SH3 binding domains in the dopamine D4 receptor

The dopamine D4 receptor is a G protein-coupled receptor (GPCR) that belongs to the dopamine D2-like receptor family. Functionally, the D2-like receptors are characterized by their ability to inhibit adenylyl cyclase. The dopamine D4 receptor as well as many other catecholaminergic receptors contain several putative SH3 binding domains. Most of these sites in the D4 receptor are located in a polymorphic repeat sequence and flanking sequences in the third intracellular loop. Here we demonstrate that this region of the D4 receptor can interact with a large variety of SH3 domains of different origin. The strongest interactions were seen with the SH2-SH3 adapter proteins Grb2 and Nck. The repeat sequence itself is not essential in this interaction. The data presented indicate that the different SH3 domains in the adapter proteins interact in a cooperative fashion with two distinct sites immediately upstream and downstream from the repeat sequence. Removal of all the putative SH3 binding domains in the third intracellular loop of the dopamine D4 receptor resulted in a receptor that could still bind spiperone and dopamine. Dopamine could not modulate the coupling of these mutant receptors to adenylyl cyclase and MAPK, although dopamine modulated receptor-G protein interaction appeared normal. The receptor deletion mutants show strong constitutive internalization that may account for the deficiency in functional activation of second messengers. The data indicates that the D4 receptor contains SH3 binding sites and that these sites fall within a region involved in the control of receptor internalization.     

Indirect bonding

A case is reported of hemolytic anemia following rifampicin administration and complicated by acute renal failure. Furthermore clotting analyses suggested a slight disseminated intravascular coagulation, very likely activated by hemolysis products. Both hemolysis and renal function impairment subsided spontaneously, after the sole withdrawal of rifampin. Direct antiglobulin test became negative within a few days, while an indirect Coomb's test was demonstrated persistently with the patient's serum using red blood cells sensitized in vitro with the drug. Otherwise from all reports in the literature, the patient developed an acute hemolytic anemia while on daily therapy and as many as twenty years after a previous treatment with rifampicin. Mechanisms of drug-induced immune hemolytic anemia and acute nephropathy are discussed (formation of drug-antibody complexes, which adhere on the red blood cells surface and are able to fix complement and induce intravascular hemolysis; tubular necrosis due to hemoglobinuria or immuno-mediated interstitial nephritis).     

Outcome of cardiac valve ring abscesses after medical treatment: attempt to identify criteria of favorable prognosis

OBJECTIVES: Identify factors predicting favorable outcome after medical management of valve ring abscesses in order to propose a surveillance schedule for conservative treatment. METHODS: A multicentric study conducted from July 1989 to February 1996 included 28 patients (mean age 64 +/- 16 years, range 26-83) hospitalized for active endocarditis and valve ring abscesses diagnosed at transthoracic or transesophageal echography. Conservative medical therapy was given because of a decision of the medico-surgical team (n = 9), high surgical risk (n = 12), or patient refusal of surgery (n = 7). Outcome was favourable in 18 patients (Group I) and unfavorable in 10 (Group II) due to death (n = 9) or subsequent surgery (n = 1). Univariate and multivariate analysis were used to determine differences between the groups in terms of clinical and laboratory data. RESULTS: Mean follow-up in Group I was 33 +/- 18 months and 15 +/- 10 months in Group II. Univariate analysis showed significant differences between Group I and II respectively for age (59 +/- 18 yr vs 72 +/- 10, p = 0.04), delay to apyrexia after antibiotics (4.3 +/- 2.8 vs 8.3 +/- 2.4 days, p < 0.0008), heart failure (5% vs 70%, p = 0.003), grade III or IV valvular regurgitation (5% vs 60%, p < 0.04), and mean surface area of the abscess (1.5 +/- 1.2 vs 5.4 +/- 6.4 cm2, p < 0.03). Independent factors at multivariate analysis were by decreasing order: lack of heart failure at admission, delay to apyrexia, abscess surface area, and age. Outcome was favorable (mean follow-up 33 +/- 10 months) in all patients with an abscess surface area < 1.5 cm2, no signs of heart failure, no grade III or IV valvular regurgitation, apyrexia after less than 8 days on antibiotics and no staphylococcus positive blood culture. CONCLUSION: Medical management of valve ring abscesses may be indicated in selected patients in care units with rigorous surveillance facilities. Further studies are needed to precisely identify surveillance and treatment criteria.     

p-aminohippurate uptake by syncytial microvillous membrane vesicles of human term placenta

The mechanism of uptake of p-aminohippurate (PAH) by syncytial microvillous membrane vesicles of human term placenta was investigated. Initial PAH uptake and efflux were increased in the presence of a pH-gradient and a Cl(-)-gradient, respectively. Forced negative and positive membrane potentials did not influence the uptake, which indicated that the transport is not electrogenic. The pH-dependent increase is probably the result of a higher rate of diffusion due to a lower degree of dissociation of PAH. Because several organic anions failed to transstimulate PAH uptake and FCCP did not decrease the uptake in the presence of an inwardly directed H(+)-gradient, ruling out a PAH/OH- antiport, an anion exchange system does not appear to be present in these membranes. Since electrogenicity and anion exchange seem not to be involved in the Cl(-)-dependent increase, an allosteric effect of Cl- on the transporter might be possible. Various organic anions were able to inhibit pH-stimulated PAH uptake significantly. Kinetic analysis of the probenecid sensitive part of uptake provided further evidence for mediated transport of PAH (Km = 7.4 +/- 2.6 mM and Vmax = 2.0 +/- 0.4 nmol/mg/15 s). Non-inhibitable diffusion accounted for the main part of total transport. Concentration dependent inhibition of PAH transport by probenecid showed a Ki of 2.5 +/- 0.9 mM. It is concluded that human placental syncytial microvillous membrane vesicles possess a low affinity transport mechanism for PAH with low specificity. The importance of this system, for placental excretion of anionic drugs, will depend on the intrasyncytial concentration of these drugs, caused by the transport across the basal membrane.     

Editorial: Special Issue on “Texture Analysis and Synthesi”

International Journal of Computer Vision -     

An overview of ultra-wideband microwave imaging via space-time beamforming for early-stage breast-cancer detection

Ultra-wideband (UWB) microwave imaging has recently been proposed for detecting small malignant breast tumors. In this article, we review the current research status of this approach. First, we introduce the concept of microwave imaging via space-time (MIST) beamforming and related signal-processing algorithms. The objective of these signal-processing techniques is to form a spatial image of scattered microwave energy, and to identify the presence and location of malignant lesions from their scattering signatures. Next, we present numerical studies based on finite-difference time-domain simulations to demonstrate the efficacy of MIST beamforming for detecting small malignant breast lesions in both prone and supine configurations. Finally, the experimental feasibility of UWB microwave imaging is demonstrated using an initial imaging prototype and multilayered breast phantoms.     

Passive-Based Walking Robot

In this article, we presented our passive-based biped Denise. Using only two foot contact switches as sensors and simple on/off pneumatic muscle action, it walks at 0.4 m/s and can handle floor disturbances up to 6 mm (leg length is 0.7 m). Its simplicity, efficiency, and die natural look of its motions make it a promising lead for the development of commercially viable humanoid robots. The aim of this article is to provide other researchers enough details so that they can reproduce the work or use it as a basis for future research.     

Axisymmetric extrusion through adaptable dies—Part 1: Flexible velocity fields and power terms

An adaptable die is one that not only produces the correct geometrical shape, but also is designed through an adaptable method to impart other desirable properties to the product or process. In this first part of a series of papers, six kinematically admissible velocity fields are developed for use in upper bound models for axisymmetric extrusion through various dies, including extrusion through adaptable dies. Three base velocity fields are presented:

(1) assuming proportional angles in the deformation zone,

(2) assuming proportional areas in the deformation zone, or

(3) assuming proportional distances from the centerline in the deformation zone.

The base velocity is modified by an additional term comprised of two functions. One function allows extra flexibility in the radial direction, and the second function allows extra flexibility in the angular direction. There are two forms of the second function, which meet the required boundary conditions. The flexibility function in the radial direction is represented by a series of Legendre polynomials, which are orthogonal over the deformation region. The power terms derived for these velocity fields for use in upper bound models are also presented.Part 2 of this series compares the results obtained in upper bound models for the six velocity fields for a spherical extrusion die. In Part 3, the use of the best velocity field for extrusion through streamlined dies is developed to determine the adaptable die shape, which minimizes the required extrusion pressure. Additionally, the adaptable die shape is compared with results from Yang and Han for arbitrarily curved and streamlined dies.