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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

[An adolescent with hemolytic anemia and coagulation disorders as manifestation of Wilson's disease, treated with liver transplantation]. / Een adolescent met hemolytische anemie en stollingsstoornissen als uiting van de ziekte van Wilson, behandeld met levertransplantatie.

A 16-year-old woman presented with anaemia, jaundice, vomiting and nosebleed. She had acute hepatic failure and haemolytic anaemia and developed acute respiratory distress syndrome (ARDS). Wilson's disease was diagnosed. After the ARDS resolved the patient underwent a successful orthotopic liver transplantation. Diagnostic combinations for Wilson's disease are ceruloplasmin < 0.2 g/l with Kayser-Fleischer rings, liver copper > 250 micrograms/g (dry weight) with Kayser-Fleischer rings, or homozygosity for a Wilson mutation on the 13th chromosome. In acute liver failure a copper excretion in 24 h-urine above 1 mg is diagnostic for Wilson's disease, while an elevated serum copper concentration makes this diagnosis very likely. Therapeutic options for Wilson's disease are chelation therapy and liver transplantation; in most cases of acute liver failure due to Wilson's disease orthotopic liver transplantation (preceded by albumin dialysis) is indicated. Nazer's index should be used in addition to the regular King's College criteria for liver transplantation indication.

[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.

Molecular characterization of immunoglobulin G4 gene isoallotypes.

The molecular bases of classical serological immunoglobulin allotypes are progressively uncovered through detailed characterization of the relevant genes. Here we describe two isoallotypic determinants of the G4 gene. In the first, Leu 309, as in G1 and G3, is changed to Val, as in G2; studies on myeloma proteins have long assigned the immunologically defined nG4 m(a)/(b) to the same position. The two molecular variants, here called IGHG4*L309 and IGHG4*V309, are allelic in IGHC haplotypes with a single G4 gene, but can be found together in cis in G4-duplicated haplotypes. A second isoallotypic variant was found at codon 409, where either Arg, as in G1 and G3, or Lys, as in G2, can be found. Both isoallotypes are associated with several 'silent isoallotypic' substitutions dispersed through the hinge, CH2 and CH3 domains. This suggests segmental gene conversion as the common mechanism of origin.

Human papillomavirus type influences the extent of chromosomal lag during mitosis in cervical intraepithelial neoplasia grade III.

The level of risk for carcinoma in the uterine cervix depends on the type of human papillomavirus (HPV) present. We examined whether the HPV type influences the proliferation rate and occurrence of mitotic figures with lagging chromosomes in the precursor of cervical carcinoma. The study group comprised 180 women who were referred because of cytologic changes indicating dysplasia and who were subsequently diagnosed with cervical intraepithelial neoplasia grade III. The HPV-16-associated lesions showed a significantly higher number of mitoses per 1,000 nuclei than the lesions without HPV (p < 0.001). The HPV-16-associated lesions also showed a significantly higher proportion of mitotic figures with lagging chromosomes than did the HPV-18- or HPV-31-associated lesions and lesions without HPV (p = 0.01, p = 0.007, and p = 0.002, respectively). Our results indicate that the differences in oncogenic potential among HPVs become apparent in the precursor lesion through the differences in the extent of chromosomal lag during mitosis.

The suitability of DNA cytometry for the prediction of the histological diagnosis in women with abnormal cervical smears.

OBJECTIVE: To analyse the suitability of DNA cytometry for predicting the histological diagnosis in women with cervical dyskaryosis. DESIGN: Survey with the use of diagnostic information to revise disease probability. SETTING: Colposcopy clinic of a university hospital. PARTICIPANTS: One hundred and ten women with two mildly or moderately dyskaryotic cervical smears and 98 women with one severely dyskaryotic smear. INTERVENTIONS: DNA cytometric analysis using cytocentrifuge preparations of single cell suspensions from a cervical scrape. The main DNA cytometric parameter was N5C (i.e. the absolute number of cells with a DNA content of more than 5C on a given surface with a predefined cell density). MAIN OUTCOME MEASURE: The probability of finding CIN II or worse. On arbitrary grounds, a positive test should point to a probability of 85% or higher. RESULTS: In the patients with cervical neoplasia, the value of N5C increased significantly with an increasing CIN grade (P < 0.001). In the patients with one severely dyskaryotic smear and in those with two mildly or moderately dyskaryotic smears, the prior probability of finding CIN II or worse was 94% and 53%, respectively. Therefore, DNA cytometric analysis might be particularly useful in women with mild or moderate dyskaryosis; further analysis was restricted to this group. All of the women in whom the N5C value was higher than 52 were diagnosed as having CIN II or worse. Only 16 (14.5%) of the 110 women had an N5C value of 52 or higher. When the N5C value was 27, the probability of finding CIN II or worse was estimated to be 85%. Only 28 (25%) patients had an N5C value of 27 or higher. CONCLUSIONS: DNA cytometry produced significant diagnostic information, as was shown by the relation between N5C and the histological diagnosis. However, the N5C value could not discriminate sufficiently between women with CIN II or worse and CIN I or better. Therefore, the management of individual patients with cytological abnormalities cannot be based on the results of DNA cytometric analysis.