Citations

Abstract Context: The process of epiphyseal fusion during puberty is regulated by estrogen, even in males. Objective: Our objective was to investigate whether anastrozole, a potent aromatase inhibitor, could delay bone age acceleration and increase predicted adult height in adolescent boys with GH deficiency. Methods: Fifty-two adolescent males with GH deficiency treated with GH were randomized to cotreatment with anastrozole or placebo daily for up to 36 months. Results: Fifty subjects completed 12 months, 41 completed 24 months, and 28 completed 36 months. Linear growth was comparable between groups; however, there was a significantly slower increase in bone age advancement from baseline in the anastrozole group vs. placebo group after 2 yr (+1.8 ± 0.1 vs. +2.7 ± 0.1 yr, P < 0.0001) and after 3 yr (+2.5 ± 0.2 vs. +4.1 ± 0.1 yr, P < 0.0001). This resulted in a net increase in predicted adult height of +4.5 ± 1.2 cm in the anastrozole group at 24 months and +6.7 ± 1.4 cm at 36 months as compared with a 1-cm gain at both time points in the placebo group. Estradiol and estrone concentrations increased less in the anastrozole group compared with placebo group. All boys on the aromatase inhibitor had normal tempo of virilization. Safety data, including glucose, and plasma lipid concentrations were comparable between groups. Conclusions: Anastrozole increases adult height potential of adolescent boys on GH therapy while maintaining normal pubertal progression after 2–3 yr. This treatment offers an alternative in promoting growth in GH-deficient boys in puberty. Long-term follow up is needed to elucidate fully the safety and efficacy of this approach.

Patients with hypertension exhibit impaired energetic coupling between the ventricle and the arterial system, leading to reduced cardiac mechanic efficiency and exercise capacity. We tested whether blood pressure normalization with current antihypertensive therapy can improve arterioventricular coupling. Eighteen hypertensive patients without other cardiovascular disease were examined before and after antihypertensive therapy. Transthoracic echocardiography was performed. Central aortic pressure waveforms, including end-systolic pressure, were derived from radial artery applanation tonometry. Afterload was increased with isometric handgrip exercise. Central aortic end-systolic pressure and ventricular volumes at rest and handgrip were used to calculate ventricular elastance, effective arterial elastance, arterioventricular coupling (effective arterial elastance/ventricular elastance), and mechanical efficiency. After 142±67 days, systolic blood pressure decreased from 150.9±14.6 to 119.8±9.2 mm Hg ( P <0.00001), diastolic blood pressure from 85.9±14.8 to 68.8±8.4 mm Hg ( P =0.00002), and cardiac output from 5.8±1.7 to 4.9±1.8 L/min ( P =0.03). Resting left ventricular end-systolic volume, ejection fraction, and septal thickness did not change. Ventricular elastance increased from 1.7±1.0 to 3.2±1.4 mm Hg/mL ( P =0.00002), whereas effective arterial elastance decreased from 1.4±0.5 to 1.2±0.4 mm Hg/mL ( P =0.02). Effective arterial elastance/ventricular elastance decreased in all patients, from 1.1±0.8 to 0.4±0.2 ( P =0.0002). Efficiency improved at rest (72.9±5.8% versus 83.5±5.7%; P <0.00001) and during handgrip (63.5±7.8% versus 78.9±7.1%; P <0.00001). In hypertensive patients, optimal brachial and central blood pressure reduction shifts arterioventricular coupling from cardiac output maximization to ventricular mechanical efficiency optimization. This occurs before significant changes in ventricular geometry and may be responsible for early clinical improvements.

Abstract MMSET, identified by its fusion to the IgH locus in t(4;14)-associated multiple myeloma, possesses domains found within chromatin regulators, including the SET domain. MMSET protein is overexpressed and highly associated with chromatin in myeloma cell lines carrying t(4;14). MMSET possesses methyltransferase activity for core histone H3 lysine 4 and histone 4 lysine 20, whereas MMSET made in cells only modified H4. Segments of MMSET fused to the Gal4 DNA binding domain repressed transcription of a chromatin-embedded Gal4 reporter gene. MMSET-mediated repression was associated with increased H4K20 methylation gene and loss of histone acetylation. Consistent with this repressive activity, MMSET could form a complex with HDAC1 and HDAC2, mSin3a, and the histone demethylase LSD1, suggesting that it is a component of corepressor complexes. Furthermore, MMSET coexpression enhances HDAC1- and HDAC2-mediated repression in transcriptional reporter assays. Finally, shRNA-mediated knockdown of MMSET compromised viability of a myeloma cell line, suggesting a biologic role for the protein in malignant cell growth. Collectively, these data suggest that, by acting directly as a modifier of chromatin as well as through binding of other chromatin-modifying enzymes, MMSET influences gene expression and potentially acts as a pathogenic agent in multiple myeloma.

Objective— The clinical use of venous stents is increasing dramatically. Although antiplatelet agents are required for arterial stent patency, optimal thrombo-prophylaxis after venous stenting remains undefined. To address this issue, PD0348292, a direct Factor Xa inhibitor, was compared with antiplatelet therapy in a porcine venous stent model. Methods and Results— Four hours before stent deployment, pigs (n=5 to 6 per group) received oral PD0348292 at 0.4, 0.9, 4.3 mg/kg, or 0.4 mg/kg plus aspirin (325 mg). Aspirin, clopidogrel (75 mg), aspirin plus clopidogrel, or vehicle (n=10) were administered daily for 2 days before the procedure. Two hours after stent placement, thrombi were quantified by autologous 111 In-platelet content and weights. Thrombus weight and platelet deposition were significantly reduced by PD0348292 at 0.4 (49±79 mg and 110±145×10 6 /cm 2 ), 0.9 (5±6 mg and 107±128×10 6 /cm 2 ), 4.3 mg/kg (0±0 mg and 87±125×10 6 /cm 2 ), and PD348292 plus aspirin (20±40 mg and 157±70×10 6 /cm 2 ) compared with vehicle (402±226 mg; 584±454×10 6 /cm 2 ). Despite prolonging bleeding times and inhibiting platelet aggregation, neither aspirin (567±683 mg and 533±622×10 6 /cm 2 ), clopidogrel (404±349 mg and 178±101×10 6 /cm 2 ), nor aspirin plus clopidogrel (247±261 mg and 231±266×10 6 /cm 2 ) significantly decreased stent thrombosis. Conclusions— PD0348292 completely inhibited thrombosis after venous stenting. Platelet accretion in these venous thrombi appear to involve pathways distinct from arachidonate metabolism or ADP P 2 Y 12 receptor activation.

In the 1970s, the suicide rate of patients with end-stage renal disease (ESRD) was calculated by conflating deaths from obvious clinical suicide attempts with deaths caused by lethal noncompliance and deaths preceded by dialysis discontinuation. Three decades later, although society's view about cessation of life-support treatment has markedly changed, relatively little is known about the psychiatric aspects of dialysis discontinuation. This paper reviews the literature and suggests a number of findings that warrant further research investigation.