bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple vaccinations with UV- attenuated cercariae in pig enhance protective immunity against Schistosoma japonicum infection as compared to single vaccination
Authors: Lin Dandan , Tian Fang , Wu Haiwei , Gao Yanan , Wu Jingjiao , Zhang Donghui , Ji Minjun , McManus Donald P , Driguez Patrick , Wu Guanling
Published: June 2011

Background

Schistosomiasis japonica is a major public health problem in the endemic areas of China, the Philippines, and Indonesia. To date, a vaccine has not been developed against this disease but immunization with UV-attenuated cercariae can induce a high level of protective immunity in Landrace/Yorkshire/Duroc crossbred pigs. To compare the efficacy of a single vaccination and multiple vaccinations with UV-attenuatedSchistosoma japonicumcercariae, two groups of pigs received either one or three exposures to 10,000 cercariae attenuated with 400 μw UV.

Results

Pigs with a single immunization had a 59.33% reduction in adult worm burden, a 89.87% reduction in hepatic eggs and a 86.27% reduction in fecal eggs at eight weeks post-challenge (P< 0.01). After three immunizations, protection increased to 77.62%, 88.8% and 99.78% reduction in adult worms, hepatic eggs and fecal eggs, respectively (P< 0.01). Humoral and cellular immunological parameters measured indicated that schistosome-specific IgG1 and IgG2 levels in the vaccinated groups were higher than in the infection-control group. Triple vaccinations resulted in higher levels of antibodies, especially IgG2, compared with a single vaccination and IFN-γ levels increased with repeated immunization with UV-irradiated cercariae.

Conclusion

The high levels of protection againstS. japonicuminfection can be achieved with a UV-attenuated vaccine in pigs, and that three vaccinations were possibly more effective than a single vaccination. Moreover, triple vaccinations evoked a more vigorous IFN-γ response and a stronger antibody-mediated response, especially an increase in the levels of IgG2 antibodies.
Human fascioliasis in Argentina: retrospective overview, critical analysis and baseline for future research
Authors: Mera y Sierra Roberto , Agramunt Veronica H , Cuervo Pablo , Mas-Coma Santiago
Published: June 2011

In Argentina, human fascioliasis has never been adequately analysed, although having a physiography, climate, animal prevalences and lymnaeids similar to those of countries where the disease is endemic such as Bolivia, Peru and Chile. We performed a literature search identifying 58 reports accounting for 619 cases, involving 13 provinces, their majority (97.7%) from high altitudes, in central mountainous areas and Andean valleys, concentrated in Cordoba (430 cases), Catamarca (73), San Luis (29) and Mendoza (28), the remaining provinces being rarely affected. This distribution does not fit that of animal fascioliasis. Certain aspects (higher prevalence in females in a local survey, although a trend non-significant throughout Argentina) but not others (patient's age 3-95 years, mean 37.1 years) resemble human endemics in Andean countries, although the lack of intensity studies and surveys in rural areas does not allow for an adequate evaluation. Human infection occurs mainly in January-April, when higher precipitation and temperatures interact with field activities during summer holidays. A second June peak may be related to Easter holidays. The main risk factor appears to be wild watercress ingestion (214) during recreational, weekend outings or holiday activities, explaining numerous family outbreaks involving 63 people and infection far away from their homes. Diagnosis mainly relied on egg finding (288), followed by serology (82), intradermal reaction (63), surgery (43), and erratic fluke observation (6). The number of fascioliasis-hydatidosis co-infected patients (14) is outstanding. Emetine appears as the drug most used (186), replaced by triclabendazole in recent years (21). Surgery reports are numerous (27.0%). A long delay in diagnosis (average almost 3.5 years) and high lithiasis proportion suggest that many patients are frequently overlooked and pose a question mark about fascioliasis detection in the country. High seroprevalences found in recent random surveys suggest human endemic situations. This analysis highlights that human fascioliasis may have been overlooked in the past and its real epidemiological situation in high risk rural, mainly altitudinal areas, may currently be underestimated. Results provide a valuable baseline on which to design appropriate multidisciplinary studies on humans, animals and lymnaeids to assess up to which level and in which areas, human fascioliasis may represent a health problem in Argentina.
Reduced renal function is associated with progression to AIDS but not with overall mortality in HIV‐infected kenyan adults not initially requiring combination antiretroviral therapy
Authors: Gupta Samir K , Ong'or Willis Owino , Shen Changyu , Musick Beverly , Goldman Mitchell , Wools‐Kaloustian Kara
Published: June 2011

Background

The World Health Organization (WHO) has recently recommended that antiretrovirals be initiated in all individuals with CD4 counts of less than 350 cells/mm3. For countries with resources too limited to expand care to all such patients, it would be of value to able to identify and target populations at highest risk of HIV progression. Renal disease has been identified as a risk factor for disease progression or death in some populations.

Methods

Times to meeting combination antiretroviral therapy (cART) initiation criteria (developing either a CD4 count < 200 cells/mm3 or WHO stage 3 or 4 disease) and overall mortality were evaluated in cART‐naïve, HIV‐infected Kenyan adults with CD4 cell counts ≥200/mm3 and with WHO stage 1 or 2 disease. Cox proportional hazard regression models were used to evaluate the associations between renal function and these endpoints.

Results

We analyzed data of 7383 subjects with a median follow‐up time of 59 (interquartile range, 27‐97) weeks. In Cox regression analyses adjusted for age, sex, WHO disease stage, CD4 cell count and haemoglobin, estimated creatinine clearance (CrCl) < 60 mL/min was significantly associated with shorter times to meeting cART initiation criteria (HR 1.34; 95% CI, 1.23‐1.52) and overall mortality (HR 1.73; 95% CI, 1.19‐2.51) compared with CrCl ≥60 mL/min. Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 was associated with shorter times to meeting cART initiation criteria (HR 1.39; 95% CI, 1.22‐1.58), but not with overall mortality. CrCl and eGFR remained associated with shorter times to cART initiation criteria, but neither was associated with mortality, in weight‐adjusted analyses.

Conclusions

In this large natural history study, reduced renal function was strongly associated with faster HIV disease progression in adult Kenyans not initially meeting cART initiation criteria. As such, renal function measurement in resource‐limited settings may be an inexpensive method to identify those most in need of cART to prevent progression to AIDS. The initial association between reduced CrCl, but not reduced eGFR, and greater mortality was explained by the low weights in this population.
Diagnostic tools in Rhinology EAACI position paper
Authors: Scadding Glenis , Hellings Peter , Alobid Isam , Bachert Claus , Fokkens Wytske , van Wijk Roy Gerth , Gevaert Philippe , Guilemany Josep , Kalogjera Livije , Lund Valerie , Mullol Joaquim , Passalacqua Giovanni , Toskala Elina , van Drunen Cornelius
Published: June 2011

This EAACI Task Force document aims at providing the readers with a comprehensive and complete overview of the currently available tools for diagnosis of nasal and sino‐nasal disease. We have tried to logically order the different important issues related to history taking, clinical examination and additional investigative tools for evaluation of the severity of sinonasal disease into a consensus document. A panel of European experts in the field of Rhinology has contributed to this consensus document on Diagnostic Tools in Rhinology.
Not all shellfish “allergy” is allergy!
Authors: Woo Chee K , Bahna Sami L
Published: June 2011

The popularity of shellfish has been increasing worldwide, with a consequent increase in adverse reactions that can be allergic or toxic. The approximate prevalence of shellfish allergy is estimated at 0.5‐2.5% of the general population, depending on degree of consumption by age and geographic regions. The manifestations of shellfish allergy vary widely, but it tends to be more severe than most other food allergens.

Tropomyosin is the major allergen and is responsible for cross‐reactivity between members of the shellfish family, particularly among the crustacea. Newly described allergens and subtle differences in the structures of tropomyosin between different species of shellfish could account for the discrepancy between in vitro cross‐antigenicity and clinical cross‐allergenicity. The diagnosis requires a thorough medical history supported by skin testing or measurement of specific IgE level, and confirmed by appropriate oral challenge testing unless the reaction was life‐threatening.

Management of shellfish allergy is basically strict elimination, which in highly allergic subjects may include avoidance of touching or smelling and the availability of self‐administered epinephrine. Specific immunotherapy is not currently available and requires the development of safe and effective protocols.
Impact of Aspergillus fumigatus in allergic airway diseases
Authors: Chaudhary Neelkamal , Marr Kieren A
Published: June 2011

For decades, fungi have been recognized as associated with asthma and other reactive airway diseases. In contrast to type I‐mediated allergies caused by pollen, fungi cause a large number of allergic diseases such as allergic bronchopulmonary mycoses, rhinitis, allergic sinusitis and hypersensitivity pneumonitis. Amongst the fungi, Aspergillus fumigatus is the most prevalent cause of severe pulmonary allergic disease, including allergic bronchopulmonary aspergillosis (ABPA), known to be associated with chronic lung injury and deterioration in pulmonary function in people with chronic asthma and cystic fibrosis (CF). The goal of this review is to discuss new understandings of host‐pathogen interactions in the genesis of allergic airway diseases caused by A. fumigatus. Host and pathogen related factors that participate in triggering the inflammatory cycle leading to pulmonary exacerbations in ABPA are discussed.
Allergy as an epithelial barrier disease
Authors: Mattila Pirkko , Joenväärä Sakari , Renkonen Jutta , Toppila‐Salmi Sanna , Renkonen Risto
Published: June 2011

The objective of this review is to focus on putative modified epithelial functions related to allergy. The dysregulation of the epithelial barrier might result in the allergen uptake, which could be the primary defect in the pathogenesis of allergic reaction. We review the literature of the role of respiratory epithelium as an active barrier, how allergens are transported through it and how it senses the hostile environmental allergens and other dangerous stimuli.
Cytokeratin-19 mRNA-positive circulating tumor cells during follow-up of patients with operable breast cancer: prognostic relevance for late relapse
Authors: Saloustros Emmanouil , Perraki Maria , Apostolaki Stella , Kallergi Galatea , Xyrafas Alexandros , Kalbakis Kostas , Agelaki Sophia , Kalykaki Antonia , Georgoulias Vassilis , Mavroudis Dimitris
Published: June 2011

Background

The detection of cytokeratin-19 (CK-19) mRNA-positive circulating tumor cells (CTC) before and/or after adjuvant chemotherapy in patients with operable breast cancer is associated with poor clinical outcome. Reliable prognostic markers for late disease relapse are not available. In this study we investigated the value of CTC detection during the first five years of follow-up in predicting late disease relapse.

Methods

Blood was analyzed from 312 women with operable breast cancer who had not experienced disease relapse during the first two years of follow-up. A real-time reverse transcriptase polymerase chain reaction (RT-PCR) for CK-19 mRNA was used to detect CTC three months after the completion of adjuvant chemotherapy and every six months thereafter for a follow-up period of five years.

Results

Eighty patients (25.6% of the study population) remained CTC free throughout the five-year period. A change in CTC status was observed in 133 patients (42.6%); 64 patients (20.5%) with initially CK-19 mRNA-positive CTC during the first 24 months turned CTC-negative afterwards while 69 (22.1%) who were initially CTC-negative became CTC-positive. Ninety-nine patients (31.7%) remained persistently CK-19 mRNA-positive. After a median follow-up period of 107 months (range: 38 to 161 months), the persistently CTC-positive patients with either hormonal receptor positive or negative tumors, had a higher risk of late-disease relapse compared to the persistently CTC-negative patients (36.4% versus 11.2%, P <0.001). Multivariate analysis revealed that persistently CTC-positive patients also had a shorter disease-free (P = 0.001) and overall survival (P = 0.001).

Conclusions

Persistent detection of CK-19 mRNA-positive CTC during the first five years of follow-up is associated with an increased risk of late relapse and death in patients with operable breast cancer and indicates the presence of chemo-and hormonotherapy-resistant residual disease. This prognostic evaluation may be useful when deciding on subsequent adjuvant systemic therapy.
2D waveform tomography applied to long-streamer MCS data from the Scotian Slope
Authors: Delescluse Matthias , Nedimović Mladen R. , Louden Keith E.
Published: June 2011

Detailed velocity models of the earth’s subsurface can be obtained through waveform tomography. The accuracy of the long-wavelength component of such velocity models, which is the background velocity field, is particularly sensitive to modeling low-frequency refracted waves that have long paths through target structures. Thus, field examples primarily have focused on the analysis of long-offset wide-angle data sets collected using autonomous receivers, in which refractions arrive at significantly earlier times than reflections. Modern marine acquisition with long streamers now offers the ability to record refracted waves with high spatial density and uniform source, both in shallow and deep water. We used 2D multichannel seismic (MCS) data acquired with a 9-km-long streamer over the Scotian Slope in water depths of ∼1600 m. The refracted arrivals, although mostly restricted to far-offset receivers, provided sufficient information to successfully invert for a high-resolution background velocity field. Using a frequency-domain acoustic code over frequencies from 8 to 24 Hz on two crossing profiles, we found that the limited refracted waves can constrain the velocity field above the depth of the turning waves (∼1.5 km below seafloor). Several important features were resolved by the waveform velocity model that were not present in the initial traveltime model. In particular, a high-velocity layer at 300 m below the seafloor, interpreted as gas hydrates, was imaged even where a characteristic bottom-simulating reflector was not visible. At 750-m depth, a strong velocity increase of 300 m/s existed beneath a gently dipping reflector along which low-velocity zones, possibly related to gas, were present. Velocity models were highly consistent at the crossing point between the two profiles. The depth extent of the MCS waveform tomography constrained by refractions could be extended by even longer streamers (e.g., 15 km) or by joint inversion with data from ocean-bottom seismographs.
Mena invasive (MenaINV) promotes multicellular streaming motility and transendothelial migration in a mouse model of breast cancer
Authors: Roussos Evanthia T. , Balsamo Michele , Alford Shannon K. , Wyckoff Jeffrey B. , Gligorijevic Bojana , Wang Yarong , Pozzuto Maria , Stobezki Robert , Goswami Sumanta , Segall Jeffrey E. , Lauffenburger Douglas A. , Bresnick Anne R. , Gertler Frank B. , Condeelis John S.
Published: June 2011

We have shown previously that distinct Mena isoforms are expressed in invasive and migratory tumor cells in vivo and that the invasion isoform (MenaINV) potentiates carcinoma cell metastasis in murine models of breast cancer. However, the specific step of metastatic progression affected by this isoform and the effects on metastasis of the Mena11a isoform, expressed in primary tumor cells, are largely unknown. Here, we provide evidence that elevated MenaINV increases coordinated streaming motility, and enhances transendothelial migration and intravasation of tumor cells. We demonstrate that promotion of these early stages of metastasis by MenaINV is dependent on a macrophage–tumor cell paracrine loop. Our studies also show that increased Mena11a expression correlates with decreased expression of colony-stimulating factor 1 and a dramatically decreased ability to participate in paracrine-mediated invasion and intravasation. Our results illustrate the importance of paracrine-mediated cell streaming and intravasation on tumor cell dissemination, and demonstrate that the relative abundance of MenaINV and Mena11a helps to regulate these key stages of metastatic progression in breast cancer cells.
Late diagnosis of HIV: could this be avoided?
Authors: Goodall L , Leen C
Published: June 2011

Many patients with HIV infection present at a late stage of disease. Late diagnosis is associated with increased morbidity and mortality. One strategy to encourage earlier HIV diagnosis is the promotion of HIV testing outside of a specialist HIV setting. This study aimed to determine whether the diagnosis of HIV could be made sooner by non-HIV specialists consulting HIV-positive patients in the year preceding diagnosis. A case note review of all newly diagnosed HIV-positive patients seen over a 12-month period ending in September 2006, was performed to analyse whether patients had consulted a doctor in the year prior to diagnosis, whether they were offered HIV testing and whether they had symptoms or risk factors suggesting HIV infection. Fifty-one newly diagnosed HIV-positive patients were seen during the study period. Twenty-nine of these patients had consulted a doctor in the year prior to diagnosis. Of these, 10 were offered HIV testing and 19 were not. All patients who were not offered HIV testing had risk factors for-, or symptoms of HIV infection. The majority of newly diagnosed HIV patients had consulted a doctor in the year prior to diagnosis. Most were not offered HIV testing despite having risk factors for HIV infection. HIV diagnosis may have been made earlier by testing for HIV outside of a specialist setting.
The prevalence of ear, nose and throat disorders in preschool children with Down's syndrome in Glasgow
Authors: Barr Emily , Dungworth Jessica , Hunter Karen , Mcfarlane Margaret , Kubba Haytham
Published: June 2011

Guidelines suggest that all children with Down's syndrome have hearing testing on a regular basis. Since 2004, the ear, nose and throat (ENT), audiology and education services have conducted a joint clinic for annual ENT health and hearing surveillance of all preschool children with Down's syndrome in Greater Glasgow. The aim of this study is to report the prevalence of ENT problems in this well-defined birth cohort, and the proportion of children for whom ENT surgery is required. A prospective database has been kept since 2004, detailing the ENT health status of every child attending the community-based surveillance clinic. Between September 2004 and September 2008, 87 preschool (aged 9 months to 6 years) children with Down's syndrome were sent appointments for the clinic. Of these, 48 (55%) were female and 39 were male. Data were available for 79 (91%). Over the course of the study, 37% were listed for surgery at some point, either adenotonsillectomy for obstructive symptoms or grommet insertion for otitis media with effusion (OME). The prevalence of OME was 93% at age 1, falling to 68% by age 5. None had significant sensorineural hearing impairment. Obstructive symptoms were also common, with 79% of children having either currently symptomatic upper airways obstruction or a history of adenotonsillectomy by age 5. One child had laryngomalacia and two had symptomatic congenital subglottic stenosis. The prevalence of ENT problems in these children is high. Surgical intervention is frequently required. We advocate a proactive approach of regular ENT and audiology surveillance leading to early intervention, with the aim of maximizing health and educational achievement in the long term.
The ubiquitin ligase Rsp5 is required for ribosome stability in Saccharomyces cerevisiae
Authors: Shcherbik Natalia , Pestov Dimitri G.
Published: June 2011

Rsp5p is a conserved HECT-domain ubiquitin ligase with diverse roles in cellular physiology. Here we report a previously unknown role of Rsp5p in facilitating the stability of the cytoplasmic ribosome pool in budding yeast. Yeast strains carrying temperature-sensitive mutations in RSP5 showed a progressive decline in levels of 18S and 25S rRNAs and accumulation of rRNA decay fragments when cells grown in rich medium were shifted to restrictive temperature. This was accompanied by a decreased number of translating ribosomes and the appearance of ribosomal subunits with an abnormally low sedimentation rate in polysome analysis. Abrogating Rsp5p function affected stability of other tested noncoding RNA species (tRNA and snoRNA), but to a lower extent than that of rRNA, and also inhibited processing of rRNA and tRNA precursors, in agreement with previous studies. The breakdown of cellular ribosomes was not affected by deletion of key genes involved in autophagy, previously implicated in ribosome turnover upon starvation. Our results suggest that functional Rsp5p is required to maintain the integrity of cytoplasmic ribosomes under rich nutrient conditions.
Binding and cleavage of unstructured RNA by nuclear RNase P
Authors: Marvin Michael C. , Walker Scott C. , Fierke Carol A. , Engelke David R.
Published: June 2011

Ribonuclease P (RNase P) is an essential endoribonuclease for which the best-characterized function is processing the 5′ leader of pre-tRNAs. Compared to bacterial RNase P, which contains a single small protein subunit and a large catalytic RNA subunit, eukaryotic nuclear RNase P is more complex, containing nine proteins and an RNA subunit in Saccharomyces cerevisiae. Consistent with this, nuclear RNase P has been shown to possess unique RNA binding capabilities. To understand the unique molecular recognition of nuclear RNase P, the interaction of S. cerevisiae RNase P with single-stranded RNA was characterized. Unstructured, single-stranded RNA inhibits RNase P in a size-dependent manner, suggesting that multiple interactions are required for high affinity binding. Mixed-sequence RNAs from protein-coding regions also bind strongly to the RNase P holoenzyme. However, in contrast to poly(U) homopolymer RNA that is not cleaved, a variety of mixed-sequence RNAs have multiple preferential cleavage sites that do not correspond to identifiable consensus structures or sequences. In addition, pre-tRNATyr, poly(U)50 RNA, and mixed-sequence RNA cross-link with purified RNase P in the RNA subunit Rpr1 near the active site in “Conserved Region I,” although the exact positions vary. Additional contacts between poly(U)50 and the RNase P proteins Rpr2p and Pop4p were identified. We conclude that unstructured RNAs interact with multiple protein and RNA contacts near the RNase P RNA active site, but that cleavage depends on the nature of interaction with the active site.
Accumulation of noncoding RNA due to an RNase P defect in Saccharomyces cerevisiae
Authors: Marvin Michael C. , Clauder-Münster Sandra , Walker Scott C. , Sarkeshik Ali , Yates John R. , Steinmetz Lars M. , Engelke David R.
Published: June 2011

Ribonuclease P (RNase P) is an essential endoribonuclease that catalyzes the cleavage of the 5′ leader of pre-tRNAs. In addition, a growing number of non-tRNA substrates have been identified in various organisms. RNase P varies in composition, as bacterial RNase P contains a catalytic RNA core and one protein subunit, while eukaryotic nuclear RNase P retains the catalytic RNA but has at least nine protein subunits. The additional eukaryotic protein subunits most likely provide additional functionality to RNase P, with one possibility being additional RNA recognition capabilities. To investigate the possible range of additional RNase P substrates in vivo, a strand-specific, high-density microarray was used to analyze what RNA accumulates with a mutation in the catalytic RNA subunit of nuclear RNase P in Saccharomyces cerevisiae. A wide variety of noncoding RNAs were shown to accumulate, suggesting that nuclear RNase P participates in the turnover of normally unstable nuclear RNAs. In some cases, the accumulated noncoding RNAs were shown to be antisense to transcripts that commensurately decreased in abundance. Pre-mRNAs containing introns also accumulated broadly, consistent with either compromised splicing or failure to efficiently turn over pre-mRNAs that do not enter the splicing pathway. Taken together with the high complexity of the nuclear RNase P holoenzyme and its relatively nonspecific capacity to bind and cleave mixed sequence RNAs, these data suggest that nuclear RNase P facilitates turnover of nuclear RNAs in addition to its role in pre-tRNA biogenesis.
Hemorrhagic and Thrombotic Events Associated with Generic Substitution of Warfarin in Patients with Atrial Fibrillation: A Retrospective Analysis
Authors: Ghate Sameer R , Biskupiak Joseph E , Ye Xiangyang , Hagan Michael , Kwong Winghan Jacqueline , Fox Eben S , Brixner Diana I
Published: June 2011

BACKGROUND:

Substitution of generic warfarin for imprint warfarin (Coumadin; DuPont/Bristol-Myers Squibb) has been a controversial issue due to bioavailability and bioequivalence concerns.

OBJECTIVE:

To assess the risk of thrombotic and hemorrhagic events following substitution of warfarin formulations in patients with atrial fibrillation (AF).

METHODS:

Historical cohort analysis was performed using a commercial insurance claims database. Adults with a diagnosis of AF between January 2003 and December 2007, with 16 or more months of continuous eligibility, a warfarin prescription within 30 days after index AF diagnosis, and at least 3 warfarin prescription fills during the follow-up period were included. Individuals with AF diagnosis or warfarin prescription during the pre-index period were excluded. Cox proportional hazard regression models controlling for sex and baseline comorbidities (Charlson comorbidity index, CCI) were used to evaluate the risks of thrombotic and hemorrhagic events following warfarin formulation switches.

RESULTS:

Of 37,756 subjects included in the analysis (mean age 70.96 years, 42.3% females), 12,996 (34.4%) switched warfarin formulations, 20,292 (53.7%) used only 1 generic product, and 4468 (11.8%) used only Coumadin during follow-up. Compared with continued use of Coumadin, switching from that product to the generic formulation was associated with a significantly higher risk of thrombotic events (HR = 1.81; 95% CI 1.42 to 2.31). Similar findings were observed for switching from generic warfarin to Coumadin (HR = 1.76; 95% CI 1.35 to 2.30), and from 1 generic to another generic product (HR = 1.89; 95% CI 1.57 to 2.29). Similarly, switching from Coumadin to generic warfarin (HR = 1.51; 95% CI 1.17 to 1.93), generic warfarin to Coumadin (HR = 1.60; 95% CI 1.23 to 2.1), and from 1 generic to another generic product (HR = 1.74; 95% CI 1.45 to 2.11) were associated with significantly higher risk of hemorrhage than remaining on Coumadin.

CONCLUSIONS:

Switching warfarin formulations exposed patients with AF to a higher risk of bleeding events compared to remaining on a single product. Maintaining patients on a product with consistent bioavailability may optimize the risk-benefit balance of anticoagulation therapy.
Effectiveness of Amlodipine-Valsartan Single-Pill Combinations: Hierarchical Modeling of Blood Pressure and Total Cardiovascular Disease Risk Outcomes (the EXCELLENT Study)
Authors: Lins Robert , Aerts Ann , Coen Nicolas , Hermans Christine , MacDonald Karen , Brié Heidi , Lee Christopher , Shen Yu-Ming , Vancayzeele Stefaan , Mecum Natalie , Abraham Ivo
Published: June 2011

BACKGROUND:

Both patient- and physician-related factors have been shown to explain variability in the outcomes of antihypertensive treatment. Total cardiovascular risk (TCVR) is increasingly used as a determinant of treatment effectiveness but has also been proposed as a treatment outcome. To our knowledge, no studies have reported how antihypertensive treatment impacts blood pressure and TCVR outcomes.

OBJECTIVE:

To examine in patients treated with a regimen including single-pill combinations (SPCs) of amlodipine/valsartan (1) blood pressure (BP) reduction and control, total cardiovascular risk (TCVR) change, and TCVR reduction of 1 class or more; (2) hierarchical patient- and physician-level determinants of these outcomes; and (3) predictors of uncontrolled BP and improved TCVR classification.

METHODS:

A prospective (90 days), multicenter, multilevel pharmacoepidemiologic study was conducted in 3546 patients with hypertension treated with SPC amlodipine/valsartan by 698 general practitioners. Statistical analysis included hierarchical linear and logistic modeling of BP and TCVR outcomes.

RESULTS:

Mean (SD) systolic BP (SBP) reductions were 20.1 (15.5) mm Hg and diastolic BP (DBP) reductions were 9.8 (10.3) mm Hg, with higher reductions among high-risk patients. SBP, DBP, and SBP/DBP control rates were 33.3%, 45.3%, and 25.5%, respectively, with lower rates among high-risk patients. Mean TCVR improvement was a reduction of 0.73 (0.96) classes (-4 [best] to +4 [worst]), with higher reductions for high-risk patients; 58.2% of patients achieved a TCVR reduction of 1 or more classes, with lower percentages for high-risk patients. Twenty-two percent of systolic variability and 26% of diastolic variability in 90-day BP values were attributable to a physician class effect, as was 16% of TCVR change.

CONCLUSIONS:

Regimens that include SPC amlodipine/valsartan formulations are effective in reducing BP and TCVR in a real-world observational setting. Hierarchical modeling identified patient- and physician-related determinants of BP values and TCVR change, as well as independent predictors of uncontrolled BP and reduced TCVR. TCVR is a scientifically feasible and clinically relevant effectiveness outcome of antihypertensive treatment.
Use of Recalibrated Serum Creatinine Concentrations for Adjustment of Drug Dosages: Determination of Values Compatible with Conventional Dosing Recommendations
Authors: Jones Michael A , Golightly Larry K , Stolpman Nancy M
Published: June 2011

BACKGROUND:

Measurement of serum creatinine concentration is central to evaluation of kidney function. Recent efforts to increase the accuracy of this evaluation have led to recalibration of laboratory instruments. Recalibrated creatinine concentrations often are lower than previously reported.

OBJECTIVES:

To derive a method for converting recalibrated serum creatinine (R-SCr) concentrations into values that are compatible with recommended equations for calculation of estimated creatinine clearance.

METHODS:

Beginning with a proprietary array of recalibrated and corresponding non-recalibrated serum creatinine (NR-SCr) numerical data provided by the instrument manufacturer, relationships were examined with exponential and linear regression analyses. The validity of derived values for NR-SCr obtained through these analyses was tested by comparison of proprietary and derived serum creatinine concentrations and calculated creatinine clearance values.

RESULTS:

Analyses revealed that relationships between R-SCr and NR-SCr creatinine were essentially linear. Rearranging and solving the equation for a straight line described this relationship as x = (y - b)/m, where x is the derived creatinine value, y is the R-SCr concentration, and, for our laboratory instrument, best parameters for m and b equal to 0.987 and −0.07, respectively. Use of these parameters to derive NR-SCr values was shown to significantly decrease positive bias in subsequent creatinine clearance calculations.

CONCLUSIONS:

As compared to R-SCr concentrations, use of derived NR-SCr values can improve the predictive performance of conventional equations used to calculate estimated creatinine clearance.
Ulipristal Acetate for Emergency Contraception
Authors: Snow Sara E , Melillo Stephanie N , Jarvis Courtney I
Published: June 2011

OBJECTIVE:

To review the pharmacology, pharmacokinetics, efficacy, and safety of data of ulipristal acetate, a new emergency contraceptive approved for use up to 120 hours after unprotected intercourse.

DATA SOURCES:

Articles pertaining to the topic were identified and reviewed through searches of PubMed (1994-March 2011) and clinicaltrials.gov , using the key terms ulipristal and CDB-2914. Ella approval documents were obtained and reviewed from Drugs@FDA on the Food and Drug Administration (FDA) Web site.

STUDY SELECTION AND DATA EXTRACTION:

All published data and FDA approval documents examining pharmacologic, pharmacokinetic, and clinical studies related to ulipristal acetate as an emergency contraceptive were evaluated. Selected studies included 3 randomized trials and 1 meta-analysis.

DATA SYNTHESIS:

Ulipristal acetate is a progesterone agonist/antagonist emergency contraceptive approved for the prevention of pregnancy to be taken as soon as possible, within 120 hours after unprotected intercourse or a known or suspected contraceptive failure. Based upon results of the Phase 3 clinical trials used to obtain approval, ulipristal acetate administration was at least as effective as levonorgestrel in the reduction of pregnancy rate when studied alone after unprotected intercourse and when taken up to 120 hours after unprotected intercourse. Commonly reported adverse effects associated with ulipristal acetate in trials included headache, breast tenderness, nausea, and abdominal pain.

CONCLUSIONS:

Ulipristal acetate is effective as an emergency contraceptive for up to 120 hours after unprotected intercourse. Because ulipristal is available only via prescription, it may be covered by insurance. However, the additional factors of travel expenses and time to make and attend a physician appointment must be taken into account when considering use of ulipristal as an emergency contraceptive. Due to the similarity of its structure to mifepristone, controversy regarding ulipristal's mechanism of action has arisen.
High-Dose Dexmedetomidine for Sedation in the Intensive Care Unit: An Evaluation of Clinical Efficacy and Safety
Authors: Jones G Morgan , Murphy Claire V , Gerlach Anthony T , Goodman Erin M , Pell Lindsay J
Published: June 2011

BACKGROUND:

Dexmedetomidine is an α2-receptor agonist used for sedation in the intensive care unit (ICU). Although dexmedetomidine is labeled for sedation in critically ill patients at doses up to 0.7 μg/kg/h, recent studies have used more liberal dosing regimens. However, to our knowledge, no study has assessed the clinical impact of doses greater than 0.7 μg/kg/h when compared to doses within the Food and Drug Administration-approved labeling.

OBJECTIVE:

To compare the clinical efficacy and safety of high (HD) and low (LD) dses of dexmedetomidine for sedation in the ICU.

METHODS:

This retrospective study included a sample of patients who received dexmedetomidine in medical, surgical, medical/surgical, and cardiothoracic ICUs between January 1, 2008, and December 1, 2009. Patients were included in the LD group if their maximum dose was less than 0.7 μg/kg/h or in the HD group if any dose was more than 0.7 μg/kg/h. Efficacy was determined by the percentage of Richmond Agitation and Sedation Scale (RASS) scores for each patient maintained at goal sedation (-1 to +1), and safety was determined by the incidence of hypotension and bradycardia.

RESULTS:

Forty-three of 133 patients received HD dexmedetomidine. Patients in the LD group had a significantly higher percentage of RASS scores at goal (60.0% vs 48.6%; p = 0.03), while those in the HD group experienced a higher percentage of RASS scores classified as undersedated (19.2% vs 4.9%; p = 0.001). There was no significant difference in the incidence of hypotension or bradycardia between groups.

CONCLUSIONS:

Patients treated with HD dexmedetomidine had fewer RASS scores at goal. Our data suggest that increasing the dose of dexmedetomidine may not enhance sedation efficacy or lead to an increased incidence of adverse effects. Patients who have not achieved goal sedation at doses of 0.7 μg/kg/h or less may not respond further to increased doses.
Oral Ferrous Sulfate Does Not Increase Preoperative Hemoglobin in Patients Scheduled for Hip or Knee Arthroplasty
Authors: Lachance Kim , Savoie Michel , Bernard Maryse , Rochon Stéphanie , Fafard Josée , Robitaille Robert , Vendittoli Pascal-André , Lévesque Sylvie , de Denus Simon
Published: June 2011

BACKGROUND:

Low hemoglobin (Hb) concentrations before lower limb joint replacement are associated with the need for blood transfusions and increased mortality. To optimize preoperative Hb, blood conservation protocols often recommend oral iron supplements, even in nonanemic patients.

OBJECTIVE:

To investigate the impact of ferrous sulfate on the change in Hb prior to hip or knee arthroplasty and evaluate the effect of oral iron on hematocrit, mean corpuscular volume (MCV), ferritin, and transferrin saturation, as well as its tolerability and treatment adherence.

METHODS:

We conducted a prospective, observational cohort study of adults with Hb concentrations between 10 and 15 g/dL who received iron supplementation prior to hip or knee arthroplasty. Systemic inflammatory diseases, vitamin B12 or folate deficiency, and current use of iron supplements, intravenous iron, or erythropoietin were exclusion criteria. All participants were prescribed ferrous sulfate 300 mg 3 times daily for a minimum of 3 weeks. Complete blood cell counts and iron studies were performed before therapy and surgery.

RESULTS:

Eighty-seven patients with a mean (SD) Hb of 13.47 (0.84) g/dL were included in the study. Preoperative Hb decreased after treatment with iron (-0.14 [0.53] g/dL, p = 0.015). Hematocrit also declined (-0.6% [1.8%], p = 0.002), whereas ferritin increased (25.8 [38.6] ng/mL, p < 0.001). No significant change was seen in MCV and transferrin saturation. The most common adverse effects were constipation (33.3%), heartburn (13.8%), and abdominal pain (12.6%). The adherence rate was 67.1%.

CONCLUSIONS:

Oral ferrous sulfate supplementation is not an effective method to increase preoperative Hb in patients scheduled for hip or knee arthroplasty, and its use is associated with adverse effects.
Methadone Toxicity Due to Smoking Cessation—A Case Report on the Drug-Drug Interaction Involving Cytochrome P450 Isoenzyme IA2
Authors: Wahawisan Joy , Kolluru Srikanth , Nguyen Tu , Molina Christina , Speake Joseph
Published: June 2011

OBJECTIVE:

To report the potential clinically significant pharmacokinetic interaction that may result from smoking cessation in patients on methadone maintenance therapy.

CASE SUMMARY:

A 46-year-old white man was admitted to the step-down intensive care unit with decreased respirations and altered mental status related to methadone toxicity. The patient had been on a stable dose of methadone for chronic back pain, and he reported a 1 pack per day, 33-year history of cigarette smoking. After methadone was held for 3 days, his mental status improved. It was later revealed that he had initiated smoking cessation. He was discharged home on a reduced dose of methadone with no further complications.

DISCUSSION:

While the potential for toxicity exists for patients who are maintained on methadone and decrease the number of cigarettes they smoke, to our knowledge, there is no recent peer-reviewed literature on this interaction. Methadone is a synthetic opioid primarily metabolized by CYP3A4 and, to a lesser degree, by other isoenzymes, including CYP1A2. Polycyclic aromatic hydrocarbons found in tobacco smoke are known CYP1A2 inducers. Decreased intake of cigarette smoke can lead to a reduction in methadone metabolism, resulting in higher serum concentrations. Our case is an example of methadone toxicity secondary to smoking cessation in a patient on methadone maintenance therapy. An objective causality assessment based on the Horn Drug Interaction Probability Scale revealed the interaction to be probable.

CONCLUSIONS:

Patients on methadone should be monitored for signs of methadone toxicity upon the start of smoking cessation, and the dose of methadone should be adjusted accordingly. Additional information and reports cautioning clinicians and patients about this potential interaction would be beneficial.
Substituting Warfarin Products: What's the Source of the Problem?
Authors: Haines Stuart T
Published: June 2011

Many clinicians have expressed concerns about the bioequivalence of warfarin products, and data suggest that substituting warfarin products may increase the risk of major bleeding and thromboembolic complications. Anecdotal reports and some retrospective studies have reported differences in anticoagulation control after a warfarin product substitution. But the best available evidence—prospective, randomized, blinded clinical trials—has failed to validate these observations. Indeed, interpatient and intrapatient variability in anticoagulation control observed before and after warfarin product substitution is very similar. So, while differences in product standardization, bioavailability, and bioequivalence make a convenient explanation, the problem lies elsewhere. Perhaps poor communication, fractionated systems of care, and errors are the culprits.
Pharmacists as Mid-Level Practitioners/Providers
Authors: Ross Leigh Ann
Published: June 2011

With recent changes in health-care delivery, the profession of pharmacy is presented with opportunities for expanded involvement in direct patient care as mid-level practitioners/providers. Will pharmacists be proactive in realizing these opportunities? Expanding current roles to improve medication-related health outcomes for patients will require that pharmacists establish collaborative practice relationships, differentiate our unique services from those of other mid-level practitioners/providers, and share these results with the public and other health-care providers. This article encourages pharmacists to advocate for advancing pharmacy practice to meet the needs of society, to continue the dialogue regarding an expanded scope of practice for pharmacists as mid-level practitioners/providers, and to actively engage in developing these new roles.
Ulipristal Acetate: Contraceptive or Contragestive?
Authors: Keenan Jeffrey A
Published: June 2011

Ulipristal acetate is the first selective progesterone receptor modulator approved for postcoital contraception in the US. It appears to be significantly more effective in inhibition of ovulation than other forms of emergency contraception. However, ulipristal acetate is structurally similar to mifepristone, and several lines of evidence suggest that a postfertilization mechanism of action is also operative. This mechanism of action is considered to be contragestive versus contraceptive. Ulipristal acetate administration is contraindicated in a known or suspected pregnancy; however, it could quite possibly be used as an effective abortifacient. Health-care providers should inform patients of the possibility of both mechanisms of action with use of this drug.
The Formation of Illite from Nontronite by Mesophilic and Thermophilic Bacterial Reaction
Authors: Jaisi Deb P. , Eberl Dennis D. , Dong Hailiang , Kim Jinwook
Published: June 2011

The formation of illite through the smectite-to-illite (S-I) reaction is considered to be one of the most important mineral reactions occurring during diagenesis. In biologically catalyzed systems, however, this transformation has been suggested to be rapid and to bypass the high temperature and long time requirements. To understand the factors that promote the S-I reaction, the present study focused on the effects of pH, temperature, solution chemistry, and aging on the S-I reaction in microbially mediated systems. Fe(III)-reduction experiments were performed in both growth and non-growth media with two types of bacteria: mesophilic (Shewanella putrefaciensCN32) and thermophilic (Thermus scotoductusSA-01). Reductive dissolution of NAu-2 was observed and the formation of illite in treatment with thermophilic SA-01 was indicated by X-ray diffraction (XRD) and high-resolution transmission electron microscopy (HRTEM). A basic pH (8.4) and high temperature (65°C) were the most favorable conditions forthe formation of illite. A long incubation time was also found to enhance the formation of illite. K-nontronite (non-permanent fixation of K) was also detected and differentiated from the discrete illite in the XRD profiles. These results collectively suggested that the formation of illite associated with the biologically catalyzed smectite-to-illite reaction pathway may bypass the prolonged time and high temperature required for the S-I reaction in the absence of microbial activity.
Epigenetic regulation of matrix metalloproteinases and their collagen substrates in cancer
Authors: Chernov Andrei V. , Strongin Alex Y.
Published: June 2011

Our review covers the recent epigenetic data that are focused on matrix metalloproteinases (MMPs), their inhibitors (tissue inhibitors of MMPs; TIMPs) and collagen substrates. Twenty-four MMPs, four TIMPs and at least 28 collagen types are known in humans. The MMP activity regulates the functionality of multiple extracellular matrix proteins, cytokines, growth factors and cell signaling and adhesion receptors. Aberrantly enhanced MMP proteolysis affects multiple cell functions, including proliferation, migration and invasion. This aberrant MMP proteolysis is frequently recorded in cancer. Recent evidence, however, indicates that several MMPs function as tumor suppressors in cancer. Their inhibition could have pro-tumorigenic effects (making them anti-targets), counterbalancing the benefits of target inhibition and leading to adverse effects in cancer patients. The current epigenetic data suggest that there are distinct multi-layered epigenetic mechanisms that regulate MMPs, TIMPs and collagens. We show that in certain cancer types, epigenetic signatures of selected MMPs exhibit stem cell-like characteristics. Epigenetic mechanisms appear to play an especially important role in glioblastoma multiforme. Glioblastomas/gliomas synthesize de novo and then deposit collagens into the brain parenchyma. The collagen deposition, combined with an enhanced MMP activity in glioblastomas/gliomas, facilitates rapid invasion of tumor cells through the brain. It is tempting to hypothesize that the epigenetic mechanisms which control MMPs, TIMPs and collagens and, consequently, tumor cell invasion, represent promising drug targets and that in the near future these targets will be challenged pharmacologically.