Simultaneous Ipsilateral Vascularized Lymph Node Transplantation and Contralateral Lymphovenous Anastomosis in Bilateral Extremity Lymphedema with Different Severities.

BACKGROUND: Extremity lymphedema can occur bilaterally with different severities on each side. The aim of this study is to investigate the treatment outcomes of such patients with bilateral extremity lymphedema of different severities. PATIENTS AND METHODS: Between 2013 and 2017, patients with bilateral extremity lymphedema of different severities according to the Taiwan Lymphoscintigraphy Staging (TLS) system were retrospectively reviewed. Ipsilateral vascularized lymph node transplantation (VLNT) was indicated in TLS total obstruction and contralateral lymphovenous anastomosis (LVA) in TLS partial obstruction with patent lymphatic vessels on indocyanine green lymphography. Outcomes were assessed using circumference improvement, frequency of cellulitis, and lymphedema-specific quality of life (LYMQoL) questionnaires. RESULTS: A total of 10 patients with bilateral extremity lymphedema with median age of 63 (range 12-75) years were included. The median symptom duration of the lymphedematous limb was 60 (range 36-168) months and 12 (range 1-60) months in the VLNT and LVA group, respectively (p < 0.05). At average follow-up of 37.5 (range 14-58) months, the average limb circumference improvement was 2.4 (range - 3.3 to 7.8) cm in the VLNT group and 2.3 (range 0.3-7) cm in the LVA group (p = 1). The median episodes of cellulitis decreased significantly from 4 to 0.5 and 1 to 0 times/year in the VLNT and LVA group, respectively (p = 0.02, p = 0.06). The overall LYMQoL score improved from 4.5 preoperatively to 7.5 postoperatively (p < 0.01). CONCLUSIONS: Limb-specific VLNT and LVA selected by TLS effectively treated bilateral extremity lymphedema with different severities.

Gly972Arg of IRS-1 and Lys121Gln of PC-1 polymorphisms act in opposite way in polycystic ovary syndrome.

PURPOSE: Polycystic ovary syndrome (PCOS) was associated with a number of polymorphisms of genes involved in insulin signaling. So far, they have been studied separately. The aim of this study was to verify the impact of the coexistence of two polymorphisms of insulin signaling. METHODS: One hundred consecutive PCOS women (diagnosed by Rotterdam criteria) and 45 age-matched healthy women were genotyped for two polymorphisms: Gly972Arg of IRS-1 and Lys121Gln of PC-1. Also, they underwent clinical evaluation, blood sampling for measurement of metabolic and hormonal indices, and a 75-g oral glucose tolerance test (OGTT). RESULTS: Comparing PCOS women with controls, the rate of homo-/heterozygosity was significantly greater (50 vs. 24.5%, P = 0.004) for IRS-1 polymorphism, but insignificantly greater (20 vs. 13.3%, P = 0.33) for PC-1 polymorphism. In PCOS women, compared with controls, the genotypes IRS-1 hetero/PC-1 wild type (WT) (36 vs. 17.8%, P = 0.03) and IRS-1 hetero/PC-1 hetero (14 vs. 6.7%, P = 0.20) were overrepresented at the expense of IRS-1 WT/PC-1 WT (44 vs. 68.8%, P = 0.005), while IRS-1 WT/PC-1 hetero was similarly represented (6 vs. 6.7%). Based on genotype, metabolic and hormonal indices changed significantly. For instance, six indices (HOMA-IR, fasting insulin, insulin area under the curve at OGTT, triglycerides, total and calculated free testosterone) were the highest in IRS-1 hetero/PC-1 WT women. CONCLUSIONS: Genetic variations in insulin signaling contribute to the extent and the variability of metabolic and hormonal derangement.

Caspase-3 activation in human melanoma A375 cell line by a novel selective sigma-2 agonist.

Two novel 8-azabicyclo[3.2.1]octan-3-ol derivatives, 11a and 11b, with high affinity for sigma-2 receptors and a very good sigma-1/sigma-2 selectivity ratio were synthesized. In comparison with several well established sigma-2 selective ligands, 11 b showed a very low sigma-1 receptor affinity. Functional assays demonstrated that 11b acts as an agonist and in A-375 human melanoma cell line is able to lower levels of procaspase-3, thus confirming a potential major role for sigma-2 pure agonists in the treatment of rapid proliferating melanoma cells.

Very high frequency of the polymorphism for the insulin receptor substrate 1 (IRS-1) at codon 972 (glycine972arginine) in Southern Italian women with polycystic ovary syndrome.

A major component of the polycystic ovary syndrome (PCOS) is the insulin resistance. Only a few studies have evaluated the IRS-1 polymorphism at codon 972, sometimes in the absence of a control group, and with great variability in frequency (0-23% in PCOS vs. 0-17% in controls), and with no unequivocal relationships between the polymorphism and clinical or biochemical indexes. The aim of the work was to evaluate the frequency of the IRS-1 polymorphism at codon 972 in PCOS, and correlate it to clinical and biochemical indexes. We assessed the rs 1801278 polymorphic variant in the IRS-1 gene (Gly972Gly=wild-type; Gly972Arg=heterozygosity; Arg972Arg=homozygosity) in genomic DNA by restriction fragment length polymorphism. The study was conducted at an academic medical center with the participation of 65 women with PCOS and 27 age-matched healthy women (controls). Compared to controls, Gly972Arg was very frequent in PCOS (77% vs. 18%, p<0.0001); one PCOS woman was homozygous. Compared to wild-type PCOS, heterozygous PCOS women had only three significantly different indexes: higher fasting insulin, insulin resistance index, and lower 120 min OGTT glucose. Moreover, in the correlation analysis between any two clinical or biochemical variables, the Pearson's correlation coefficients were frequently of different magnitude in heterozygous PCOS versus wild-type PCOS. Overall, heterozygous PCOS had a greater number of statistically significant relationships between different clinical, metabolic and hormonal indexes: 44 direct and 9 inverse versus 6 and 3, respectively. The IRS-1 Gly972Arg has the highest frequency reported world-wide for PCOS women. This variant is associated with insulin resistance and higher fasting insulin in PCOS women.

Effect of clinical signs, endocrinopathies, timing of surgery, hyperlipidemia, and hyperbilirubinemia on outcome in dogs with gallbladder mucocele.

Gallbladder mucocele (GBM) is a common extra-hepatic biliary syndrome in dogs with death rates ranging from 7 to 45%. Therefore, the aim of this study was to identify the association of survival with variables that could be utilized to improve clinical decisions. A total of 1194 dogs with a gross and histopathological diagnosis of GBM were included from 41 veterinary referral hospitals in this retrospective study. Dogs with GBM that demonstrated abnormal clinical signs had significantly greater odds of death than subclinical dogs in a univariable analysis (OR, 4.2; 95% CI, 2.14-8.23; P<0.001). The multivariable model indicated that categorical variables including owner recognition of jaundice (OR, 2.12; 95% CI, 1.19-3.77; P=0.011), concurrent hyperadrenocorticism (OR 1.94; 95% CI, 1.08-3.47; P=0.026), and Pomeranian breed (OR, 2.46; 95% CI 1.10-5.50; P=0.029) were associated with increased odds of death, and vomiting was associated with decreased odds of death (OR, 0.48; 95% CI, 0.30-0.72; P=0.001). Continuous variables in the multivariable model, total serum/plasma bilirubin concentration (OR, 1.03; 95% CI, 1.01-1.04; P<0.001) and age (OR, 1.17; 95% CI, 1.08-1.26; P<0.001), were associated with increased odds of death. The clinical utility of total serum/plasma bilirubin concentration as a biomarker to predict death was poor with a sensitivity of 0.61 (95% CI, 0.54-0.69) and a specificity of 0.63 (95% CI, 0.59-0.66). This study identified several prognostic variables in dogs with GBM including total serum/plasma bilirubin concentration, age, clinical signs, concurrent hyperadrenocorticism, and the Pomeranian breed. The presence of hypothyroidism or diabetes mellitus did not impact outcome in this study.

A molecular dynamics approach to the structural characterization of amyloid aggregation.

A novel computational approach to the structural analysis of ordered beta-aggregation is presented and validated on three known amyloidogenic polypeptides. The strategy is based on the decomposition of the sequence into overlapping stretches and equilibrium implicit solvent molecular dynamics (MD) simulations of an oligomeric system for each stretch. The structural stability of the in-register parallel aggregates sampled in the implicit solvent runs is further evaluated using explicit water simulations for a subset of the stretches. The beta-aggregation propensity along the sequence of the Alzheimer's amyloid-beta peptide (Abeta(42)) is found to be highly heterogeneous with a maximum in the segment V(12)HHQKLVFFAE(22) and minima at S(8)G(9), G(25)S(26), G(29)A(30), and G(38)V(39), which are turn-like segments. The simulation results suggest that these sites may play a crucial role in determining the aggregation tendency and the fibrillar structure of Abeta(42). Similar findings are obtained for the human amylin, a 37-residue peptide that displays a maximal beta-aggregation propensity at Q(10)RLANFLVHSSNN(22) and two turn-like sites at G(24)A(25) and G(33)S(34). In the third application, the MD approach is used to identify beta-aggregation "hot-spots" within the N-terminal domain of the yeast prion Ure2p (Ure2p(1-94)) and to design a double-point mutant (Ure2p-N4748S(1-94)) with lower beta-aggregation propensity. The change in the aggregation propensity of Ure2p-N4748S(1-94) is verified in vitro using the thioflavin T binding assay.

(18)F-FDG PET/CT, cytoreductive surgery and intraperitoneal chemohyperthermia for the therapeutic management in peritoneal carcinomatosis: A pilot study.

AIM: Peritoneal carcinomatosis is a common evolution of neoplasms and the terminal stage of disease. A new therapeutic technique, based on the total surgical removal of peritoneal lesions (peritonectomy procedure - PP) combined with the intraperitoneal chemohyperthermia (IPCH), has been developed. Proper patient selection is mandatory for optimizing the results of treatment. The aim of this study was to investigate the role of [(18)F]fluoro-2-deoxy-d-glucose Positron Emission Tomography/Computed Tomography ((18)F-FDG PET/CT) in patients with peritoneal carcinosis selected to undergo PP and IPCH. Furthermore, we aimed to identify characteristic patterns of abdominal(18)F-FDG uptake and to correlate these patterns with available anatomic findings after surgery. METHODS: Patients with either histologically confirmed peritoneal carcinosis or suspected upon clinical follow-up and/or imaging findings were prospectively submitted to pre-surgery (18)F-FDG PET/CT scan. Only those patients without evidence of extra-peritoneal metastases at PET/CT scan were treated with PP and IPCH. RESULTS: 11 patients with peritoneal carcinomatosis (5 colorectal, 4 ovarian, 1 pancreatic) and 1 unknown primitive cancer, were eligible for the study. In all cases PET/CT scan showed multiple peritoneal implants. In 6 out of 11 cases (54%) metastases were evidenced by (18)F-FDG PET/CT: 2 cases with liver metastases; 1 case with bone metastases; 3 patients with lymph-node lesions. Two distinct imaging patterns, with focal or diffuse increased (18)F-FDG uptake, were recognized. CONCLUSIONS: PP+IPCH of patients selected by (18)F-FDG PET/CT seems to be safe and feasible. PET/CT scan appears as a reliable tool for the detection, characterization of peritoneal implants with potential impact in the therapeutic management of these patients.

Non-peptide ligands for opioid receptors. Design of kappa-specific agonists.

A series of phenyl carboxyl esters 5a-d derived from N-(cyclopropylmethyl)normetazocine was synthesized and evaluated for its selectivity at mu, kappa, and delta opioid receptors. Compound 5a, although 43 times less potent than the reference compound U50488, was specific for kappa receptors, having no detectable affinity for either mu or delta receptors. Greater binding affinity was seen with the diastereoisomer having the 1'R,2'S stereochemistry in the cyclopropyl ring of the nitrogen substituent, which was only 12 times less active than U50488. Antinociceptive activity in the mouse tail flick was only slightly lower than that of U50488 (ED50 = 7.66 vs 4.52 mg/kg). Naloxone fully prevented antinociception induced by (1'R,2'S)-5a at the doses of 2.0 mg/kg. Compound (1'R,2'S)-5a is one of the most kappa-selective non-peptide compounds reported to date. The implications of these results in terms of requirements for kappa ligands are discussed.

(+)-cis-N-ethyleneamino-N-normetazocine derivatives. Novel and selective sigma ligands with antagonist properties.

A series of (+)-cis-N-normetazocine derivatives has been described, and their affinities for sigma1, sigma2, and phencyclidine (PCP) sites and opioid, muscarinic (M2), dopamine (D2), and serotonin (5-HT2) receptors were evaluated. The effect of the N-substitution with a substituted ethylamino spacer was investigated. Compounds 8c-11c displayed high affinities for sigma1 sites and for opioid receptors. Substitution of the second basic nitrogen either with alkyl or cycloalkyl substituents give compounds (1a-6a) with high affinity and selectivity for sigma1 binding sites. Compounds 1a-5a were further characterized in vivo, and their agonist/antagonist activity was evaluated. In mouse, compound 1a and 2a as well as haloperidol suppressed in a dose-related manner the stereotyped behavior induced by (+)-SKF 10,047. Compounds 3a-5a and (+)-pentazocine do not affect the stereotyped behavior induced by ip injection of (+)-SKF 10,047. Therefore, from this series of compounds we identified potent and selective sigma1 ligands which might prove useful to unveil the functional role of sigma1 sites.

Berberis aetnensis C. Presl. extracts: antimicrobial properties and interaction with ciprofloxacin.

Previous research showed that berberine-containing Berberis species synthesise the substances 5'-methoxyhydnocarpin-D (5'-MHC-D) and pheophorbide a, which have no antimicrobial activity but inhibit the expression of multidrug resistant efflux pumps (MDRs) in Staphylococcus aureus and potentiate the action of berberine. The MDR pumps extrude synthetic and natural antimicrobials from bacterial cells. We searched for these compounds in Berberis aetnensis C. Presl. (Berberidaceae), an endemic plant of the volcano Mount Etna. This work confirms the presence of pheophorbide a and permits us to hypothesise the presence of 5'-MHC-D in leaf extracts. In fact, the activity of ciprofloxacin was improved when two chromatographic fractions isolated from leaf extracts were added. These results are indicative of the presence of MDR pump inhibitors. Moreover, crude extracts were tested on several micro-organisms and showed antimicrobial activity mainly against Gram-positive bacteria and yeasts.

Frequency decomposition and compounding of ultrasound medical images with wavelet packets.

Ultrasound beams propagating in biological tissues undergo distortions due to local inhomogeneities of the acoustic parameters and the nonlinearity of the medium. The spectral analysis of the radio-frequency (RF) backscattered signals may yield important clinical information in the field of tissue characterization, as well as enhancing the detectability of tissue parenchymal diseases. In this paper, we propose a new tissue spectral imaging technique based on the wavelet packets (WP) decomposition. In a conventional ultrasound imaging system, the received echo-signals are generally decimated to generate a medical image, with a loss of information. With the proposed approach, all the RF data are processed to generate a set of frequency subband images. The ultrasound echo signals are simultaneously frequency decomposed and decimated, by using two quadrature mirror filters, followed by a dyadic subsampling. In addition, to enhance the lesion detectability and the image quality, we apply a nonlinear filter to reduce noise in each subband image. The proposed method requires simple additional signal processing and it can be implemented on any real-time imaging system. The frequency subband images, which are available simultaneously, can be either used in a multispectral display or summed up together to reduce speckle noise. To localize the different frequency response in the tissues, we propose a multifrequency display method where three different subband images, chosen among those available, are encoded as red, green, and blue intensities (RGB) to create a false-colored RGB image. According to the clinical application, different choices can evidence different spectral proprieties in the biological tissue under investigation. To enhance the lesion contrast in a grey-level image, one of the possible methods is the summation of the images obtained from narrow frequency subbands, according to the frequency compounding technique. We show that by adding the denoised subband images created with the WP decomposition, the contrast-to-noise ratio in two phantom images is largely increased.

Dense and sparse 2-D array radiation patterns in lossy media.

Two-dimensional (2-D) transducer arrays are potentially able to generate real-time volumetric images of internal organs of the human body, and much work has been done on the subject in recent years. A 2-D array with high resolution and low grating lobe level requires a prohibitively large number of elements for existing technology. A successful solution to reduce the number of elements, without sacrificing the above mentioned characteristics, is to select a limited number of elements in a random way or combining transmitting and receiving apertures with element spacing greater than one-half of a wavelength. In this work, the effect of the human body attenuation on the performances of these so-called sparse arrays is investigated. We analytically demonstrate that, for continuous wave excitation and under paraxial approximation, the medium losses can be modeled as a Gaussian weighting function, acting off-axis in the observation plane. The variance of this weighting function decreases with the covered distance. Radiation patterns computed with both this simple model and with a more exact expression, are presented for sparse and dense 2-D arrays under continuous and pulsed wave operation. Comparisons between the results obtained with and without attenuation also are shown.

A piezoelectric motor using flexural vibration of a thin piezoelectric membrane.

This paper describes a new implementation of a disk-type piezoelectric motor, whose stator is a commercial available piezomembrane composed of a nickel alloy disk to which a piezoceramic disk is bonded. The two disks are concentric, and the total thickness is very small. Ultrasonic motors are based on the concept of driving a rotor by mechanical vibration excited on a stator, via the piezoelectric effect. The rotor is in contact with the stator, and the driving force is the frictional force between rotor and stator. To transform the mechanical vibration of the stator in the rotor rotation, a traveling wave must be excited on the stator surface. The proposed motor can be regarded as a disk-type, single wavelength motor in which the traveling wave is due to the natural flexural vibration of the piezomembrane at low frequency. The behavior of the stator is analyzed both theoretically, by using the theory of isotropic and homogeneous vibrating plates, and by means of a commercial finite element computer code, finding a good agreement with the experimental results. The main features of the motor are very small thickness, appreciable torque, and high speed, obtained with low input power at low voltage; the intended application is to substitute the moving-coil in analogic instrumentation.

An approximated 3-D model of cylinder-shaped piezoceramic elements for transducer design.

In this paper an approximated 3-D model of cylinder shaped piezoceramics is described. In the hypothesis of axial symmetry, the element vibration in the extensional and radial directions is described by two coupled differential wave equations. The model is obtained choosing, as solution of these equations, two orthogonal wave functions, each depending only on one axis, corresponding to the propagation direction. The mechanical boundary conditions are applied imposing continuity between the stresses and the external forces on the surfaces of the element in an integral way, while, as far as the electrical boundary condition is concerned, two possibilities are explored: to neglect the piezoelectric constant in the transverse direction and to impose an integral condition also for the electric field. Comparisons with experimental results show this last approach to give better results. The model predicts with sufficient accuracy only the first radial and the first thickness modes of the cylinder-shaped piezoceramic element of arbitrary aspect ratio; but, for these modes, it is able to compute all the relations between the input applied voltage and the output forces and velocities on every external surface. Because only these two modes are of relevance in the practical applications of piezoceramic elements as ultrasonic transducers, the model can be used as a simple and useful tool in transducer design and optimization. Experimental validations of the model are also shown in the work.

A coupled-mode theory for periodic piezoelectric composites.

A coupled oscillator model to calculate the resonance spectrum of a one-dimensional piezoelectric composite plate, used in ultrasonic transducers, is proposed. Two resonant modes, one produced by the elastic wave reflection on the plate boundaries (thickness resonance) and the other by the reflection on the periodic discontinuities (lateral resonance) are considered. A Kronig-Penney model is used to calculate the lateral resonances. The thickness resonance is obtained with an effective medium model. The coupling of these two modes is described by a biquadratic equation whose solutions are the resonant frequencies of the piezoelectric composite plate. A criterion for a distribution of phases to keep the spurious lateral resonances away from the thickness resonance vicinity is obtained.

A new approach for the design of ultrasono-therapy transducers.

In this paper we describe a new approach for the design of ultrasono-therapy transducers. Usually, in this kind of transducer, a lambda/2 front plate is inserted only in order to ensure a good mechanical protection of the active crystal from the surrounding medium. However, with an accurate design, the plate can also be used to match the piezoelectric element to the load both in terms of gain and bandwidth. To this end we apply the technique normally used in acoustical imaging and nondestructive testing, and, by means of a distributed matrix model, we optimize the thickness and impedance of the plate in order to obtain a strong response and a large bandwidth at the working frequency. Using a front plate of thickness about lambda/3, the model predicts better performances than the ones obtained with the classical design, also in terms of efficiency. An experimental comparison between a transducer realized according to the proposed design and a commercial half wave transducer shows better performances the former and therefore validates the new design criterion.

Optimization of wide-band linear arrays.

An optimization method is proposed for linear arrays to be used in ultrasound systems under wide-band operation. A fast algorithm, the threshold accepting, has been utilized to determine the element positions and weight coefficients of a linear array that generates a desired beam pattern. To reduce the computational burden in the optimization procedure, an efficient numerical routine for the beam pattern evaluation has been implemented. We address the optimization problem of both dense and sparse wide-band arrays. In the first case, the goal is to minimize the side-lobe energy by varying the element weights; we compare the optimized beam pattern with that obtained with classical shading functions, showing that better results can be achieved with a wide-band optimization. We also consider the optimization of the layout (positions and weights) of a sparse linear array to achieve a desired beam pattern with a fixed or minimum number of array elements. The comparison of the proposed method with a narrow-band optimization algorithm is presented, showing that better performances (about -7 dB further reduction of the side-lobe level) can be achieved with a wide-band sparse array optimization. Further numerical simulations are given, showing that the proposed method yields better results than wide-band sparse random arrays and periodic arrays with the same aperture width.

Analysis of the radial symmetrical modes of thin piezoceramic rings.

In this work, the radial symmetric vibration modes of thin piezoceramic rings have been analyzed by means of a previously proposed theoretical model. Both the resonance frequencies and the effective electromechanical coupling factor (k(eff)), as a function of the aspect ratio G between the inner and outer radii of the ring, were computed. The results have shown that the disk structure (G-->0) has only one radial symmetrical mode (with its harmonics), but, for the ring structure (G-->1), two different modes are clearly distinguished: the ring mode, which has no harmonics, and a width-like mode, with its harmonics. Moreover, the results show that the ring structure can be assumed to be definitely reached for G>0.6. An analysis of the material coupling factor in the ring geometry is reported as well.

Efficient transmit beamforming in pulse-echo ultrasonic imaging.

A high performance ultrasound imaging system requires accurate control of the amplitude of the array elements, as well as of the time delays between them, both in the transmit and receive modes. In transmission, conventional array aperture windowing implies a different driving voltage for each element of the array, an expensive solution for systems with a large number of channels. In this paper, we present a simple, versatile, and inexpensive beamforming method that operates the aperture windowing in the transmit mode, simply controlling the lengths of the electric pulses driving the array elements. Computer simulations and experimental measurements are presented for different types of arrays. They confirm that the proposed beamforming technique improves the contrast resolution of the imaging system, reducing the off-axis intensity of the radiated field pattern. Moreover, the axial resolution is slightly enhanced, because the overall length of the transmitted ultrasonic pulse is reduced.