The Qu-Prolog unification algorithm: Formalisation and correctness

Qu-Prolog is an extension of Prolog which performs meta-level computations over object languages, such as predicate calculi and lambda-calculi, which have object-level variables, and quantifier or binding symbols creating local scopes for those variables. As in Prolog, the instantiable (meta-level) variables of Qu-Prolog range over object-level terms, and in addition other Qu-Prolog syntax denotes the various components of the object-level syntax, including object-level variables. Further, the meta-level operation of substitution into object-level terms is directly represented by appropriate Qu-Prolog syntax. Again as in Prolog, the driving mechanism in Qu-Prolog computation is a form of unification, but this is substantially more complex than for Prolog because of Qu-Prolog's greater generality, and especially because substitution operations are evaluated during unification. In this paper, the Qu-Prolog unification algorithm is specified, formalised and proved correct. Further, the analysis of the algorithm is carried out in a frame-work which straightforwardly allows the 'completeness' of the algorithm to be proved: though fully explicit answers to unification problems are not always provided, no information is lost in the unification process.

The interaction between N-category and N-ratio as a new tool to improve lymph node metastasis staging in gastric cancer: Results of a single cancer center in Brazil

Background: Depth of tumor invasion (T-category) and the number of metastatic lymph nodes (N-category) are the most important prognostic factors in patients with gastric cancer. Recently, the ratio between metastatic and dissected lymph nodes (N-ratio) has been established as one. The aim of this study is to evaluate the impact of N-ratio and its interaction with N-category as a prognostic factor in gastric cancer. Methods: This was a retrospective study in which we reviewed clinical and pathological data of 165 patients who had undergone curative surgery at our institution through a 9-year period. The exclusion criteria included metastases, gastric stump tumors and gastrectomy with less than 15 lymph nodes dissected. Results: The median age of the patients was 63 years and most of them were male. Total gastrectomy was the most common procedure and 92.1% of the patients had a D2-lymphadenectomy. Their 5-year overall survival was 57.7%. T-category, N-category, extended gastrectomy, and N-ratio were prognostic factors in overall and disease-free survival in accordance with univariate analysis. In accordance with TNM staging, N1 patients who have had NR1 had 5-year survival in 75.5% whereas in the NR2 group only 33% of the cases had 5-year survival. In the multivariate analysis, the interaction between N-category and N-ratio was an independent prognostic factor. Conclusion: Our findings confirmed the role of N-ratio as prognostic factor of survival in patients with gastric cancer surgically treated with at least 15 lymph nodes dissected. The relationship between N-category and N-ratio is a better predictor than lymph node metastasis staging. (C) 2010 Elsevier Ltd. All rights reserved.

Skip metaskses in medullary thyroid carcinoma: A single-center experience

Purpose. Total thyroidectomy (TT) with level VI and VII central neck dissection is the initial treatment for medullary thyroid carcinoma (MTC) without identifiable neck metastasis. Level II to V lateral neck dissection is performed if neck metastasis is present or suspected. We conducted this study to identify the frequency and clinical determinants of skip neck metastasis in MTC. Methods. We reviewed the medical records of 32 patients who underwent TT and bilateral neck dissection for MTC. The clinical features were correlated with pN status in the central versus lateral compartments of the neck. Results. Neck lymph node metastasis (pN+) was found in 20 patients (62.5%) and skip metastases were found in 7 (35%) patients. The sensitivity of the pN status of the central compartment of the neck to predict the pN status of the lateral compartment of the neck was 53.8% and specificity was 63.2%. We found pN+ in 90% of the patients with lymph nodes > 15mm in diameter versus 50% in those with lymph nodes < 1.5mm in diameter. Conclusions. There is skip metastasis in MTC. It is unsafe to use the lymph node status of the central compartment of the neck to define the pN status of the lateral neck. A lymph node greater than 15 mm in diameter is related to pN status.

Determination of the force constant of a single-beam gradient trap by measurement of backscattered light

A single-beam gradient trap could potentially be used to hold a stylus for scanning force microscopy. With a view to development of this technique, we modeled the optical trap as a harmonic oscillator and therefore characterized it by its force constant. We measured force constants and resonant frequencies for 1-4-mu m-diameter polystyrene spheres in a single-beam gradient trap using measurements of back-scattered light. Force constants were determined with both Gaussian and doughnut laser modes, with powers of 3 and 1 mW, respectively. Typical values for spring constants were measured to be between 10(-6) and 4 x 10(-6) N/m. The resonant frequencies of trapped particles were measured to be between 1 and 10 kHz, and the rms amplitudes of oscillations were estimated to be around 40 nm. Our results confirm that the use of the doughnut mode for single-beam trapping is more efficient in the axial direction. (C) 1996 Optical Society of America.

Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel

Fast synaptic neurotransmission is mediated by transmitter-activated conformational changes in ligand-gated ion channel receptors, culminating in opening of the integral ion channel pore. Human hereditary hyperekplexia, or startle disease, is caused by mutations in both the intracellular or extracellular loops flanking the pore-lining M2 domain of the glycine receptor alpha 1 subunit. These flanking domains are designated the M1-M2 loop and the M2-M3 loop respectively. We show that four startle disease mutations and six additional alanine substitution mutations distributed throughout both loops result in uncoupling of the ligand binding sites from the channel activation gate. We therefore conclude that the M1-M2 and M2-M3 loops act in parallel to activate the channel. Their locations strongly suggest that they act as hinges governing allosteric control of the M2 domain. As the members of the ligand-gated ion channel superfamily share a common structure, this signal transduction model may apply to all members of this superfamily.

Simulation of mixing in unsteady flow through a periodically obstructed channel

Fluid mixing in steady and unsteady Bow through a channel containing periodic square obstructions has been studied using a finite-difference simulation to determine fluid velocities, followed by the use of passive marker particle advection to look at fluid transport out of the cavities formed between each of the obstructions. The geometry and Bow conditions were chosen from the work by Perkins (1989, M.S. Thesis, Lehigh University; 1992, Ph.D. Thesis, Lehigh University); who investigated heat transfer enhancement due to unsteady flow through such an obstructed channel. Particle advection shows that Bow regimes which are predicted to give good mixing based on snapshots of instantaneous streamline contour plots were not necessarily able to efficiently mix fluid which started in the cavity regions throughout the channel. The use of Poincare sections shows regular regions existing under these conditions which inhibit efficient fluid transport. These regular regions are found to disappear when the unsteady Bow velocity is increased. (C) 1997 Elsevier Science Ltd.

SINGLE MEASUREMENTS OF C-REACTIVE PROTEIN AND DISEASE ACTIVITY SCORES ARE NOT PREDICTORS OF CAROTID ATHEROSCLEROSIS IN RHEUMATOID ARTHRITIS PATIENTS

Background: Although inflammation has a defined role in the pathogenesis of atherosclerosis, the link between rheumatoid arthritis (RA) parameters of disease activity and atherosclerotic findings are not defined. Objective: To investigate the association between subclinical carotid atherosclerosis and clinical/laboratorial parameters of RA systemic inflammatory activity. Methods: Seventy-one RA patients were consecutively selected and compared to 53 healthy controls. Smoking, diabetes and hypertension were excluded, as well as the use of statins or fibrates. B-mode carotid ultrasound was performed in all subjects. CRP, ESR and fibrinogen were determined in both groups. Clinical assessment of RA activity included DAS 28 and SDAI. Correlation between plaques and intima-media thickness (IMT) of common carotid arteries and inflammatory parameters was evaluated. Results: Carotid plaques were more prevalent in RA patients than in controls (14.1% vs. 1.9 %, p=0.02) and marginally increased IMT was observed (0.72 +/- 0.17 vs. 0.67 +/- 0.15mm, p=0.07). RA patients with plaques had older age (p=0.001) and increased IMT (p<0.001), but low SDAI (p=0.025) compared to those without plaques. RA patients with plaques had also longer disease duration, although this difference did not reach statistical significance (p=0.06). No significant correlations were found between IMT and ESR (p=0.80), CRP (p=0.75), fibrinogen (p=0.94), HAQ (p=0.89) and DAS 28 (p=0.13). Conclusions: Carotid atherosclerosis is more frequently detected in RA but its prevalence was not correlated with isolated inflammatory markers measurement or noncumulative activity scores. These findings reinforce the need to evaluate subclinical atherosclerosis in RA patients, and to find predictors of atherosclerotic lesions.

A single dose of zoledronic acid reverses the deleterious effects of glucocorticoids on titanium implant osseointegration

This study evaluates the effect of zoledronic acid (ZOL) on the osseointegration of titanium implants in rabbits with glucocorticoid (GC)-induced bone loss, and our findings demonstrated that a single dose of ZOL is able to reverse the detrimental effects of GCs on the osseointegration of titanium implants. The purpose of this study is to evaluate the effect of ZOL on the osseointegration of titanium implants in rabbits with GC-induced bone loss. Three groups of six NZW rabbits were treated for 18 weeks with saline (SALINE), GC (methylprednisolone, 0.35 mg/kg three times a week), or GC + ZOL (methylprednisolone + single dose of ZOL, 0.1 mg/kg). The animals received a titanium implant in the left tibia after 6 weeks and were killed at the 18th week. Bone mineral density (BMD) was measured with dual-energy X-ray absorptiometry at baseline, eighth week (W8), and 18th week (W18) after treatment to determine the change upon treatment (a dagger BMD). Histomorphometric and serum bone alkaline phosphatase analysis (BAP) were also performed. At W8, GC group had a significant reduction in lumbar spine and tibia BMD compared with SALINE (p = 0.003 and p = 0.000), as also observed for GC + ZOL group (p = 0.014 and p = 0.003) just 2 weeks after ZOL treatment. In contrast, at W18, the GC + ZOL had an evident BMD rescue with similar lumbar spine and tibia a dagger BMD compared with SALINE (0.043 +/- 0.006 vs. 0.055 +/- 0.009 g/cm(2), p = 0.457 and 0.027 +/- 0.003 vs. 0.041 +/- 0.011 g/cm(2), p = 0.232) and a significantly higher a dagger BMD compared with the GC (p = 0.024 and p = 0.001). Histomorphometry revealed that osseointegration was significantly reduced in GC (tibia cortical thickness and diameter, bone-implant contact, total and peri-implant bone area) whereas GC + ZOL had these parameters similar to SALINE (p > 0.05). Likewise, ZOL reversed the BAP alteration induced by GC. Our findings demonstrated that a single dose of ZOL is able to reverse the detrimental effects of glucocorticoids on the osseointegration of titanium implants, suggesting that ZOL therapy may improve the outcome of bone implants in patients with glucocorticoid-induced osteoporosis.

Encephalitogenicity of murine, but not bovine, DM20 in SJL mice is due to a single amino acid difference in the immunodominant encephalitogenic epitope

Myelin proteolipid protein (PLP) contains 2 immunodominant encephalitogenic epitopes in SJL mice, namely PLP residues 139-151 and 178-191. DM20, a minor isoform of PLP, lacks residues 116-150 and consequently contains only the single major encephalitogenic epitope 178-191. However, it has been found previously that bovine DM20 is not encephalitogenic in SJL mice. Since residue 188 within peptide 178-191 is phenylalanine (F) in murine DM20 and alanine (A) in bovine DM20, we tested the effect of this difference on the immune responses and induction of EAE. SJL mice were immunized with either highly purified murine or bovine DM20. Residues 178-191 were found to be immunodominant for each, but only murine and not bovine DM20 was encephalitogenic. A synthetic peptide corresponding to the murine 178-191 sequence (F188) was also encephalitogenic, whereas the peptide corresponding to the bovine sequence (A188) was not. Both F188 and A188 bind with high affinity to I-A(s) and both are recognized by the SJL T cell repertoire. A188-specific T cell lines reacted to both A188 and F188, but F188-specific T cell lines were not stimulated by A188. F188-specific T cell lines produced mRNA for the Th1 cytokines IL2 and IFN gamma and, in passive transfer experiments, were encephalitogenic upon stimulation with F188, but not A188. In contrast, A188-specific T cell lines produced mRNA for IL4, IL5 and IL10, in addition to IL2 and IFN gamma, and were not encephalitogenic after stimulation with either F188 or A188. Cotransfer of A188-specific T cell lines with F188-specific T cell lines resulted in protection from EAE. Thus, A188 induces a functionally different phenotype of T cells from that induced by F188. Taken together these data suggest that the failure of bovine DM20 to induce EAE may be attributable to induction of protective rather than pathogenic T cells by the immunodominant epitope.

Solution structure of the sodium channel antagonist conotoxin GS: A new molecular caliper for probing sodium channel geometry

Background: The venoms of Conus snails contain small, disulfide-rich inhibitors of voltage-dependent sodium channels. Conotoxin GS is a 34-residue polypeptide isolated from Conus geographus that interacts with the extracellular entrance of skeletal muscle sodium channels to prevent sodium ion conduction. Although conotoxin GS binds competitively with mu conotoxin GIIIA to the sodium channel surface, the two toxin types have little sequence identity with one another, and conotoxin GS has a four-loop structural framework rather than the characteristic three-loop mu-conotoxin framework. The structural study of conotoxin GS will form the basis for establishing a structure-activity relationship and understanding its interaction with the pore region of sodium channels. Results: The three-dimensional structure of conotoxin GS was determined using two-dimensional NMR spectroscopy. The protein exhibits a compact fold incorporating a beta hairpin and several turns. An unusual feature of conotoxin GS is the exceptionally high proportion (100%) of cis-imide bond geometry for the three proline or hydroxyproline residues. The structure of conotoxin GS bears little resemblance to the three-loop mu conotoxins, consistent with the low sequence identity between the two toxin types and their different structural framework. However, the tertiary structure and cystine-knot motif formed by the three disulfide bonds is similar to that present in several other polypeptide ion channel inhibitors. Conclusions: This is the first three-dimensional structure of a 'four-loop' sodium channel inhibitor, and it represents a valuable new structural probe for the pore region of voltage-dependent sodium channels. The distribution of amino acid sidechains in the structure creates several polar and charged patches, and comparison with the mu conotoxins provides a basis for determining the binding surface of the conotoxin GS polypeptide.

Analyzing the connectivity between regions of interest: An approach based on cluster Granger causality for NRI data analysis

The identification, modeling, and analysis of interactions between nodes of neural systems in the human brain have become the aim of interest of many studies in neuroscience. The complex neural network structure and its correlations with brain functions have played a role in all areas of neuroscience, including the comprehension of cognitive and emotional processing. Indeed, understanding how information is stored, retrieved, processed, and transmitted is one of the ultimate challenges in brain research. In this context, in functional neuroimaging, connectivity analysis is a major tool for the exploration and characterization of the information flow between specialized brain regions. In most functional magnetic resonance imaging (fMRI) studies, connectivity analysis is carried out by first selecting regions of interest (ROI) and then calculating an average BOLD time series (across the voxels in each cluster). Some studies have shown that the average may not be a good choice and have suggested, as an alternative, the use of principal component analysis (PCA) to extract the principal eigen-time series from the ROI(s). In this paper, we introduce a novel approach called cluster Granger analysis (CGA) to study connectivity between ROIs. The main aim of this method was to employ multiple eigen-time series in each ROI to avoid temporal information loss during identification of Granger causality. Such information loss is inherent in averaging (e.g., to yield a single ""representative"" time series per ROI). This, in turn, may lead to a lack of power in detecting connections. The proposed approach is based on multivariate statistical analysis and integrates PCA and partial canonical correlation in a framework of Granger causality for clusters (sets) of time series. We also describe an algorithm for statistical significance testing based on bootstrapping. By using Monte Carlo simulations, we show that the proposed approach outperforms conventional Granger causality analysis (i.e., using representative time series extracted by signal averaging or first principal components estimation from ROIs). The usefulness of the CGA approach in real fMRI data is illustrated in an experiment using human faces expressing emotions. With this data set, the proposed approach suggested the presence of significantly more connections between the ROIs than were detected using a single representative time series in each ROI. (c) 2010 Elsevier Inc. All rights reserved.

Analysis and implementation of a new constant acceleration subcycling algorithm

An algorithm for explicit integration of structural dynamics problems with multiple time steps is proposed that averages accelerations to obtain subcycle states at a nodal interface between regions integrated with different time steps. With integer time step ratios, the resulting subcycle updates at the interface sum to give the same effect as a central difference update over a major cycle. The algorithm is shown to have good accuracy, and stability properties in linear elastic analysis similar to those of constant velocity subcycling algorithms. The implementation of a generalised form of the algorithm with non-integer time step ratios is presented. (C) 1997 by John Wiley & Sons, Ltd.

Peritonectomy for Peritoneal Carcinomatosis: Long-Term Outcomes from a Single Brazilian Institution

The objective of this study was to evaluate the long-term outcomes of a single institution, Hospital Sirio-Libanes in SA o pound Paulo, Brazil, regarding the treatment of peritoneal carcinomatosis. Between October 2002 and October 2006, 46 consecutive patients were treated with radical cytoreduction and hyperthermic peritoneal chemotherapy. There were 21 patients with peritoneal surface malignancy (PSM) from colorectal origin (among whom 8 had an appendiceal primary), 15 with ovarian carcinomas, 2 with primary peritoneal mesotheliomas, and 8 with other cancers. The median age was 49 years (range 18-77 years). All patients were followed for a median of 20 months. Demographic data, tumor histology, the peritoneal carcinomatosis index (PCI), operative procedures (extension of resection, lymphadenectomy), and hyperthermic intraperitoneal chemotherapy (HIPEC) characteristics (drugs, temperature, duration) were prospectively recorded. Perioperative mortality and morbidity and the long-term outcome were assessed. Complete cytoreduction was achieved in 45 patients. The median PCI was 11, and the mean operating time was 17 h. There were no procedure-related deaths, but major morbidity was observed in 52% and included fistulas, abscesses, and hematologic complications. The overall Kaplan-Meier 4-year estimated survival was 56%. Among patients with PSM from colorectal carcinoma, the estimated 3-year survival was 70%. Nine (42%) patients had a recurrence, three with peritoneal disease. The median disease-free-interval was 16 months. The ovarian cancer patients had an estimated 4-year survival rate of 75% and median disease-free survival duration of 21 months. Cytoreductive surgery with HIPEC may improve survival of selected patients with peritoneal carcinomatosis, with acceptable morbidity.