bluuebunny/crossref_metadata_2025 huggingface dataset:
Adhesion to and biofilm formation on IB3-1 bronchial cells by Stenotrophomonas maltophilia isolates from cystic fibrosis patients
Authors: Pompilio Arianna , Crocetta Valentina , Confalone Pamela , Nicoletti Mauro , Petrucca Andrea , Guarnieri Simone , Fiscarelli Ersilia , Savini Vincenzo , Piccolomini Raffaele , Di Bonaventura Giovanni
Published: April 2010

Background

Stenotrophomonas maltophilia has recently gained considerable attention as an important emerging pathogen in cystic fibrosis (CF) patients. However, the role of this microorganism in the pathophysiology of CF lung disease remains largely unexplored. In the present study for the first time we assessed the ability of S. maltophilia CF isolates to adhere to and form biofilm in experimental infection experiments using the CF-derived bronchial epithelial IB3-1cell line. The role of flagella on the adhesiveness of S. maltophilia to IB3-1 cell monolayers was also assessed by using fliI mutant derivative strains.

Results

All S. maltophilia CF isolates tested in the present study were able, although at different levels, to adhere to and form biofilm on IB3-1 cell monolayers. Scanning electron and confocal microscopy revealed S. maltophilia structures typical of biofilm formation on bronchial IB3-1 cells. The loss of flagella significantly (P < 0.001) decreased bacterial adhesiveness, if compared to that of their parental flagellated strains. S. maltophilia CF isolates were also able to invade IB3-1 cells, albeit at a very low level (internalization rate ranged from 0.01 to 4.94%). Pre-exposure of IB3-1 cells to P. aeruginosa PAO1 significantly increased S. maltophilia adhesiveness. Further, the presence of S. maltophilia negatively influenced P. aeruginosa PAO1 adhesiveness.

Conclusions

The main contribution of the present study is the finding that S. maltophilia is able to form biofilm on and invade CF-derived IB3-1 bronchial epithelial cells, thus posing a rationale for the persistence and the systemic spread of this opportunistic pathogen in CF patients. Experiments using in vivo models which more closely mimic CF pulmonary tissues will certainly be needed to validate the relevance of our results.
Genome-wide association analysis of total cholesterol and high-density lipoprotein cholesterol levels using the Framingham Heart Study data
Authors: Ma Li , Yang Jing , Runesha H Birali , Tanaka Toshiko , Ferrucci Luigi , Bandinelli Stefania , Da Yang
Published: April 2010

Background

Cholesterol concentrations in blood are related to cardiovascular diseases. Recent genome-wide association studies (GWAS) of cholesterol levels identified a number of single-locus effects on total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels. Here, we report single-locus and epistasis SNP effects on TC and HDL-C using the Framingham Heart Study (FHS) data.

Results

Single-locus effects and pairwise epistasis effects of 432,096 SNP markers were tested for their significance on log-transformed TC and HDL-C levels. Twenty nine additive SNP effects reached single-locus genome-wide significance (p < 7.2 × 10-8) and no dominance effect reached genome-wide significance. Two new gene regions were detected, theRAB3GAP1-R3HDM1-LCT-MCM6region of chr02 for TC identified by six new SNPs, and theOSBPL8-ZDHHC17region (chr12) for HDL-C identified by one new SNP. The remaining 22 single-locus SNP effects confirmed previously reported genes or gene regions. For TC, three SNPs identified two gene regions that were tightly linked with previously reported genes associated with TC, including rs599839 that was 10 bases downstreamPSRC1and 3.498 kb downstreamCELSR2, rs4970834 inCELSR2, and rs4245791 inABCG8that slightly overlapped withABCG5. For HDL-C,LPLwas confirmed by 12 SNPs 8-45 kb downstream,CETPby two SNPs 0.5-11 kb upstream, and theLIPG-ACAA2region by five SNPs inside this region. Two epistasis effects on TC and thirteen epistasis effects on HDL-C reached the significance of "suggestive linkage". The most significant epistasis effect (p = 5.72 × 10-13) was close to reaching "significant linkage" and was a dominance × dominance effect of HDL-C betweenLMBRD1(chr06) and theLRIG3region (chr12), and this pair of gene regions had six other D × D effects with "suggestive linkage".

Conclusions

Genome-wide association analysis of the FHS data detected two new gene regions with genome-wide significance, detected epistatic SNP effects on TC and HDL-C with the significance of suggestive linkage in seven pairs of gene regions, and confirmed some previously reported gene regions associated with TC and HDL-C.
A prospective, randomized, double-blinded single-site control study comparing blood loss prevention of tranexamic acid (TXA) to epsilon aminocaproic acid (EACA) for corrective spinal surgery
Authors: Verma Kushagra , Errico Thomas J , Vaz Kenneth M , Lonner Baron S
Published: April 2010

Background

Multilevel spinal fusion surgery has typically been associated with significant blood loss. To limit both the need for transfusions and co-morbidities associated with blood loss, the use of anti-fibrinolytic agents has been proposed. While there is some literature comparing the effectiveness of tranexamic acid (TXA) to epsilon aminocaproic acid (EACA) in cardiac procedures, there is currently no literature directly comparing TXA to EACA in orthopedic surgery.

Methods/Design

Here we propose a prospective, randomized, double-blinded control study evaluating the effects of TXA, EACA, and placebo for treatment of adolescent idiopathic scoliosis (AIS), neuromuscular scoliosis (NMS), and adult deformity (AD) via corrective spinal surgery. Efficacy will be determined by intraoperative and postoperative blood loss. Other clinical outcomes that will be compared include transfusion rates, preoperative and postoperative hemodynamic values, and length of hospital stay after the procedure.

Discussion

The primary goal of the study is to determine perioperative blood loss as a measure of the efficacy of TXA, EACA, and placebo. Based on current literature and the mechanism by which the medications act, we hypothesize that TXA will be more effective at reducing blood loss than EACA or placebo and result in improved patient outcomes.

Trial Registration

ClinicalTrials.gov ID: NCT00958581
Building capacity in health facility management: guiding principles for skills transfer in Liberia
Authors: Rowe Laura A , Brillant Sister Barbara , Cleveland Emily , Dahn Bernice T , Ramanadhan Shoba , Podesta Mae , Bradley Elizabeth H
Published: April 2010

Background

Management training is fundamental to developing human resources for health. Particularly as Liberia revives its health delivery system, facility and county health team managers are central to progress. Nevertheless, such management skills are rarely prioritized in health training, and sustained capacity building in this area is limited. We describe a health management delivery program in which a north and south institution collaborated to integrate classroom and field-based training in health management and to transfer the capacity for sustained management development in Liberia.

Methods

We developed and implemented a 6-month training program in health management skills (i.e. strategic problem solving, financial management, human resource management and leadership) delivered by Yale University and Mother Patern College from Liberia, with support from the Clinton HIV/AIDS Initiative. Over three 6-month cycles, responsibility for course instruction was transferred from the north institution to the south institution. A self-administered survey was conducted of all participants completing the course to measure changes in self-rated management skills, the degree to which the course was helpful and met its stated objectives, and faculty members' responsiveness to participant needs as the transfer process occurred.

Results

Respondents (n = 93, response rate 95.9%) reported substantial improvement in self-reported management skills, and rated the helpfulness of the course and the degree to which the course met its objectives highly. Levels of improvement and course ratings were similar over the three cohorts as the course was transferred to the south institution. We suggest a framework of five elements for implementing successful management training programs that can be transferred and sustained in resource-limited settings, including: 1) use a short-course format focusing on four key skill areas with practical tools; 2) include didactic training, on-site projects, and on-site mentoring; 3) collaborate with an in-country academic institution, willing and able to scale-up and maintain the training; 4) provide training for the in-country academic faculty; and 5) secure Ministry-level support to ensure participation.

Conclusion

Our findings demonstrate key elements for scaling up and replicating educational initiatives that address management skills essential for long-term health systems strengthening in resource-poor settings.
A novel and safe technique in closed tube thoracostomy
Authors: Dural Koray , Gulbahar Gultekin , Kocer Bulent , Sakinci Unal
Published: April 2010

Background

Tube thoracostomy (TT) is the most commonly performed surgical procedure in thoracic surgery clinics. The procedure might have to be repeated due to ineffective drainage in patients with tube malposition (TM), in whom the drain is not directed to the apex or located in the fissure. Trocar technique, which is used to prevent TM, is not recommended because of its potential for severe complications.

Methods

The study involved 180 patients who required TT application for any etiology within one year. The patients were divided into two groups as Group A, who had undergone classical surgical technique (n = 90) and Group B, who had undergone a combination of surgery and trocar techniques (n = 90). The groups were compared for TM, the effect of TM on the drain removal, and other insertion related complications.

Results

In Group A, 23 patients had TM, 4 of whom developed associated ineffective drainage, while the patients in Group B had no insertion related complications (p = 0.001). The mean drain removal time of the patients with TM was 5 ± 2.25 days. In the patients who did not develop TM, it was 3.39 ± 1.18 days (p = 0.001).

Conclusions

The modified combination technique is a reliable method in preventing TM and its potential complications.
Applying mass spectrometry based proteomic technology to advance the understanding of multiple myeloma
Authors: Micallef Johann , Dharsee Moyez , Chen Jian , Ackloo Suzanne , Evans Ken , Qiu Luqui , Chang Hong
Published: April 2010

Multiple myeloma (MM) is the second most common hematological malignancy in adults. It is characterized by clonal proliferation of terminally differentiated B lymphocytes and over-production of monoclonal immunoglobulins. Recurrent genomic aberrations have been identified to contribute to the aggressiveness of this cancer. Despite a wealth of knowledge describing the molecular biology of MM as well as significant advances in therapeutics, this disease remains fatal. The identification of biomarkers, especially through the use of mass spectrometry, however, holds great promise to increasing our understanding of this disease. In particular, novel biomarkers will help in the diagnosis, prognosis and therapeutic stratification of MM. To date, results from mass spectrometry studies of MM have provided valuable information with regards to MM diagnosis and response to therapy. In addition, mass spectrometry was employed to study relevant signaling pathways activated in MM. This review will focus on how mass spectrometry has been applied to increase our understanding of MM.
A large-scale survey of the novel 15q24 microdeletion syndrome in autism spectrum disorders identifies an atypical deletion that narrows the critical region
Authors: McInnes L Alison , Nakamine Alisa , Pilorge Marion , Brandt Tracy , Jiménez González Patricia , Fallas Marietha , Manghi Elina R , Edelmann Lisa , Glessner Joseph , Hakonarson Hakon , Betancur Catalina , Buxbaum Joseph D
Published: April 2010

Background

The 15q24 microdeletion syndrome has been recently described as a recurrent, submicroscopic genomic imbalance found in individuals with intellectual disability, typical facial appearance, hypotonia, and digital and genital abnormalities. Gene dosage abnormalities, including copy number variations (CNVs), have been identified in a significant fraction of individuals with autism spectrum disorders (ASDs). In this study we surveyed two ASD cohorts for 15q24 abnormalities to assess the frequency of genomic imbalances in this interval.

Methods

We screened 173 unrelated subjects with ASD from the Central Valley of Costa Rica and 1336 subjects with ASD from 785 independent families registered with the Autism Genetic Resource Exchange (AGRE) for CNVs across 15q24 using oligonucleotide arrays. Rearrangements were confirmed by array comparative genomic hybridization and quantitative PCR.

Results

Among the patients from Costa Rica, an atypical de novo deletion of 3.06 Mb in 15q23-q24.1 was detected in a boy with autism sharing many features with the other 13 subjects with the 15q24 microdeletion syndrome described to date. He exhibited intellectual disability, constant smiling, characteristic facial features (high anterior hairline, broad medial eyebrows, epicanthal folds, hypertelorism, full lower lip and protuberant, posteriorly rotated ears), single palmar crease, toe syndactyly and congenital nystagmus. The deletion breakpoints are atypical and lie outside previously characterized low copy repeats (69,838-72,897 Mb). Genotyping data revealed that the deletion had occurred in the paternal chromosome. Among the AGRE families, no large 15q24 deletions were observed.

Conclusions

From the current and previous studies, deletions in the 15q24 region represent rare causes of ASDs with an estimated frequency of 0.1 to 0.2% in individuals ascertained for ASDs, although the proportion might be higher in sporadic cases. These rates compare with a frequency of about 0.3% in patients ascertained for unexplained intellectual disability and congenital anomalies. This atypical deletion reduces the minimal interval for the syndrome from 1.75 Mb to 766 kb, implicating a reduced number of genes (15 versus 38). Sequencing of genes in the 15q24 interval in large ASD and intellectual disability samples may identify mutations of etiologic importance in the development of these disorders.
miRTRAP, a computational method for the systematic identification of miRNAs from high throughput sequencing data
Authors: Hendrix David , Levine Michael , Shi Weiyang
Published: April 2010

MicroRNAs (miRs) have been broadly implicated in animal development and disease. We developed a novel computational strategy for the systematic, whole-genome identification of miRs from high throughput sequencing information. This method, miRTRAP, incorporates the mechanisms of miR biogenesis and includes additional criteria regarding the prevalence and quality of small RNAs arising from the antisense strand and neighboring loci. This program was applied to the simple chordate Ciona intestinalis and identified nearly 400 putative miR loci.
Endothelial damage induced by Shiga toxins delivered by neutrophils during transmigration
Authors: Brigotti Maurizio , Tazzari Pier Luigi , Ravanelli Elisa , Carnicelli Domenica , Barbieri Stefania , Rocchi Laura , Arfilli Valentina , Scavia Gaia , Ricci Francesca , Bontadini Andrea , Alfieri Roberta R , Petronini Pier Giorgio , Pecoraro Carmine , Tozzi Alberto E , Caprioli Alfredo
Published: April 2010

Intoxicated endothelial cells release pro-inflammatory cytokines involved in renal damage; amount of cytokines inversely correlates with the amount of toxin carried by PMN.

The endothelial damage induced by Stx represents the main pathogenic event in the HUS associated with STEC infections in humans. Stx, released in the gut by bacteria, enter the bloodstream and are targeted to renal endothelia. The role of PMN as a toxin carrier has been the object of controversy. In this paper, we confirm the binding of Stx1 to PMN, also showing its degranulating effects on full-loaded leukocytes, and support the carrier role of PMN by using a two-chamber transmigration device, in which PMN, loaded in vitro with different amounts of Stx1, transmigrated through confluent monolayers of endothelial cells, mimicking the toxin-induced renal endothelial injury. Stx1 was transferred during PMN transmigration, impairing protein synthesis and triggering production of proinflammatory cytokines in endothelial cells. PMN, carrying low toxin amounts, induced the release of high levels of cytokines in viable endothelial cells, whereas cytokine production was blocked in cells challenged with PMN fully loaded with Stx as a result of an almost total impairment of translation and of the activation of the apoptotic program. In agreement with previous unexplained observations in animal models, the results obtained with our experimental setting suggest that a self-amplifying circle triggered by low doses of toxin may lead to the production of proinflammatory mediators of renal damage in HUS.
Adrenoceptor Expression and Diurnal Rhythms of Melatonin and Its Precursors in the Pineal Gland of Type 2 Diabetic Goto-Kakizaki Rats
Authors: Bach Andreas Gunter , Mühlbauer Eckhard , Peschke Elmar
Published: April 2010

A decrease in the nighttime release of the pineal hormone melatonin is associated with aging and chronic diseases in animals an humans. Melatonin has a protective role in type 2 diabetes; however, its synthesis itself is affected in the disease. The aim of this study was to detect crucially impaired steps in the pineal melatonin synthesis of type 2 diabetic Goto-Kakizaki (GK) rats. Therefore, plasma melatonin concentrations and the pineal content of melatonin and its precursors (tryptophan, 5-hydroxytryptophan, serotonin, and N-acetylserotonin) were quantified in GK rats compared with Wistar rats (each group 8 and 50 wk old) in a diurnal manner (four animals per group and per time point). Additionally, the expression of pineal adrenoceptor subtype mRNA was investigated. We found that in diabetic GK rats, 1) inhibitory α-2-adrenoceptors are significantly more strongly expressed than in Wistar rats, 2) the formation of 5-hydroxytryptophan is crucially impaired, and 3) the pineal gland protein content is significantly reduced compared with that in Wistar rats. This is the first time that melatonin synthesis is examined in a type 2 diabetic rat model in a diurnal manner. The present data unveil several reasons for a reduced melatonin secretion in diabetic animals and present an important link in the interaction between melatonin and insulin.
Circulating Estrogens in Endometrial Cancer Cases and Their Relationship with Tissular Expression of Key Estrogen Biosynthesis and Metabolic Pathways
Authors: Lépine Johanie , Audet-Walsh Etienne , Grégoire Jean , Têtu Bernard , Plante Marie , Ménard Vincent , Ayotte Pierre , Brisson Jacques , Caron Patrick , Villeneuve Lyne , Bélanger Alain , Guillemette Chantal
Published: April 2010

Background: Endometrial cancer is the most common gynecological malignancy. Estrogen exposure is strongly associated with endometrial cancer. Whereas this cancer occurs predominantly in postmenopausal women lacking estrogen production by ovaries, the conversion of adrenal androgen-estrogen precursors to estradiol (E2), estrone (E1), and its sulfate (E1-S) has been well documented in peripheral tissues.

Experimental Design: We initially explored whether circulating levels of estrogens, measured by validated mass spectrometry assays, differ in women with endometrial cancer (n = 126) compared with healthy women (n = 110). We then evaluated by quantitative real-time PCR from purified RNA whether the expression profile of 19 estrogen-related synthesis and metabolic genes is modified in peritumoral normal endometrium (n = 36) compared with tumoral (n = 49) tissues.

Results: In endometrial cancer cases, circulating levels of E1, E2, and E1-S were significantly higher compared with unaffected controls. In agreement with plasma levels, findings support an enhanced biosynthesis of E2 in tumors. The expression of E2 biosynthesis pathways [E1-S (sulfatase) → E1 (17β-hydroxysteroid dehydrogenase) → E2] was shown to predominate in peritumoral normal endometrium and was significantly increased in tumors. In addition, the inactivation pathways mediated by several uridine diphosphate-glucuronosyltransferases were also enhanced in endometrial tumors compared with peritumoral normal endometrium.

Conclusion: We concluded that the higher levels of circulating estrogens in women with endometrial cancer are likely associated with an imbalance of multiple biotransformation pathways in endometrial tumor tissues.
Strategies of Power: Favorites and Women Household Clients at Louis Xiii's Court
Authors: Kettering Sharon
Published: April 2010

Using household clients to acquire and keep royal favor was a widespread power strategy at the courts of early modern Europe. Trustworthy clients were placed in royal households to manipulate and report on their members and through them to influence the king. Favorites needed their help because their longevity in favor and thus in power depended on the king's continued goodwill. This article looks at the ways in which two minister-favorites of Louis XIII, Charles d'Albert, duc de Luynes, and his successor, Armand-Jean du Plessis, Cardinal de Richelieu, used their household clients to stay in power, demonstrating what has long been assumed but never proven. Specifically, it looks at fourteen noblewomen who were Luynes's clients, mostly in the young queen's household, and fifteen noblewomen who were Richelieu's clients in the queen mother's and the queen's households. Luynes used his clients and the tactic of rewards to influence members of the household and the king. In contrast, Richelieu used his clients and the tactic of punishment for the same purpose. Despite the difference in tactics both favorites succeeded in their goals.

L'utilisation d'une clientèle «domestique» dans le but de conquérir et conserver la faveur royale était courante dans les cours princières de l'Europe moderne. Des clients fidèles furent placés dans les maisons royales pour manipuler, mais aussi pour faire des rapports sur leurs membres et par leur intermédiaire influencer le roi. Les favoris avaient besoin d'eux, car la durée de leur faveur et pouvoir dépendait de la bienveillance du roi. Cet article examine comment deux ministres-favoris de Louis XIII, Charles d'Albert, duc de Luynes, et son successeur, Armand-Jean du Plessis, cardinal de Richelieu, employèrent leurs clients domestiques pour rester au pouvoir. Ainsi cet article démontre ce que les historiens ont longtemps pensé sans le prouver. Plus précisément, il analyse le cas de quatorze femmes nobles clientes du duc de Luynes qui servirent dans la maison de la jeune reine, Anne d'Autriche, et quinze femmes nobles clientes de Richelieu placées dans les maisons de la reine mère et de la reine régnante. Pour influencer certains membres de la maison du roi et le roi lui-même, de Luynes proposa à ses clientes des récompenses en cas de réussite. Richelieu faisait planer sur les siennes la menace de la punition. Malgré ces différences de tactique, les deux ministres finirent par atteindre leurs objectifs.
Adherence to a Fixed-Dose Combination of Rosiglitazone/Glimepiride in Subjects Switching from Monotherapy or Dual Therapy with a Thiazolidinedione and/or a Sulfonylurea
Authors: Thayer Sarah , Arondekar Bhakti , Harley Carolyn , Darkow Theodore E
Published: April 2010

BACKGROUND:

In 2005, a fixed-dose combination therapy (FDCT) of rosiglitazone maleate and glimepiride became available for treatment of type 2 diabetes mellitus. It is hypothesized that FDCTs increase adherence by decreasing the number of required tablets.

OBJECTIVE:

To assess changes in medication adherence and hemoglobin A1c (A1C) values in subjects switching from monotherapy with either a sulfonylurea or rosiglitazone or dual therapy with both to rosiglitazone/glimepiride FDCT.

METHODS:

This retrospective database analysis included subjects with 1 or more prescription fills for rosiglitazone, a sulfonylurea, or rosiglitazone/glimepiride FDCT during the identification period of January 1, 2006, to September 30, 2006. Subjects were grouped according to baseline and follow-up period treatment regimens: sulfonylurea or rosiglitazone monotherapy switched to sulfonylurea and rosiglitazone dual therapy (Mono/Dual), monotherapy to rosiglitazone/glimepiride FDCT (Mono/FDCT), sulfonylurea and rosiglitazone dual therapy in both periods (Dual/Dual), and dual therapy to rosiglitazone/glimepiride FDCT (Dual/FDCT). The medication possession ratio (MPR) was calculated as a measure of adherence. The change in A1C from the baseline period to the follow-up period was assessed for each cohort.

RESULTS:

The study included 16,490 subjects. From baseline to follow-up, MPR decreased for both the Mono/FDCT cohort and the Mono/Dual cohort, but the magnitude of this decrease was less for the Mono/FDCT cohort (−0.02 vs −0.10; p < 0.001). Mean MPR significantly improved for the Dual/FDCT cohort compared with the Dual/Dual cohort (+0.10 vs +0.05; p < 0.001). The mean absolute A1C reduction did not differ significantly between the Mono/FDCT cohort (−1.08%) and the Mono/Dual cohort (−0.77%). Compared with the Dual/Dual cohort, the Dual/FDCT cohort experienced a greater absolute reduction in A1C (−0.06% vs −0.51%; p = 0.004). The results remained statistically significant in the multivariate model.

CONCLUSIONS:

Switching to rosiglitazone/glimepiride FDCT, in comparison with switching to dual therapy, was associated with improvements in medication adherence and glycemic control.
Successful Experience Utilizing Dexrazoxane Treatment for an Anthracycline Extravasation
Authors: Tyson Abby Mercer , Gay Wendy E
Published: April 2010

OBJECTIVE:

To describe a successful case of dexrazoxane treatment after an extravasation of doxorubicin and share a creative solution for formulary cost management.

CASE SUMMARY:

A 42-year-old female diagnosed with breast cancer was receiving doxorubicin as adjuvant treatment. The patient recently underwent a right mastectomy for a 3-centimeter grade 3 invasive ductal carcinoma. Three of 20 lymph nodes were positive, and the patient was stage 2B at presentation, with an estrogen receptor/progesterone receptor-positive and HER-2/neu-negative tumor. At an outside hospital, the patient was receiving doxorubicin through an infusion port when extravasation was noted after approximately 15 mL had been infused. She was transferred to Riverside Methodist Hospital and dexrazoxane treatment was initiated within 6 hours after extravasation. She received a full 3-day course of dexrazoxane treatment without complication and was discharged home. Significant delays in chemotherapy administration were avoided, and the patient successfully completed her planned chemotherapy course.

DISCUSSION:

Dexrazoxane has the potential to minimize tissue damage and treatment delays after an anthracycline extravasation. Although dexrazoxane is commercially marketed for 2 separate treatment indications, Totect is the Food and Drug Administration-approved product for anthracycline extravasations. Facilities administering anthracyclines should proactively resolve how to obtain, process, prepare, and administer this antidote to a patient within 6 hours of an extravasation event. Developing a preprinted chemotherapy extravasation order may facilitate the incorporation of the most recent Oncology Nursing Society guidelines to utilize dexrazoxane for an anthracycline extravasation. Cost sharing with other institutions may offer a creative solution to lessen the financial impact of stocking dexrazoxane therapy.

CONCLUSIONS:

Ensuring expedient treatment and accessibility to dexrazoxane therapy after an anthracycline extravasation is critical to the success of the treatment. All facilities utilizing anthracycline chemotherapy should purchase dexrazoxane or secure agreements with other facilities to guarantee the administration of this medication should extravasation occur.
Risk of Venous Thromboembolism with Drospirenone in Combined Oral Contraceptive Products
Authors: Sehovic Naida , Smith Katherine P
Published: April 2010

OBJECTIVE:

To review primary literature regarding the risk of venous thromboembolism (VTE) in users of combined oral contraceptives (COCs) containing drospirenone compared to COCs containing other progestins.

DATA SOURCES:

A literature search of MEDLINE and EMBASE (1950-January 2010) was conducted using the following search terms: VTE, thrombosis, thromboembolism, COC, combined hormonal contraceptives, drospirenone, Yasmin, and Yaz. Additional references were retrieved from reference citations.

STUDY SELECTION AND DATA EXTRACTION:

All English-language primary literature studies were evaluated for relevance. Five studies were identified for evaluation: 1 prescription event monitoring study, 2 prospective postmarketing cohort studies, 1 validation study, and 1 retrospective cohort study.

DATA SYNTHESIS:

Use of a COC is associated with a 3- to 6-fold increase in VTE risk compared to nonuse. This risk may vary among different oral contraceptives due to the progestin component. Studies evaluated showed that women utilizing a drospirenone-containing COC did not have a higher risk of VTE when compared to women utilizing other progestins. The crude incidence rate ratio for VTE in women taking a COC containing drospirenone compared to a COC containing other progestins ranged from 0.9 to 1.7 (95% CI 0.5 to 2.4). While the studies evaluating VTE risk were mostly large and long term, most failed to consider important risk factors for VTE such as prolonged immobility, obesity, smoking history, and family history of VTE (which could suggest a genetic predisposition to thrombotic events). It was also unclear with some of the studies whether equivalent estrogen doses were used in the comparisons.

CONCLUSIONS:

Several studies have evaluated the risk of VTE in users of COC-containing drospirenone compared with other progestins, and none were able to show a significantly increased risk of VTE with drospirenone. The recent media attention regarding VTE risk and drospirenone-containing COCs does not seem to be well supported by the research currently available.
Raltegravir Plasma Concentrations in Treatment-Experienced Patients Receiving Salvage Regimens Based on Raltegravir with and without Maraviroc Coadministration
Authors: Baroncelli Silvia , Villani Paola , Weimer Liliana E , Ladisa Nicoletta , Francisci Daniela , Tommasi Chiara , Vullo Vincenzo , Preziosi Roberta , Cicalini Stefania , Cusato Maria , Galluzzo Clementina M , Floridia Marco , Regazzi Mario
Published: April 2010

BACKGROUND:

Raltegravir and maraviroc represent new, important resources for HIV-infected patients with intolerance or resistance to other antiretroviral agents. The safety and efficacy of both drugs have been investigated, but there is no information on possible pharmacokinetic interactions between these 2 drugs in clinical practice.

OBJECTIVE:

To evaluate raltegravir plasma concentrations in heavily treatment-experienced patients receiving salvage regimens and explore, in a preliminary assessment, the potential influence of maraviroc coadministration and other cofactors on raltegravir trough concentrations (Ctrough).

METHODS:

Fifty-four HIV-infected patients with triple class (nucleoside reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitor, protease inhibitor) treatment experience starting raltegravir 400 mg twice daily, with (n = 11) or without (n = 43) concomitant maraviroc 300 mg twice daily, were evaluated. All regimens included at least 3 drugs of at least 2 different classes. Raltegravir plasma Ctrough, after at least 1 month of treatment, were analyzed to compare groups of patients taking raltegravir only and raltegravir plus maraviroc. Immunovirological (CD4, HIV-RNA) and clinical data after 6 months of treatment were also collected and described.

RESULTS:

Raltegravir plasma Ctrough showed a large variability (range <0.020-2.47 μg/mL). Median levels were similar in the 2 groups (raltegravir + maraviroc 0.104 μg/mL, range 0.025−0.826; raltegravir 0.090 μg/mL, range <0.020-2.47, p = 0.400). Detectable (>0.02 μg/mL) raltegravir concentrations were observed in all patients receiving raltegravir + maraviroc and in 74% of patients receiving raltegravir alone (p = 0.060). After 6 months of treatment, the 2 groups had similar clinical, virologic, and immunologic conditions.

CONCLUSIONS:

Coadministration of maraviroc does not seem to have any relevant effects on raltegravir plasma Ctrough in heavily treatment-experienced patients receiving salvage regimens. Further studies should evaluate the potential additional benefits of maraviroc coadministration in terms of virologic and immunologic response.
High-Dose Continuous Infusion β-Lactam Antibiotics for the Treatment of Resistant Pseudomonas Aeruginosa Infections in Immunocompromised Patients
Authors: Moriyama Brad , Henning Stacey A , Childs Richard , Holland Steven M , Anderson Victoria L , Morris John C , Wilson Wyndham H , Drusano George L , Walsh Thomas J
Published: April 2010

OBJECTIVE:

To report a case series of high-dose continuous infusion β-lactam antibiotics for the treatment of resistant Pseudomonas aeruginosa infections.

CASE SUMMARY:

Continuous infusion ceftazidime or aztreonam was administered to achieve target drug concentrations at or above the minimum inhibitory concentration, when possible, in 3 patients with P. aeruginosa infections. The maximal calculated target drug concentration was 100 mg/L. In the first patient, with primary immunodeficiency, neutropenia, and aggressive cutaneous T-cell lymphoma/leukemia, continuous infusion ceftazidime (6.5-9.6 g/day) was used to successfully treat multidrug-resistant P. aeruginosa bacteremia. In the second patient, with leukocyte adhesion deficiency type 1, continuous infusion aztreonam (8.4 g/day) was used to successfully treat multidrug-resistant P. aeruginosa wound infections. In the third patient, with severe aplastic anemia, continuous infusion ceftazidime (7-16.8 g/day) was used to treat P. aeruginosa pneumonia and bacteremia. In each patient, bacteremia cleared, infected wounds healed, and pneumonia improved in response to continuous infusion ceftazidime or aztreonam.

DISCUSSION:

Treatment strategies for multidrug-resistant P. aeruginosa infections are limited. A novel treatment strategy, when no other options are available, is the continuous infusion of existing β-lactam antibiotics to maximize their pharmacodynamic activity. High-dose continuous infusion ceftazidime or aztreonam was used for the successful treatment of resistant systemic P. aeruginosa infections in 3 chronically immunocompromised patients.

CONCLUSIONS:

Continuous infusion β-lactam antibiotics are a potentially useful treatment strategy for resistant P.aeruginosa infections in immunocompromised patients.
Adverse Drug Reactions in Hospitalized Psychiatric Patients
Authors: Thomas Michele , Boggs Angela A , DiPaula Bethany , Siddiqi Shahida
Published: April 2010

BACKGROUND:

Reducing adverse drug reactions (ADRs) is a critical element in providing safe medication use to hospitalized patients. There is an abundance of literature describing ADRs and preventable ADRs (pADRs) in hospitalized patients; however, little has been published specific to psychiatric inpatients. Further knowledge of the most common pADRs in hospitalized psychiatric patients will allow targeted patient safety initiatives to be developed.

OBJECTIVE:

To determine the most frequent ADRs and pADRs in a psychiatric hospital, with emphasis on identifying factors for prevention.

METHODS:

Three years of ADRs at a psychiatric hospital were analyzed and evaluated according to type of medication, preventability, severity, and factors associated with preventability.

RESULTS:

From July 1, 2006, to June 30, 2009, 93 ADRs were reported; 19 (20.4%) were classified as preventable. Psychiatric medications accounted for 45 (48.4%) of the ADRs and nonpsychiatric medications were associated with 48 (51.6%). Cardiovascular agents (n = 17) and antiepileptics (n = 17) were responsible for most ADRs. Of the 19 pADRs, lithium was the drug reported most frequently, followed by phenytoin and anxiolytics. Nine (47%) of the pADRs were severe and required a medical transfer for management; 3 of the 9 were lithium toxicity. The most common preventability factor involved drug interactions. A pharmacy intervention involving staff education to reduce lithium pADRs is presented.

CONCLUSIONS:

Awareness of the most frequent drug classes associated with ADRs and pADRs in a psychiatric hospital allows opportunity for education, medication management system changes, and improved patient safety. Lithium, followed by phenytoin and anxiolytics, were the most common drugs associated with pADRs. A drug-drug interaction was the most frequent factor associated with pADRs.
Migration, Development and a New Rurality in the Valle Alto, Bolivia
Authors: Yarnall Kaitlin , Price Marie
Published: April 2010

La relación entre migración y desarrollo ha sido discutida a menudo pero pocas veces demostrada empíricamente. En este estudio en Bolivia, examinamos los impactos que la migración ha tenido en la región pequeña de emigración denominada Valle Alto, en el Departamento de Cochabamba. Usando datos colectados de entrevistas, encuestas, y observaciones, el estudio identifica sistemas de migración y movimientos de remesas que son únicos a la región y muestra como contribuyen al desarrollo de la zona. El estudio muestra los diversos destinos que los emigrantes buscan para mantener ganancias de remesas, el movimiento circular de dichas ganancias, y la construcción de redes de conocimiento sobre la diáspora. En ciertas instancias, se observa una ruralidad nueva, en donde se percibe que las comunidades rurales tienen más recursos materiales que los pueblos coloniales. Aunque Valle Alto ofrece muchos ejemplos de migración que estimula el desarrollo económico, hay preocupación sobre la sostenibilidad de algunas de estas redes cuando la migración circular, particularmente entre los Estados Unidos y Bolivia, se vuelve más difícil y costosa.
Overwhelming the Medium: Fiction and the Trauma of Pandemic Influenza in 1918
Authors: Belling Catherine
Published: April 2010

Few illness narratives have been published about the 1918–1919 influenza pandemic. This essay links this silence to representational problems posed by mass trauma that happened before response to the Holocaust began our present era of attention to the narrative testimonies of suffering. In a pandemic, the collective replaces the individual as protagonist, and the health of the public takes precedence over the particular and subjective. History turns to statistics. Beginning with Katherine Anne Porter's Pale Horse, Pale Rider , her novella about her experience during the pandemic, and speculating on the entanglement of Virginia Woolf's accounts of influenza with Porter's strategies for recounting her sickness, the essay then examines two 2006 novels—Thomas Mullen's The Last Town on Earth , and Myla Goldberg's Wickett's Remedy —to show how narrative representations of the 1918 flu grapple with recounting the experience of sickness, a struggle repeatedly troped as waking from and remembering a nightmarish sleep. The value of these fictional accounts lies less in their historical accuracy than in the attention they draw to the representational demands that pandemic disease makes as it threatens to overwhelm the narrative medium.
Involvement of the calcium sensor GCAP1 in hereditary cone dystrophies
Authors: Behnen Petra , Dell'Orco Daniele , Koch Karl-Wilhelm
Published: April 2010

Progressive visual impairment leading to blindness is often associated with inherited retinal dystrophies. These disorders correlate in most cases with mutations in genes that code for proteins of the visual transduction system in rod and cone photoreceptor cells. Recent progress has highlighted the involvement of a neuronal calcium sensor protein that is specifically expressed in rod and cone cells and operates as a guanylate cyclase-activating protein (GCAP). A group of patients suffering from cone or cone-rod dystrophies carry mutations in the GCAP1 gene, and biochemical analysis of GCAP1 function revealed that for most of these mutations GCAP1 exhibits a disturbance in its Ca2+-sensing and its guanylate cyclase-activating properties. Cellular consequences of different GCAP1 mutations are compared and discussed.
RIM proteins and their role in synapse function
Authors: Mittelstaedt Tobias , Alvaréz-Baron Elena , Schoch Susanne
Published: April 2010

Active zones are specialized areas of the plasma membrane in the presynaptic nerve terminal that mediate neurotransmitter release and synaptic plasticity. The multidomain proteins RIM1 and RIM2 are integral components of the cytomatrix at the active zone, interacting with most other active zone-enriched proteins as well as synaptic vesicle proteins. In the brain, RIMs are present in multiple isoforms (α, β, γ) diverging in their structural composition, which mediate overlapping and distinct functions. Here, we summarize recent findings about the specific roles of the various RIM isoforms in basic synaptic vesicle release as well as long- and short-term presynaptic plasticity.
Cathepsin L in metastatic bone disease: therapeutic implications
Authors: Leto Gaetano , Sepporta Maria Vittoria , Crescimanno Marilena , Flandina Carla , Tumminello Francesca Maria
Published: April 2010

Cathepsin L is a lysosomal cysteine proteinase primarily devoted to the metabolic turnover of intracellular proteins. However, accumulating evidence suggests that this endopeptidase might also be implicated in the regulation of other important biological functions, including bone resorption in normal and pathological conditions. These findings support the concept that cathepsin L, in concert with other proteolytic enzymes involved in bone remodeling processes, could contribute to facilitate bone metastasis formation. In support of this hypothesis, recent studies indicate that cathepsin L can foster this process by triggering multiple mechanisms which, in part, differ from those of the major cysteine proteinase of osteoclasts, namely cathepsin K. Therefore, cathepsin L can be regarded as an additional target in the treatment of patients with metastatic bone disease. This review discusses the clinical and therapeutic implications related to these findings.
Activated T-Cells Inhibit Neurogenesis by Releasing Granzyme B: Rescue by Kv1.3 Blockers
Authors: Wang Tongguang , Lee Myoung-Hwa , Johnson Tory , Allie Rameeza , Hu Lina , Calabresi Peter A. , Nath Avindra
Published: April 2010

There is a great need for pharmacological approaches to enhance neural progenitor cell (NPC) function particularly in neuroinflammatory diseases with failed neuroregeneration. In diseases such as multiple sclerosis and stroke, T-cell infiltration occurs in periventricular zones where NPCs are located and is associated with irreversible neuronal loss. We studied the effect of T-cell activation on NPC functions. NPC proliferation and neuronal differentiation were impaired by granzyme B (GrB) released by the T-cells. GrB mediated its effects by the activation of a Gi-protein-coupled receptor leading to decreased intracellular levels of cAMP and subsequent expression of the voltage-dependent potassium channel, Kv1.3. Importantly, blocking channel activity with margatoxin or blocking its expression reversed the inhibitory effects of GrB on NPCs. We have thus identified a novel pathway in neurogenesis. The increased expression of Kv1.3 in pathological conditions makes it a novel target for promoting neurorestoration.
Roles of the Primate Motor Thalamus in the Generation of Antisaccades
Authors: Kunimatsu Jun , Tanaka Masaki
Published: April 2010

In response to changes in our environment, we select from possible actions depending on the given situation. The underlying neural mechanisms for this flexible behavioral control have been examined using the antisaccade paradigm. In this task, subjects suppress saccades to the sudden appearance of visual stimuli (prosaccade) and make a saccade in the opposite direction. Because recent imaging studies showed enhanced activity in the thalamus and basal ganglia during antisaccades, we hypothesized that the corticobasal ganglia loop may be involved. To test this, we recorded from neurons in the paralaminar part of the ventroanterior (VA), ventrolateral (VL) and mediodorsal (MD) nuclei of the thalamus when 3 monkeys performed pro/antisaccade tasks. For many VL and some VA neurons, the firing rate was greater during anti- than prosaccades. In contrast, neurons in the MD thalamus showed much variety of responses. For the population as a whole, neuronal activity in the VA/VL thalamus was strongly enhanced during antisaccades compared with prosaccades, while activity in the MD nucleus was not. Inactivation of the VA/VL thalamus resulted in an increase in the number of error trials in the antisaccade tasks, indicating that signals in the motor thalamus play roles in the generation of antisaccades. Enhancement of firing modulation during antisaccades found in the thalamus and those reported previously in the supplementary eye field and the basal ganglia suggest a strong functional linkage between these structures. The neuronal processes through the thalamocortical pathways might be essential for the volitional control of saccades.
The Short Splice Variant of the γ2 Subunit Acts as an External Modulator of GABAAReceptor Function
Authors: Boileau Andrew J. , Pearce Robert A. , Czajkowski Cynthia
Published: April 2010

GABAAreceptors (GABAARs) regulate the majority of fast inhibition in the mammalian brain and are the target for multiple drug types, including sleep aids, anti-anxiety medication, anesthetics, alcohol, and neurosteroids. A variety of subunits, including the highly distributed γ2, allow for pharmacologic and kinetic differences in particular brain regions. The two common splice variants γ2S (short) and γ2L (long) show different patterns of regional distribution both in adult brain and during the course of development, but show few notable differences when incorporated into pentameric receptors. However, results presented here show that the γ2S variant can strongly affect both GABAAR pharmacology and kinetics by acting as an external modulator of fully formed receptors. Mutation of one serine residue can confer γ2S-like properties to γ2L subunits, and addition of a modified γ2 N-terminal polypeptide to the cell surface recapitulates the pharmacological effect. Thus, rather than incorporation of a separate accessory protein as with voltage-gated channels, this is an example of an ion channel using a common subunit for dual purposes. The modified receptor properties conferred by accessory γ2S have implications for understanding GABAAR pharmacology, receptor kinetics, stoichiometry, GABAergic signaling in the brain during development, and altered function in disease states such as epilepsy.