Neuropeptide Y (NPY)

Neuropeptides such as neuropeptide Y (NPY) have long been proposed to play a role in the pathogenesis of inflammatory diseases. NPY is a 36 amino acid neuropeptide which participates in the regulation of a large number of physiological and pathophysiological processes in the cardiorespiratory system, immune system, nervous system and endocrine system. Serum levels of NPY are increased during exacerbations of asthma, whereas the number of NPY-immunoreactive nerves in the airways remains constant in the airways of patients with inflammatory airway diseases such asthma or rhinitis. Next to a role in the regulation of glandular activity, NPY exerts a major influence on humoral and cellular immune functions. In this respect, NPY is known to modulate potent immunological effects such as immune cell distribution, T helper cell differentiation, mediator release, or natural killer cell activation. In addition to these direct effects, NPY also acts as an immunomodulator by influencing the effects of a variety of other neurotransmitters. Whereas the peptide has been focused for therapeutic options in the central nervous system, a potential use in the treatment of pulmonary inflammatory disorders has not been revealed so far due to the complex pulmonary effects of NPY. However, since selective antagonists and agonists and gene-depleted animals for the different receptors are now available, NPY may be of value for future strategies in airway nerve modulation.     

Cholesterol levels and cholesterol lowering in idiopathic dilated cardiomyopathy.

We read with great interest the recent article of Dr Christet al.¹ about the prognostic significance of serum cholesterollevels in     

Athlete's heart: right and left ventricular mass and function in male endurance athletes and untrained individuals determined by magnetic resonance imaging

OBJECTIVES: Athlete's heart represents a structural and functional adaptation to regular endurance exercise. BACKGROUND: While left ventricular (LV) hypertrophy of the athlete's heart has been examined in many studies, the extent of right ventricular (RV) hypertrophy is still uncertain because of its complex shape and trabecular structure. To examine RV hypertrophy, we used magnetic resonance imaging (MRI) and hypothesized that athlete's heart is characterized by similar LV and RV hypertrophy. METHODS: The LV and RV mass, volume, and function in 21 male endurance athletes (A) (27 +/- 4 years; 70 +/- 8 kg; 178 +/- 7 cm; maximal oxygen uptake [VO(2)max]: 68 +/- 5 ml/min per kg) and 21 pair-matched untrained control subjects (C) (26 +/- 3 years; 71 +/- 9 kg; 178 +/- 6 cm; VO(2)max: 42 +/- 6 ml/min per kg) were analyzed by MRI (Magnetom Vision 1.5T, Siemens, Erlangen, Germany). RESULTS: Left ventricular masses: (A: 200 +/- 20 g; C: 148 +/- 17 g) and RV masses (A: 77 +/- 10 g; C: 56 +/- 8 g) differed significantly between the groups (p < 0.001). The LV and RV end-diastolic volumes (EDV) (LV-EDV 167 +/- 28 ml [A]; 125 +/- 16 ml [C]; RV-EDV 160 +/- 26 ml [A]; 128 +/- 10 ml [C]), and stroke volumes (SV) (LV-SV: 99 +/- 18 ml [A], 74 +/- 11 ml [C]; RV-SV: 102 +/- 18 ml [A], 79 +/- 8 ml [C]) were significantly different between the athletes and control subjects (p < 0.001), whereas ejection fractions (EF) (LV-EF: 59 +/- 3% [A]; 59 +/- 6% [C]; RV-EF: 63 +/- 3% [A], 62 +/- 3% [C]) and LV-to-RV ratios were similar for both groups (LV-to-RV mass: 2.6 +/- 0.2 [A], 2.6 +/- 0.3 [C]; LV-to-RV EDV: 1.05 +/- 0.14 [A], 0.99 +/- 0.14 [C]; LV-to-RV SV: 0.98 +/- 0.17 [A], 0.95 +/- 0.17 [C]; LV-to-RV EF: 0.93 +/- 0.07 [A], 0.96 +/- 0.10 [C]). CONCLUSIONS: Regular and extensive endurance training results in similar changes in LV and RV mass, volume, and function in endurance athletes. This leads to the conclusion that the athlete's heart is a balanced enlarged heart.     

Natural resistance-associated macrophage protein 1 polymorphisms are associated with microscopy-positive tuberculosis

The natural resistance-associated macrophage protein 1 (NRAMP1) is implicated in the pathophysiology of mycobacterial infections. We investigated by polymerase chain reaction previously published Nramp1 genotypes at 4 loci-INT4, N543D, 3'UTR, and 5'(CA)(n) microsatellite markers-in 104 human immunodeficiency virus-negative patients with tuberculosis and 176 healthy control subjects living in Denmark. No significant difference in genotype frequency was found between white patients with tuberculosis and control subjects (P>.16), but carriage of Nramp1 variant alleles at loci INT4 and 5'(CA)(n) conferred a significantly increased risk of having microscopy-positive compared with microscopy-negative tuberculosis (65% vs. 35% [P=.0004] and 63% vs. 38% [P=.047], respectively). The Nramp1 alleles were not associated with increased risk for the development of cavities seen on chest radiographs, or with extrapulmonary tuberculosis. These results indicate that variant alleles in the Nramp1 gene are associated with increased mycobacterial replication rather than susceptibility for tuberculosis and may thus confer increased risk of severe disease.     

Local paclitaxel delivery for the prevention of restenosis: biological effects and efficacy in vivo

OBJECTIVE

The aim of this study was to evaluate the potential of paclitaxel to prevent restenosis in vivo.

BACKGROUND

Paclitaxel (Taxol) is a microtubule-stabilizing compound with potent antitumor activity. It influences the cytoskeleton equilibrium by increasing the assembly of altered microtubules, thereby inducing cellular modifications that result in reduced proliferation, migration and signal transduction.

METHODS

Before the in vivo study, delivery efficiency was determined with radiolabeled paclitaxel in porcine hearts. After induction of a defined plaque in the right carotid arteries of 76 New Zealand rabbits by electrical stimulation, 27 animals underwent balloon dilation and subsequent local paclitaxel delivery (10 ml, 10 μmol/liter) with a double-balloon catheter. Twenty-nine animals served as control with angioplasty only, 10 animals underwent local delivery of vehicle only (0.9% NaCl solution) and 10 animals were solely electrostimulated. Vessels were excised one, four, and eight weeks after intervention.

RESULTS

The extent of stenosis in paclitaxel-treated animals was significantly reduced compared with balloon-dilated control animals (p = 0.0012, one, four and eight weeks after intervention: 14.6%, 24.6% and 20.5%, vs. 24.9%, 33.8% and 43.1%, respectively). Marked vessel enlargement compared with balloon-dilated control animals could be observed (p = 0.0001, total vessel area after one, four and eight weeks: paclitaxel group: 1.983, 1.700 and 1.602 mm², control: 1.071, 1.338 and 1.206 mm², respectively). Tubulin staining and electron microscopy revealed changes in microtubule assembly, which were limited to the intimal area. Vasocontractile function after paclitaxel treatment showed major impairment.

CONCLUSIONS

Local delivery of paclitaxel resulted in reduced neointimal stenosis and enlargement in vessel size. Both these effects contribute to a preservation of vessel shape and are likely to be caused by a structural alteration of the cytoskeleton.     

Agonistic AT(1) receptor autoantibodies and monocyte stimulation in hypertensive patients

BACKGROUND: Agonistic AT(1) receptor autoantibodies (AT(1)-AA) have been described in hypertensive and preeclamptic patients. Furthermore, monocytes are activated in hypertensive patients. We investigated and compared the ability of angiotensin II (Ang II) and AT(1)-AA to stimulate monocytes from hypertensive and normotensive persons. The adhesiveness of the monocytes to endothelial cell layers, tissue factor expression, and chemiluminescence were determined. METHODS: Blood samples were obtained from 17 patients with essential hypertension and from 20 normotensive subjects. Peripheral blood monocytes were isolated by Dynabeads and used in adhesion experiments. Adherence assays, Western blotting, and reactive oxygen species release by chemiluminescence were done. RESULTS: Monocyte adhesion to human aortic or umbilical vein endothelial cell layers was significantly higher after stimulation with AT(1)-AA, compared to Ang II or no stimulation. The effect was blocked with tissue factor antibody or epitope peptide preincubation. Eposartan was partially effective in blocking the effects. Western blotting after AT(1)-AA or Ang II stimulation showed that the monocytes expressed tissue factor. The AT(1)-AA and Ang II induced significantly higher chemiluminescence in monocytes from hypertensive than control subjects. Endothelial cells, on the other hand, showed much less chemiluminescence. CONCLUSIONS: These data show that monocytes can be stimulated by AT(1)-AA and Ang II to adhere, produce tissue factor, and probably reactive oxygen species. They underscore the importance of monocyte activation in hypertensive patients. The relevance of AT(1)-AA in hypertension will require further studies.     

The SAVI-TF Registry: 1-Year Outcomes of the European Post-Market Registry Using the ACURATE neo Transcatheter Heart Valve Under Real-World Conditions in 1,000 Patients

Objectives

The SAVI-TF (Symetis ACURATE neo Valve Implantation Using Transfemoral Access) registry was initiated to study the ACURATE neo transcatheter heart valve in a large patient population treated under real-world conditions.

Cytotoxic effects of SMAC-mimetic compound LCL161 in head and neck cancer cell lines

Objectives

Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumor entities worldwide. Unfortunately, recent drug developments in other fields of oncology have yielded no efficacy in the treatment of oral squamous cell carcinoma. As a new starting point, we investigated the impact of Fas ligand (FasL) and the SMAC-mimetic compound LCL161 in mono- and combination treatment in HNSCC cell lines.

Methods

Five different cell lines of HNSCC were treated with FasL and LCL161 in mono- and combination treatment. Cytotoxicity was measured via a crystal violet assay. The cell lines were characterized for CD95 (FasL receptor) expression via flow cytometry. The degradation of cellular inhibitor of apoptosis protein 1 (cIAP1) was detected via Western blot.

Results

Incubation with FasL led to a significant decrease in three out of five cell lines. Combination treatment with LCL161 enhanced cytotoxicity significantly. Two cell lines were FasL resistant, but one of them could be resensitized with LCL161. In all cell lines, Western blot analysis showed degradation of cIAP1 after LCL161 application. However, one cell line showed only minor vulnerability to the FasL and LCL161 combination.

Conclusion

This is the first study investigating combination treatment of FasL and LCL161 in head and neck cancer cell lines. Pro-apoptotic effects of the combination were detected in the majority of the cell lines. Interestingly, one of two FasL-resistant cell lines was sensitive to the combination therapy with FasL and LCL161.

Clinical relevance

SMAC-mimetic compounds show promising results in the treatment of other tumor entities in vitro and might be useful drugs to improve HNSCC therapy.

     

Osteomalacia and osteitis fibrosa in a man ingesting aluminum hydroxide antacid

A 53-year-old man with a history of long-term aluminum hydroxide antacid ingestion reported diffuse bone pain and multiple stress fractures over a two-year period. An undecalcified transiliac bone biopsy specimen revealed osteomalacia with osteitis fibrosa; plasma parathyroid hormone and cyclic AMP levels were normal. Following withdrawal of antacids and treatment with calcium and phosphorus, an initially elevated plasma, 1,25-dihydroxyvitamin D level fell to within the normal range, accompanied by decreased bone pain, healed stress fractures, and increased axial bone mineral content as determined by computed tomography of lumbar trabecular bone. Phosphate deprivation and 1,25-dihydroxyvitamin D excess may contribute to the poor mineralization and exaggerated resorption of bone observed in this syndrome. The clinical, biochemical, radiologic, and histologic features of previously reported cases are reviewed. Early recognition of this syndrome is important, since appropriate therapy promotes skeletal remineralization and prevents morbidity.     

TAVR for Failed Surgical Aortic Bioprostheses Using a Self-Expanding Device: 1-Year Results From the Prospective VIVA Postmarket Study

ObjectivesThe VIVA (Valve in Valve) trial was designed to systematically and prospectively collect data regarding the use of transcatheter aortic valve replacement in patients with failing surgical aortic bioprostheses at high-risk for reoperation.BackgroundSurgical aortic valve replacement has been the standard of care in symptomatic patients with aortic valve disease. However, bioprosthetic valves degenerate over time, requiring redo surgery.MethodsVIVA is an international, observational, single-arm, postmarket study conducted at 23 sites that enrolled 202 patients with symptomatic degeneration of an aortic bioprosthesis eligible for elective treatment with a CoreValve or Evolut R self-expanding transcatheter aortic valve.ResultsPatients were elderly (mean age 79.9 years), 47.5% were men, and they had a mean Society of Thoracic Surgeons score of 6.6%. Although 41.8% of patients had surgical bioprostheses with labeled size ≤21 mm, valve hemodynamic parameters were markedly improved from baseline (mean aortic valve gradient 35.0 ± 16.3 mm Hg) to discharge (17.5 ± 8.6 mm Hg) and were sustained at 1 year (15.5 ± 7.5 mm Hg). At 1 year, total aortic regurgitation greater than mild was measured in 1.1% of patients. Clinical outcomes at 30 days demonstrated low mortality (2.5%), no disabling strokes, a 0.5% rate of acute kidney injury, and an 8.0% rate of new pacemaker implantation. At 1 year, the mortality rate remained low (8.8%), with 1 disabling stroke (0.6%). Five patients (2.5%) experienced coronary artery obstructions, 3 during and 1 immediately after the procedure and 1 several months later.ConclusionsDegenerated surgical bioprostheses can be safely treated with the CoreValve or Evolut R platform using the catheter-based valve-in-valve procedure. Excellent 1-year clinical and hemodynamic outcomes were achieved in this real-world patient population. (CoreValve VIVA Study Evaluation of the Clinical Outcomes of CoreValve in Degenerative Surgical Aortic Bioprosthesis; NCT02209298)