Oral cancer treatments and adherence: medication event monitoring system assessment for capecitabine

Background: Oncological treatments are traditionally administered via intravenous injection by qualified personnel. Oral formulas which are developing rapidly are preferred by patients and facilitate administration however they may increase non-adherence. In this study 4 common oral chemotherapeutics are given to 50 patients, who are still in the process of inclusion, divided into 4 groups. The aim is to evaluate adherence and offer these patients interdisciplinary support with the joint help of doctors and pharmacists. We present here the results for capecitabine. Materials and Methods: The final goal is to evaluate adhesion in 50 patients split into 4 groups according to oral treatments (letrozole/exemestane, imatinib/sunitinib, capecitabine and temozolomide) using persistence and quality of execution as parameters. These parameters are evaluated using a medication event monitoring system (MEMS®) in addition to routine oncological visits and semi-structured interviews. Patients were monitored for the entire duration of treatment up to a maximum of 1 year. Patient satisfaction was assessed at the end of the monitoring period using a standardized questionary. Results: Capecitabine group included 2 women and 8 men with a median age of 55 years (range: 36−77 years) monitored for an average duration of 100 days (range: 5-210 days). Persistence was 98% and quality of execution 95%. 5 patients underwent cyclic treatment (2 out of 3 weeks) and 5 patients continuous treatment. Toxicities higher than grade 1 were grade 2−3 hand-foot syndrome in 1 patient and grade 3 acute coronary syndrome in 1 patient both without impact on adherence. Patients were satisfied with the interviews undergone during the study (57% useful, 28% very useful, 15% useless) and successfully integrated the MEMS® in their daily lives (57% very easily, 43% easily) according to the results obtained by questionary at the end of the monitoring period. Conclusion: Persistence and quality of execution observed in our Capecitabine group of patients were excellent and better than expected compared to previously published studies. The interdisciplinary approach allowed us to better identify and help patients with toxicities to maintain adherence. Overall patients were satisfied with the global interdisciplinary follow-up. With longer follow up better evaluation of our method and its impact will be possible. Interpretation of the results of patients in the other groups of this ongoing trial will provide us information for a more detailed analysis.

PACHYCHOROID: an inherited condition?

PURPOSE: Thick choroid (pachychoroid) is associated with central serous chorioretinopathy (CSC), but whether pachychoroid is inherited is unknown. METHODS: In a prospective observational study, first- or second-degree relatives (16 individuals) of 5 patients with CSC had refraction and visual acuity measurement, fundus examination, nonmydriatic photography, and autofluorescence photography. Eyes were graded using the following criteria: 0: normal fundus and autofluorescence photography, 1: focal retinal pigment epithelium hyperfluorescence and/or hypofluorescence and/or retinal pigment epithelial detachment, 2: CSC or diffuse retinal epitheliopathy. Choroid thickness was measured by enhanced depth imaging mode on optical coherence tomography. RESULTS: Considering 395 μm as the threshold limit for normal subfoveal choroidal thickness, 50% of the eyes from relatives had a thick choroid. Nine eyes of Grade 0 (28%) with an isolated pachychoroid would thus have been considered normal, if choroidal thickness was not included as a screening sign predisposing for CSC. CONCLUSION: Our observation suggests that pachychoroid could be an inherited condition with potentially a dominant transmission mode. Its inclusion in the phenotype of CSC for genetic studies should be considered.

A prediction rule to identify low-risk patients with pulmonary embolism.

BACKGROUND: A simple prognostic model could help identify patients with pulmonary embolism who are at low risk of death and are candidates for outpatient treatment. METHODS: We randomly allocated 15,531 retrospectively identified inpatients who had a discharge diagnosis of pulmonary embolism from 186 Pennsylvania hospitals to derivation (67%) and internal validation (33%) samples. We derived our rule to predict 30-day mortality using classification tree analysis and patient data routinely available at initial examination as potential predictor variables. We used data from a European prospective study to externally validate the rule among 221 inpatients with pulmonary embolism. We determined mortality and nonfatal adverse medical outcomes across derivation and validation samples. RESULTS: Our final model consisted of 10 patient factors (age > or = 70 years; history of cancer, heart failure, chronic lung disease, chronic renal disease, and cerebrovascular disease; and clinical variables of pulse rate > or = 110 beats/min, systolic blood pressure < 100 mm Hg, altered mental status, and arterial oxygen saturation < 90%). Patients with none of these factors were defined as low risk. The 30-day mortality rates for low-risk patients were 0.6%, 1.5%, and 0% in the derivation, internal validation, and external validation samples, respectively. The rates of nonfatal adverse medical outcomes were less than 1% among low-risk patients across all study samples. CONCLUSIONS: This simple prediction rule accurately identifies patients with pulmonary embolism who are at low risk of short-term mortality and other adverse medical outcomes. Prospective validation of this rule is important before its implementation as a decision aid for outpatient treatment.

Magma generation at the easternmost section of the Hellenic arc: Hf, Nd, Pb and Sr isotope geochemistry of Nisyros and Yali volcanoes (Greece)

Geochemical and petrographical studies of lavas and ignimbrites from the Quaternary Nisyros-Yali volcanic system in the easternmost part of the Hellenic arc (Greece) reveal insight into magma generating processes. A compositional gap between 61 and 68 wt.% SiO2 is recognized that coincides with the stratigraphic distinction between pre-caldera and postcaldera volcanic units. Trace element systematics support the subdivision of Nisyros and Yali volcanic units into two distinct suites of rocks. The variation of Nd and Hf present day isotope data and the fact that they are distinct from the isotope compositions of MORB rule out an origin by pure differentiation and require assimilation of a crustal component. Lead isotope ratios of Nisyros and Yali volcanic rocks support mixing of mantle material with a lower crust equivalent. However, Sr-87/Sr-86 ratios of 0.7036-0.7048 are incompatible with a simple binary mixing scenario and give low depleted mantle extraction ages (< 0.1 Ga), in contrast with Pb model ages of 0.3 Ga and Hf and Nd model ages of ca. 0.8 Ga. The budget of fluid-mobile elements Sr and Pb is likely to be dominated by abundant hydrous fluids characterised by mantle-like Sr isotope ratios. Late stage fluids probably were enriched in CO2, needed to explain the high Th concentrations. The occurrence of hydrated minerals (e.g., amphibole) in the first post-caldera unit with the lowermost Sr-87/Sr-86 ratio of 0.7036 +/- 2 can be interpreted as the result of the increased water activity in the source. The presence of two different plagioclase phenocryst generations in the first lava subsequent to the caldera-causing event is indicative for a longer storage time of this magma at a shallower level. A model capable of explaining these observations involves three evolutionary stages. First stage, assimilation of lower crustal material by a primitive magma of mantle origin (as modelled by Nd-Hf isotope systematics). This stage ended by an interruption in replenishment that led to an increase of crystallization and, hence, an increase in viscosity, suppressing eruption. During this time gap, differentiation by fractional crystallization led to enrichment of incompatible species, especially aqueous fluids, to silica depolymerisation and to a decrease in viscosity, finally enabling eruption again in the third stage. (c) 2005 Elsevier B.V. All rights reserved.

Acute coronary syndromes or myocarditis in young people: a difficult daily diagnostic challenge

Background: Chest pain (CP) represents about 5% of admissions to emergency departments (ED), even in young people. Acute coronary syndrome (ACS) and myocarditis are among the most important diagnoses to rule out. Clinical and ECG findings are not specific for either condition and separating both diagnoses is a challenge. Aim of the study: To evaluate the prevalence of ACS and myocarditis in young patients presenting with CP and elevated cardiac biomarkers to the ED and to determinate the differences in their clinical presentation. Methods: Retrospective study of all consecutive patients < 40 years old admitted to our ED from January 2009 to June 2011 for CP with elevated serum troponin concentration. All clinical, angiographic and cardiac magnetic resonance (CMR) data from the local database was reviewed. Clinical follow-up was obtained to assess all cause mortality, myocardial infarction and re-hospitalisation for CP. Results: 1588 patients < 40 years old were admitted to the ED with chest pain. 49 (3%) patients presenting with an elevated troponin I (> 0.09ug/l) were included in the study. 32.7% (16/49) were diagnosed with ACS (11 STEMI and 5 NSTEMI) and 59.2% (29/49) with myocarditis. Among the 29 patients with myocarditis, 17 presented with typical subepicardial late enhancement on CMR and 12 were diagnosed based on clinical presentation (6 had no complementary workup, 3 normal coronary angiogram and 3 inconclusive CMR). 8.1% (4/49) of patients had other diagnoses. Compared to patients with myocarditis, ACS patients were older (34.1±3.9 vs 26.9±6.4, p=0.0002) with significantly more cardiovascular risk factors (mean 2.06 vs 0.69, p<0.0001). Diabetes (18.8% vs 0%, p=0.004), dyslipidemia (56.3% vs 3.4%, p=0.0001) and family history of coronary artery disease (CAD) (37.5% vs 10.3%, p=0.050) were significantly associated with ACS. No significant association was found for smoking, hypertension and obesity. Fever (>38°C) or recent viral illness were present in 75.9% (22/29) of patients with myocarditis, and in 0% of ACS patients. During follow-up (mean 19.9 months ± 8.6), only 2 patients with myocarditis were re-admitted for chest pain. Conclusions: In this study, 32.7% of patients < 40 year old admitted to an ED with CP and elevated troponin had an ACS. Key clinical factors include diabetes, dyslipidemia, family history of CAD, fever or recent viral illness, and may help to differentiate ACS from myocarditis.

Concerted action of ENaC, Nedd4-2, and Sgk1 in transepithelial Na(+) transport.

The epithelial Na(+) channel (ENaC), located in the apical membrane of renal aldosterone-responsive epithelia, plays an essential role in controlling the Na(+) balance of extracellular fluids and hence blood pressure. As of now, ENaC is the only Na(+) transport protein for which genetic evidence exists for its involvement in the genesis of both hypertension (Liddle's syndrome) and hypotension (pseudohypoaldosteronism type 1). The regulation of ENaC involves a variety of hormonal signals (aldosterone, vasopressin, insulin), but the molecular mechanisms behind this regulation are mostly unknown. Two regulatory proteins have gained interest in recent years: the ubiquitin-protein ligase neural precursor cell-expressed, developmentally downregulated gene 4 isoform Nedd4-2, which negatively controls ENaC cell surface expression, and serum glucocorticoid-inducible kinase 1 (Sgk1), which is an aldosterone- and insulin-dependent, positive regulator of ENaC density at the plasma membrane. Here, we summarize present ideas about Sgk1 and Nedd4-2 and the lines of experimental evidence, suggesting that they act sequentially in the regulatory pathways governed by aldosterone and insulin and regulate ENaC number at the plasma membrane.

From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions.

Peroxisome proliferator-activated receptors (PPARs) compose a family of three nuclear receptors which act as lipid sensors to modulate gene expression. As such, PPARs are implicated in major metabolic and inflammatory regulations with far-reaching medical consequences, as well as in important processes controlling cellular fate. Throughout this review, we focus on the cellular functions of these receptors. The molecular mechanisms through which PPARs regulate transcription are thoroughly addressed with particular emphasis on the latest results on corepressor and coactivator action. Their implication in cellular metabolism and in the control of the balance between cell proliferation, differentiation and survival is then reviewed. Finally, we discuss how the integration of various intra-cellular signaling pathways allows PPARs to participate to whole-body homeostasis by mediating regulatory crosstalks between organs.

The alpha 1a and alpha 1b-adrenergic receptor subtypes: molecular mechanisms of receptor activation and of drug action.

In this chapter we summarize some aspects of the structure-functional relationship of the alpha 1a and alpha 1b-adrenergic receptor subtypes related to the receptor activation process as well as the effect of different alpha-blockers on the constitutive activity of the receptor. Molecular modeling of the alpha 1a and alpha 1b-adrenergic receptor subtypes and computational simulation of receptor dynamics were useful to interpret the experimental findings derived from site directed mutagenesis studies.

Condition-dependent genetic benefits of extrapair fertilization in female blue tits Cyanistes caeruleus.

In many socially monogamous birds, both partners perform extrapair copulations (EPC). As this behaviour potentially inflicts direct costs on females, they are currently hypothesized to search for genetic benefits for descendants, either as 'good' or 'complementary' genes. Although these hypotheses have found some support, several studies failed to find any beneficial consequence of EPC, and whether this behaviour is adaptive to females is subject to discussion. Here, we test these two hypotheses in a natural population of blue tits by accounting for the effect of most parameters known to potentially affect extrapair fertilization. Results suggest that female body mass affected the type of extrapair genetic benefits obtained. Heavy females obtained extrapair fertilizations when their social male was of low quality (as reflected by sexual display) and produced larger extrapair than within-pair chicks. Lean females obtained extrapair fertilizations when their social mate was genetically similar, thereby producing more heterozygous extrapair chicks. Our results suggest that mating patterns may be condition-dependent.