Beta-blocker/ACE inhibitor therapy differentially impacts the steady state signaling landscape of failing and non-failing hearts.

Heart failure is a multifactorial disease that affects an estimated 38 million people worldwide. Current pharmacotherapy of heart failure with reduced ejection fraction (HFrEF) includes combination therapy with angiotensin-converting enzyme inhibitors (ACEi) and ß-adrenergic receptor blockers (ß-AR blockers), a therapy also used as treatment for non-cardiac conditions. Our knowledge of the molecular changes accompanying treatment with ACEi and ß-AR blockers is limited. Here, we applied proteomics and phosphoproteomics approaches to profile the global changes in protein abundance and phosphorylation state in cardiac left ventricles consequent to combination therapy of ß-AR blocker and ACE inhibitor in HFrEF and control hearts. The phosphorylation changes induced by treatment were profoundly different for failing than for non-failing hearts. HFrEF was characterized by profound downregulation of mitochondrial proteins coupled with derangement of ß-adrenergic and pyruvate dehydrogenase signaling. Upon treatment, phosphorylation changes consequent to HFrEF were reversed. In control hearts, treatment mainly led to downregulation of canonical PKA signaling. The observation of divergent signaling outcomes depending on disease state underscores the importance of evaluating drug effects within the context of the specific conditions present in the recipient heart.

Influence of organised sports practice during adolescence on health of adult women with special emphasis on participation in aesthetic sports.

This study aimed to assess the differences in psychosocial health and cardiometabolic risk during adulthood in women based on previously organised sport (OS) participation during adolescence and current activity levels, with emphasis on participation in aesthetic sports. The study included 1947 women aged 18-55 years who were categorised into four groups: 355 aesthetic athletes during adolescence, 494 non- aesthetic athletes during adolescence, 791 non-athletes during adolescence with similar current levels of physical activity (PA) to OS groups and 307 currently inactive non-athletes during adolescence. Participants answered questionnaires regarding sport participation, psychosocial health and cardiometabolic risk. The results show that non-athletes during adolescence who are currently inactive reported significantly lower psychosocial health and higher cardiometabolic risk scores. Women with currently homogenous PA levels (χ² = 0.514) reported similar physical quality of life (QoL), exercise addiction, anxiety and depression symptoms regardless of participation in OS during adolescence (P > .05), except aesthetic athletes who reported the worst sleep and mental QoL. Very high training volumes in aesthetic athletes did not influence psychological outcomes and cardiometabolic risk in adulthood compared to lower training volumes. In conclusion, the effects of PA during adulthood appear to be powerful enough to induce beneficial adaptations in health outcomes that match those observed in women who participate in OS during adolescence, except for aesthetic sports participants, who show a high risk of lower quality of sleep in adulthood. PA should be promoted in adults and especially women who have not participated in OS during adolescence.

Bivalent Histone Codes on WNT5A during Odontogenic Differentiation.

Lineage-committed differentiation is an essential biological program during odontogenesis, which is tightly regulated by lineage-specific genes. Some of these genes are modified by colocalization of H3K4me3 and H3K27me3 marks at promoter regions in progenitors. These modifications, named "bivalent domains," maintain genes in a poised state and then resolve for later activation or repression during differentiation. Wnt5a has been reported to promote odontogenic differentiation in dental mesenchyme. However, relatively little is known about the epigenetic modulations on Wnt5a activation during tooth development. Here, we investigated the spatiotemporal patterns of H3K4me3 and H3K27me3 marks in developing mouse molars. Associated H3K4me3 methylases (mixed-lineage leukemia [MLL] complex) and H3K27me3 demethylases (JMJD3 and UTX) were dynamically expressed between early and late bell stage of human tooth germs and in cultured human dental papilla cells (hDPCs) during odontogenic induction. Poised WNT5A gene was marked by bivalent domains containing repressive marks (H3K27me3) and active marks (H3K4me3) on promoters. The bivalent domains tended to resolve during inducted differentiation, with removal of the H3K27me3 mark in a JMJD3-dependent manner. When JMJD3 was knocked down in cultured hDPCs, odontogenic differentiation was suppressed. The depletion of JMJD3 epigenetically repressed WNT5A activation by increased H3K27me3 marks. In addition, JMJD3 could physically interact with ASH2L, a component of the MLL complex, to form a coactivator complex, cooperatively modulating H3K4me3 marks on WNT5A promoters. Overall, our study reveals that transcription activities of WNT5A were epigenetically regulated by the negotiated balance between H3K27me3 and H3K4me3 marks and tightly mediated by JMJD3 and MLL coactivator complex, ultimately modulating odontogenic commitment during dental mesenchymal cell differentiation.

[Precision treatment after resistance to first-generation EGFR-TKI in patients with non-small cell lung cancer].

Recently, with the research progress in molecular classification, the treatment of advanced non-small cell lung cancer (NSCLC) has been established as a model of anti-tumor treatment of precision medicine. The discovery of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) has transformed the treatment of NSCLC from platinum based doublet chemotherapy into era of target therapy. EGFR-TKI, such as erlotinib and gefitinib, have been recommended as standard first-line treatment of patients with EGFR mutation. However, acquired resistance, defined as tumor progression after initial response, seems to be an inevitable consequence of this treatment approach. Clinical modes of EGFR-TKI failure are classified into three types: dramatic progression, gradual progression and local progression. A threonine-to-methionine substitution (T790M) in exon 20 of the EGFR gene is the most common mechanism of resistance. Other mechanisms of resistance include MET amplification, epithelial to mesenchymal transition, small cell transformation, and PIK3CA mutation. This brief comment will provide an overview of the complex and heterogeneous problem of acquired resistance to EGFR-TKI therapy in NSCLC, and the clinical treatment options and new targeted drugs overcoming EGFR-TKI acquired resistance.

Distribution of plantar pressures during gait in different zones of the foot in healthy children: the effects of laterality.

The objective was to determine whether gait is symmetric in healthy children 6-7 years of age and to assess the effects of laterality and the anatomical zone of the foot. 46 children were subjected to gait symmetry analysis in which the plantar and lateral pressures associated with kicking a ball, static balance, and dynamic support were measured. There were no significant differences in the average pressure exerted by the right and left feet based on the laterality of the child. Independent of each laterality test, a greater pressure on the right rearfoot was observed compared to the left rearfoot and on the left midfoot and forefoot compared to the right.

Measurement of mothers' confidence to care for children assisted with tracheostomy technology in family homes.

The purpose of this research was to develop an objective, linear measure of mothers' confidence to care for children assisted with tracheostomy medical technology in their homes. Caregiver confidence is addressed in this research for three technologies, namely, a) trachesotomy, b) tracheostomy and ventilator, and c) BiPAP/CPAP although detailed measurement results are only reported for tracheostomy, and its co-calibration with tracheostomy and ventilator caregiving items. The sample consisted of 53 mothers responding to several caregiver questionnaires based on a caregiving task matrix after content and clinical validation. A major challenge was integrating this construct with overarching principles already established by Functional Caregiving, a multi-level humanistic caregiving model for children with intellectual disabilities. Empirical analyses included principal components analysis, and then linear transformation of Tracheostomy item ratings to an objective, equal-interval scale with a Rasch model. Results show caregiver separation on the Tracheostomy caregiving scale was 2.66 and reliability, .88. In general, co-calibration improved measurement properties without affecting mothers' caregiving confidence measures. Although sample size was small, measuring mothers' confidence to care for a child supported by complex medical technologies appears very promising.

Investigation of bipolar resistive switching and the time-dependent SET process in silver sulfide/silver thin films and nanowire array structures.

We report on the bipolar resistive switching (RS) behaviour observed from silver sulfide/silver (Ag2S/Ag) nanowire array and thin film structures fabricated under similar conditions. By examining the RS parameters measured using electrical probing with a similar tungsten probe on both types of structures, we conclude that the larger SET voltage and lower ON-state conductance in the thin film structures are the result of the longer conductive filamentary paths formed during the SET process. In addition, we found that the metal filament can be established at a constant voltage bias which is much lower than the measured SET voltage for a sweeping voltage bias, as long as the constant bias/stress voltage is applied for a sufficiently long duration. This time dependency in the SET process is possibly related to the migration and reduction of silver ions to form silver atoms at the filamentary formation site. Experimental results also show that an applied voltage bias, either with increasing magnitude or duration, will increase the ON-state conductance. This is explained by the increased cross-sectional area of the conductive filamentary path. From the comparative investigation of the RS parameter values obtained from the two different structures, it is concluded that nanostructuring of the Ag2S/Ag heterostructure from a two-dimensional thin film to a one-dimensional nanowire structure results in an improvement in the SET process parameters.

Prognostic factors affecting the outcome of early cervical cancer treated with radical hysterectomy and post-operative adjuvant therapy.

The purpose of this study is to investigate the clinical and histological features that may affect the survival of the patients and to evaluate the impact of post-operative adjuvant therapy on the outcomes of patients with stage IB and IIA carcinoma of the cervix. From August 1998 to January 2005, 140 patients with International Federation of Gynecology and Obstetrics stage IB and IIA cervical cancer were treated with radical hysterectomy and post-operative pelvic radiation therapy with or without chemotherapy. The median age was 55 years (range, 29-86 years). Seventy-six patients had stage IB and 64 patients had stage IIA disease. Tumour size was <4 cm in 96 patients and > or = 4 cm in 44 patients. One hundred and eleven patients had histology of squamous cell carcinoma, 12 patients has adenocarcinoma and 17 patients had other histologic types. Depth of stromal invasion was <2/3 in 20 patients and > or = 2/3 in 120 patients. Twenty-three patients had parametrial invasion and 117 patients had no parametrial invasion. Thirteen patients had lymphovascular space invasion and 127 had no lymphovascular space invasion. Nine patients had positive surgical margin and 131 patients had negative margin. Twenty-seven patients had pelvic lymph node metastasis and 113 patients had no pelvic lymph node metastasis. Seventy-five patients received concurrent chemoradiotherapy and 65 patients received radiotherapy alone. The 5-year overall survival (OAS) and disease-free survival were 83% and 72% respectively. In the log rank test, tumour size (P = 0.0235), pararmetrial invasion (P = 0.0121), pelvic lymph node metastasis (P < 0.0001) and adjuvant chemotherapy + radiotherapy (P = 0.0119) were significant prognostic factors for OAS, favouring tumour size <4 cm, absence of parametrial invasion and pelvic lymph node metastasis, and those who received adjuvant chemoradiotherapy. The patients who received radiation with concomitant chemotherapy had a 5-year OAS rate of 90% versus those who received radiotherapy alone, with a rate of 76%. For patients with high-risk early stage cervical cancer who underwent a radical hysterectomy and pelvic lymphadenectomy, adjuvant chemoradiotherapy resulted in better survival than radiotherapy alone. The addition of weekly cisplatin to radiotherapy is recommended. The treatment-related morbidity is tolerable.

Lovastatin sensitized human glioblastoma cells to TRAIL-induced apoptosis.

Synergy study with chemotherapeutic agents is a common in vitro strategy in the search for effective cancer therapy. For non-chemotherapeutic agents, efficacious synergistic effects are uncommon. Here, we have examined two non-chemotherapeutic agents for synergistic effects: lovastatin and Tumor Necrosis Factor (TNF)-related apoptosis-inducing ligand (TRAIL) for synergistic effects; on three human malignant glioblastoma cell lines, M059K, M59J, and A172. Cells treated with lovastatin plus TRAIL for 48 h showed 50% apoptotic cell death, whereas TRAIL alone (1,000 ng/ml) did not, suggesting that lovastatin sensitized the glioblastoma cells to TRAIL attack. Cell cycle analysis indicated that lovastatin increased G0-G1 arrest in these cells. Annexin V study demonstrated that apoptosis was the predominant mode of cell death. We conclude that the combination of lovastatin and TRAIL enhances apoptosis synergistically. Moreover, lovastatin sensitized glioblastoma cells to TRAIL, suggesting a new strategy to treat glioblastoma.

Primary plasmacytoma of the uterine cervix treated with three-dimensional conformal radiotherapy.

Primary plasmacytoma of the uterine cervix is a rare neoplasm with limited known data, and only several cases sporadically reported in the published literature. Radiotherapy might have a role in the treatment of plasmacytoma of the uterine cervix. We describe primary plasmacytoma of the uterine cervix in a 45-year-old woman treated with three-dimensional conformal radiotherapy, and also reviewed the literature to evaluate the treatment modality and therapeutic outcome of this rare disease.

Nonequivalent survey consolidation: an example from functional caregiving.

Functional Caregiving (FC) is a construct about mothers caring for children (both old and young) with intellectual disabilities, which is operationally defined by two nonequivalent survey forms, urban and suburban, respectively. The purposes of this research are, first, to generalize school-based achievement test principles to survey methods by equating two nonequivalent survey forms. A second purpose is to expand FC foundations by a) establishing linear measurement properties for new caregiving items, b) replicate a hierarchical item structure across an urban, school-based population, c) consolidate survey forms to establish a calibrated item bank, and d) collect more external construct validity data. Results supported invariant item parameters of a fixed item form (96 items) for two urban samples (N = 186). FC measures also showed expected construct relationships with age, mental depression, and health status. However, only five common items between urban and suburban forms were statistically stable because suburban mothers' age and child's age appear to interact with medical information and social activities.

Rasch analysis of a new construct: functional caregiving for adult children with intellectual disabilities.

This research examined empirical evidence for a new construct, Functional Caregiving, which is a theory about mothers' caregiving of their adult children with intellectual disabilities. A sample of 108 biological mothers and primary caregivers rated survey items about their confidence to perform caregiving tasks. Rasch rating scale analysis found 61 items defined an empirical construct with three caregiving levels: Advocacy, Personal Caregiving, and Community. Results show item separation was 3.11 with high reliability, .91, and mother separation was 2.93 and reliability, .90. Both items and mothers showed adequate INFIT and OUTFIT values. Item invariance was confirmed between older and younger mothers, and principle components analysis of item residuals did not reveal any major dimensionality threats. Item decomposition analysis showed FC content theory to account for 58 percent of item calibration variance (R2 = .58, F = 42.3, p < .001). These results have important practical implications for health and social services, as well as family caregiving, interdisciplinary practices, and health policy development.

Development of an instrument measuring family care.

This study developed and evaluated an instrument to measure the quality of care given by family members to a patient in the home. The Family Care Measure consisted of 11 items, each of which was rated on a visual analogue scale. Fifteen registered nurses rated the care given by families of 72 eligible patients for whom the nurses had provided nursing care. Estimation of the reliability resulted in a high internal consistency. With deletion of five items from the measure, the internal consistency reliability resulted in a Cronbach's alpha coefficient of .93. The six-item instrument correlated moderately, as predicted, with a scale of family coping (r = .76). With acceptable reliability and evidence of construct validity, this measure may be used in research studies, but further testing to assess its usefulness in clinical situations is recommended.

[Impregnation and liberation of nicotine with hydrogen copolymer discs]. / Imprégnation et libération de nicotine à partir de disques de copolymère hydrogel réticulé.

Reticulated copolymers with products N-vinyl-2 pyrrolidone (NVP), hydroxy-2 ethyl (HEMA) and methyl methacrylate (MMA) were realized in disc form. Nicotine was used as active principle. On these discs the following study was carried out: permeation, percentage of liquid absorbed, texture, as well as nicotine release kinetics. A 2-variable (NVP and HEMA/MMA), 5-level experimental plan has enabled the outlining of the significant differences on the action of these parameters. The release kinetics show particularly that these discs behave as forms of prolonged released and that the released quantities are sufficient to envisage the use of these reticulated copolymers within the framework of a transdermal system.