Detection and characterization of the electron paramagnetic resonance-silent glutathionyl-5,5-dimethyl-1-pyrroline N-oxide adduct derived from redox cycling of phenoxyl radicals in model systems and HL-60 cells

Rapidly growing knowledge about the nature and behaviour of breast cancer has led to many treatment modalities. Consequently, the possibilities of individualizing the treatment of breast cancer increase. The major tool for the determination of an optimal treatment plan is the estimation of the extent of the disease: in other words, staging. As a consequence, together with the expected result of the treatment, the stage of the disease gives information on the prognosis of the patient. Current staging systems insufficiently describe the clinically important features of breast cancer with respect to management and outcome: local and regional extent, invasiveness, aggressiveness, the state of dissemination, and the effectiveness of different treatment modalities. For staging of the local and regional extent, histology plays a prominent role and should be incorporated in future staging systems. Histological workup therefore needs standardisation. Histological parameters as tumour size, grade, nodal status, and vascular invasion are also the most important prognostic factors. Many so-called biological prognostic factors are related to the invasiveness and aggressiveness (metastatic potential) of the tumour, and therefore to the prognosis of the patient. However, these factors do not necessarily predict the effectiveness of certain systemic treatments. Only if the biological foundation of a prognostic factor is completely clarified can treatment be based on this knowledge, and the factor will become a predictor for the treatment effect. Many "biological" prognostic factors do not fulfil this main criterion and are therefore not useful for clinical decision making. A clinically useful staging system covers three primary aims: (1) to guide locoregional treatment, (2) to prognosticate the chance of survival, and (3) to indicate who needs what kind of adjuvant treatment. For the conception of a new staging system the following steps should be taken: standardization of all aspects of histology, identification of regional nodal involvement, and validation of prognostic factors with respect to their predictive value to treatment outcome.     

A chondroitin sulfate/keratan sulfate proteoglycan, PG-1000, forms complexes which are concentrated in the reticular laminae of electric organ basement membranes

Previously, we identified PG-1000 as part of a disulfide-linked complex of two large proteoglycans (PG-1000 and the beta component) and three smaller proteins purified from the extracellular matrix of elasmobranch electric organ (Iwata and Carlson, 1991, J. Biol. Chem. 266: 323-333). PG-1000 is a chondroitin sulfate/keratan sulfate proteoglycan with a molecular mass of about 1.2 x 16(6) daltons. When visualized in the electron microscope, PG-1000 has the typical "bottle-brush" appearance expected for a proteoglycan with an average total length of about 345 nm and about 20 chains of approximately 110 nm (Carlson and Wight, 1987, J. Cell Biol. 105: 3075-3086). Using immunocytochemical methods, we now demonstrate that PG-1000 is a component of the interstitial extracellular matrix of the electric organ. PG-1000 immunoreactivity is found throughout the interstitial matrix, but it is highly concentrated in that region of the matrix immediately adjacent to the basal lamina, the reticular lamina. The reticular and basal laminae together form the basement membrane. PG-1000 immunoreactivity is especially apparent on basal laminae that surround nerve fibers and nerve terminals. When the disulfide-linked PG-1000 complexes are purified and examined in the electron microscope following rotary shadowing, they appear as bottle-brush structures which are often attached at a central region and radiate like spokes of a wheel. These aggregates contain two to six proteoglycan monomers. We hypothesize that the PG-1000 complexes are disulfide-stabilized parts of an extended network of linked proteoglycans in the reticular lamina.     

Surgical anatomy for endoscopic subfascial division of perforating veins

PURPOSE: This study was undertaken to define the surgical anatomy of the medial perforating veins (PVs) of the leg and to provide information on how to gain access to all medial PVs from the superficial posterior compartment during a subfascial endoscopic procedure. METHODS: The venous anatomy of 40 limbs (from 23 cadavers) were studied. Medial PVs located between the ankle and the tibial tuberosity were dissected. None of the subjects had pathologic evidence of venous disease. Each PV's type (direct or indirect), size (< 1 mm, 1 to 2 mm, > 2 mm), location (distances from ankle [D1], and tibia [D2]), and accessibility from the superficial posterior compartment were recorded. RESULTS: Five hundred fifty-two PVs were identified (mean, 13.8; range, 7 to 22). Two hundred eighty-seven PVs (52%) directly connected the superficial with the deep systems, 228 (41%) were indirect muscle perforators, and 37 PVs (7%) were undetermined. One hundred thirty-seven PVs (25%) were > 2 mm. Sixty-three percent of PVs were accessible from the superficial posterior compartment. In the distal half of the leg, two groups of direct PVs could be identified (Cockett II: D1, 7 to 9 cm; Cockett III: D1, 10 to 12 cm). In the proximal half of the leg, paratibial direct PVs (D2 < or = 1 cm) were found clustered in three groups (D1, 18 to 22 cm; D1, 23 to 27 cm; D1, 28 to 32 cm). CONCLUSIONS: Our study confirmed the presence of the Cockett II and III PVs and three groups of proximal paratibial PVs, including the "24-cm" perforators. Two thirds of the medial direct PVs are accessible for endoscopic division from the superficial posterior compartment. To divide paratibial PVs, however, incision of the paratibial deep fascia is frequently required.     

The evaluation of lyophilized polymer matrices for administering recombinant human bone morphogenetic protein-2

Novel unitary devices, prepared by lyophilization of viscous solutions of sodium carboxymethylcellulose (CMC) and methylcellulose (MC), were evaluated as sustained-release delivery systems for recombinant human bone morphogenetic protein-2 (rhBMP-2). In vitro characterization of the unitary devices, which contained rhBMP-2-loaded poly (d,l lactide-co-glycolide) (PLGA) bioerodible particles (BEPs), was conducted over a 2-month period. Determinations included buffer uptake, mass and molecular weight loss and rhBMP-2 release from the unitary devices. CMC devices imbibed approximately 16 times their weight of buffer, while with MC, equilibrium uptake was approximately 6 times the dry weight of the devices. Overall mass loss percentages were approximately 55 and 35%, respectively, for CMC and MC devices. rhBMP-2 release from the devices was essentially a triphasic process: an initial phase during which "free" protein (rhBMP-2 present on the surface and within the pores of the PLGA BEPs) was released, a lag period during which no release was discerned, and then release of "bound" rhBMP-2 (protein adsorbed to the BEPs). The release of bound protein correlated with the mass loss of the polymer which began after 3 weeks. Release from the unitary devices was lower than that from the BEPs alone, due to a retardation effect of the gelled CMC/MC polymers. In rabbits in which full-thickness cranial bone defects were created, the implants were well tolerated and induced significant new bone growth during an 8-week evaluation period. The CMC devices appear to have induced bone earlier (at 2 weeks), but this did not affect eventual 8-week results. CMC devices without rhBMP-2 appeared to provide some bone conduction, in contrast to the blank MC devices.     

Protein topology of presenilin 1

Mutations in a gene encoding a multitransmembrane protein, termed presenilin 1 (PS1), are causative in the majority of early-onset cases of AD. To determine the topology of PS1, we utilized two strategies: first, we tested whether putative transmembranes are sufficient to export a protease-sensitive substrate across a lipid bilayer; and second, we examined the binding of antibodies to specific PS1 epitopes in cultured cells selectively permeabilized with the pore-forming toxin, streptolysin-O. We document that the "loop," N-terminal, and C-terminal domains of PS1 are oriented toward the cytoplasm.     

A new approach for generating efficient sample from market basket data

Classical data mining algorithms require expensive passes over the entire database to generate frequent items and hence to generate association rules. With the increase in the size of database, it is becoming very difficult to handle large amount of data for computation. One of the solutions to this problem is to generate sample from the database that acts as representative of the entire database for finding association rules in such a way that the distance of the sample from the complete database is minimal. Choosing correct sample that could represent data is not an easy task. Many algorithms have been proposed in the past. Some of them are computationally fast while others give better accuracy. In this paper, we present an algorithm for generating a sample from the database that can replace the entire database for generating association rules and is aimed at keeping a balance between accuracy and speed. The algorithm that is proposed takes into account the average number of small, medium and large 1-itemset in the database and average weight of the transactions to define threshold condition for the transactions. Set of transactions that satisfy the threshold condition is chosen as the representative for the entire database. The effectiveness of the proposed algorithm has been tested over several runs of database generated by IBM synthetic data generator. A vivid comparative performance evaluation of the proposed technique with the existing sampling techniques for comparing the accuracy and speed has also been carried out.     

Unsupervised strategies for shilling detection and robust collaborative filtering

Collaborative filtering systems are essentially social systems which base their recommendation on the judgment of a large number of people. However, like other social systems, they are also vulnerable to manipulation by malicious social elements. Lies and Propaganda may be spread by a malicious user who may have an interest in promoting an item, or downplaying the popularity of another one. By doing this systematically, with either multiple identities, or by involving more people, malicious user votes and profiles can be injected into a collaborative recommender system. This can significantly affect the robustness of a system or algorithm, as has been studied in previous work. While current detection algorithms are able to use certain characteristics of shilling profiles to detect them, they suffer from low precision, and require a large amount of training data. In this work, we provide an in-depth analysis of shilling profiles and describe new approaches to detect malicious collaborative filtering profiles. In particular, we exploit the similarity structure in shilling user profiles to separate them from normal user profiles using unsupervised dimensionality reduction. We present two detection algorithms; one based on PCA, while the other uses PLSA. Experimental results show a much improved detection precision over existing methods without the usage of additional training time required for supervised approaches. Finally, we present a novel and highly effective robust collaborative filtering algorithm which uses ideas presented in the detection algorithms using principal component analysis.     

Bidirectional differential on-chip wave-pipelined serial interconnect with surfing

In the literature, surfing technique has been proposed for differential on-chip wave-pipelined serial interconnects with uniform repeaters (UR) and non-uniform repeaters to increase the data transfer rate for unidirectional schemes. In this paper, a novel bidirectional data transfer through the differential wave-pipelined serial interconnects with surfing for UR is proposed. A new circuit called ‘Bidirectional surfing inverter pair’ is proposed for differential wave-pipelined serial interconnects. The method of logical effort is used for the design of surfing circuits. To evaluate the efficiency of these techniques, 40 mm metal 4 interconnects using the proposed surfing techniques are implemented along with transmitter, receiver and delay locked loop in UMC 180 nm technology and their performances are studied through post layout simulations. The proposed bidirectional differential surfing scheme has a maximum data transfer rate of 2 Gb/s and has allowable jitter of 52 ps on both directions through the same interconnects.     

On constructing an optimal consensus clustering from multiple clusterings

Computing a suitable measure of consensus among several clusterings on the same data is an important problem that arises in several areas such as computational biology and data mining. In this paper, we formalize a set-theoretic model for computing such a similarity measure. Roughly speaking, in this model we have k>1 partitions (clusters) of the same data set each containing the same number of sets and the goal is to align the sets in each partition to minimize a similarity measure. For k=2, a polynomial-time solution was proposed by Gusfield (Information Processing Letters 82 (2002) 159-164). In this paper, we show that the problem is MAX-SNP-hard for k=3 even if each partition in each cluster contains no more than 2 elements and provide a -approximation algorithm for the problem for any k.     

Efficacy of psychotherapy. Asking the right questions

Economic pressures and "value" judgments both compel and contaminate the current debate on the efficacy of psychotherapy. Too often, complex clinical trial outcome studies ignore the clinical or treatment process, as well as personality or contextual variables. Thus, they fail to build the foundations of a clinical science that makes possible the development of individually tailored treatment approaches and outcome predictions for specific patients with unique personalities, symptoms, and life circumstances. The real challenge, therefore, is for each psychotherapeutic approach to delineate its "process steps" and relate these steps to different outcomes. The "process" is the "final common pathway" for a number of patient, therapist, technique, and contextual variables. The capacity to predict the relationship between process and outcome at each stage in a therapeutic procedure is the relevant clinical test of "efficacy."