Reproducibility of tissue Doppler parameters of asynchrony in patients with advanced LV dysfunction.

AIMS: To assess the reproducibility of tissue Doppler myocardial velocities in patients with dilated ventricles and markedly reduced systolic function (ejection fraction <35%). METHODS AND RESULTS: Forty-one patients referred for cardiac resynchronization therapy (CRT) were evaluated using tissue Doppler echocardiography. The inter and intra-individual reproducibility of peak systolic myocardial velocities and the intra-ventricular delay in three apical projections was assessed by repeated evaluation of each registered data set. Variability (measured by the coefficient of variation) ranged between 18 and 56% for the peak systolic velocities and between 32 and 117% for the time intervals. CONCLUSION: The reproducibility of the tissue Doppler echocardiography parameters (peak systolic myocardial velocity and intra-ventricular delay) was poor in our set of patients with dilated left ventricles and low ejection fraction. The most probable causes of our poor results are discussed including the missing standardization of the TDI measurements.     

New insights into the effects of biomaterial chemistry and topography on the morphology of kidney epithelial cells

Increasing incidence of renal pathology in the western world calls for innovative research for the development of cell‐based therapies such as a bioartificial kidney (BAK) device. To fulfil the multitude of kidney functions, the core component of the BAK is a living membrane consisting of a tight kidney cell monolayer with preserved functional organic ion transporters cultured on a polymeric membrane surface. This membrane, on one side, is in contact with blood and therefore should have excellent blood compatibility, whereas the other side should facilitate functional monolayer formation. This work investigated the effect of membrane chemistry and surface topography on kidney epithelial cells to improve the formation of a functional monolayer. To achieve this, microtopographies were fabricated with high resolution and reproducibility on polystyrene films and on polyethersulfone‐polyvinyl pyrrolidone (PES‐PVP) porous membranes. A conditionally immortalized proximal tubule epithelial cell line (ciPTEC) was cultured on both, and subsequently, the cell morphology and monolayer formation were assessed. Our results showed that L‐dopamine coating of the PES‐PVP was sufficient to support ciPTEC monolayer formation. The polystyrene topographies with large features were able to align the cells in various patterns without significantly disruption of monolayer formation; however, the PES‐PVP topographies with large features disrupted the monolayer. In contrast, the PES‐PVP membranes with small features and with large spacing supported well the ciPTEC monolayer formation. In addition, the topographical PES‐PVP membranes were compatible as a substrate membrane to measure organic cation transporter activity in Transwell® systems. Copyright © 2016 John Wiley & Sons, Ltd.     

Synthesis and Evaluation of Long-Acting D-Penicillamine Derivatives

This study extends the use of two lathyrogens, β-aminopropionitrile (BAPN) and D-penicillamine (DPA) from daily systemic or local-topical administration to long-time acting agents. This was achieved by converting the hydrophilic drugs into lipophilic derivatives. The synthesis of functional derivatives of DPA consisted in esterification with methyl-, hexyl-, or benzyl alcohols in the presence of thionylchloride. The esters formed were hydrochlorides, acidic and soluble in water. During neutralization in vitro or in vivo by tissue fluid, an oily substance is formed that elutes from a hydrogel polymer at a much slower rate than hydroplilic DPA itself. The degree of lipophilicity, measured as a partition coefficient between octanol/water, was highest for hexyl ester and lowest for methyl ester DPA. A single injection of either DPA hexyl ester HCl or 3-hexyl(amino) propionitrile into the full thickness skin incision wound in rats significantly lowered the breaking strength of the wound 12 days after injection, indicating the interference with collagen cross-linking. Both agents injected into the breast adenocarcinoma in Fisher rats significantly inhibited tumor growth without any signs of local or systemic toxicity. We conclude that these lipophilic lathyrogens with prolonged effectiveness are suitable in the treatment of pathologies, consisting of excessively cross-linked or deposited collagen (fibrotic adhesions, strictures, stenosis, and scar contractures) and in the treatment of single, solitary tumors, malignant and benign.     

Odontoblasts in odontogenic tumors

Odontoblasts are secretory cells displaying epithelial and mesenchymal features, which exist in a monolayer at the interface between the dentin and pulp of a tooth. During embryogenesis, these cells form a dentin shell and throughout life continue to produce dentin while, also acting as sensor cells helping to mediate tooth sensitivity. In this process, odontoblasts are forced to migrate inwards, resulting in an ongoing loss of pulp volume. Correspondingly, there is also a decrease in the surface area of the dentin which supports the odontoblast cell layer. As these events transpire, odontoblasts maintain a tightly controlled monolayer relationship to each other as well as to their dentin substrate. Stability is maintained laterally by epithelial attachment structures and transversely by complex cytoplasmic extensions into the supporting dentin. As a result, it is not possible for the layer to buckle to relieve the mechanical stresses, which develop during the inward migration. A theoretical consequence of this distinctive self-generated niche is the development of long term compressive stresses within the odontoblast population. We present a mechanobiology model, which causally relates the increase in cellular compressive stresses to contact inhibition of proliferation. We link this hypothesis to the observation that there are no reports of pulpal odontoblasts showing neoplasia or acquisition of changes suggestive of a pre-neoplastic phenotype.     

Somatic Alterations Contributing to Metastasis of a Castration‐Resistant Prostate Cancer

Metastatic castration‐resistant prostate cancer (mCRPC) is a lethal disease, and molecular markers that differentiate indolent from aggressive subtypes are needed. We sequenced the exomes of five metastatic tumors and healthy kidney tissue from an index case with mCRPC to identify lesions associated with disease progression and metastasis. An Ashkenazi Jewish (AJ) germline founder mutation, del185AG in BRCA1, was observed and AJ ancestry was confirmed. Sixty‐two somatic variants altered proteins in tumors, including cancer‐associated genes, TMPRSS2‐ERG, PBRM1, and TET2. The majority (n = 53) of somatic variants were present in all metastases and only a subset (n = 31) was observed in the primary tumor. Integrating tumor next‐generation sequencing and DNA copy number showed somatic loss of BRCA1 and TMPRSS2‐ERG. We sequenced 19 genes with deleterious mutations in the index case in additional mCRPC samples and detected a frameshift, two somatic missense alterations, tumor loss of heterozygosity, and combinations of germline missense SNPs in TET2. In summary, genetic analysis of metastases from an index case permitted us to infer a chronology for the clonal spread of disease based on sequential accrual of somatic lesions. The role of TET2 in mCRPC deserves additional analysis and may define a subset of metastatic disease.     

Estrogen reduces atherosclerotic lesion development in apolipoprotein E-deficient mice.

We have studied the effects of endogenous and exogenous estrogen on atherosclerotic lesions in apolipoprotein E-deficient mice. Female mice ovariectomized (OVX) at weaning displayed increases (P < 0.01) in fatty streak lesions in the proximal aorta and aortic sinus compared with female mice with intact ovarian function. These differences between the OVX and sham controls were apparent in both chow- and "Western-type" diet-fed mice. Moreover, increases in lesion size following OVX occurred without changes in plasma cholesterol. Hormone replacement with subdermal 17-beta-estradiol pellets releasing either 6, 14, or 28 micrograms/day significantly decreased (P < 0.001) atherosclerotic lesion area in both male and OVX female mice. In contrast, neither 17-alpha-estradiol (28 micrograms/day) or tamoxifen (85 micrograms/day) affected lesion progression in OVX female mice. In the Western diet-fed group, exogenous estradiol markedly reduced plasma cholesterol and triglycerides, whereas, in animals fed the chow diet, exogenous estrogen and tamoxifen treatment only decreased plasma and very low density lipoprotein triglycerides. However, lesion area was only weakly correlated with plasma cholesterol and triglycerides, 0.35 and 0.44 tau values, respectively (P < 0.01). In summary, in the apolipoprotein E-deficient mouse 17-beta-estradiol protects against atherosclerotic lesion formation, and this can only be partially explained through effects on plasma lipoprotein levels.     

Moderate Sodium Restriction Enhances the Pressor Response to Hyperlipidemia in Obese, Hypertensive Patients

The effect of dietary sodium restriction on insulin, lipids, and blood pressure has been controversial. Evidence suggests that adverse short-term effects in response to very low-salt diets do not persist long-term with modest sodium restriction. In this study, the effects of modest dietary sodium restriction (60 and 120 mmol sodium) were measured for 3 weeks in 12 lean normotensives and 10 obese hypertensives. Blood pressure, plasma lipids, and the pressor response to an infusion of Intralipid and heparin were obtained. In contrast to previous reports concerning very low-salt diets, obese hypertensives did not manifest a pressor response or an adverse lipid effect with moderate salt restriction. Obese hypertensives were not more salt-sensitive than lean normotensives and did not manifest a different hemodynamic response to 4-hour infusion of Intralipid and heparin while on the 120-mmol/day salt diet. During the 60-mmol/day salt diet, however, plasma triglycerides increased more in obese than in lean volunteers during the Intralipid and heparin infusion (398±38 vs. 264±18 mg/dL; p<0.05), and there were greater increases in mean blood pressure (12±2 vs. 7±2 mm Hg; p<0.05) and systemic vascular resistance (111±38 vs. −25±44 dyne.sec cm—5) as well as a larger decrease in small artery compliance (−2.5±0.6 vs. −0.4±0.6 mL/mm Hg × 100; p<0.05). These data suggest that modest dietary sodium restriction in obese hypertensives does not adversely affect baseline blood pressure or lipids, but it does magnify their adverse lipid and hemodynamic response to fat loading.     

Entrapment of circular mapping catheter in the mitral valve

BACKGROUND: Ablation procedures in the left atrium for treatment of atrial fibrillation are becoming increasingly common. The procedure often involves placing one or two circular mapping catheters in the left atrium. Entrapment of an ablation catheter in the mitral valve during ablations of left-sided accessory pathways by the retrograde approach has been described in two earlier published reports. More recently, several reports describe similar entrapment of a mapping catheter. In a recently published review, however, only one case of unspecified valve damage was registered among 8745 atrial fibrillation procedures. OBJECTIVE: The purpose of this study was to evaluate patients with entrapment. METHODS: Retrospective analysis of electrophysiological results. RESULTS: We describe three patients with entrapment during ablations for atrial fibrillation. The entrapments occurred with three different operators at three different electrophysiological laboratories within 2 years. The complication described here may be more common than is widely appreciated. CONCLUSIONS: From our figures, we estimate the incidence of the complication to 0.9% (95% confidence interval, 0.2-2.5%).