Force-field perturbations and muscle vibration strengthen stability-related foot placement responses during steady-state gait in healthy adults.

Mediolateral gait stability can be maintained by coordinating our foot placement with respect to the center-of-mass (CoM) kinematic state. Neurological impairments can reduce the degree of foot placement control. For individuals with such impairments, interventions that could improve foot placement control could thus contribute to improved gait stability. In this study we aimed to better understand two potential interventions, by investigating their effect in neurologically intact individuals. The degree of foot placement control can be quantified based on a foot placement model, in which the CoM position and velocity during swing predict subsequent foot placement. Previously, perturbing foot placement with a force-field resulted in an enhanced degree of foot placement control as an after-effect. Moreover, timed muscle vibration enhanced the degree of foot placement control whilst the vibration was applied. Here, we replicated these two findings and further investigated whether Q1) timed muscle vibration leads to an after-effect and Q2) whether combining timed muscle vibration with force-field perturbations leads to a larger after-effect, as compared to force-field perturbations only. In addition, we evaluated several potential contributors to the degree of foot placement control, by considering foot placement errors, CoM variability and the CoM position gain (ßpos) of the foot placement model, next to the R2 measure as the degree of foot placement control. Timed muscle vibration led to a higher degree of foot placement control as an after-effect (Q1). However, combining timed muscle vibration and force-field perturbations did not lead to a larger after-effect, as compared to following force-field perturbations only (Q2). Furthermore, we showed that the improved degree of foot placement control following force-field perturbations and during/following muscle vibration, did not reflect diminished foot placement errors. Rather, participants demonstrated a stronger active response (higher ßpos) as well as higher CoM variability.

The value of frozen section biopsy in diagnosing necrotizing fasciitis: proposal of a new grading system.

GOALS AND OBJECTIVES: Necrotizing fasciitis is a serious disease entity, with only limited pathognomic features. PURPOSE: In necrotizing fasciitis a rapid diagnosis is necessary in order to reduce morbidity and mortality. In this study the investigation focused on specific features in the frozen section biopsy for diagnosing necrotizing fasciitis. METHODS: A total of ten patients are described with final pathological examination of resected tissue. RESULTS: A new grading system is suggested for frozen section biopsy in patients with necrotizing fasciitis. In the herein reported study it was found that granulocytes were present in both the frozen section biopsy and in the definitive paraffin coupes, in the subcutis and fascia layer. CONCLUSION: Frozen section biopsy could be useful in diagnosing necrotizing fasciitis.

The effect of external lateral stabilization on ankle moment control during steady-state walking.

External lateral stabilization can help identify stability control mechanisms during steady-state walking. The degree of step-by-step foot placement control and step width are known to decrease when walking with external lateral stabilization. Here, we investigated the effect of external lateral stabilization on ankle moment control in healthy participants. Ankle moment control complements foot placement, by allowing a corrective center-of-pressure shift once the foot has been placed. This is reflected by a model predicting this center-of-pressure shift based on the preceding foot placement error. Here, the absolute explained variance accounted for by this model decreased when walking with external lateral stabilization. In other words, we found a reduction in the contribution of step-by-step ankle moment control to mediolateral gait stability when externally stabilized. Concurrently, foot placement error and the average center-of-pressure shift remained unchanged.

Can foot placement during gait be trained? Adaptations in stability control when ankle moments are constrained.

Accurate coordination of mediolateral foot placement, relative to the center of mass kinematic state, is one of the mechanisms which ensures mediolateral stability during human walking. Previously, we found that shoes constraining ankle moments decreased the degree of foot placement control with respect to the center of mass kinematic state. As such, ankle moment constraints can be seen as a perturbation of foot placement. Direct mechanical perturbations of the swing leg trajectory can improve the degree of foot placement control as an after-effect. Here, we asked whether constrained ankle moments could have a similar effect. If confirmed, this would offer a simple training tool for individuals with impaired foot placement control. Participants walked in three conditions; normal (baseline) while wearing shoes constraining ankle moments (training) and normal again (after-effects). The degree of foot placement control was calculated as the percentage of variance in foot placement that could be predicted based on the center of mass kinematic state in the preceding swing phase. During training, the degree of foot placement control decreased initially compared to baseline, but it gradually improved over time. In the after-effect condition, it was higher than during baseline, yet not significantly so. During training, we observed increased step width, decreased stride time and reduced local dynamic stability. In conclusion, constraining ankle moment control deteriorates the degree of foot placement control. A non-significant trend towards an improved degree of foot placement control after prolonged exposure to constrained ankle moments, allows for speculation on a training potential.

Differential effects of ankle constraints on foot placement control between normal and split belt treadmills.

Mediolateral ankle moment control contributes to gait stability. Ankle moments can be constrained by walking with a shoe with a ridge underneath the sole, narrowing the mediolateral support surface. In our previous study, such ankle moment constraints resulted in an increased step width and a decrease in the degree of foot placement control, as defined by the percentage of variance in foot placement that can be explained by CoM state. However, since our previous study was performed on a split-belt treadmill and the narrow ridge could fit inside the gap between the belts, it is not evident whether these effects can be attributed to the constrained ankle moment control or to avoidance of this gap. Therefore, we investigated if the effects of ankle moment constraints are dependent on whether participants walk on a normal treadmill or a split-belt treadmill. We included fourteen healthy young adults. Walking with constrained ankle moment control resulted in a wider step width on both treadmills. Yet, the increase in step width was larger on the split-belt treadmill compared to on the normal treadmill. We only found a decreased degree of foot placement control on the split-belt treadmill, whilst the degree of foot placement control increased on the normal treadmill. We conclude that the effects of ankle moment constraints reported in our previous study were confounded by the use of a split-belt treadmill. For future research, we recommend using a normal treadmill whenever possible, because the gap in a split-belt treadmill might affect gait parameters.

Dynamic Contrast-enhanced and Diffusion-weighted Magnetic Resonance Imaging for Response Evaluation After Single-Dose Ablative Neoadjuvant Partial Breast Irradiation.

Purpose: We aimed to evaluate changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) scans acquired before and after single-dose ablative neoadjuvant partial breast irradiation (NA-PBI), and explore the relation between semiquantitative MRI parameters and radiologic and pathologic responses. Methods and Materials: We analyzed 3.0T DCE and DW-MRI of 36 patients with low-risk breast cancer who were treated with single-dose NA-PBI, followed by breast-conserving surgery 6 or 8 months later. MRI was acquired before NA-PBI and 1 week, 2, 4, and 6 months after NA-PBI. Breast radiologists assessed the radiologic response and breast pathologists scored the pathologic response after surgery. Patients were grouped as either pathologic responders or nonresponders (<10% vs ≥10% residual tumor cells). The semiquantitative MRI parameters evaluated were time to enhancement (TTE), 1-minute relative enhancement (RE1min), percentage of enhancing voxels (%EV), distribution of washout curve types, and apparent diffusion coefficient (ADC). Results: In general, the enhancement increased 1 week after NA-PBI (baseline vs 1 week median - TTE: 15s vs 10s; RE1min: 161% vs 197%; %EV: 47% vs 67%) and decreased from 2 months onward (6 months median - TTE: 25s; RE1min: 86%; %EV: 12%). Median ADC increased from 0.83 × 10-3 mm2/s at baseline to 1.28 × 10-3 mm2/s at 6 months. TTE, RE1min, and %EV showed the most potential to differentiate between radiologic responses, and TTE, RE1min, and ADC between pathologic responses. Conclusions: Semiquantitative analyses of DCE and DW-MRI showed changes in relative enhancement and ADC 1 week after NA-PBI, indicating acute inflammation, followed by changes indicating tumor regression from 2 to 6 months after radiation therapy. A relation between the MRI parameters and radiologic and pathologic responses could not be proven in this exploratory study.

Ankle muscles drive mediolateral center of pressure control to ensure stable steady state gait.

During steady-state walking, mediolateral gait stability can be maintained by controlling the center of pressure (CoP). The CoP modulates the moment of the ground reaction force, which brakes and reverses movement of the center of mass (CoM) towards the lateral border of the base of support. In addition to foot placement, ankle moments serve to control the CoP. We hypothesized that, during steady-state walking, single stance ankle moments establish a CoP shift to correct for errors in foot placement. We expected ankle muscle activity to be associated with this complementary CoP shift. During treadmill walking, full-body kinematics, ground reaction forces and electromyography were recorded in thirty healthy participants. We found a negative relationship between preceding foot placement error and CoP displacement during single stance; steps that were too medial were compensated for by a lateral CoP shift and vice versa, steps that were too lateral were compensated for by a medial CoP shift. Peroneus longus, soleus and tibialis anterior activity correlated with these CoP shifts. As such, we identified an (active) ankle strategy during steady-state walking. As expected, absolute explained CoP variance by foot placement error decreased when walking with shoes constraining ankle moments. Yet, contrary to our expectations that ankle moment control would compensate for constrained foot placement, the absolute explained CoP variance by foot placement error did not increase when foot placement was constrained. We argue that this lack of compensation reflects the interdependent nature of ankle moment and foot placement control. We suggest that single stance ankle moments do not only compensate for preceding foot placement errors, but also assist control of the subsequent foot placement. Foot placement and ankle moment control are 'caught' in a circular relationship, in which constraints imposed on one will also influence the other.

Discrepancies in digital hematopathology diagnoses for consultation and expert panel analysis.

Digital pathology with whole-slide imaging (WSI) has a large potential to make the process of expert consultation and expert panel diagnosis more rapid and more efficient. However, comparison with the current methods is necessary for validation of the technique. In this study, we determined if digital assessment of whole-slide images of hematopathology specimens with a focus on the assessment of lymphoma can be used for consultation and panel diagnostics. Ninety-three histological specimens with a suspicion for lymphoma were assessed both with conventional microscopy and digital microscopy with a wash out period between assessments. A consensus diagnosis was based on full concordance between the pathologists or, in case of discordances, was reached at a joint session at a multi-headed microscope. In 81% of the cases, there was a full concordance between digital and light microscopical assessment for all three pathologists. Discordances between conventional microscopy and digital pathology were present in 3% of assessments. In comparison with the consensus diagnosis, discordant diagnoses were made in 5 cases with digital microscopy and in 3 cases with light microscopy. The reported level of confidence and need for additional investigations were similar between assessment by conventional and by digital microscopy. In conclusion, the performance of assessment by digital pathology is in general comparable with that of conventional light microscopy and pathologists feel confident using digital pathology for this subspecialty.

Tumor-Infiltrating Lymphocytes in Low-Risk Patients With Breast Cancer Treated With Single-Dose Preoperative Partial Breast Irradiation.

PURPOSE: Preoperative partial breast irradiation (PBI) has the potential to induce tumor regression. We evaluated the differences in the numbers of preirradiation tumor infiltrating lymphocytes (TILs) between responders and nonresponders after preoperative PBI in low-risk patients with breast cancer. Furthermore, we evaluated the change in number of TILs before and after irradiation. METHODS AND MATERIALS: In the prospective ABLATIVE study, low-risk patients with breast cancer underwent treatment with single-dose preoperative PBI (20 Gy) to the tumor and breast-conserving surgery after 6 or 8 months. In the preirradiation diagnostic biopsy and postirradiation resection specimen, numbers of TILs in 3 square regions of 450 × 450 µm were counted manually. TILs were visualized with CD3, CD4, and CD8 immunohistochemistry. Differences in numbers of preirradiation TILs between responders and nonresponders were tested using Mann-Whitney U test. Responders were defined as pathologic complete or near-complete response, and nonresponders were defined "as all other response." Changes in numbers of TILs after preoperative PBI was evaluated with the Wilcoxon signed rank test. RESULTS: Preirradiation tissue was available from 28 patients, postirradiation tissue from 29 patients, resulting in 22 pairs of preirradiation and postirradiation tissue. In these 35 patients, 15 had pathologic complete response (43%), 11 had a near-complete response (31%), 7 had a partial response (20%), and 2 had stable disease (6%). The median numbers of CD3+ TILs, CD4+ TILs, and CD8+ TILs in the preirradiation tumor tissue were 49 (interquartile range [IQR], 36-80), 45 (IQR, 28-57), and 19 (IQR, 8-35), respectively. The number of preirradiation TILs did not differ significantly between responders and nonresponders. The median numbers of CD3+ TILs, CD4+ TILs, and CD8+ TILs in postirradiation tumor tissue were 17 (IQR, 13-31), 26 (IQR, 16-35), and 7 (IQR, 5-11), respectively. CONCLUSIONS: After preoperative PBI in this limited cohort, the number of TILs in tumor tissue decreased. No differences in numbers of preirradiation TILs between responders and nonresponders were observed.

Active foot placement control ensures stable gait: Effect of constraints on foot placement and ankle moments.

Step-by-step foot placement control, relative to the center of mass (CoM) kinematic state, is generally considered a dominant mechanism for maintenance of gait stability. By adequate (mediolateral) positioning of the center of pressure with respect to the CoM, the ground reaction force generates a moment that prevents falling. In healthy individuals, foot placement is complemented mainly by ankle moment control ensuring stability. To evaluate possible compensatory relationships between step-by-step foot placement and complementary ankle moments, we investigated the degree of (active) foot placement control during steady-state walking, and under either foot placement-, or ankle moment constraints. Thirty healthy participants walked on a treadmill, while full-body kinematics, ground reaction forces and EMG activities were recorded. As a replication of earlier findings, we first showed step-by-step foot placement is associated with preceding CoM state and hip ab-/adductor activity during steady-state walking. Tight control of foot placement appears to be important at normal walking speed because there was a limited change in the degree of foot placement control despite the presence of a foot placement constraint. At slow speed, the degree of foot placement control decreased substantially, suggesting that tight control of foot placement is less essential when walking slowly. Step-by-step foot placement control was not tightened to compensate for constrained ankle moments. Instead compensation was achieved through increases in step width and stride frequency.

Tumor Response After Neoadjuvant Magnetic Resonance Guided Single Ablative Dose Partial Breast Irradiation.

PURPOSE: To assess the pathologic and radiologic response in patients with low-risk breast cancer treated with magnetic resonance (MR) guided neoadjuvant partial breast irradiation (NA-PBI) and to evaluate toxicity and patient-reported outcomes (PROs). METHODS AND MATERIALS: For this single-arm prospective trial, women with unifocal, non-lobular tumors with a maximum diameter of 20 mm (age, 50-70 years) or 30 mm (age, ≥70 years) and tumor-negative sentinel node(s) were eligible. Patients were treated with a single ablative dose of NA-PBI followed by breast-conserving surgery after an interval of 6 to 8 months. Target volumes were defined on radiation therapy planning computed tomography scan and additional magnetic resonance imaging. Prescribed doses to gross tumor volume and clinical target volume (gross tumor volume plus 20 mm margin) were 20 Gy and 15 Gy, respectively. Primary outcome was pathologic complete response (pCR). Secondary outcomes were radiologic response (on magnetic resonance imaging), toxicity (Common Terminology Criteria for Adverse Events), PROs (European Organisation for Research and Treatment of Cancer QLQ-BR23, Hospital Anxiety and Depression Scale), and cosmesis (assessed by patient, radiation oncologist, and BCCT.core software). RESULTS: Thirty-six patients were treated with NA-PBI, and pCR was reported in 15 patients (42%; 95% confidence interval, 26%-59%). Radiologic complete response was observed in 15 patients, 10 of whom had pCR (positive predictive value, 67%; 95% confidence interval, 39%-87%). After a median follow-up of 21 months (range, 12-41), all patients experienced grade 1 fibrosis in the treated breast volume. Transient grade 2 and 3 toxicity was observed in 31% and 3% of patients, respectively. Local recurrences were absent. No deterioration in PROs or cosmetic results was observed. CONCLUSIONS: NA-PBI has the potential to induce pCR in a substantial proportion of patients, with acceptable toxicity. This treatment seems a feasible alternative to standard postoperative irradiation and could even result in postponement or omission of surgery if pCR can be accurately predicted in selected low-risk patients.

Bilateral vanishing hips, coincidence or systemic disease? A case report and overview of current literature.

Rapidly progressive hip disease (RDHD) is a rare condition of the hip joint, causing destruction of the femoral head. The pathogenesis is unknown. The disease is self-limiting, there is no treatment to stop the disease. Hip arthroplasty is a successful way to relieve pain and restore function. We present a case where both hips were involved and analysed. A favourable result was obtained by bilateral total hip arthroplasty.

Are disseminated tumor cells in bone marrow and tumor-stroma ratio clinically applicable for patients undergoing surgical resection of primary colorectal cancer? The Leiden MRD study.

PURPOSE: Current TNM staging does not appropriately identify high-risk colorectal cancer (CRC) patients. The aim of this study was to evaluate whether the presence of disseminated tumor cells (DTCs) in the bone marrow (BM) and the presence of stroma in the primary tumor, i.e., the tumor-stroma ratio (TSR), in patients undergoing surgical resection of primary CRC provides information relevant for disease outcome. METHODS: Patients with primary CRC (n = 125), consecutively admitted for curative resection between 2001 and 2007, were included in the study. All patients underwent BM aspiration before surgery. Detection of tumor cells was performed using immunocytochemical staining for cytokeratin (CK-ICC). The TSR was determined on diagnostic H&E stained sections of primary tumors. RESULTS: DTCs were detected in the BM of 23/125 patients (18 %). No association was found between BM status and overall survival (HR 0.97 (95 % CI 0.45-2.09), p = 0.93). Also, no significant difference was found in their 5-year survival rate (resp. 72 % and 68 % for BM-positive versus BM-negative patients). The TSR was found to be associated with a worse overall survival (HR 2.16, 95 % CI 1.02-4.57, p = 0.04) with 5-year survival rates of 84 % versus 62 % for stroma-low and stroma-high patients, respectively. No relation was found between the presence of DTCs and TSR. CONCLUSIONS: Our data indicate that the presence of DTCs in the BM of CRC patients is not associated with disease outcome. The TSR was, however, found to be associated with a worse overall survival, which indicates that for CRC the tumor microenvironment plays an important role in its behavior and prognosis.

Production and characterization of monoclonal antibodies raised against recombinant human granzymes A and B and showing cross reactions with the natural proteins.

The human serine proteases granzymes A and B are expressed in cytoplasmic granules of activated cytotoxic T lymphocytes and natural killer cells. Recombinant granzyme A and granzyme B proteins were produced in bacteria, purified and then used to raise specific mouse monoclonal antibodies. Seven monoclonal antibodies (mAb) were raised against granzyme A, which all recognized the same or overlapping epitopes. They reacted specifically in an immunoblot of interleukin-2 (IL-2) stimulated PBMNC with a disulfide-linked homodimer of 43 kDa consisting of 28 kDa subunits. Seven mAb against granzyme B were obtained, which could be divided into two groups, each recognizing a different epitope. On an immunoblot, all mAb reacted with a monomer of 33 kDa protein. By immunohistochemistry, these mAb could be used to detect granzymes A and B expression in activated CTL and NK cells. The availability of these mAb may facilitate studies on the role of human cytotoxic cells in various immune reactions and may contribute to a better understanding of the role of granzymes A and B in the cytotoxic response in vivo.

Atypical mitotic figures and the mitotic index in cervical intraepithelial neoplasia.

We surveyed cervical intraepithelial neoplasia (CIN) to quantify the proliferation rate and the presence of normal and atypical mitotic figures. In the cervical tissue specimens of 127 women with CIN, the area with the highest cell proliferation was identified and, at that site, the proliferation rate was assessed by calculating the mitotic index (MI). Lesions with an MI < 2 were not considered further. In the area with the highest proliferation rate, 228 mitoses were classified into one of the following groups: normal mitotic figures (NMFs), lag-type mitoses (OLTMs) comprising three group metaphases (3GMs), two group metaphases (2GMs) and other lag-type mitoses (LTMs), multipolar mitoses (MPMs) comprising tripolar mitoses (3PMs) and quadripolar mitoses (4PMs), and other atypical mitotic figures (OAMFs). The median value of the MI increased significantly from 3 in CIN I through 4 in CIN II to 9 in CIN III (P < 0.001). The occurrence of the different LTMs was mutually correlated. The frequency of LTMs increased significantly with increasing CIN grade (P < 0.001), whereas the frequency of NMFs decreased significantly with increasing CIN grade (P < 0.001). The frequency of OAMFs was not related to CIN grade (P = 0.94). MPMs were present in low numbers in a minority of the lesions. Spearman's rank correlation coefficient (with 95% confidence limits) between the MI and the number of LTMs, OAMFs and NMFs was 0.66 (0.53; 0.75), -0.14 (-0.32; 0.05) and -0.51 (-0.63; -0.35), respectively. Increasing CIN grade is associated with increasing MI, increasing numbers of LTMs, and decreasing numbers of NMFs. MPMs are very rare events in CIN. The abundant presence of OAMFs seems to be independent of CIN grade and MI.

Genes on chromosome 14q and their role in the pathogenesis of HLA-B27 associated diseases.

Genetic factors other than HLA-B27 may play a role in the pathogenesis of ankylosing spondylitis (AS), acute anterior uveitis (AAU) and Reiter's syndrome (RS). Studies by Brewerton et al. and Kijlstra et al. showed associations between the MZ phenotype of alpha 1-antitrypsin and the Gm phenotype zafngb of IgG in patients with AAU, who developed AS. The loci for alpha 1-antitrypsin (PI) and Gm allotypes (IGH) are situated on the tip of the long arm of chromosome 14. In the present study we tried to clarify and extend the above studies. In 41 B27+ AAU patients with AS the alpha 1-antitrypsin and Gm phenotype and allotype frequencies were not statistically different from those in B27+ AS patients developing AAU and in B27+ AAU patients without AS, in B27+ AS patients without AAU, B27+ patients with Reiter's syndrome, B27+ patients with low back pain, B27- AAU patients and normal controls. It is therefore unlikely that genes on the tip of chromosome 14 play a role in the pathogenesis of B27 associated diseases. A hypothesis was formed suggesting that a bacterial-derived modifying factor may replace the position of beta 2 microglobulin in the HLA-B27 molecule resulting in an impaired cytotoxic T cell reactivity.

Contrasting effects of acute and chronic volume expansion on orthostatic blood pressure control in a patient with autonomic circulatory failure.

We studied the effects of acute and chronic volume expansion on orthostatic blood pressure control in a 22-year-old female with hypoadrenergic orthostatic hypotension. Acute volume expansion on two occasions had unexpected effects: a decrease respectively no change in orthostatic tolerance and no change in upright blood pressure immediately after volume expansion followed by a marked improvement 8 h thereafter. The time course of changes in haematocrit and serum protein indicated an initial extravasation of plasma followed by a subsequent larger fluid shift back to the intravascular space. These effects had vanished after 3 days. Chronic volume expansion by head-up tilt at night and fludrocortisone resulted in a marked improvement in orthostatic blood pressure control at a comparable increment in body weight and sodium balance for the next 7 years until now. The circadian circulatory variation with orthostatic blood pressure lowest in the morning remained present after chronic volume expansion. We conclude in this patient that the effects of acute volume expansion on orthostatic blood pressure in autonomic failure are complex and not predictive for the beneficial effects of chronic volume expansion.

[Policy in no-resuscitation orders. Work Group of the Central Guidance Organ for Intercollegiate Testing CBO]. / Beleid bij niet-reanimeren. Werkgroep van het Centraal Begeleidingsorgaan voor de Intercollegiale Toetsing CBO.

Discussions on the inappropriateness of cardiopulmonary resuscitation have led to installation of a working committee by the scientific council of the National Organization for Quality Assurance in Hospitals. The report of this committee contains recommendations on the process by which the decision to write a Do-Not-Resuscitate order can be reached. In the report some practical advice is given and the responsibilities of physicians are made clear. The patient's wish remains the central issue.

[Chronic hepatitis ascribed to the use of sotalol]. / Chronische hepatitis toegeschreven aan het gebruik van sotalol.

In a 68-year-old woman with severe chronic hepatitis an extensive investigation revealed no other cause than the use of sotalol for 10 months due to atrial fibrillation. Once the use of the medication had been discontinued the patient's symptoms quickly disappeared and the liver function disorders normalised within 5 months. Sotalol is a beta-adrenergic receptor blocking and anti-arrhythmic agent. It is widely used in patients with supraventricular and ventricular arrhythmias. An adverse effect in terms of liver damage is not known. The pathogenesis of the observed hepatitis remained an enigma because sotalol is a hydrophilic substance which is not metabolized by the liver and is cleared by the kidneys unchanged.