Quality of life,satisfaction with life,and functional mobility of young adults with arthrogryposis after leaving pediatric care

The aim of this study was to describe satisfaction and quality of life (QOL) of young adults with arthrogryposis after leaving pediatric care. Twenty‐three adults with arthrogryposis multiplex congenital (AMC) followed at a single pediatric orthopedic hospital (average age 23.6 years; range 18–36 years; 9 males, 14 females) completed questionnaires related to demographics, mobility, and activities of daily living. The Patient Reported Outcomes Measure Information System and Satisfaction with Life Scale were utilized to evaluate QOL and life satisfaction. Eighty‐three percent reported general health as good/excellent, 30% lived independently, 69% were ambulatory in the community, and 57% were employed. QOL scores for physical function were lower, but other QOL scores were consistent with the general U.S. population. Average pain intensity was mild at 2.6 out of 10, with pain frequently reported in the legs and feet. Fifty‐six percent were satisfied to extremely satisfied with life. Five individuals who were dissatisfied with life also reported lower physical function, higher anxiety, depression and fatigue, and pain in multiple joints. Although most young adults with AMC presented with mild pain and limitations in physical function; overall, they reported good QOL. Findings from the current study will help clinicians anticipate the needs of individuals with AMC as they transition from pediatric to adult care.     

Evaluation of glucose metabolism and reproductive hormones in polycystic ovary syndrome on the basis of peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala genotype

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala polymorphism has been suggested as a protective factor for polycystic ovary syndrome (PCOS). In this study, we aimed to investigate metabolic features and reproductive hormones in women with PCOS and compare these features with control women on the basis of Pro12Ala genotype. METHODS: This study involved 60 randomly selected women with PCOS and 60 controls. Main outcome measures were anthropometric measures, variables of glucose metabolism and reproductive hormones. All the patients were genotyped for Pro12Ala variant of PPAR-gamma2 gene. RESULTS: Patients with Pro12Ala polymorphism were more obese in both groups. Furthermore, they had lower fasting insulin levels, were less insulin-resistant and were less glucose-intolerant as demonstrated by 2 h glucose concentrations. However, there was no difference in reproductive hormone levels on the basis of Pro12Ala genotype. CONCLUSIONS: Both control women and women with PCOS had significant differences in glucose metabolism on the basis of PPAR-gamma2 Pro12Ala polymorphism. Pro12Ala variant may break the process that leads to PCOS in susceptible women, instead of being a direct causal relationship between Pro12Ala polymorphism and PCOS.     

Estradiol induces JNK-dependent apoptosis in glioblastoma cells

Estrogens exert multiple regulatory actions on cellular events in a variety of tissues including the brain. In the present study, the signaling mechanisms of the concentration-dependent effects of 17-β-estradiol (estradiol) on glioblastoma cells were investigated. Cell viability was evaluated by the trypan blue exclusion assay. Cell growth and kinase activities were evaluated by immunocytochemistry and Western blotting. The results showed that high concentrations of estradiol inhibit growth and induce apoptosis in C6 rat glioma and T98G human glioblastoma cells. The blockade of the c-jun NH(2)-terminal kinase (JNK) signaling pathway prevented these effects of estradiol, indicating the critical role of the JNK/c-jun signaling cascade in glioblastoma cell growth inhibition and cell death in response to high concentrations of estradiol. Collectively, these findings highlight the potential of new discoveries in sensitizing estrogen-sensitive tumors to chemotherapeutic drugs, and may lead to the development of new JNK-based effective therapies.     

Phase 2 randomized study of enzastaurin (LY317615) for lung cancer prevention in former smokers

BACKGROUND:

Chemoprevention for lung cancer with nutraceutical or anti‐inflammatory agents has had mixed clinical benefit. Novel targeted agents hold the promise of greater efficacy and selectivity. The authors of this report evaluated enzastaurin, a selective protein kinase C‐β (PKC‐β) inhibitor with antiproliferative and proapoptotic properties, in former smokers.

METHODS:

The primary objective of this study was to compare the average fraction of Ki‐67–stained cells (the Ki‐67 labeling index [LI]) in bronchial biopsy specimens that were collected before and after treatment. Participants were randomized (2:1) to receive either 6 months of daily oral enzastaurin (500 mg) or placebo. Stratification was based on morphology, history of lung cancer, and airway obstruction.

RESULTS:

In pretrial investigations, the rationale for PKC‐β inhibition and pathway interrogation was established in premalignant lesions and early stage lung cancer. In an intent‐to‐treat analysis, of 40 randomized participants, there was no significant difference in the pretreatment/post‐treatment change in the Ki‐67 LI between the enzastaurin group and the placebo group (P = .53). Six participants discontinued enzastaurin, including 4 participants who had adverse events, including abdominal distension, deep vein thrombosis, hyponatremia, and rash, and 2 participants who decided to discontinue. One participant in the placebo group was discontinued on the study because of noncompliance. Two participants had ≥1 serious adverse event (bradycardia, deep vein thrombosis, and hypotension).

CONCLUSIONS:

To the authors' knowledge, this represents the first chemoprevention trial with a non‐US Food and Drug Administration‐approved, oral, small‐molecule–targeted agent. Although the primary endpoint was not met, enzastaurin was tolerable for 6 months by 75% of participants, and there was a suggestion of response in a subset analysis that was restricted to those who had metaplastic or dysplastic lesions. Cancer 2013. © 2012 American Cancer Society.     

Impact of transcutaneous aortic valve implantation on myocardial deformation

Aims: To define the impact of transcutaneous aortic valve implantation (TAVI) using the CoreValve prosthesis on myocardial deformation in a serial echocardiographic study with analysis of strain and strain rate. Methods: In 36 patients (83 ± 6 years; EuroScore: 26 ± 13%) with severe aortic stenosis scheduled for CoreValve implantation serial echocardiographic studies pre‐ and postintervention (within 1 month) were performed. Midparasternal short‐axis and three apical views were acquired. Using customized computer software which allows automatic frame‐by‐frame tracking of acoustic markers during the heart cycle circumferential, radial, and longitudinal strain (CS, RS, and LS) and strain rate (CSR, RSR, and LSR) were calculated for each segment in a 16 segment model of the left ventricle. Results: Longitudinal strain, systolic, and early diastolic longitudinal strain rate increased significantly within 1 month after TAVI (LS from –15.8 ± 3.6% to –17.6 ± 3.1%; P < 0.001; LSR(S) from –1.03 ± 0.21 s^?1 to –1.21 ± 0.19 s^?1; P < 0.001 and LSR (E) from –1.15 ± 0.42 s^?1 to 1.51 ± 0.44 s^?1; P < 0.001). Circumferential strain and strain rate values remained unchanged after CoreValve implantation. RS (29.1 ± 17.1 to 34.0 ± 15.8%; ns), RSR (S) (1.56 ± 0.69 to 1.91 ± 0.87 s^?1; ns) and RSR(E) (–1.56 ± 0.78 to –1.81 ± 0.82 s^?1; ns) increased only nonsignificantly after TAVI. Analysis of covariance showed only chronic kidney disease to have a relevant impact on early diastolic LSR (P = 0.01). Conclusions: Mainly longitudinal mechanics respond to unloading of the left ventricle after TAVI for severe aortic stenosis while radial and circumferential deformation is substantially unchanged. Pacemaker implantation or onset of left bundle brunch block after TAVI do not influence early myocardial deformation parameters. (Echocardiography 2011;28:397‐401)     

Glibenclamide attenuates the antiarrhythmic effect of endotoxin with a mechanism not involving K(ATP) channels

The role of K(ATP) channels in the antiarrhythmic effect of Escherichia coli endotoxin-induced nitric oxide synthase (iNOS) was examined in an anesthetised rat model of myocardial ischemia and reperfusion arrhythmia by using glibenclamide (1 mg kg(-1)), nateglinide (10 mg kg(-1)) and repaglinide (0.5 mg kg(-1)). Endotoxin (1 mg kg(-1)) was administered intraperitoneally 4 h before the occlusion of the left coronary artery and glibenclamide, nateglinide or repaglinide was administered 30 min before coronary artery occlusion. We also evaluated the effects of K(ATP) channel blockers and nonselective K(+) channel blocker tetraethylammonium (TEA) on cardiac action potential configuration in the atria obtained from endotoxemic rats. The mean arterial blood pressure of rats receiving endotoxin was lower during both the occlusion and reperfusion periods. Endotoxin significantly reduced the total number of ectopic beats and the duration of ventricular tachycardia. Glibenclamide, but not nateglinide and repaglinide, prevented the hypotension and antiarrhythmic effects of endotoxin. Atria obtained from endotoxin-treated rats had prolonged action potential duration. This effect was abolished with pretreatment of iNOS inhibitors, l-canavanine and dexamethasone and perfusion of glibenclamide, but not with TEA and non-sulfonylurea drug, nateglinide. We demonstrated that glibenclamide inhibits the antiarrhythmic effect of endotoxin and this effect does not appear to involve K(ATP) channels.     

JNK pathway regulates estradiol-induced apoptosis in hormone-dependent human breast cancer cells

Estrogen is known to stimulate breast cancer development in humans. Ironically, high doses of estrogen can induce regression of hormone-dependent breast cancer in postmenopausal women. The mechanism by which estrogen induces tumour regression in breast cancer is still unknown. We found that under low growth-stimulated conditions, high concentrations of 17-β-estradiol (estradiol) induces apoptosis and concomitantly increases phosphorylation of c-jun in estrogen receptor (ER)-positive breast cancer cell line, MCF-7, but not in ER-negative breast cancer cell line MDA-MB 231 suggesting an ER-mediated event. Interestingly, when the c-jun NH₂-terminal kinase (JNK) signalling pathway was disrupted by the JNK inhibitor SP600125, the ability of estradiol to inhibit the growth of MCF-7 cells and to induce apoptosis was completely blocked. These data suggest that JNK plays a central role in mediating the anticancer effect of high concentrations of estradiol in MCF-7 cells. Our data showing the apoptotic effect of estradiol in low growth-stimulated conditions suggest potential implications for the pharmacological control of breast cancer with high dose estrogen in postmenopausal women. Furthermore, our results indicate that augmenting JNK activity could be an efficient novel approach for treating breast cancer.