bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of radiotherapy in the treatment of desmoid tumours. An international survey of 110 patients. A study of the Rare Cancer Network
Authors: Baumert Brigitta G , Spahr Martin O , Hochstetter Arthur Von , Beauvois Sylvie , Landmann Christine , Fridrich Katrin , Villà Salvador , Kirschner Michael J , Storme Guy , Thum Peter , Streuli Hans K , Lombriser Norbert , Maurer Robert , Ries Gerhard , Bleher Ernst-Arnold , Willi Alfred , Allemann Juerg , Buehler Ulrich , Blessing Hugo , Luetolf Urs M , Davis J Bernard , Seifert Burkhardt , Infanger Manfred
Published: March 2007

Purpose

A multi-centre study to assess the value of combined surgical resection and radiotherapy for the treatment of desmoid tumours.

Patients and methods

One hundred and ten patients from several European countries qualified for this study. Pathology slides of all patients were reviewed by an independent pathologist. Sixty-eight patients received post-operative radiotherapy and 42 surgery only. Median follow-up was 6 years (1 to 44). The progression-free survival time (PFS) and prognostic factors were analysed.

Results

The combined treatment with radiotherapy showed a significantly longer progression-free survival than surgical resection alone (p smaller than 0.001). Extremities could be preserved in all patients treated with combined surgery and radiotherapy for tumours located in the limb, whereas amputation was necessary for 23% of patients treated with surgery alone. A comparison of PFS for tumour locations proved the abdominal wall to be a positive prognostic factor and a localization in the extremities to be a negative prognostic factor. Additional irradiation, a fraction size larger than or equal to 2 Gy and a total dose larger than 50 Gy to the tumour were found to be positive prognostic factors with a significantly lower risk for a recurrence in the univariate analysis. This analysis revealed radiotherapy at recurrence as a significantly worse prognostic factor compared with adjuvant radiotherapy. The addition of radiotherapy to the treatment concept was a positive prognostic factor in the multivariate analysis.

Conclusion

Postoperative radiotherapy significantly improved the PFS compared to surgery alone. Therefore it should always be considered after a non-radical tumour resection and should be given preferably in an adjuvant setting. It is effective in limb preservation and for preserving the function of joints in situations where surgery alone would result in deficits, which is especially important in young patients.
Single Serum Activin A Testing to Predict Ectopic Pregnancy
Authors: Florio Pasquale , Severi Filiberto Maria , Bocchi Caterina , Luisi Stefano , Mazzini Massimo , Danero Secondo , Torricelli Michela , Petraglia Felice
Published: March 2007

Context: Ectopic pregnancy (EP) is an important cause of maternal deaths in early pregnancy because most fatal cases result from delayed diagnosis and inappropriate investigation.

Objective: We evaluated whether the measurement of activin A may be useful in the diagnosis of EP in women with unknown pregnancy location.

Design: The study was designed as an open observational study.

Setting: The study was set in a tertiary referral center for obstetric care.

Patients: Patients were women with unknown pregnancy location (n = 536) who had complaints of bleeding, pain, or cramping.

Interventions: Interventions included clinical examination; transvaginal ultrasound scan; human chorionic gonadotropin (hCG), progesterone, and activin A measurements; laparoscopy; uterine curettage; and histological examination.

Main Outcome Measures: Main outcome measures were pregnancy outcomes and evaluation of sensitivity, specificity, and predictive values of hCG, progesterone, and activin A as diagnostic tests for the detection of EP.

Results: Pregnancy outcomes included 155 (28.9%) viable intrauterine pregnancies (IUP), 305 (56.9%) first-trimester spontaneous abortion (SAB), and 76 (14.2%) EP. SAB had the lowest (P < 0.0001) hCG and progesterone concentrations, significantly lower than EP (P < 0.001) and IUP (P < 0.001). In EP, levels were significantly (P < 0.001) lower than in IUP. On the contrary, activin A levels were lowest (P < 0.0001) in EP, significantly lower than in SAB (P < 0.001) and IUP (P < 0.001). IUP had significantly (P < 0.001) lower activin A levels than SAB. When evaluated by the receiver operating curve analysis, activin A at the cutoff of 0.37 ng/ml combined a sensitivity and a specificity of 100 and 99.6%, respectively, for prediction of EP. When activin A concentrations were below the cutoff, the positive predictive value for EP was 97.43%, and 0% for concentrations higher than 0.37 ng/ml.

Conclusions: Activin A measurement may identify patients at risk of EP with a high sensibility and specificity.
Germline Mutation in the Aryl Hydrocarbon Receptor Interacting Protein Gene in Familial Somatotropinoma
Authors: Toledo Rodrigo A. , Lourenço Delmar M. , Liberman Bernardo , Cunha-Neto Malebranche B. C. , Cavalcanti Maria G. , Moyses Cinthia B. , Toledo Sergio P. A. , Dahia Patricia L. M.
Published: March 2007

Context: Acromegaly is usually sporadic, but familial cases occur in association with several familial pituitary tumor syndromes. Recently mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were associated with familial pituitary adenoma predisposition.

Objective: The objective of the study was to investigate the status of AIP in a pituitary tumor predisposition family.

Settings: The study was conducted at a nonprofit academic center and medical centers.

Patients: Eighteen members of a Brazilian family with acromegaly were studied.

Results: A novel germline mutation in the AIP gene, Y268X, predicted to generate a protein lacking two conserved domains, was identified in four members of this family: two siblings with early-onset acromegaly; a third, 41-yr-old sibling with a microadenoma but no clinical features of disease, and his 3-yr-old son. No changes were found in 14 unaffected at-risk relatives or 92 healthy controls.

Conclusions: We confirm the role of the AIP gene in familial acromegaly. This finding increases the spectrum of molecular defects that can give rise to pituitary adenoma susceptibility. Establishment of genotype-phenotype correlations in AIP mutant tumors will determine whether AIP screening can be used as a tool for clinical surveillance and genetic counseling of families with pituitary tumor predisposition. The underlying basis for the phenotypic variation within AIP-mutant families and the mechanism of AIP-mediated tumorigenesis remain to be defined.
Initiation and resolution of interhomolog connections: crossover and non-crossover sites along mouse synaptonemal complexes
Authors: Moens Peter B. , Marcon Edyta , Shore Joel S. , Kochakpour Nazafarin , Spyropoulos Barbara
Published: March 2007

Programmed double-strand breaks at prophase of meiosis acquire immunologically detectable RAD51-DMC1 foci or early nodules (ENs) that are associated with developing chromosome core segments; each focus is surrounded by a γH2AX-modified chromosome domain. The 250-300 ENs per nucleus decline in numbers during the development of full-length cores and the remaining foci are relatively evenly distributed along the mature cores (gamma distribution of ν=2.97). The ENs become transformed nodules (TNs) by the acquisition of RPA, BLM, MSH4 and topoisomerases that function in repair and Holliday junction resolution. At the leptotene-zygotene transition, TNs orient to positions between the aligned cores where they initiate structural interhomolog contacts prior to synaptonemal complex (SC) formation, possibly future crossover sites. Subsequently, TNs are associated with SC extension at the synaptic forks. Dephosphorylation of TN-associated histone γH2AX chromatin suggests annealing of single strands or repair of double-strand breaks DSBs at this time. Some 200 TNs per pachytene nucleus are distributed proportional to SC length and are evenly distributed along the SCs (ν=∼4). At this stage, γH2AX-modified chromatin domains are associated with transcriptionally silenced sex chromosomes and autosomal sites. Immunogold electron microscope evidence shows that one or two TNs of the 10-15 TNs per SC acquire MLH1 protein, the hallmark of reciprocal recombination, whereas the TNs that do not acquire MLH1 protein relocate from their positions along the midline of the SCs to the periphery of the SCs. Relocation of TNs may be associated with the conversion of potential crossovers into non-crossovers.
Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer
Authors: Arora Puneeta , Ricks Tiffany K. , Trejo J.
Published: March 2007

Protease-activated receptors (PARs) are G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. PARs play crucial roles in hemostasis and thrombosis, as well as in inflammation and vascular development. Coagulant proteases, which are generated at sites of vascular injury, act mainly through PARs to elicit signalling in a variety of cell types. Since PARs are irreversibly activated signalling must be tightly regulated. Desensitization and trafficking of proteolytically activated PARs control the magnitude, duration and spatial aspects of receptor signalling. Recent studies have revealed novel endocytic sorting mechanisms that regulate PAR signalling. PARs have also been implicated in tumor progression. PARs are overexpressed in several types of malignant cancer, transmit signals in response to tumor-generated proteases and promote tumor growth, invasion and metastasis. Recent work also indicates that matrix metalloprotease 1 (MMP-1) signals through PAR1 to promote tumor growth and invasion. In addition to PAR overexpression, tumor cells display aberrant PAR1 trafficking, which causes persistent signalling and cellular invasion. Thus, a novel type of gain-of-function in GPCR signalling in cancer can be acquired through dysregulation of receptor trafficking.
Interactions of DNR1 with the apoptotic machinery ofDrosophilamelanogaster
Authors: Primrose David A. , Chaudhry Sidharth , Johnson A. George D. , Hrdlicka Adam , Schindler Anja , Tran Dave , Foley Edan
Published: March 2007

Caspases are crucial activators of apoptosis and NF-κB signaling in vertebrates and invertebrates. In Drosophila, the caspase-9 counterpart Dronc is essential for most apoptotic death, whereas the caspase-8 homolog Dredd activates NF-κB signaling in response to gram-negative bacterial infection. The mechanics of caspase regulation are conserved and include the activities of a family of inhibitor of apoptosis (IAP) proteins. The RING-domain-bearing protein Defense repressor 1 (Dnr1), blocks ectopic Dredd-mediated induction of an NF-κB reporter in the Drosophila S2 cell line. In this study, we present novel data indicating that Dnr1 impacts on Dronc-dependent regulation of the apoptotic program. We show that depletion of Dnr1 results in elevated Dronc protein levels, which translates to increased caspase activation and activity upon induction of apoptosis. Conversely, we demonstrate that overexpression of Dnr1 blocks apoptotic caspase activity and prevents induction of apoptosis in tissue culture assays. Furthermore, we show that Dnr1 overexpression significantly reduces Dronc protein levels and identify the domains of Dnr1 necessary for these effects. From these data, we propose that Dnr1 inhibits initiator caspases in S2 cells.
Cost-Justification of a Clinical Pharmacist-Managed Anticoagulation Clinic
Authors: Gray David R. , Garabedian-Ruffalo Susan M. , Chretien Steven D.
Published: March 2007

A cost-benefit evaluation of a clinical pharmacistmanaged anticoagulation clinic (AC) was performed. Outpatient and hospital records were examined for 26 patients in the treatment group with an AC clinic and 26 patients in the control group. Therapeutic prothrombin times were maintained within the treatment group to a significantly greater extent than within the control group (p < 0.001).

The AC was successful in preventing hospitalizations resulting from hemorrhage or thromboembolism (p < 0.01). The abnormal prothrombin times on admission in the control group correlated with hemorrhagic and thromboembolic admissions (p < 0.05, p < 0.005, respectively).

Patients were hospitalized 3.22 days and .048 days per patient-treatment-year in the control and treatment groups, respectively. The net savings in reduced hospitalization costs per year in the treatment group was $211776. The benefit:cost ratio (B:C) was 6.55, suggesting the program is socially valuable.

This clinical pharmacist-managed AC was effective in maintaining therapeutic prothrombin times, and reducing the incidence of hospitalizations resulting from anticoagulation complications, and can be cost-justified based on a cost-benefit analysis.
Universal versus Selective Iron Supplementation for Infants and the Risk of Unintentional Poisoning in Young Children: A Comparative Study of Two Populations
Authors: Finkelstein Yaron , Wahl Michael S , Bentur Yedidia , Schechter Tal , Garty Ben Zion , Erickson Timothy B , Chodick Gabby , Cahana Alfred , Mounstephen Bill J , Koren Gideon , Aks Steven E
Published: March 2007

Background:

Iron continues to be a common cause of poisoning in young children, in part due to its widespread use and easy accessibility.

Objective:

To determine differences in the epidemiology and outcome of unintentional iron ingestion by young children in populations practicing selective (eg, US) versus universal (eg, Israel) iron supplementation to infants.

Methods:

All cases of unintentional iron ingestion in children younger than 7 years in a one year period were identified through the poison control center databases of 2 sites (Illinois and Israel). Parameters compared include patient sex and age; type, form, and dose of iron preparation; circumstances and clinical manifestations; management; and outcome.

Results:

A total of 602 children were identified: 459 in Illinois and 143 in Israel. The majority of Illinois children ingested multivitamin preparations (94%), whereas Israeli children ingested single-ingredient iron preparations (78%) (p < 0.001). Iron doses ingested were higher in Israel (median 14.5 vs 6.6 mg/kg; p < 0.001) but remained within the nontoxic range for most children. No deaths or severe poisonings were reported, and 93% of children in both groups were asymptomatic. The majority of ingestions in both locations were due to unintentional self-ingestion. However, parental miscalculation occurred more frequently in Israel (16%) than in Illinois (1%).

Conclusions:

Universal iron supplementation to infants was not associated with a negative impact on the outcome of pediatric unintentional ingestions. Low-dose exposures were safely managed by on-site observation.
Opioid-Related Adverse Drug Events in Surgical Hospitalizations: Impact on Costs and Length of Stay
Authors: Oderda Gary M , Said Qayyim , Evans R Scott , Stoddard Gregory J , Lloyd Jim , Jackson Kenneth , Rublee Dale , Samore Matthew H
Published: March 2007

Background:

Opioid analgesics remain a mainstay in the treatment of pain associated with surgical procedures. Such use is associated with adverse drug events (ADEs).

Objective:

To investigate the impact of opioid-related ADEs on total hospital costs and length of stay (LOS) in adult surgical patients.

Methods:

This was a retrospective matched cohort study using data from computerized medical records. ADE cases were prospectively detected using computerized surveillance and verified by pharmacists. Surgical patients treated at LDS Hospital in Salt Lake City from January 1, 1998, to December 31, 2003, were included. The primary outcomes were costs and hospital LOS associated with opioid-related ADEs and the relationship of opioid dose to ADE events.

Results:

Patients experiencing opioid-related ADEs had significantly increased median total hospital costs (7.4% increase; 95% CI 3.83 to 10.96; p < 0.001) and increased median LOS (10.3% increase; 95% CI 6.5 to 14.2; p < 0.001) compared with matched non-ADE contrals. The increased costs attributable to ADEs, by surgery type, were general surgery ($676.51; 95% CI 351.50 to 1001.50), orthopedics ($861.50; 95% CI 448.20 to 1274.80), and obstetrics/gynecology ($540.90; 95% CI 281.40 to 800.40). Similarly, increased LOS attributable to ADEs, by surgery type, were general surgery (0.64 days; 95% CI 0.40 to 0.88), orthopedics (0.52 days; 95% CI 0.33 to 0.71), and obstetrics/gynecology (0.53 days; 95% CI 0.33 to 0.72). Higher doses of opioids were associated with increased risk of experiencing ADEs (OR 1.3; 95% CI 1.07 to 1.60; p = 0.01).

Conclusions:

Opioid-related ADEs following surgery were associated with significantly increased LOS and hospitalization costs. These ADEs occurred more frequently in patients receiving higher doses of opioids.
CD4+ Cell Count Decline Despite HIV Suppression: A Probable Didanosine–Valganciclovir Interaction
Authors: Tseng Alice L , Salit Irving E
Published: March 2007

Objective:

To describe a case of significant CD4+ cell decline despite complete viral suppression in an HIV-positive patient receiving didanosine and valganciclovir.

Case Summary:

A 68-year-old woman diagnosed with HIV and cytomegalovirus (CMV) enteritis (CD4+ cell count 22 cells/mm3, viral load 88 898 [4.95 log] copies/mL) was treated with valganciclovir and began lamivudine, didanosine, and lopinavir/ritonavir. Three months later, her viral load was less than 50 copies/mL and CD4+ cell count was 317 cells/mm3. Over the next 9 months, her viral load remained suppressed, but the CD4+ cell count declined to 83 cells/mm3 and she experienced ongoing symptoms of didanosine toxicity. Didanosine was replaced with abacavir, leading to a complete CD4+ cell recovery and resolution of symptoms.

Discussion:

Paradoxical declines in CD4+ cell counts have been reported in HIV-infected patients virally suppressed on tenofovir/didanosine regimens, presumably via inhibition of purine nucleoside phosphorylase (PNP) by tenofovir and enhancement of didanosine toxicity. Ganciclovir and its prodrug valganciclovir also inhibit PNP and increase didanosine concentrations; thus, a similar immunological effect with this combination is possible. This hypothesis is consistent with observations from a historic multicenter CMV retinitis study, where a negative CD4+ cell response was observed in patients receiving ganciclovir, while those treated with foscarnet experienced a C04+ cell increase and a mortality advantage. Of the subjects who received any type of nucleoside therapy during this study, didanosine use was proportionally higher in the ganciclovir arm versus the foscarnet arm. According to the Naranjo probability scale, our patient experienced a probable adverse reaction associated with the combination of didanosine and valganciclovir.

Conclusions:

Patients receiving didanosine-containing highly active antiretroviral therapy and ganciclovir or valganciclovir for treatment of CMV infection should be monitored for didanosine toxicity and unexpected CD4+ cell loss or failure of CD4+ cell recovery. Reduction of didanosine dosage or substitution with an alternative antiretroviral may be necessary.
Gynecomastia Associated with Fenofibrate
Authors: Gardette Virginie , Vezzosi Delphine , Maiza Jean-Christophe , Montastruc Jean-Louis , Olivier Pascale
Published: March 2007

Objective:

To report a case of probable fenofibrate-induced gynecomastia.

Case Summary:

A 56-year-old white hypercholesterolemic man was treated with fenofibrate 160 mg/day for 1 year. During the course of treatment, he developed gynecomastia on the left side, which resolved after the drug was stopped and replaced with alpha tocopherol acetate. Sixteen months after fenofibrate discontinuation, the patient was rechallenged and subsequently developed gynecomastia symptoms on the right side. The usual etiologies of gynecomastia were excluded by careful assessment of the patient's medical history, physical examination, and results of diagnostic tests such as chest X-ray, mammography, scrotal ultrasonography, routine blood chemistry, and extensive hormonal panel. Gynecomastia again resolved after discontinuation of fenofibrate.

Discussion:

In this case, the resolution of gynecomastia on discontinuation of fenofibrate and recurrence after rechallenge highly suggest the role of fenofibrate. Use of the Naranjo probability scale registered causality as probable. Case reports of gynecomastia caused by different drugs have been previously published, but, to our knowledge, this is the first report linking gynecomastia to the use of fenofibrate. The pathogenesis of this adverse drug reaction remains unclear.

Conclusions:

Although fenofibrate-induced gynecomastia appears to be uncommon, patients receiving this medication should be monitored for this adverse drug reaction.
Prevalence of Patients Using Drugs Metabolized by Cytochrome P450 2D6 in Different Populations: a Cross-Sectional Study
Authors: Mulder Hans , Heerdink Eibert R , lersel Elsje E van , Wilmink Frederik W , Egberts Antoine CG
Published: March 2007

Background:

Despito a large number of studies investigating the potential clinical relevance of CYP2D6 genotyping in preventing treatment failure (eg, insufficient efficacy and/or unacceptable adverse effects), the prevalence of patients using drugs metabolized by that isoenzyme is relatively unknown.

Objective:

To investigate the prevalence of patients in different populations using drugs metabolized by CYP2D6.

Methods:

In this cross-sectional study. 6 different patient populations were investigated: general, general hospital, geriatric, psychogoriatric, psychiatric, and mentally retarded. From every population, 150 adults using at least one drug were randomly selected. Primary outcome was the prevalence of patients using at least one drug metabolized by CYP2D6. The prevalence of patients using at least one CYP2D6 substrate in different populations was compared with the general population using χ2 statistics. Data were expressed as a relative risk with a 95% confidence interval.

Results:

Patients from the general hospital (RR 1.81; 95% CI 1.26 to 2.62), geriatric patients (RR 2.16; 95% CI 1.26 to 2.62), psychogeriatric patients (RR 2.31; 95% CI 1.63 to 3.27), and psychiatric patients (RR 2.44; 95% CI 1.73 to 3.44) were treated more frequently with at least one drug metabolized by CYP2D6 compared with patients in the general population. Approximately 50% of psychiatric (52%), psychogeriatric (49%), and geriatric (46%) patients used at least one drug metabolized by CYP2D6. In total, 416 drugs metabolized by CYP2D6 were prescribed, with 257 (62%) of these classified as an antidepressant (Anatomical and Therapeutic Chemical [ATC] category N06A) or antipsychotic (ATC N05A).

Conclusions:

Several patient populations (eg, psychiatric, psychogeriatric, geriatric) have a high prevalence of patients treated with at least one drug metabolized by CYP2D6. This study does not provide evidence regarding the clinical evidence of CYP2D6 genotyping, but shows that, if CYP2D6 genotyping is relevant for patient care, the highest probability of cost-effectiveness will, most likely, be in specific populations.
Low-Dose Ketamine in Addition to Propofol for Procedural Sedation and Analgesia in the Emergency Department
Authors: Loh Gabriel , Dalen Dawn
Published: March 2007

Objective:

To evaluate the efficacy and safety of low-dose intravenous ketamine in addition to intravenous propofol for procedural sedation and analgesia in the emergency department (ED).

Data Sources:

Articles were identified using PubMed (1949'February 2007), MEDLINE (1966'February 2007), EMBASE (1980'February 2007), BioMed Central (to February 2007), the Cochrane Library (to February 2007), International Pharmaceutical Abstracts, and Google Scholar (until February 2007). Reference citations from retrieved publications were also reviewed. Search terms included ketamine, propofol, ketamine–propofol, ketofol, combination, sedation, procedural sedation, conscious sedation, and emergency department.

Study Selection And Data Extraction:

All articles on prospective procedural sedation that were published or translated into English and that compared combination ketamine–propofol with an appropriate comparator group were included. Clinically relevant safety endpoints included the frequency of significant hemodynamic and respiratory compromise warranting medical intervention, nausea, vomiting, and emergence reactions. Time until hospital discharge criteria were met and patient satisfaction scores were efficacy endpoints of interest.

Data Synthesis:

Of the 11 trials included in this review, most had small sample sizes and were conducted in non-ED settings. The ketamine-propofol combination demonstrated no additional efficacy over propofol in terms of time to discharge. Although fewer patients given the ketamine-propofol combination experienced significant hemodynamic and respiratory compromise, need for active interventions, including fluid or vasopressor administration, supplemental oxygen, or assisted ventilation did not differ between groups. Patients who received higher doses of adjuvant ketamine reported an increased incidence of nausea, vomiting, and emergence reactions following the procedure. Few studies reported patient satisfaction scores postprocedure, and effect of ketamine-propofol on time-to-discharge criteria met was inconclusive.

Conclusions:

At this time, insufficient clinica) evidence exists to recommend the routine use of low-dose ketamine with propofol for procedural sedation in the ED setting.
Electrocardiographic and Hemodynamic Effects of Coenzyme Q10 in Healthy Individuals: A Double-Blind, Randomized Controlled Trial
Authors: Shah Sachin A , Sander Stephen , Cios Deborah , Lipeika Jenny , Kluger Jeffrey , White C Michael
Published: March 2007

Background:

Coenzyme Q10 (C0Q10) is an endogenous cofactor required for mitochondrial energy production and touted to treat heart failure and prevent statin-induced myopathy. In guinea pig ventricular myocytes, C0Q10 prolongs action potential duration, an effect that might prolong the QTc interval in humans. Additionally, C0Q10 reduced blood pressure in patients with essential hypertension.

Objective:

To determine the electrocardiographic (ECG) and hemodynamic impact of C0Q10 in healthy individuals.

Methods:

Healthy volunteers (N = 26; 62% male, age 24 ± 3 y) were randomized to receive a single dose of C0Q10 50 mg and matching placebo in a crossover fashion with a 7 day washout period between treatments. Twelve-lead ECGs, systolic and diastolic blood pressure, and other hemodynamic parameters (cardiac index and systemic vascular resistance index) were evaluated immediately before (baseline) and 1, 3, 5, and 8 hours after ingestion of the study drug. ECG parameters (P wave and QRS complex duration; PR, QT, QTc, and RR intervals) were measured in lead II by one blinded investigator. For each time point, duplicate blood pressure levels were taken manually and then averaged. Hemodynamic parameters were measured using bioelectrical impedance cardiography.

Results:

C0Q10 had no effect on any of the evaluated ECG parameters. The maximum postdosing systolic blood pressure showed a statistically significant increase with C0Q10 (117 ± 10 vs 119 ± 10 mm Hg; p = 0.037), an effect driven by increases in cardiac index (3.09 vs 2.95 L/min/m2; p = 0.017). However, blood pressure elevation was most evident at the 5 hour timepoint (116 ± 10 vs 113 ± 11 mm Hg; p = 0.049) and was only transient. There were no differences between groups for maximum postdosing diastolic blood pressure.

Conclusions:

One dose of CoQ10 does not have any effect on ECG variables and exhibits only mild and transient effect on systolic blood pressure in young, healthy people.
Retisert: Is the New Advance in Treatment of Uveitis a Good One?
Authors: Mohammad Dina A , Sweet Burgunda V , Elner Susan G
Published: March 2007

Objective:

To review the use of corticosteroids for the treatment of uveitis, with a focus on the pharmacology, efficacy, and safety of a newer delivery device, Retisert.

Data Sources:

A PubMed/MEDLINE search from 1950 through February 2007 was conducted, and manufacturer-provided data were reviewed.

Study Selection And Data Extraction:

Animal studies and Phase II and III clinical trials evaluating the safety and efficacy of Retisert for the treatment of uveitis were considered. The data were extracted from Pub Med/MEDLINE using the search terms fluocinolone acetonide, corticosteroids, intravitreal implant, uveitis, ocular steroids, and Retisert.

Data Synthesis:

The findings of the clinical studies showed, with use of Retisert, a reduction in the recurrence of uveitis, improvement in visual acuity, and a decreased need for adjunctive therapy with corticosteroids and immunosuppressant agents, There are currently no studies directly comparing Retisert with other treatment options. The most commonly reported adverse events (ADEs) in clinical trials included cataracts, increased intraocular pressure, post-procedural complications associated with implant insertion, and ocular pain. Other ocular ADEs included decreased visual acuity, glaucoma, blurred vision, an abnormal sensation in the eye, eye irritation, and a change in tearing. These ADEs are similar to those seen with chronic corticosteroid therapy delivered by other ocular routes.

Conclusions:

Retisert implants have been shown to deliver sufficient drug for a longer period of time compared with the traditional steroid delivery methods. Promising efficacy results show a significant reduction in recurrence rate and improvement in visual acuity for approximately 3 years after implant. However, the drug carries the risks associated with the implant procedure and with chronic exposure of the eye to steroids. Until more data on the long-term safety are known, Retisert should be reserved for patients who are no longer tolerant of or responsive to more traditional treatment modalities.
The Role of the Pharmacist—Prayer and Spirituality in Healing
Authors: Rosenbaum Cathy Creger
Published: March 2007

Are you a “spiritual” pharmacist? I define being spiritual as having an ongoing relationship with God regardless of whether one is physically healthy, “stressed out,” or sick; I encourage pharmacists to pray for, and with, their patients when opportunities present themselves and patients are receptive. Spiritual healing can be as dramatic as physical and emotional healing. Holistic healing encompassing all 3 components is important for lasting, abundant wellness for professionals and patients alike.

Spiritual practice, including a reliance on prayer in the healing process, demonstrates pharmacists' gratitude for the gifts and humility received through their relationships with patients. Imagine office-based and hospital employees, from accounting, to housekeeping, to pharmacy, to nurses and physicians, praying daily.

Many patients and their healthcare providers believe that faith-based prayers to God are important instruments for healing, and spiritual pharmacists may wish to consider integrating prayer into their professional practice.
Solifenacin for Overactive Bladder with Incontinence: Symptom Bother and Health-Related Quality of Life Outcomes
Authors: Garely Alan D , Lucente Vincent , Vapnek Jonathan , Smith Neila
Published: March 2007

Background:

Approximately one-third of patients with overactive bladder (OAB) experience incontinence, a bothersome symptom with a clear negative effect on quality of life.

Objective:

To assess OAB patients' perceptions of improvements in symptom bother and quality of life after taking solifenacin under conditions reflecting day-today practice.

Methods:

VOLT (the VESIcare Open-Label Trial) was a prospective, open-label study in patients with OAB (defined as urgency, urge urinary incontinence, daytime frequency, or nocturia for ≥3 mo) who were treated with flexibly dosed, once-daily solifenacin for 12 weeks. This study included subjects enrolled in VOLT who, at baseline, had urge incontinence and reported incontinence as their most bothersome symptom. All patients were started on solifenacin 5 mg/day; at week 4, the dosage could be increased to 10 mg/day and at week 8 could be maintained or decreased back to 5 mg/day. Efficacy was assessed by 3 independent patient-reported outcomes: the Patient Perception of Bladder Condition (PPBC) scale, a visual analog scale (VAS) for assessing individual symptoms, and the Overactive Bladder Questionnaire (OAB-q).

Results:

Of the 2205 patients in the VOLT full analysis set, 1586 (71.9%) had urge incontinence at baseline, of which 582 (36.7%) reported incontinence as their most bothersome symptom. In this cohort, mean PPBC score at baseline was 4.6 (indicating moderate-to-severe problems) and at endpoint had decreased significantly to 2.9 (very minor to some minor problems; p < 0.001). At endpoint, 80.4% of patients achieved improvement in their PPBC score. These patients reported significant improvements from baseline in urinary urgency, urge incontinence, frequency, and nocturia on the VAS (p < 0.001) and all OAB-q domains (symptom severity, coping, concern, sleep, social, health-related quality of life) at endpoint (p < 0.001).

Conclusions:

Patients reporting urge incontinence as their most bothersome OAB symptom can be expected to demonstrate significant improvements in multiple patient-related outcomes following treatment with flexibly dosed solifenacin.
New Serum Creatinine Assay Standardization: Implications for Drug Dosing
Authors: Wade William E , Spruill William J
Published: March 2007

Objective:

To describe the development of new serum creatinine assay standards and discuss their implications for various drug dosing scenarios.

Data Sources:

A MEDLINE search (1990–August 2006) was performed to identify literature on newly developed serum creatinine assay standards and the impact those standards will have on drug dosing.

Study Selection And Data Extraction:

Data on the development of new creatinine assay procedures and the effect that these new values will have on drug dosing were extracted from identified references.

Data Synthesis:

The National Kidney Foundation's current practice guidelines recommend standardization of serum creatinine assay calibration to increase assay accuracy. This will result in a lower than the current range of values being considered normal, as well as lower value patient values. These lower creatinine values will result in higher calculated glomerular filtration rates and creatinine clearance (Clcr) estimates, resulting in the difficulty of clinicians applying these values to current manufacturers' recommended drug dose modification tables in patients with declining renal function. Newer creatinine values may be as much as 5–20% lower than older assay values.

Conclusions:

Worldwide implementation of new serum creatinine calibration standards will produce more accurate serum creatinine values. These values may be slightly lower than those obtained with older methods. This, in turn, may cause slightly higher Clcr estimates that may no longer match drug manufacturers' data for dosage adjustment in renal insufficiency, given that manufacturers' dosing tables were based on older creatinine values. If this is deemed clinically significant in a specific patient, increasing the creatinine value obtained with new assay techniques by 5–20% may give the clinician a value that more closely approximates that used by the drug manufacturer in developing these tables. This revised value can then be used for dosage adjustments.
Confocal Microscopy-based Linescan Methodologies for Intra-Golgi Localization of Proteins
Authors: Dejgaard Selma Yilmaz , Murshid Ayesha , Dee Kristina M. , Presley John F.
Published: March 2007

Localization of resident Golgi proteins to earlier ( cis) or later ( trans) Golgi compartments has traditionally required quantitative immunocytochemistry and electron microscopy, which are inaccessible to many researchers. For this reason, light microscopy has often been used, initially for localization of Golgi glycotransferases and, more recently, for other Golgi proteins (e.g., Arf1, GBF1, Rab6). Quantitation of light microscopic intra-Golgi localization can be problematic. We describe here a novel quantitative light microscopic methodology using linescans crossing the Golgi ribbon. Our method determines a localization for the unknown protein in a one-dimensional coordinate system in which 0.0 corresponds to localization of a cis marker and 1.0 to localization of a trans marker. We also describe a variant of this methodology in which Golgi morphology is simplified by nocodazole-induced dispersal into ministacks, allowing a fully automated analysis. In our assay, β1,4-galactosyltransferase-YFP and Golgin97 localize similarly to trans markers, whereas p115, GBF1, and p58-YFP are similarly near other cis markers. The medial Golgi protein α1,3–1,6-mannosidase II gives an intermediate localization in this assay. These methodologies may prove useful in instances where electron microscopy is technically difficult as well as when rapid analysis of large numbers of samples is required.
Twist Relates to Tubular Epithelial-Mesenchymal Transition and Interstitial Fibrogenesis in the Obstructed Kidney
Authors: Kida Yujiro , Asahina Kinji , Teraoka Hirobumi , Gitelman Inna , Sato Tetsuji
Published: March 2007

Epithelial-mesenchymal transition (EMT) is a critical step in renal fibrosis. It has been recently reported that a transcription factor, Twist, plays a pivotal role in metastasis of breast tumors by inducing EMT. In this study, we examined whether Twist relates to renal fibrogenesis including EMT of tubular epithelia, evaluating Twist expression level in the unilateral ureteral obstruction (UUO) model. Kidneys of mice subjected to UUO were harvested 1, 3, 7, and 10 days after obstruction. Compared with control kidneys, Twist mRNA-level significantly increased 3 days after UUO (UUO day 3 kidney) and further augmented until 10 days after UUO. Twist expression increased in tubular epithelia of the dilated tubules and the expanded interstitial areas of UUO kidneys, where cell-proliferating appearances were frequently found in a time-dependent manner. Although a part of tubular cells in whole nephron segment were immunopositive for Twist in UUO day 7 kidneys, tubular epithelia downstream of nephron more frequently expressed Twist than upstream of nephron. In UUO day 7 kidneys, some tubular epithelia were confirmed to coexpress Twist and fibroblast-specific protein-1, a marker for EMT, indicating that Twist is involved in tubular EMT under pathological state. Twist was expressed also in a number of α-smooth muscle actin-positive myofibroblasts located in the expanded interstitial area of UUO kidneys. From these findings, the present investigation suggests that Twist is associated with tubular EMT, proliferation of myofibroblasts, and subsequent renal fibrosis in obstructed kidneys.
β1 Integrins Control the Formation of Cell Chains in the Adult Rostral Migratory Stream
Authors: Belvindrah Richard , Hankel Sabine , Walker John , Patton Bruce L. , Müller Ulrich
Published: March 2007

The subventricular zone (SVZ) of the lateral ventricle is the major site of neurogenesis in the adult brain. Neuroblasts that are born in the SVZ migrate as chains along the rostral migratory stream (RMS) to the olfactory bulb. Little is known about the mechanisms that control interactions between neuroblasts during their migration. Here we show that migrating neuroblasts express β1integrins and that the integrin ligand laminin is localized to cell chains. Using genetically modified mice and time-lapse video recordings of SVZ explants, we demonstrate that β1 integrins and laminin promote the formation of cell chains. Laminin also induces the aggregation of purified neuroblasts. We conclude that the formation of cell chains in the RMS is controlled in part by β1 integrins via binding to laminin. In addition, we provide evidence that β1 class integrins are required for the maintenance of the glial tubes and that defects in the glial tubes lead to the ectopic migration of neuroblasts into the surrounding tissue.
Active β-Amyloid Immunization Restores Spatial Learning in PDAPP Mice Displaying Very Low Levels of β-Amyloid
Authors: Chen Guiquan , Chen Karen S. , Kobayashi Dione , Barbour Robin , Motter Ruth , Games Dora , Martin Stephen J. , Morris Richard G. M.
Published: March 2007

The behavioral and biochemical impact of active immunization against human β-amyloid (Aβ) was assessed using male transgenic (Tg) mice overexpressing a human mutant amyloid precursor protein (heterozygous PDAPP mice) and littermate controls. Administration of aggregated Aβ42occurred at monthly intervals from 7 months (“prevention”) or 11 months (“reversal”), followed by double-blind behavioral training at 16 months on a cued task, then serial spatial learning in a water maze. Using a 2 × 2 design, with Aβ42adjuvanted with MPL-AF (adjuvant formulation of monophosphoryl lipid A) or MPL-AF alone, PDAPP mice were impaired compared with non-Tg littermates on two separate measures of serial spatial learning. Immunization caused no overall rescue of learning but limited the accumulation of total Aβ and Aβ42levels in cortex and hippocampus by up to 60%. In immunized PDAPP mice, significant negative correlations were observed between hippocampal and cortical Aβ levels and learning capacity, particularly in the prevention study, and correlations between learning capacity and antibody titer. Moreover, a subset of PDAPP mice with very low Aβ levels (hippocampal Aβ levels of <6000 ng/g or cortical Aβ levels of <1000 ng/g) was indistinguishable from non-Tg controls. Mice in the prevention study were also rescued from cognitive impairment more effectively than those in the reversal study. The combination of variability in antibody response and differential levels of Aβ accumulation across the population of immunized PDAPP mice may be responsible for success in cognitive protection with only a subset of these animals, but the similarity to the findings of certain human vaccination trials is noteworthy.
Sciatic Nerve Ligation-Induced Proliferation of Spinal Cord Astrocytes Is Mediated by κ Opioid Activation of p38 Mitogen-Activated Protein Kinase
Authors: Xu Mei , Bruchas Michael R. , Ippolito Danielle L. , Gendron Louis , Chavkin Charles
Published: March 2007

Partial sciatic nerve ligation (pSNL) markedly increased glial fibrillary acidic protein immunoreactivity (GFAP-IR) 1 week after lesion in the L4–L5 spinal dorsal horn of wild-type, but not in dynorphin knock-out, mice lacking κ opioid receptors (KOR−/−) or in wild-type mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). A direct effect of KOR on glial cell proliferation was suggested by the findings that primary cultures of type II GFAP-immunoreactive astrocytes isolated from mouse spinal cord express KOR. Sustained treatment with the κ agonist U50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrolytinil)-cyclohexyl]-benzeneacetamide methane sulfonate) significantly increased the proliferation rate of GFAP-immunoreactive astrocytes isolated from wild-type mice, and this effect was blocked by norBNI pretreatment. Proliferation of cultured type II astrocytes may have been stimulated by mitogen-activated protein kinase (MAPK) activation by KOR because (1) U50,488 treatment increased phospho-p38 MAPK-immunoreactivity 247 ± 44% over untreated cells, (2) the increase in phospho-p38 induced by U50,488 was blocked by norBNI and not evident inKOR−/−cultures, and (3) GFAP-immunoreactive astrocyte proliferation induced by U50,488 was blocked by the p38 MAPK inhibitor SB 203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole]. Similar mechanisms of astrocyte activation may also be responsiblein vivobecause intrathecal injection of SB 203580 blocked the increased GFAP-IR in lumbar spinal cord induced by pSNL. Although the relationship between κ-stimulated astrocyte proliferation and neuropathic pain mechanisms was not directly established in these studies, the results support the hypothesis that KOR activation induces spinal astrocyte proliferation, which may contribute to cellular reorganization after sciatic nerve damage.
Interaction of Genetic and Environmental Factors in aDrosophilaParkinsonism Model
Authors: Chaudhuri Anathbandhu , Bowling Kevin , Funderburk Christopher , Lawal Hakeem , Inamdar Arati , Wang Zhe , O'Donnell Janis M.
Published: March 2007

Catastrophic loss of dopaminergic neurons is a hallmark of Parkinson's disease. Despite the recent identification of genes associated with familial parkinsonism, the etiology of most Parkinson's disease cases is not understood. Environmental toxins, such as the herbicide paraquat, appear to be risk factors, and it has been proposed that susceptibility is influenced by genetic background. The genetic model organismDrosophilais an advantageous system for the identification of genetic susceptibility factors. Genes that affect dopamine homeostasis are candidate susceptibility factors, because dopamine itself has been implicated in neuron damage. We find that paraquat can replicate a broad spectrum of parkinsonian behavioral symptoms inDrosophilathat are associated with loss of specific subsets of dopaminergic neurons. In parallel with epidemiological studies that show an increased incidence of Parkinson's disease in males, maleDrosophilaexhibit paraquat symptoms earlier than females. We then tested the hypothesis that variation in dopamine-regulating genes, including those that regulate tetrahydrobiopterin, a requisite cofactor in dopamine synthesis, can alter susceptibility to paraquat-induced oxidative damage.Drosophilamutant strains that have increased or decreased dopamine and tetrahydrobiopterin production exhibit variation in susceptibility to paraquat. Surprisingly, protection against the neurotoxicity of paraquat is conferred by mutations that elevate dopamine pathway function, whereas mutations that diminish dopamine pools increase susceptibility. We also find that loss-of-function mutations in a negative regulator of dopamine production,Catecholamines-up, delay the onset of neurological symptoms, dopaminergic neuron death, and morbidity during paraquat exposure but confer sensitivity to hydrogen peroxide.
Synapse-Associated Protein 102/dlgh3 Couples the NMDA Receptor to Specific Plasticity Pathways and Learning Strategies
Authors: Cuthbert Peter C. , Stanford Lianne E. , Coba Marcelo P. , Ainge James A. , Fink Ann E. , Opazo Patricio , Delgado Jary Y. , Komiyama Noboru H. , O'Dell Thomas J. , Grant Seth G. N.
Published: March 2007

Understanding the mechanisms whereby information encoded within patterns of action potentials is deciphered by neurons is central to cognitive psychology. The multiprotein complexes formed by NMDA receptors linked to synaptic membrane-associated guanylate kinase (MAGUK) proteins including synapse-associated protein 102 (SAP102) and other associated proteins are instrumental in these processes. Although humans with mutations in SAP102 show mental retardation, the physiological and biochemical mechanisms involved are unknown. Using SAP102 knock-out mice, we found specific impairments in synaptic plasticity induced by selective frequencies of stimulation that also required extracellular signal-regulated kinase signaling. This was paralleled by inflexibility and impairment in spatial learning. Improvement in spatial learning performance occurred with extra training despite continued use of a suboptimal search strategy, and, in a separate nonspatial task, the mutants again deployed a different strategy. Double-mutant analysis of postsynaptic density-95 and SAP102 mutants indicate overlapping and specific functions of the two MAGUKs. Thesein vivodata support the model that specific MAGUK proteins couple the NMDA receptor to distinct downstream signaling pathways. This provides a mechanism for discriminating patterns of synaptic activity that lead to long-lasting changes in synaptic strength as well as distinct aspects of cognition in the mammalian nervous system.