Expression of chemokines CXCL4 and CXCL7 by synovial macrophages defines an early stage of rheumatoid arthritis.

BACKGROUND AND OBJECTIVES: For our understanding of the pathogenesis of rheumatoid arthritis (RA), it is important to elucidate the mechanisms underlying early stages of synovitis. Here, synovial cytokine production was investigated in patients with very early arthritis. METHODS: Synovial biopsies were obtained from patients with at least one clinically swollen joint within 12 weeks of symptom onset. At an 18-month follow-up visit, patients who went on to develop RA, or whose arthritis spontaneously resolved, were identified. Biopsies were also obtained from patients with RA with longer symptom duration (>12 weeks) and individuals with no clinically apparent inflammation. Synovial mRNA expression of 117 cytokines was quantified using PCR techniques and analysed using standard and novel methods of data analysis. Synovial tissue sections were stained for CXCL4, CXCL7, CD41, CD68 and von Willebrand factor. RESULTS: A machine learning approach identified expression of mRNA for CXCL4 and CXCL7 as potentially important in the classification of early RA versus resolving arthritis. mRNA levels for these chemokines were significantly elevated in patients with early RA compared with uninflamed controls. Significantly increased CXCL4 and CXCL7 protein expression was observed in patients with early RA compared with those with resolving arthritis or longer established disease. CXCL4 and CXCL7 co-localised with blood vessels, platelets and CD68(+) macrophages. Extravascular CXCL7 expression was significantly higher in patients with very early RA compared with longer duration RA or resolving arthritis CONCLUSIONS: Taken together, these observations suggest a transient increase in synovial CXCL4 and CXCL7 levels in early RA.

Investigating the aspect of asymmetry in brain-first versus body-first Parkinson's disease.

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. Recent literature has proposed two subgroups of PD. The "body-first subtype" is associated with a prodrome of isolated REM-sleep Behavior Disorder (iRBD) and a relatively symmetric brain degeneration. The "brain-first subtype" is suggested to have a more asymmetric degeneration and a prodromal stage without RBD. This study aims to investigate the proposed difference in symmetry of the degeneration pattern in the presumed body and brain-first PD subtypes. We analyzed 123I-FP-CIT (DAT SPECT) and 18F-FDG PET brain imaging in three groups of patients (iRBD, n = 20, de novo PD with prodromal RBD, n = 22, and de novo PD without RBD, n = 16) and evaluated dopaminergic and glucose metabolic symmetry. The RBD status of all patients was confirmed with video-polysomnography. The PD groups did not differ from each other with regard to the relative or absolute asymmetry of DAT uptake in the putamen (p = 1.0 and p = 0.4, respectively). The patient groups also did not differ from each other with regard to the symmetry of expression of the PD-related metabolic pattern (PDRP) in each hemisphere. The PD groups had no difference in symmetry considering mean FDG uptake in left and right regions of interest and generally had the same degree of symmetry as controls, while the iRBD patients had nine regions with abnormal left-right differences (p < 0.001). Our findings do not support the asymmetry aspect of the "body-first" versus "brain-first" hypothesis.

Window-based example selection in learning vector quantization.

A variety of modifications have been employed to learning vector quantization (LVQ) algorithms using either crisp or soft windows for selection of data. Although these schemes have been shown in practice to improve performance, a theoretical study on the influence of windows has so far been limited. Here we rigorously analyze the influence of windows in a controlled environment of gaussian mixtures in high dimensions. Concepts from statistical physics and the theory of online learning allow an exact description of the training dynamics, yielding typical learning curves, convergence properties, and achievable generalization abilities. We compare the performance and demonstrate the advantages of various algorithms, including LVQ 2.1, generalized LVQ (GLVQ), Learning from Mistakes (LFM) and Robust Soft LVQ (RSLVQ). We find that the selection of the window parameter highly influences the learning curves but not, surprisingly, the asymptotic performances of LVQ 2.1 and RSLVQ. Although the prototypes of LVQ 2.1 exhibit divergent behavior, the resulting decision boundary coincides with the optimal decision boundary, thus yielding optimal generalization ability.

Simulation of self-assembled nanopatterns in strained 2D alloys on the face centered cubic (111) surface.

We investigate the formation of nanostructures in 2D strained alloys on face centered cubic (111) surfaces by means of equilibrium Monte Carlo simulations. In the framework of an off-lattice model, we consider one monolayer of two bulk-immiscible adsorbates A and B with negative and positive misfit relative to the substrate, respectively. Simulations show that the adsorbates partly self-organize into island or stripe-like patterns. We show how these structures depend on the relative misfits, interaction, and concentration of components. The morphology is quite different for phase separation and intermixing regimes.

A combination of nutrition and genetics is able to reduce age at puberty in Nelore heifers to below 18 months.

Nelore heifers usually begin their reproductive life at ⩾24 months of age mainly due to suboptimal nutritional conditions and genetics. This study aimed to determine the effect of expected progeny difference (EPD) for age at first calving and average daily gain (ADG) on puberty in Nelore (Bos taurus indicus) heifers. A total of 58 weaned heifers (initial BW=174±6 kg; age=9±1 months) were allocated into 28 feedlot pens. Heifers were born from four sires, of which two had low EPD for age at first calving (L; n=33) and two had high EPD for age at first calving (H; n=25). Then, heifers of each EPD were randomly assigned to high ADG (HG; 0.7 kg) or low ADG (LG; 0.3 kg), resulting in four treatments: heifers from L sires were submitted to either HG (LHG; n=17) or LG (LLG; n=16), and heifers from H sires were submitted to either HG (HHG; n=12), or LG (HLG; n=13). The HG heifers were fed a 75% grain diet, whereas the LG heifers received 93% of forage in their diet. Blood samples were collected at 9, 14, 18, 24 and 28 months of age for IGF1 and leptin determination. There was a treatment effect (P<0.01) on the proportion of heifers that attained puberty by 18 (62%, 0%, 0% and 0%), 24 (100%, 6%, 54% and 0%) or 36 (100%, 100%, 100% and 38%) months of age for LHG, LLG, HHG and HLG treatments, respectively. In addition, mean age at puberty was different across treatments (P<0.01). Heifers from the LHG achieved puberty at the earliest age when compared with cohorts from other treatments (18.1, 28.9, 23.9 and 34.5 months for LHG, LLG, HHG and HLG, respectively). Serum IGF1 concentrations were higher for L heifers compared with H cohorts at 9, 14, 18, 24 and 28 months of age (P<0.01; treatment×age interaction), whereas circulating leptin concentrations were higher (P<0.01; age effect) as heifers became older, regardless of the treatments. In conclusion, only Nelore heifers with favorable genetic merit for age at first calving were able to attain puberty by 18 months of age. In heifers with unfavorable genetic merit for age at first calving, supplementary feeding to achieve high ADG was unable to shift the age at puberty below 24 months.

[Bone Marrow Lesion - Risk-Factors and Pathophysiological Relevance: Systematic Review]. / Bone Marrow Lesion - Risikofaktoren und pathophysiologische Bedeutung: systematisches Review.

AIM: The objective of this systematic review and meta-analysis is to obtain information about risks and associated factors for knee symptoms and the progression of osteoarthritis in idiopathic bone marrow lesion (BML). MATERIALS AND METHODS: The primary search on 31. 12. 2013 included the databases PubMed, EMBASE, Web of Science and Cochrane by the search strategy [[bone marrow edema] AND [knee]]. This review was continuously updated up to 31. 10. 2015. RESULTS: A total of 30 studies (from 1331 primary findings) were included in the final evaluation. The mean frequency of BML in all studies was 37.2 %. The occurrence of BML was strongly dependent on the MRI technique used (1.0 to 3.0 T). In longitudinal studies, the incidence of BML was 3.2 (95 % CI 1.7-6.3)/1000 person-months. Weakly associated factors included female gender (OR = 1.3 [95 % CI 1.1-1.7], p = 0.009), increasing age (OR = 1.05 [95 % CI 0.9-1.3], p = 0.127), and overweight or obesity (OR = 1.1 [95 % CI 1.1-1.2]; p < 0.01). BMLs are significantly associated with cartilage lesions (OR = 5.5 [95 % CI 1.3-22.5]). Radiological osteoarthritis is also significantly associated with the development of BML (OR = 3.6 [95 % CI 1.2-10.6]) and the progression of osteoarthritis within a 3-year interval (OR = 4.4 [95 % CI 3.1-6.4]). CONCLUSIONS: The occurrence of BML is an important index for severe degenerative pathologies in the knee. It appears that MRT symptoms predict the progression of the disease. The clinical relevance and possible consequences for treatment are unclear.

Efficacy of the implantable cardioverter-defibrillator in the elderly.

OBJECTIVES: We sought to assess the effect of advanced age on the outcome of patients with an implantable cardioverter-defibrillator (ICD). BACKGROUND: ICDs are effective in preventing sudden cardiac death in susceptible patients, but their beneficial effect on survival is attenuated by the high rate of nonsudden cardiac death in those treated. Although advanced age is an important variable in determining cardiovascular mortality, its impact on the outcome of patients with an ICD has been inadequately studied. METHODS: We performed multivariate analysis of a data base consisting of 769 consecutive patients with an ICD. Seventy-four patients > or = 75 years old at ICD implantation (Group 1) were compared with the remaining 695 patients (Group 2). RESULTS: The two groups were similar in clinical presentation, left ventricular function and gender distribution. The mean follow-up time was 29 and 42 months, respectively, for patients in Group 1 and Group 2. Actuarial survival at 4 years was 57% in Group 1 versus 78% in Group 2 (p = 0.0001). This difference was primarily due to a higher rate of nonsudden cardiac death in Group 1. On multivariate analysis, age > or = 75 years, New York Heart Association functional class III, left ventricular ejection fraction < 30% and appropriate shocks during follow-up were independently associated with increased mortality (odds ratio 3.56, 1.8, 1.6 and 1.39, respectively). CONCLUSIONS: Among patients with similar functional class and ejection fraction, the mortality risk is increased threefold in those > or = 75 years old at the time of ICD implantation. Extrapolation of results from younger patients is likely to overestimate ICD benefit in the elderly.

Feasibility of atrial fibrillation detection and use of a preceding synchronization interval as a criterion for shock delivery in humans with atrial fibrillation.

OBJECTIVES: This study assessed the feasibility of detecting atrial fibrillation (AF) and delivery of appropriately timed R wave shocks using an implantable atrial defibrillator. BACKGROUND: For atrial defibrillation therapy to be feasible in an implantable form, AF must be detected in a specific fashion, and the risk of ventricular proarrhythmia should be minimized. METHODS: Eleven patients with AF underwent testing with an implantable atrial defibrillator (METRIX 3000 Automatic Atrial Defibrillator, InControl, Inc.). Wideband electrograms (EGMs) were recorded from the right ventricular (RV) bipolar catheter and from the multipolar catheters located in the right atrium (RA) and coronary sinus (CS). Atrial fibrillation detection was performed using two serial algorithms-quiet interval analysis and baseline crossing analysis-that detect atrial activity on the RA-CS channel. Ventricular sensing using a minimal preceding synchronization interval of 500 ms as a criterion for synchronous shock delivery was performed from filtered RV and RV-CS EGMs. RESULTS: The AF detection algorithms were applied to 53 AF data segments and 18 normal sinus rhythm data segments. Atrial fibrillation was detected appropriately in 49 instances, and the specificity for detecting AF and normal sinus rhythm was 100%. Synchronization criterion efficacy was assessed by delivering shock markers and shocks. Of the 2,025 R waves processed, 557 (27.5%) were marked as suitable for shock delivery. In addition, 69 therapeutic and 11 test shocks were delivered during AF. All shock markers and shocks were delivered synchronously with the R wave, and the synchronization criterion was never violated. CONCLUSIONS: Atrial fibrillation can be detected in a specific fashion using the RA-CS lead configuration and serial detection algorithms for atrial sensing. The delivery of properly timed shocks is feasible and should minimize the risk of ventricular proarrhythmia.

Distribution of atrial electrogram types during atrial fibrillation: effect of rapid atrial pacing and intercaval junction ablation.

OBJECTIVES: This study examined the anatomic distribution types and possible determinant of atrial electrogram types during atrial fibrillation. BACKGROUND: Different types of atrial electrograms during atrial fibrillation have been observed and classified, but their anatomic distribution patterns, determinants and potential usefulness in guiding future catheter ablation are unknown. METHODS: Two animal models of atrial fibrillation were used: the sterile pericarditis model (n = 10) and the rapid atrial pacing model (400 beats/min for 6 weeks, n = 6). The atrial electrogram of atrial fibrillation and the atrial effective refractory period were obtained from multiple sites of the right and left atrium. In addition, decremental rapid atrial stimulation was applied to the site of shortest and longest atrial effective refractory periods until atrial fibrillation induction in a subgroup of nine dogs. Ablation of the intercaval junction was performed using the radiofrequency catheter technique in dogs with atrial fibrillation duration > 1 min. RESULTS: In both models, organized atrial electrograms (type I) were predominantly observed at the left atrial sites and the right atrial appendage, whereas disorganized atrial electrograms (type III) were mainly observed at the right posterolateral atrium. The distribution of the atrial electrogram types closely followed that of the atrial effective refractory period, with the shortest atrial effective refractory period corresponding to organized atrial electrograms (type I) and the longest atrial effective refractory period corresponding to disorganized atrial electrograms (type III). The correlation of atrial electrogram type with the atrial effective refractory period was further demonstrated by the effect of rapid atrial stimulation. When rapid atrial stimulation was applied to the site with the shortest atrial effective refractory period, disorganized atrial electrograms were observed at sites with the longest atrial effective refractory period, whereas 1:1 atrial capture was still present at the stimulation site. Ablation of the intercaval junction made atrial fibrillation noninducible or tended to shorten the atrial fibrillation duration (from 26.4 +/- 24.2 to 8.8 +/- 22.6 min in the pericarditis group, p = 0.02, and from 33.7 +/- 29.2 to 12.1 +/- 23.8 min in the rapid pacing group, p = 0.09) but did not change the atrial electrogram types during atrial fibrillation. CONCLUSIONS: Various types of atrial electrograms are present at different locations during atrial fibrillation. The atrial electrogram characteristics of atrial fibrillation at a specific location are related to the atrial effective refractory period, with short effective refractory periods associated with organized atrial electrograms and long effective refractory periods associated with disorganized electrograms.

Unmasking the trifascicular left intraventricular conduction system by ablation of the right bundle branch.

Twenty-five patients underwent transcatheter right bundle ablation either for bundle branch reentrant tachycardias or inadvertent or deliberate right bundle ablation during atrioventricular junctional ablation for rate control. Electrophysiologic data and 12-lead electrocardiograms before and after right bundle ablation were available in all patients. Eleven of the patients had no significant intraventricular conduction abnormalities by surface electrocardiograms (group I), whereas 14 patients had underlying intraventricular conduction delays (group II). All group I patients had typical electrocardiographic changes of right bundle branch block after right bundle ablation, with minimal changes in initial or mean QRS axis. In group II, 5 patients had an initial 40 ms QRS axis shift of > 45 degrees, in 7 patients the mean QRS axis changed significantly (leftward in 4 and rightward in 3), and a qR pattern in V1 was seen in 12 of 14 patients including 2 with structurally normal hearts. These changes, namely new Q waves, and rightward and leftward axis shifts are most likely the result of septal fascicular, left posterior fascicular, and left anterior fascicular delay/block, which were exposed by exclusive conduction via a diseased left bundle and its fascicles. The trifascicular nature of left intraventricular conduction is more apparent when diseased and unmasked by concomitant block in the right bundle branch.

The role of behavioral experience in judging risks.

This study used conditional risk assessments to examine the role of behavioral experiences in risk judgments. Adolescents and young adults (ages 10-30; N = 577) were surveyed on their risk judgments for natural hazards and behavior-linked risks, including their personal experiences with these events. Results indicated that participants who had experienced a natural disaster or engaged in a particular risk behavior estimated their chance of experiencing a negative outcome resulting from that event or behavior as less likely than individuals without such experience. These findings challenge the notion that risk judgments motivate behavior and instead suggest that risk judgments may be reflective of behavioral experiences. The results have implications for health education and risk communication.

Pharmacokinetics of tiqueside (beta-tigogenin cellobioside) in dogs, rats, rabbits, and monkeys.

Tiqueside (CP-88,818, beta-tigogenin cellobioside) is an effective cholesterol absorption inhibitor that may be useful in the treatment of hypercholesteremia. We have investigated the pharmacokinetics of tiqueside in dogs, rats, rabbits, and monkeys. In dogs, the volume of distribution (Vdss) was 2.11 L/kg, clearance was 0.58 mL/min-kg, and half-life was 45 h following a 1.4 mg/kg intravenous dose. Absolute bioavailability in fed dogs decreased from 6.7% for a 30 mg/kg dose to 1.7% for a 375 mg/kg dose. The oral bioavailability at a dose of 375 mg/kg was approximately 4-fold lower in fasted dogs than fed dogs. AUC-(0-24) for doses up to 2000 mg/kg were only slightly greater than AUC-(0-24) for a 375 mg/kg dose. In rats dosed intravenously at 8.0 mg/kg, Vdss was 3.52 L/kg, clearance was 14.6 mL/min-kg, and half-life was 3.6 h. Estimated bioavailability for rats dosed in feed at 250-2000 mg/kg/day was less than 0.5%. In rabbits dosed at 4.0 mg/kg i.v., Vdss was 2.95 L/kg, clearance was 0.59 mL/min-kg, and half-life was 61 h. Bioavailability for rabbits dosed in feed at 62.5 or 125 mg/kg/day was approximately 7%. Systemic exposure in rhesus monkeys after oral dosing was lower than that for dogs and rabbits. Thus, low systemic exposure to tiqueside following oral administration has been demonstrated in several animal species.

Adolescents' and adults' understanding of probability expressions.

PURPOSE: To examine whether there are differences between adolescents and adults in their interpretation of probability terms. METHODS: Participants were 20 fifth graders, 54 seventh graders, 45 ninth graders, and 34 young adults (mean adult age = 26.24 years, standard deviation = 2.09) from the San Francisco Bay area. They completed a self-administered survey asking them to assign percentage estimates (0% to 100%) to 30 randomly ordered probability terms. RESULTS: Significant age differences in the mean percentage estimates for 8 of the 30 terms were shown. Moreover, we found large variation in the interpretation of most probability terms studied, with larger variation among the adolescents than adults. Finally, all age groups had some difficulty correctly differentiating between "possibly" and "probably". CONCLUSIONS: Owing to wide variation in the interpretation of probability terms, both within and across age groups, we suggest health practitioners use percentages rather than probability terms to convey risk to both adolescents and adults.

[Computer-assisted visualization of digital mammography images]. / Computergestützte Visualisierung digitaler Mammogramme.

PURPOSE: In a clinical study, the feasibility of using a mammography workstation for the display and interpretation of digital mammography images was evaluated and the results were compared with the corresponding laser film hard copies. MATERIALS AND METHODS: Digital phosphorous plate radiographs of the entire breast were obtained in 30 patients using a direct magnification mammography system. The images were displayed for interpretation on the computer monitor of a dedicated mammography workstation and also presented as laser film hard copies on a film view box for comparison. The images were evaluated with respect to the image handling, the image quality and the visualization of relevant structures by 3 readers. RESULTS: Handling and contrast of the monitor displayed images were found to be superior compared with the film hard copies. Image noise was found in some cases but did not compromise the interpretation of the monitor images. The visualization of relevant structures was equal with both modalities. Altogether, image interpretation with the mammography workstation was considered to be easy, quick and confident. CONCLUSIONS: Computer-assisted visualization and interpretation of digital mammography images using a dedicated workstation can be performed with sufficiently high diagnostic accuracy.

The requirement of GnRH at the beginning of the five-day CO-Synch + controlled internal drug release protocol in beef heifers.

The objective of this study was to determine if the omission of GnRH at controlled internal drug release device (CIDR) insertion would impact pregnancy rates to timed AI (TAI) in beef heifers enrolled in a 5-d CO-Synch + CIDR protocol that used 1 PGF2α dose given at CIDR removal. Yearling beef heifers in Ohio in 2 consecutive breeding seasons (2011, n = 151, and 2012, n = 143; Angus × Simmental), Utah (2012, n = 265; Angus × Hereford), Idaho (2012, n = 127; Charolais), and Wyoming (2012, n = 137; Angus) were enrolled in the 5-d CO-Synch + CIDR protocol. At CIDR insertion (d -5), heifers were randomly assigned either to receive 100 µg GnRH (GnRH+; n = 408) or not to receive GnRH (GnRH-; n = 415). At CIDR removal (d 0 of the experiment), 25 mg PGF2α was administered to all heifers. All heifers were inseminated by TAI and given 100 µg GnRH 72 h after PGF2α (d 3). In heifers at the Ohio locations (n = 294), presence of a corpus luteum (CL) at CIDR insertion (d -5) was determined via assessment of progesterone concentrations (2011) and ovarian ultrasonography (2012). Subsequently, in both years, ovarian ultrasound was conducted on d 0 to determine the presence of a new CL. In this same subgroup of heifers, blood samples for progesterone analysis were collected on d 3 to assess luteal regression. Pregnancy diagnosis was performed between 32 and 38 d after TAI. At CIDR withdrawal, presence of a new CL was greater (P < 0.05) in the GnRH+ (55.8%, 82/147) than GnRH- (26.5%, 39/147) treatment. Incidence of failed luteal regression did not differ between the GnRH+ (3.4%) and GnRH- (0.7%) treatments. Pregnancy rate to TAI did not differ between the GnRH+ (50.5%) and GnRH- (54.9%) treatments. In conclusion, although the incidence of a new CL at CIDR removal was increased in the GnRH+ treatment, omission of the initial GnRH treatment in the 5-d CO-Synch + CIDR protocol did not influence TAI pregnancy rate in yearling beef heifers. In addition, a single dose of PGF2α at CIDR removal was effective at inducing luteolysis in yearling beef heifers enrolled in the 5-d CO-Synch + CIDR protocol, regardless of whether or not the initial GnRH treatment was given.

Assessment of acrosome state in boar spermatozoa heads using n-contours descriptor and RLVQ.

This paper proposes a method for assessing the acrosome state of boar spermatozoa heads using digital image processing. We use gray level images in which spermatozoa have been labeled as acrosome-intact or acrosome damaged using the information of a coupled fluorescent image. The heads are segmented obtaining the outer head contour. A set of "n" inner contours separated by a logarithmic distance function is calculated later. For each point of the, in this case, seven contours a number of local texture features are computed. We have compared the classification performance of Relevance Learning Vector Quantization, class conditional means and KNN, employing cross-validation for the evaluation. Gradient magnitude data offer the best result with an overall test error of only 1%. This result outperforms previously applied methods and suggests this approach as an interesting automatized approach to this veterinarian problem.

Legal problems of health care cost containment.

Employers faced with rising health care costs are exploring various means to control them. One way is prospective utilization review, although this may pose significant legal risks. Another is the capitation form of payment in which an employer contracts with a health care provider either directly or through an employer-sponsored HMO. The authors discuss these alternatives and the implications for employers.

Efficiently learning multilayer perceptrons.

A learning algorithm for multilayer perceptrons is presented which is based on finding the principal components of a correlation matrix computed from the example inputs and their target outputs. For large networks our procedure needs far fewer examples to achieve good generalization than traditional on-line algorithms.

Singularity spectra of rough growing surfaces from wavelet analysis

We apply the wavelet transform modulus maxima method [A. Arneodo, N. Decoster, and S. G. Roux, Phys. Rev. Lett. 83, 1255 (1999)] to the analysis of simulated surfaces grown by molecular-beam epitaxy. In contrast to the structure function approach commonly used in the literature, this method permits an investigation of the complete singularity spectrum. We focus on a kinetic Monte Carlo model with Arrhenius dynamics, which in particular takes into consideration the process of thermally activated desorption of particles. We find a wide spectrum of Holder exponents, which reflects the multiaffine surface morphology. Although our choice of parameters yields small desorption rates (<3%), we observe a dramatic change in the singularity spectrum, which is shifted toward smaller Holder exponents. Our results offer a mathematical foundation of anomalous scaling: We identify the global exponent alpha(g) with the Holder exponent that maximizes the singularity spectrum.