Combined functional and viability cardiac MR imaging in a single breathhold

The combination of cardiac viability and functional information enhances the identification of different heart tissues in the setting of ischemic heart disease. A method has recently been proposed for obtaining black-blood delayed-enhancement (DE) viability images using the stimulated-echo acquisition mode (STEAM) MRI pulse sequence in a single short breathhold. The method was validated against conventional inversion-recovery (IR) DE images for identifying regions of myocardial infarction (MI). The method was based on the acquisition of three consecutive images of the same anatomical slice. One image has T(1)-weighted contrast in which infarction appears bright. The two other images are used to construct an anatomical image of the heart, which is combined with the first image to produce a black-blood viability image. However, using appropriate modulation and demodulation frequencies, the latter two images bear useful information about myocardial deformation that results in a cardiac strain-encoding (SENC) functional image. In this work, a method is proposed for obtaining three consecutive SENC images in a single acquisition that can be combined to produce a composite image of the heart, which shows both functional and viability information. The proposed technique reduces scan time by one-half, compared with separate acquisitions of functional and viability images, and alleviates misregistration problems caused by separate breathholds.

New combined serum creatinine and cystatin C quadratic formula for GFR assessment in children.

BACKGROUND AND OBJECTIVES: The estimated GFR (eGFR) is important in clinical practice. To find the best formula for eGFR, this study assessed the best model of correlation between sinistrin clearance (iGFR) and the solely or combined cystatin C (CysC)- and serum creatinine (SCreat)-derived models. It also evaluated the accuracy of the combined Schwartz formula across all GFR levels. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Two hundred thirty-eight iGFRs performed between January 2012 and April 2013 for 238 children were analyzed. Regression techniques were used to fit the different equations used for eGFR (i.e., logarithmic, inverse, linear, and quadratic). The performance of each model was evaluated using the Cohen κ correlation coefficient and the percentage reaching 30% accuracy was calculated. RESULTS: The best model of correlation between iGFRs and CysC is linear; however, it presents a low κ coefficient (0.24) and is far below the Kidney Disease Outcomes Quality Initiative targets to be validated, with only 84% of eGFRs reaching accuracy of 30%. SCreat and iGFRs showed the best correlation in a fitted quadratic model with a κ coefficient of 0.53 and 93% accuracy. Adding CysC significantly (P<0.001) increased the κ coefficient to 0.56 and the quadratic model accuracy to 97%. Therefore, a combined SCreat and CysC quadratic formula was derived and internally validated using the cross-validation technique. This quadratic formula significantly outperformed the combined Schwartz formula, which was biased for an iGFR≥91 ml/min per 1.73 m(2). CONCLUSIONS: This study allowed deriving a new combined SCreat and CysC quadratic formula that could replace the combined Schwartz formula, which is accurate only for children with moderate chronic kidney disease.

Combined Electrostatic and Covalent Polymer Networks for Cell Microencapsulation

Two types of hydrogel microspheres have been developed. Fast ionotropic gelation of sodium alginate (Na-alg) in the presence of calcium ions was combined with slow covalent cross-linking of poly(ethylene glycol) (PEG) derivatives. For the first type, the fast obtainable Ca-alg hydrogel served as spherical matrix for the simultaneously occurring covalent cross-linking of multi-arm PEG derivative. A two-component interpenetrating network was formed in one step upon extruding the mixture of the two polymers into the gelation bath. For the second type, heterobifunctional PEG was grafted onto Na-alg prior to gelation. Upon extrusion of the polymer solution into the gelation bath, fast Ca-alg formation ensured the spherical shape and was accompanied by cross-linker-free covalent cross-linking of the PEG side chains. Thus, one-component hydrogel microspheres resulted. We present the physical properties of the hydrogel microspheres and demonstrate the feasibility of cell microencapsulation for both types of polymer networks.

Characterization and distribution of Pogonomyrmex harvester ant lineages with genetic caste determination.

Genetic caste determination has been described in two populations of Pogonomyrmex harvester ants, each comprising a pair of interbreeding lineages. Queens mate with males of their own and of the alternate lineage and produce two types of diploid offspring, those fertilized by males of the queens' lineage which develop into queens and those fertilized by males of the other lineage which develop into workers. Each of the lineages has been shown to be itself of hybrid origin between the species Pogonomyrmex barbatus and Pogonomyrmex rugosus, which both have typical, environmentally determined caste differentiation. In a large scale genetic survey across 35 sites in Arizona, New Mexico and Texas, we found that genetic caste determination associated with pairs of interbreeding lineages occurred frequently (in 26 out of the 35 sites). Overall, we identified eight lineages with genetic caste determination that always co-occurred in the same complementary lineage pairs. Three of the four lineage pairs appear to have a common origin while their relationship with the fourth remains unclear. The level of genetic differentiation among these eight lineages was significantly higher than the differentiation between P. rugosus and P. barbatus, which questions the appropriate taxonomic status of these genetic lineages. In addition to being genetically isolated from one another, all lineages with genetic caste determination were genetically distinct from P. rugosus and P. barbatus, even when colonies of interbreeding lineages co-occurred with colonies of either putative parent at the same site. Such nearly complete reproductive isolation between the lineages and the species with environmental caste determination might prevent the genetic caste determination system to be swept away by gene flow.

Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study.

This study presents the results of a multicenter investigation of the efficacy of acamprosate in the treatment of patients with chronic or episodic alcohol dependence. One hundred eighteen patients were randomly assigned to either placebo or acamprosate, and both groups were stratified for concomitant voluntary use of disulfiram. Treatment lasted for 360 days, with an additional 360-day follow-up period. The primary efficacy parameters evaluated were: relapse rate and cumulative abstinence duration (CAD). Results were analyzed according to Intention-To-Treat principles using chi2, t, and multiple regression analyses where appropriate. After 30 days on study medication, 40 of 55 (73%) acamprosate-treated patients were abstinent, compared with 26 of 55 (43%) placebo-treated patients (p = 0.019). The treatment advantage remained throughout the study medication period and was statistically significant until day 270 (p = 0.028). Twenty-seven percent of patients on acamprosate and 53% of patients on placebo had a first drink within the first 30 days of the study. The mean CAD was 137 days (40% abstinent days) for the patients treated with acamprosate and 75 days (21% abstinent days) for the placebo group (p = 0.013). No adverse interaction between acamprosate and disulfiram occurred, and the subgroup who received both medications had a better outcome on CAD than the those on only one or no medication. Acamprosate was well tolerated. Diarrhea was the only significant treatment-induced effect. It was concluded that acamprosate was a useful and safe pharmacotherapy in the long-term treatment of alcoholism. Concomitant administration of disulfiram improved the effectiveness of acamprosate.

Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. METHODS: In this multicentre, open-label, phase 3 study, we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries. Eligible patients (newly diagnosed, histologically proven supratentorial glioblastoma, methylated MGMT promoter, and age ≥18 years) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and centrally randomised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group). Patients and investigators were unmasked to treatment allocation. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects. The primary endpoint was overall survival. We analysed survival outcomes by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00689221. FINDINGS: Overall, 3471 patients were screened. Of these patients, 3060 had tumour MGMT status tested; 926 patients had a methylated MGMT promoter, and 545 were randomly assigned to the cilengitide (n=272) or control groups (n=273) between Oct 31, 2008, and May 12, 2011. Median overall survival was 26·3 months (95% CI 23·8-28·8) in the cilengitide group and 26·3 months (23·9-34·7) in the control group (hazard ratio 1·02, 95% CI 0·81-1·29, p=0·86). None of the predefined clinical subgroups showed a benefit from cilengitide. We noted no overall additional toxic effects with cilengitide treatment. The most commonly reported adverse events of grade 3 or worse in the safety population were lymphopenia (31 [12%] in the cilengitide group vs 26 [10%] in the control group), thrombocytopenia (28 [11%] vs 46 [18%]), neutropenia (19 [7%] vs 24 [9%]), leucopenia (18 [7%] vs 20 [8%]), and convulsion (14 [5%] vs 15 [6%]). INTERPRETATION: The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug. Nevertheless, integrins remain a potential treatment target for glioblastoma. FUNDING: Merck KGaA, Darmstadt, Germany.

High prevalence of severe vitamin D deficiency in combined antiretroviral therapy-naive and successfully treated Swiss HIV patients.

OBJECTIVES: To evaluate the prevalence of 25-hydroxyvitamin D [25(OH)D] deficiency in HIV-positive patients, a population at risk for osteoporosis. DESIGN: Retrospective assessment of vitamin D levels by season and initiation of combined antiretroviral therapy (cART). METHODS: 25(OH)D was measured in 211 HIV-positive patients: samples were taken before initiation of cART from February to April or from August to October as well as 12 (same season) and 18 months (alternate season) after starting cART. 1,25-Dihydroxyvitamin D [1,25(OH)2D] was measured in a subset of 74 patients. Multivariable analyses included season, sex, age, ethnicity, BMI, intravenous drug use (IDU), renal function, time since HIV diagnosis, previous AIDS, CD4 cell count and cART, in particular nonnucleoside reverse transcriptase inhibitor (NNRTI) and tenofovir (TDF) use. RESULTS: At baseline, median 25(OH)D levels were 37 (interquartile range 20-49) nmol/l in spring and 57 (39-74) nmol/l in the fall; 25(OH)D deficiency less than 30 nmol/l was more prevalent in spring (42%) than in fall (14%), but remained unchanged regardless of cART exposure. In multivariable analysis, 25(OH)D levels were higher in white patients and those with a longer time since HIV diagnosis and lower in springtime measurements and in those with active IDU and NNRTI use. 1-Hydroxylation rates were significantly higher in patients with low 25(OH)D. Hepatitis C seropositivity, previous AIDS and higher CD4 cell counts correlated with lower 1,25(OH)2D levels, whereas BMI and TDF use were associated with higher levels. In TDF-treated patients, higher 1,25(OH)2D correlated with increases in serum alkaline phosphatase. CONCLUSION: Based on the high rate of vitamin D deficiency in HIV-positive patients, systematic screening with consideration of seasonality is warranted. The impact of NNRTIs on 25(OH)D and TDF on 1,25(OH)2D needs further attention.

Comparative vascular and renal tabular effects of angiotensin II receptor blockers combined with a thiazide diurectic in humans

Rapport de synthese :Comparaison des effets vasculaires et tubulaires rénaux de plusieurs antagonistes des récepteurs de |'angiotensine II en combinaison avec un diurétique thiazidique chez l'humainObjectif : Le but de ce travail était d'investiguer si les antagonistes des récepteurs AT1 de l'angiotensine II (ARA2) entraînent un blocage équivalent des récepteurs au niveau vasculaire et au niveau rénal, en particulier lorsque le système rénine- angiotensine est stimulé par l'administration d'un diurétique thiazidique. Méthode : trente volontaires masculins en bonne santé ont participé à cette étude randomisée, contrôlée, en simple insu. Nous avons mesuré les variations de pression artérielle, d'hémodynamique rénale ainsi que la réponse tubulaire rénale à une perfusion d'angiotensine II 3ng/kg/min administrée sur 1 heure. Ceci avant traitement puis après sept jours d'administration, 24 heures après la dernière dose de médicament. Nous avons comparé l'irbésartan 300 mg seul ou en association avec 12.5 ou 25 mg d'hydrochlorothiazide. (irbésartan 300/12.5 ; irbésartan 300/25). Nous avons également comparé les effets de l'irbésartan 300/25 au losartan 100 mg, au valsartan 160 mg ainsi qu'à l'olmésartan 20 mg, tous administrés avec 25 mg d'hydrochlorothiazide. Chaque participant a été randomisé pour recevoir 2 traitements de 7 jours espacés d'une période d'une semaine sans traitement. Résultats: La réponse de la pression artérielle à |'angiotensine II exogène était bloquée >90% avec l'irbésartan 300 mg seul ou en association avec le diurétique. Il en était de même avec l'olmésartan 20/25. Par contre le blocage n'était que de 60% environ dans les groupes valsartan 160/25 et losartan 100/25. Au niveau rénal, |'angiotensine II exogène réduisait le flux plasmatique rénal de 36% en pré- traitement. Dans les groupes recevant l'irbésartan 300 mg et l'olmésartan 20 mg associés à l'hydrochlorothiazide 25 mg, la vasoconstriction rénale était bloquée presque entièrement alors qu'el|e ne |'était que partiellement avec le valsartan 160/25 et le losartan 100/25 (34 et 45%, respectivement). En pré-traitement, au niveau tubulaire, l'angiotensine II exogène réduisait le volume urinaire de 84% et l'excrétion urinaire de sodium de 65 %. Les effets tubulaires n'étaient que partiellement bloqués par l'administration d'ARA2. Conclusion: Ces résultats démontrent que les ARA; aux doses maximales recommandées ne bloquent pas aussi efficacement les récepteurs ATI au niveau tubulaire qu'au niveau vasculaire. Cette observation pourrait constituer une justification à l'hypothèse selon laquelle des doses plus importantes d'ARA2 seraient nécessaires afin d'obtenir une meilleure protection d'organe. De plus, nos résultats confirment qu'i| y a d'importantes différences entre les ARA2, relatives à leur capacité d'induire un blocage prolongé sur 24 heures des récepteurs AT1 au niveau vasculaire et tubulaire.

Timing effects of combined radioimmunotherapy and radiotherapy on a human solid tumor in nude mice.

Timing effects of radioimmunotherapy (RIT) combined with external-beam radiotherapy (RT) were assessed in human colon carcinoma xenografts. Initially, dose effects of fractionated RT and RIT were evaluated separately. Then, 30 Gy RT (10 fractions over 12 days) were combined with three weekly i.v. injections of 200 microCi of 131I-labeled anti-carcinoembryonic antigen monoclonal antibodies in four different treatment schedules. RIT was given either prior to, concurrently, immediately after, or 2 weeks after RT administration. The longest regrowth delay (RD) of 105 days was observed in mice treated by concurrent administration of RT and RIT, whereas the RDs of RT and RIT alone were 34 and 20 days, respectively. The three sequential combination treatments produced significantly shorter RDs ranging from 62 to 70 days. The tumor response represented by the minimal volume (MV) also showed that concurrent administration of RT and RIT gave the best result, with a mean MV of 4.5% as compared to MVs from 26 to 53% for the three sequential treatments. The results were confirmed in a second experiment, in which a RT of 40 Gy was combined with an identical RIT as above (three injections of 200 microCi of 131I-labeled monoclonal antibodies). At comparable toxicity levels, the maximum tolerated RT or RIT alone gave shorter RDs and less tumor shrinkage compared to simultaneous RT+ RIT. These results may be useful for designing clinical protocols of combined RIT and RT.

Safety of combined heat and moisture exchanger filters in long-term mechanical ventilation.

STUDY OBJECTIVE: To evaluate the safety of a combined heat and moisture exchanger filter (HMEF) for the conditioning of inspired gas in long-term mechanical ventilation (MV). DESIGN: Randomized controlled trial. SETTING: Medical ICU in a large teaching hospital. PATIENTS: One hundred fifteen consecutive patients who required > or = 48 h of MV. INTERVENTIONS: Patients were randomized at intubation time (day 1) to receive inspired gas conditioned either by a water-bath humidifier heated at 32 degrees C (HWBH) or by an HMEF (Hygroster; DAR; Mirandola, Italy). MEASUREMENTS AND MAIN RESULTS: The two study groups were comparable in terms of primary pathologic condition at the time of hospital admission, disease severity as measured by the Simplified Acute Physiology Score, and ICU mortality. They did not differ with respect to ventilator days per patient (mean +/- SD: HMEF, 7.6 +/- 6.5; HWBH, 7.8 +/- 5.8), incidence of endotracheal tube obstruction (HMEF, 0/59; HWBH, 1/56), and incidence of hypothermic episodes (HMEF, five; HWBH, two). In 41 patients receiving MV for > or = 5 days, the morphologic integrity of respiratory epithelium was evaluated on day 1 and day 5, using a cytologic examination of tracheal aspirate smears. The state of ciliated epithelium was scored on a scale from 0 (poorest integrity) to 1,200 (maximum integrity), according to a well-described method. In both patient groups, the scores slightly but significantly decreased from day 1 to day 5 (mean +/- SD: HWBH, from 787 +/- 104 to 745 +/- 88; HMEF, from 813 +/- 79 to 739 +/- 62; p < 0.01 for both groups); there were no statistically significant differences between groups. CONCLUSIONS: These data indicate acceptable safety of HMEFs of the type used in the present study for long-term mechanical ventilation.

Genetic caste determination in Pogonomyrmex harvester ants imposes costs during colony founding.

Some populations of Pogonomyrmex harvester ants comprise genetically differentiated pairs of interbreeding lineages. Queens mate with males of their own and of the alternate lineage and produce pure-lineage offspring which develop into queens and inter-lineage offspring which develop into workers. Here we tested whether such genetic caste determination is associated with costs in terms of the ability to optimally allocate resources to the production of queens and workers. During the stage of colony founding, when only workers are produced, queens laid a high proportion of pure-lineage eggs but the large majority of these eggs failed to develop. As a consequence, the number of offspring produced by incipient colonies decreased linearly with the proportion of pure-lineage eggs laid by queens. Moreover, queens of the lineage most commonly represented in a given mating flight produced more pure-lineage eggs, in line with the view that they mate randomly with the two types of males and indiscriminately use their sperm. Altogether these results predict frequency-dependent selection on pairs of lineages because queens of the more common lineage will produce more pure-lineage eggs and their colonies be less successful during the stage of colony founding, which may be an important force maintaining the coexistence of pairs of lineages within populations.

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma.

BACKGROUND: Sorafenib (Sb) is a multiple kinase inhibitor targeting both tumour cell proliferation and angiogenesis that may further act as a potent radiosensitizer by arresting cells in the most radiosensitive cell cycle phase. This phase I open-label, noncontrolled dose escalation study was performed to determine the safety and maximum tolerated dose (MTD) of Sb in combination with radiation therapy (RT) and temozolomide (TMZ) in 17 patients with newly diagnosed high-grade glioma. METHODS: Patients were treated with RT (60 Gy in 2 Gy fractions) combined with TMZ 75 mg m(-2) daily, and Sb administered at three dose levels (200 mg daily, 200 mg BID, and 400 mg BID) starting on day 8 of RT. Thirty days after the end of RT, patients received monthly TMZ (150-200 mg m(-2) D1-5/28) and Sb (400 mg BID). Pharmacokinetic (PK) analyses were performed on day 8 (TMZ) and on day 21 (TMZ&Sb) (Clinicaltrials ID: NCT00884416). RESULTS: The MTD of Sb was established at 200 mg BID. Dose-limiting toxicities included thrombocytopenia (two patients), diarrhoea (one patient) and hypercholesterolaemia (one patient). Sb administration did not affect the mean area under the curve(0-24) and mean Cmax of TMZ and its metabolite 5-amino-imidazole-4-carboxamide (AIC). Tmax of both TMZ and AIC was delayed from 0.75 (TMZ alone) to 1.5 h (combined TMZ/Sb). The median progression-free survival was 7.9 months (95% confidence interval (CI): 5.4-14.55), and the median overall survival was 17.8 months (95% CI: 14.7-25.6). CONCLUSIONS: Although Sb can be combined with RT and TMZ, significant side effects and moderate outcome results do not support further clinical development in malignant gliomas. The robust PK data of the TMZ/Sb combination could be useful in other cancer settings.