Aortic root replacement: twenty years of experience

BACKGROUND: Aortic root replacement is a complex surgical procedure which has undergone major technical modifications with time. In order to assess the early and long-term outcome after aortic root replacement with this procedure, our entire experience of a two decade period was reviewed. METHODS: Between January 1979 and March 1997, 156 aortic root replacement operations were performed. One hundred and twenty five patients (80%) were male and 31 female; their mean age was 50 +/- 16 years. Diagnosis was annuloaortic ectasia in 79 patients, aortic dissection in 51 (acute 22, chronic 29), isolated aortic valve pathology in 24 and aneurysm of sinus of Valsalva in 5. Thirty nine patients had aortic root replacement using the standard "Bentall" technique, 73 using the "modified Bentall" technique, 15 using the Cabrol technique. Biologic substitutes of the aortic root were used in 29 patients (19 autografts, 4 homografts, 6 xenografts). Mean follow-up time was 41 +/- 40 months (range 1 month-18 years). RESULTS: There were 12 (7.6%) hospital deaths. Hospital mortality in elective cases was 5% (7/134) and 22% (5/22) in emergent (p = 0.01). A trend toward reduced early mortality was demonstrated in recent years. Mortality was 5% for the "modified Bentall" group, 3% for the "Biologic root" group, 10% for the "Bentall" group and 20% for the "Cabrol" group. Hospital mortality was significant higher in "Cabrol" group than in "modified Bentall" group (p = 0.04). The overall long-term survival rate was 78 +/- 4% at 5 years, 71 +/- 6% at 10 years and 51 +/- 13% at 15 years. No significant difference in survival rate nor freedom from complications was observed among patient groups. Need for reoperation and valve-related adverse events become prevalent after 10 years of follow-up. CONCLUSION: The decrease in early mortality and the satisfying late results demonstrate that aortic root replacement is a low risk surgical procedure and an effective and durable treatment. The availability of biologic substitutes for the aortic root has allowed the extension of this operation to all patient age group, with results comparable to these obtained with composite grafts.     

Stabilization of optical characteristics of DNA cholesteric liquid-crystalline dispersions

Abnormal optical properties of liquid-crystalline dispersions (phases) formed as a result of phase exclusion of double-stranded DNA and RNA from water-salt poly(ethylene glycol) solutions and X-ray parameters of these phases are compared. It is shown that the cholesteric packing of nucleic acid molecules is realized at the certain osmotic pressure of a solvent only. A comparison of the optical properties of liquid-crystalline phases (dispersions) to their X-ray parameters allows one to put forward a suggestion on various hydratation (fluctuation) regimes of the nucleic acid behaviour under the condensed phases formation and factors, influencing the mode of packing of these molecules in phases formed. It is shown as well, that immobilization of DNA cholesteric liquid-crystalline particles in the content of polymeric matrix is accompanied by the stabilization of these particles and, hence, their specific abnormal optical activity as well as by formation of particles having a structure, which corresponds to the "optically isotropic ordered liquid" without abnormal optical activity. Data on stabilization of the cholesteric structure of liquid-crystalline DNA dispersions by creation of polymeric chelate bridges between the neighbouring DNA molecules, fixed in the structure of liquid-crystalline dispersions, are shown.     

Stimulation of 5-HT2A receptors on astrocytes in primary culture opens voltage-independent Ca2+ channels

A two-step exocytosis/endocytosis protocol was used in rat pancreatic acini to study membrane trafficking events at the apical plasma membrane (APM) as a function of extracellular pH. Exocytosis, as measured by cholecystokinin (CCK)-8-induced release of amylase into the incubation medium, was relatively insensitive to changes in extracellular pH from 5.5 to 9.0. In contrast, endocytosis, as measured by temperature-dependent uptake of horseradish peroxidase (HRP), was robust at pH values between 6.5 and 8.3 but abolished at acidic pH values of 5.5 to 6.0. Energy metabolism and cell viability were maintained during pH 6-induced cessation of HRP uptake, and the vesicular block could be reversed upon raising the luminal pH to 7.4. Histochemical and morphometric studies of HRP uptake examined by electron microscopy indicated that extracellular pH regulates endocytosis at the apical plasma membrane. At pH 6.0 in prestimulated cells, HRP uptake at the APM was abolished, and acinar lumen membranes remained markedly dilated with decreased density of microvilli and "arrested" exocytic images. At pH 7.4, HRP was taken up into endolysosomal structures within the Golgi complex, and acinar lumen membranes were contracted. Cleavage of GP2, a glycosyl phosphatidylinositol-anchored protein, was associated with the pH-dependent activation of HRP uptake. These studies demonstrate that acinar lumen pH regulates endocytic but not exocytic activity at the APM and suggest that alkalinization of the acinar lumen by duct cells is required for retrieval of exocytic membranes into the acinar cell via vesicular uptake mechanisms. The role of acid-base interactions within the acinar lumen provides a novel basis for understanding the cellular and luminal defects observed within the exocrine pancreas in cystic fibrosis.     

Three-dimensional analysis of contrast-filled microvessel diameters

Organ blood flow is controlled, in part, by changes in diameter of resistance vessels. In thick tissue, vessels can be imaged with a microscope using contrast-enhancing methods (e.g., fluorescence) and image analysis techniques can be used for quantitative diameter estimations. However, a change in the position of a vessel with respect to the plane of focus can be misinterpreted as a diameter change. In order to address this problem, a 3D image in a light microscope is obtained by serial optical sectioning, and a 3D deconvolution procedure (Avinash et al., 1991, "Fourteenth Association for Research in Otolaryngology Midwinter Meeting, St. Petersberg, FL," Abstract 156) is used to deblur 3D image data. Deblurred sections are computationally projected onto a 2D plane to give an extended-focus image, from which diameter estimates of microvessels are made using a quantitative, 2D diameter-tracking algorithm (Miles, 1987, "Semiautomatic Quantitative Image Analysis of Dynamic in Vivo Cochlear Microvessel Diameters." Ph.D. dissertation, Univ. Michigan; Miles and Nuttall, 1992, IEEE Trans. Biomed. Eng.). Justification for 3D preprocessing before diameter analysis is provided by absolute and relative error analyses using computer-generated synthetic vessels. The 3D diameter analysis technique is validated using a capillary tube of known diameter, filled with fluorescent solution. Demonstration of its applicability is shown in diameter measurements from the vessels of guinea pig cochlea. Our approach, using extended-focus images, minimizes overestimation of microvascular diameters and underestimation of relative diameter changes. Therefore, unambiguous diameter measurements are possible with extended-focus images.     

Detecting and discriminating the direction of motion of luminance and colour gratings

Human observers were required to discriminate the direction of motion of vertically moving, 1 c/deg luminance and colour gratings. The gratings had different contrasts and moved at temporal frequencies between 0.5 and 32 Hz. Sensitivity [the reciprocal of the contrast at which performance reached 75% correct in a temporal two-alternative forced-choice (2 AFC) discrimination task] was a band-pass function of temporal frequency for luminance gratings, and a low-pass function of temporal frequency for colour gratings. Further, when colour contrast was expressed in terms of the modulation in cone excitation produced by the stimulus, sensitivity to colour gratings was greater than sensitivity to luminance gratings at frequencies below 2 Hz. On the other hand, at temporal frequencies above 4 Hz, sensitivity to colour gratings was comparable with sensitivity to luminance gratings of double the temporal frequency. Detection sensitivity was measured for luminance and colour gratings of 1, 4 and 16 Hz. With either colour or luminance gratings, detection thresholds were very similar to those for direction-of-motion discrimination. This result confirms findings of Mullen and Boulton [(1992) Vision Research, 32, 483-488] and Cavanagh and Anstis [(1991) Vision Research, 31, 2109-2148], but is different from that reported by Lindsey and Teller [(1990) Vision Research, 30, 1751-1761] who used a smaller stimulus seen in a parafoveal region and found that motion discrimination thresholds were higher than detection threshold for colour gratings. We repeated our threshold measurements using parafoveal viewing conditions similar to those used by Lindsey and Teller (1990). We found that, although for luminance gratings detection thresholds were very close to direction-discrimination thresholds, for colour gratings, they were lower. The result is in qualitative agreement with Lindsey and Teller (1990). Our results suggest that low-level, or "first-order" motion mechanisms are not as sensitive to chromatic gratings as are colour-detection mechanisms.     

Systemic lupus erythematosus in children: the complex problems of diagnosis and treatment encountered in 101 such patients at the Mayo Clinic

Between 1945 and 1970, 101 children (86 girls and 15 boys) with systemic lupus erythematosus were evaluated at the Mayo Clinic. Only 9 children were less than 9 years old at the time of diagnosis. The most frequent presenting complaint was arthralgia; fever, fatigue, and a "butterfly" malar rash also were common. Renal involvement, found in more than 76 per cent of patients, was a prognostically poor sign. The overall survival of children with renal involvement is improved by the use of adequate steroid therapy.     

Adaptive Quadrature for Maximum Likelihood Estimation of a Class of Dynamic Latent Variable Models

Maximum likelihood estimation of models based on continuous latent variables generally requires to solve integrals that are not analytically tractable. Numerical approximations represent a possible solution to this problem. We propose to use the adaptive Gaussian–Hermite (AGH) numerical quadrature approximation for a particular class of continuous latent variable models for time-series and longitudinal data. These dynamic models are based on time-varying latent variables that follow an autoregressive process of order 1, AR(1). Two examples are the stochastic volatility models for the analysis of financial time series and the limited dependent variable models for the analysis of panel data. A comparison between the performance of AGH methods and alternative approximation methods proposed in the literature is carried out by simulation. Empirical examples are also used to illustrate the proposed approach.     

N-(Anilinoethyl)amide Melatonergic Ligands with Improved Water Solubility and Metabolic Stability

The MT₂-selective melatonin receptor ligand UCM765 (N-(2-((3-methoxyphenyl)(phenyl)amino)ethyl)acetamide), showed interesting sleep inducing, analgesic and anxiolytic properties in rodents, but suffers from low water solubility and modest metabolic stability. To overcome these limitations, different strategies were investigated, including modification of metabolically liable sites, introduction of hydrophilic substituents and design of more basic derivatives. Thermodynamic solubility, microsomal stability and lipophilicity of new compounds were experimentally evaluated, together with their MT₁ and MT₂ binding affinities. Introduction of a m-hydroxymethyl substituent on the phenyl ring of UCM765 and replacement of the replacement of the N,N-diphenyl-amino scaffold with a N-methyl-N-phenyl-amino one led to highly soluble compounds with good microsomal stability and receptor binding affinity. Docking studies into the receptor crystal structure provided a rationale for their binding affinity. Pharmacokinetic characterization in rats highlighted higher plasma concentrations for the N-methyl-N-phenyl-amino derivative, consistent with its improved microsomal stability and makes this compound worthy of consideration for further pharmacological investigation.     

Reporting risks and benefits of therapy by use of the concepts of unqualified success and unmitigated failure: applications to highly cited trials in cardiovascular medicine

BACKGROUND: The NNT (number needed to treat) and NNH (number needed to harm) are useful in conveying the results of clinical trials because they emphasize the effort that must be expended to accomplish a single, tangible outcome. But NNT conveys the effort required to achieve a positive outcome without distinguishing between the presence or absence of treatment-related adverse events. Similarly, NNH conveys harm without accounting for the achievement or lack of achievement of the benefit of therapy. Consequently, a mathematical model was developed to extend the NNT and NNH to represent the effort required to achieve "unqualified success" (NNTUS, treatment success without treatment-induced side effects) and "unmitigated failure" (NNHUF, lack of treatment success with treatment-induced side effects). METHODS AND RESULTS: NNTUS was calculated by adjusting the absolute risk reduction to allow for the probability of not incurring a treatment-related adverse event. NNHUF was similarly calculated by adjusting the absolute risk of incurring a treatment-related adverse event by the probability of not incurring any treatment-related benefit. The impact of conveying clinical trial data by the use of NNT, NNTUS, NNH, and NNHUF is illustrated by means of 11 highly cited trials identified systematically from the cardiovascular literature. The treatment effort measured by the NNTUS and the NNHUF was consistently higher than that given by the traditional NNT and NNH. These increments ranged from 1% to several hundred percent. CONCLUSIONS: The NNTUS and the NNHUF represent the treatment effort required on average to achieve 1 unqualified success and 1 unmitigated failure. NNTUS and NNHUF balance benefit and harm in an objective way and are relevant for making service delivery decisions.     

Phosphatidylinositol 3-kinase is required for CD28 but not CD3 regulation of the TEC family tyrosine kinase EMT/ITK/TSK: functional and physical interaction of EMT with phosphatidylinositol 3-kinase

Ligation of the TCR or CD28 induces activation of phosphatidylinositol 3-kinase (PI3K), the TEC family protein tyrosine kinase, EMT/ITK/TSK (EMT), and the SRC family tyrosine kinase, LCK. LCK is required for the activation and phosphorylation of EMT induced by ligation of the TCR or CD28 placing LCK upstream of EMT in T cell signaling cascades. We report herein that inhibition of PI3K activity with the specific inhibitors LY294002 and wortmannin markedly decreased EMT activation induced by CD28 cross-linking but not by CD3 cross-linking. Further, inhibition of PI3K markedly decreased EMT in vitro autokinase activity induced by activated LCK. In contrast, PI3K inhibitors did not alter CD28 or CD3 cross-linking or LCK-induced EMT phosphorylation. Consistent with the requirement of PI3K activity for CD28 but not CD3-induced stimulation of the EMT in vitro autokinase activity, a small but significant portion of cellular EMT associates with PI3K following CD28 cross-linking but not following CD3 cross-linking. CD28-induced association of EMT with PI3K also requires functional expression of LCK. Fusion proteins containing the SRC homology 2 domain of EMT interact with PI3K or a PI3K-associated molecule in a tyrosine phosphorylation-dependent manner. Taken together, the data suggest that EMT is differentially regulated and recruited to different signaling complexes following ligation of CD28 or the TCR complex, perhaps contributing to the disparate roles that EMT appears to play downstream of CD28 and the TCR.