itself in ways that are personal, empathic and domesticated. But there are also similarities among these projects in their aims to generate a range of social, educational and economic benefits within a community-health framework, and they are successfully regenerating traditional cultural forms to create public participation in health promotion. Process evaluation may provide a framework in which community-based arts in health projects, especially if they are networked together to share practice and thinking, can assess their ability to address health inequalities and focus better on health outcomes.