Rest-Activity Rhythm, Pain, and Motor Activity in Multiple Sclerosis.

BACKGROUND: Although the relationships among physical disability, mood disorders, and pain are well described in multiple sclerosis (MS), little is known about whether those symptoms are associated with sleep disturbances. METHODS: Forty-six patients with MS experiencing pain participated. Sleep was indirectly measured by assessing rest-activity rhythm via actigraphy: interdaily stability, intradaily variability, and relative amplitude. Pain was assessed using visual and verbal analog scales, mood by the Beck Depression Inventory and Symptom Checklist-90, and physical disability by the Expanded Disability Status Scale. RESULTS: Incorporating mood, pain, and physical disability into 1 regression model resulted in a significant association with interdaily stability. CONCLUSIONS: Compared with intradaily variability and relative amplitude, interdaily stability seems to be the most vulnerable actigraphy variable for mood disturbances, pain, and physical disabilities.

ABC-Transporter Expression Does Not Correlate with Response to Irinotecan in Patients with Metastatic Colorectal Cancer.

BACKGROUND: Active efflux of irinotecan by ATP-binding cassette (ABC)-transporters, in particular ABCB1 and ABCG2, is a well-established drug resistance mechanism in vitro and in pre-clinical mouse models, but its relevance in colorectal cancer (CRC) patients is unknown. Therefore, we assessed the association between ABC-transporter expression and tumour response to irinotecan in patients with metastatic CRC. METHODS: Tissue microarrays of a large cohort of metastatic CRC patients treated with irinotecan in a prospective study (CAIRO study; n=566) were analysed for expression of ABCB1 and ABCG2 by immunohistochemistry. Kaplan-Meier and Cox proportional hazard regression analyses were performed to assess the association of ABC transporter expression with irinotecan response. Gene expression profiles of 17 paired tumours were used to assess the concordance of ABCB1/ABCG2 expression in primary CRC and corresponding metastases. RESULTS: The response to irinotecan was not significantly different between primary tumours with positive versus negative expression of ABCB1 (5.8 vs 5.7 months, p=0.696) or ABCG2 (5.7 vs 6.1 months, p=0.811). Multivariate analysis showed neither ABCB1 nor ABCG2 were independent predictors for progression free survival. There was a mediocre to poor concordance between ABC-transporter expression in paired tumours. CONCLUSION: In metastatic CRC, ABC-transporter expression in the primary tumour does not predict irinotecan response.

Performance of local optimization in single-plane fluoroscopic analysis for total knee arthroplasty.

Fluoroscopy-derived joint kinematics plays an important role in the evaluation of knee prostheses. Fluoroscopic analysis requires estimation of the 3D prosthesis pose from its 2D silhouette in the fluoroscopic image, by optimizing a dissimilarity measure. Currently, extensive user-interaction is needed, which makes analysis labor-intensive and operator-dependent. The aim of this study was to review five optimization methods for 3D pose estimation and to assess their performance in finding the correct solution. Two derivative-free optimizers (DHSAnn and IIPM) and three gradient-based optimizers (LevMar, DoNLP2 and IpOpt) were evaluated. For the latter three optimizers two different implementations were evaluated: one with a numerically approximated gradient and one with an analytically derived gradient for computational efficiency. On phantom data, all methods were able to find the 3D pose within 1mm and 1° in more than 85% of cases. IpOpt had the highest success-rate: 97%. On clinical data, the success rates were higher than 85% for the in-plane positions, but not for the rotations. IpOpt was the most expensive method and the application of an analytically derived gradients accelerated the gradient-based methods by a factor 3-4 without any differences in success rate. In conclusion, 85% of the frames can be analyzed automatically in clinical data and only 15% of the frames require manual supervision. The optimal success-rate on phantom data (97% with IpOpt) on phantom data indicates that even less supervision may become feasible.

The effect of mutations near the T1 copper site on the biochemical characteristics of the small laccase from Streptomyces coelicolor A3(2).

Bacterial laccases show low activities but can be of biotechnological interest due to industrially suitable characteristics such as thermostability and tolerance to alkaline pH. In this study, three separate mutations (M298F, V290N and V290A) were introduced at or near the T1 copper site of the small laccase (SLAC) from Streptomyces coelicolor A3(2) and biochemical properties were assessed in comparison with the native enzyme. The mutation, V290N showed approximately double the activity of SLAC when ABTS was used as substrate while the specific activity of SLAC-M298F was 4-5 times higher than that of SLAC when the assays were performed at ≥70°C. There was no significant difference in activity with 2,6-dimethoxyphenol (2,6-DMP); however, there was a significant shift in the optimal pH from pH 9.5 (SLAC) to 7.5 (SLAC-V290N). Optimal temperature for activity was not significantly altered but thermostability was reduced in all three mutants. The substrate range of the mutant variants remained largely unchanged, with the exception of SLAC-M298F which was unable to oxidise veratryl alcohol. Interestingly, the "typical" laccase inhibitor, sodium azide, had no significant inhibitory effect on the activity of SLAC-M298F, which also exhibited increased resistance to inhibition by sulfhydryl compounds. SLAC-V290N showed higher catalytic efficiency for 2,6-DMP (kcat/Km=2.226mM(-1)s(-1)) and ABTS (kcat/Km=1.874mM(-1)s(-1)) compared to SLAC (kcat/Km=1.615mM(-1)s(-1) for 2,6-DMP and kcat/Km=1.611mM(-1)s(-1) for ABTS). This study has shown that three ligands that are closely associated with the T1 copper in SLAC play a key role in maintaining enzymatic activity. Whilst the introduction of mutations at these sites negated favourable characteristics such as thermostability, several favourable effects were observed. This study has also extended the knowledge base on the biochemical characteristics of SLAC, and its suitability as a template for engineering with the aim of widening its potential range of industrial applications.

Detecting condylar contact loss using single-plane fluoroscopy: a comparison with in vivo force data and in vitro bi-plane data.

Knee contact mechanics play an important role in knee implant failure and wear mechanics. Femoral condylar contact loss in total knee arthroplasty has been reported in some studies and it is considered to potentially induce excessive wear of the polyethylene insert.Measuring in vivo forces applied to the tibial plateau with an instrumented prosthesis is a possible approach to assess contact loss in vivo, but this approach is not very practical. Alternatively, single-plane fluoroscopy and pose estimation can be used to derive the relative pose of the femoral component with respect to the tibial plateau and estimate the distance from the medial and lateral parts of the femoral component towards the insert. Two measures are reported in the literature: lift-off is commonly defined as the difference in distance between the medial and lateral condyles of the femoral component with respect to the tibial plateau; separation is determined by the closest distance of each condyle towards the polyethylene insert instead of the tibia plateau.In this validation study, lift-off and separation as measured with single-plane fluoroscopy are compared to in vivo contact forces measured with an instrumented knee implant. In a phantom study, lift-off and separation were compared to measurements with a high quality bi-plane measurement.The results of the in vivo contact-force experiment demonstrate a large discrepancy between single-plane fluoroscopy and the in vivo force data: single-plane fluoroscopy measured up to 5.1mm of lift-off or separation, whereas the force data never showed actual loss of contact. The phantom study demonstrated that the single-plane setup could introduce an overestimation of 0.22mm±±0.36mm. Correcting the out-of-plane position resulted in an underestimation of medial separation by -0.20mm±±0.29mm.In conclusion, there is a discrepancy between the in vivo force data and single-plane fluoroscopic measurements. Therefore contact loss may not always be determined reliably by single plane fluoroscopy analysis.

Maspin is a marker for early recurrence in primary stage III and IV colorectal cancer.

BACKGROUND: Little is known about the factors that drive metastasis formation in colorectal cancer (CRC). Here, we set out to identify genes and proteins in patients with colorectal liver metastases that correlate with early disease recurrence. Such factors may predict a propensity for metastasis in earlier stages of CRC. METHODS: Gene expression profiling and proteomics were used to identify differentially expressed genes/proteins in resected liver metastases that recurred within 6 months following liver surgery vs those that did not recur for >24 months. Expression of the identified genes/proteins in stage II (n=243) and III (n=176) tumours was analysed by immunohistochemistry on tissue microarrays. Correlation of protein levels with stage-specific outcome was assessed by uni- and multivariable analyses. RESULTS: Both gene expression profiling and proteomics identified Maspin to be differentially expressed in colorectal liver metastases with early (<6 months) and prolonged (>24 months) time to recurrence. Immunohistochemical analysis of Maspin expression on tumour sections revealed that it was an independent predictor of time to recurrence (log-rank P=0.004) and CRC-specific survival (P=0.000) in stage III CRC. High Maspin expression was also correlated with mucinous differentiation. In stage II CRC patients, high Maspin expression did not correlate with survival but was correlated with a right-sided tumour location. CONCLUSION: High Maspin expression correlates with poor outcome in CRC after spread to the local lymph nodes. Therefore, Maspin may have a stage-specific function possibly related to tumour cell dissemination and/or metastatic outgrowth.

The value of miRNA in diagnosing thyroid cancer: a systematic review.

Thyroid cancer is the most common endocrine neoplasm accounting for approximately 1,7% of total cancer diagnoses. The gold standard for evaluation of thyroid nodules is cytology from fine needle aspiration. In 30% of biopsies there is no conclusive diagnosis and patients undergo a diagnostic hemithyroidectomy. Somatic mutations occur frequently in thyroid cancer, the value of testing FNA biopsies on different mutation is analyzed, it improves accuracy, but their sensitivity is low. Another class of molecules with potential diagnostic value are miRNAs (miRNA, miR). MiRNAs function as gene regulators thereby controlling many cellular processes including cell growth, differentiation, proliferation, and apoptosis. Several studies have analyzed the expression of miRNAs in thyroid cancer, either by performing microarray analyses or validating a set of miRNAs. Recent reports focused on the diagnostic value of miRNAs in indeterminate FNA biopsies. In this systematic review we will provide an overview of all miRNAs found to be up- or downregulated in the different types of thyroid carcinomas, give an overview of the value of validated sets of microRNAs or single microRNAs in distinguishing malignant from benign lesions and conclude with a clinical view on future study strategies.

Integrated contour detection and pose estimation for fluoroscopic analysis of knee implants.

With fluoroscopic analysis of knee implant kinematics the implant contour must be detected in each image frame, followed by estimation of the implant pose. With a large number of possibly low-quality images, the contour detection is a time-consuming bottleneck. The present paper proposes an automated contour detection method, which is integrated in the pose estimation. In a phantom experiment the automated method was compared with a standard method, which uses manual selection of correct contour parts. Both methods demonstrated comparable precision, with a minor difference in the Y-position (0.08 mm versus 0.06 mm). The precision of each method was so small (below 0.2 mm and 0.3 degrees) that both are sufficiently accurate for clinical research purposes. The efficiency of both methods was assessed on six clinical datasets. With the automated method the observer spent 1.5 min per image, significantly less than 3.9 min with the standard method. A Bland-Altman analysis between the methods demonstrated no discernible trends in the relative femoral poses. The threefold increase in efficiency demonstrates that a pose estimation approach with integrated contour detection is more intuitive than a standard method. It eliminates most of the manual work in fluoroscopic analysis, with sufficient precision for clinical research purposes.

An fMRI study of prefrontal dysfunction and symptomatic recovery in schizophrenia.

OBJECTIVE: Prefrontal cortical dysfunction has been implicated in the pathophysiology of schizophrenia but it is unclear to what extent these are related to changes in symptomatology as well as task demand. METHOD: We examined the neural correlates of symptom change and task demand during a longitudinal functional magnetic resonance imaging (fMRI) study using a verbal fluency task with differential task demands in patients with schizophrenia and matched healthy control subjects. The fMRI data were acquired using clustered acquisition technique, enabling ongoing monitoring of behavioural responses, in the patient group on two occasions separated by 6-8 weeks, and the control group at baseline. RESULTS: Positive psychotic symptoms were significantly reduced over the 6-8-week duration of the study. This change was associated with increased activation within the left middle frontal gyrus and decreased activation of the left precuneus. An interaction between symptom change and task demand was evident in the activation of the left middle frontal gyrus. The decrease in positive symptoms was associated with normalisation of activation in the dorsolateral prefrontal cortex and a decrease in parietal activation during the verbal fluency task. CONCLUSION: The data supports the role of dysfunctional prefronto-parietal relationships in the genesis of positive psychotic symptoms.

Detecting femur-insert collisions to improve precision of fluoroscopic knee arthroplasty analysis.

Fluoroscopic analysis is an important tool for assessing in vivo kinematics of knee prostheses. Most commonly, a single-plane fluoroscopic setup is used to capture the motion of prostheses during a particular task. Unfortunately, single-plane fluoroscopic analysis is imprecise in the out-of-plane direction. This can result in reconstructing physically impossible poses, in which--for example--the femoral component intersects with the insert, as the normal pose estimation process does not take into account the relation between the components. In the proposed method, the poses of both components are estimated simultaneously, while preventing femur-insert collisions. In a phantom study, the accuracy and precision of the new method in estimating the relative pose of the femoral component were compared to those of the original method. With reverse engineered models, the errors in estimating the out-of-plane position decreased from 2.0+/-0.7 to 0.1+/-0.1 mm, without effects on the errors in rotations and the in-plane positions. With CAD models, the errors in estimating the out-of-plane position decreased from 5.3+/-0.7 mm (mean+/-SD) to 0.0+/-0.4 mm, at the expense of a decreased precision for the other position or orientation parameters. In conclusion, collision detection can prevent reconstructing impossible poses and it improves the position and motion estimation in the out-of-plane direction.

Diagnosis and management of patients with hand and wrist problems in general practice.

OBJECTIVES: 1) To describe diagnoses made by general practitioners (GPs) in patients with hand or wrist problems, 2) to describe management, and 3) to determine the association between diagnostic information and two outcomes: persistent symptoms and specialist referral. METHODS: GPs recruited patients with hand or wrist problems and completed a standardized form recording information about patient history, observations, palpation, and physical tests. Patients were sent a questionnaire at baseline, 3, and 12 months, containing questions on characteristics and symptom severity. Logistic regression analyses were used to determine the association between diagnostic information and the odds of persistent symptoms or specialist referral. RESULTS: The three most frequently recorded diagnoses were osteoarthritis (17%), tenosynovitis (16%), and nerve entrapment (13%). "Wait and see" (30%) and painkillers (24%) were most often advised. Higher probability of persistent symptoms at both 3 and 12 months was associated with being female, higher age, long baseline symptom duration, and higher baseline pain intensity score; positive DeQuervain test was associated with lower probability of persistent symptoms. Having a recurrent problem was associated with higher odds of specialist referral. CONCLUSION: In primary care, physical tests and information about physical signs are of importance in diagnosing patients with hand or wrist problems, but provide limited prognostic information.

Handling modular hip implants in model-based RSA: combined stem-head models.

Migration measurements of hip prostheses using marker-based Roentgen stereophotogrammetric analysis (RSA) require the attachment of markers to the prostheses. The model-based approach, which does not require these markers, is, however, less precise. One of the reasons may be the fact that the spherical head has not been modelled. Therefore, we added a 3D surface model of the spherical head and estimated the position and orientation of the combined stem-head model. The new method using a combined stem-head model was compared in a phantom study on five prostheses (of different types) and in a clinical study using double examinations of implanted hip prostheses, with two existing methods: a standard model-based approach and one using elementary geometrical shapes. The combined model showed the highest precision for the rotation about the longitudinal axis in the phantom experiments. With a standard deviation of 0.69 degrees it showed a significant improvement (p=0.02) over the model-based approach (0.96 degrees ) on the phantom data, but no improvement on the clinical data. Overall, the use of elementary geometrical shapes was worse with respect to the model-based approach, with a standard deviation of 1.02 degrees on the phantom data and 0.79 degrees on the clinical data. This decrease in precision was significant (p<0.01) on the clinical data. With relatively small differences in the other migration directions, these results demonstrate that the new method with a combined stem-head model can be a useful alternative to the standard model-based approach.

Clinical course and prognosis of hand and wrist problems in primary care.

OBJECTIVE: To describe the course of a new episode of hand and wrist problems in general practice and to identify predictors that are associated with poor outcome at short-term and long-term followup. METHODS: Patients consulting their general practitioner with hand or wrist problems (no prior consultation in the preceding 3 months) were sent a questionnaire at baseline and at 3, 6, and 12 months of followup. Potential predictors included sociodemographic variables, characteristics of the symptoms, physical activity, and psychosocial factors. General practitioners recorded information on symptoms, signs, and medical diagnosis. The main outcome measure was insufficient improvement of symptoms using the Symptom Severity Scale at short-term (3 months) and long-term (12 months) followup. RESULTS: Twenty-three percent of patients reported complete recovery after 3 months, increasing to 42% at 1 year after first presentation. Higher probability of poor outcome at 3 months was associated with being female, low pain intensity at baseline, and lower personal control at baseline; at 12 months it was associated with older age, being female, reporting symptoms for >3 months at baseline, low scores on the coping strategy "reducing demands," and a higher score on somatization. Discriminative ability of the models was moderate, with areas under the curve after bootstrapping of 0.60 and 0.69 at 3 and 12 months, respectively. CONCLUSION: More than half of all patients reported residual symptoms at 1 year. Although poor outcome was difficult to predict, age, sex, duration of symptoms, and psychosocial factors were associated with poor outcome of hand and wrist problems.

Requirements analysis of information services for patients on a general practitioner's website--patient and general practitioner's perspectives.

OBJECTIVE: To elicit and analyze information needs of patients and primary care physicians (GPs) regarding the information services (static and functional) that a GP's practice website should provide. METHODS: To find candidate information services, we conducted a literature search and examined primary care physicians' websites, especially Dutch websites. Semi-structured depth interviews with the stakeholders, Dutch patients and GPs, were done to arrive at a final checklist. We then conducted a survey to elicit the level of importance associated with each service on the checklist. The data underwent statistical analysis and relevant requirements were formulated. The requirements were then validated by interviews. General website quality and usability aspects were elicited from the literature. RESULTS: The research resulted in a checklist of 38 selected information services including their priority ratings for patients and GPs; a discrepancy list between GP and patient priorities; and a requirements document containing information services (14 static and 6 functional), and general quality and usability aspects (8 and 5). CONCLUSION: The following items occurred in the top 10 of both user groups: general practice information, information of local public health institutions, self-help information, repeat prescription, links to health web sites. At the bottom on both priority lists were: links to journals, tests and forums. Dutch GPs are much more selective in terms of which information services to provide on-line. Discrepancy between the two groups concerns on-line services that seem to require a change to the GP's workflow, or those services that are not recognized for reimbursing the GP. Although the Dutch patients' requirements seem to generalize to other patients, the conflict list might depend on the primary care system.

Hand and wrist problems in general practice--patient characteristics and factors related to symptom severity.

OBJECTIVES: Hand and wrist problems are common, but little is known about characteristics of patients consulting the general practitioner (GP) for these problems. The objectives are: (i) to describe wrist and hand problems presented to the GP in terms of severity of symptoms, and their impact on physical, emotional and social functioning; (ii) to describe patient and disease characteristics across different diagnostic categories; and (iii) to study factors related to the severity of hand or wrist problems. METHODS: Patients consulting their GP with hand or wrist problems were sent a questionnaire containing questions on socio-demographic variables, characteristics of the complaint, physical activity and psychosocial factors. The GP recorded information on symptoms, signs and medical diagnosis. We studied the cross-sectional association between a variety of factors and severity of hand or wrist problems, using the Symptom Severity Scale as the outcome measure. RESULTS: Mean age of the 267 participants was 49.3 yrs and 74% were female. The three most frequently recorded diagnoses were osteoarthritits (17%), tenosynovitis (16%) and nerve entrapment (12%). The characteristics of patients varied slightly across diagnostic categories. Patients who did not have paid work, had longer duration of symptoms, diagnosis of entrapment, higher pain intensity, higher body mass index and higher scores on worrying reported significantly higher scores on severity of hand or wrist problems (P-value <0.10). CONCLUSION: Primary care patients with hand or wrist problems report pain and reduced function. Impact on other aspects of perceived health is limited. Severity seems to be associated with socio-demographic, physical and psychosocial factors, more than with medical diagnosis.

The relationship of disease duration to foot function, pain and disability in rheumatoid arthritis patients with foot complaints.

OBJECTIVE: To assess the relationship between disease duration and foot function (expressed as pressure and gait parameters), foot pain and disability, in patients with foot complaints secondary to rheumatoid arthritis (RA). METHODS: Sixty-two patients with RA-related foot complaints were included. Disease duration was defined as the time since RA was diagnosed. A pressure platform was used to measure both pressure parameters (i.e. pressure-time integrals and peak pressures in the forefoot) and gait parameters (i.e. total loading time and loading time in different foot regions). In addition, measurements of foot pain, disability (i.e. walking time and self reported disability), forefoot joint damage and disease activity were obtained. Data were analysed using partial correlations (Spearman), correcting for age. RESULTS: Disease duration was significantly correlated with the maximum pressure-time integral (PTI) measured under the forefoot (r = 0.330, p = 0.01). Disease duration was also significantly correlated with gait parameters, i.e. total loading time (r = 0.265, p = 0.04), duration of heel loading and duration of toe loading (r = 0.326, p = 0.01 and r = -0.288, p = 0.03 respectively), and walking time (r = 0.297, p = 0.02). Disease duration did not correlate with self-reported foot pain or disability. CONCLUSION: In patients with RA-related foot complaints, longer disease duration is associated with impaired foot function and reduced walking speed. These findings are interpreted as an alteration in pressure distribution and gait pattern during the course of disease, with a shift from a heel-to-toe roll-over process to a more shuffling gait.

Granzyme B is expressed in mouse mast cells in vivo and in vitro and causes delayed cell death independent of perforin.

Mast cells respond to pathogens and allergens by secreting a vast array of preformed and newly synthesized mediators, including enzymes, vasoactive amines, lipid mediators, cytokines and chemokines, thereby affecting innate and adaptive immune responses and pathogenesis. Here, we present evidence that skin-, but not lung-associated primary mast cells as well as in vitro-differentiated bone marrow-derived mast cells (BMMC) express granzyme (gzm) B, but not gzmA or perforin (perf). GzmB is associated with cytoplasmic granules of BMMC and secreted after Fcepsilon-receptor-mediated activation. BMMC from wild type but not gzmB-deficient mice cause cell death in susceptible adherent target cells, indicating that the perf-independent cytotoxicity of BMMC is executed by gzmB. Furthermore, gzmB induces a disorganization of endothelial cell-cell contacts. The data suggest that activated mast cells contribute, via secreted gzmB, to cell death, increased vascular permeability, leukocyte extravasation and subsequent inflammatory processes in affected tissues.

Specification of adaxial and abaxial stomata, epidermal structure and photosynthesis to CO2 enrichment in maize leaves.

Acclimation to CO2 enrichment was studied in maize plants grown to maturity in either 350 or 700 microl l-1 CO2. Plants grown with CO2 enrichment were significantly taller than those grown at 350 microl l-1 CO2 but they had the same number of leaves. High CO2 concentration led to a marked decrease in whole leaf chlorophyll and protein. The ratio of stomata on the adaxial and abaxial leaf surfaces was similar in all growth conditions, but the stomatal index was considerably increased in plants grown at 700 microl l-1 CO2. Doubling the atmospheric CO2 content altered epidermal cell size leading to fewer, much larger cells on both leaf surfaces. The photosynthesis and transpiration rates were always higher on the abaxial surface than the adaxial surface. CO2 uptake rates increased as atmospheric CO2 was increased up to the growth concentrations on both leaf surfaces. Above these values, CO2 uptake on the abaxial surface was either stable or increased as CO2 concentration increased. In marked contrast, CO2 uptake rates on the adaxial surface were progressively inhibited at concentrations above the growth CO2 value, whether light was supplied directly to this or the abaxial surface. These results show that maize leaves adjust their stomatal densities through changes in epidermal cell numbers rather than stomatal numbers. Moreover, the CO2-response curve of photosynthesis on the adaxial surface is specifically determined by growth CO2 abundance and tracks transpiration. Conversely, photosynthesis on the abaxial surface is largely independent of CO2 concentration and rather independent of stomatal function.