Enrichment of high-grade tumors in breast cancer gene expression studies.

PURPOSE: Gene expression (GE) profiling for breast cancer classification and prognostication has become increasingly used in clinical diagnostics. GE profiling requires a reasonable tumor cell percentage and high-quality RNA. As a consequence, a certain amount of samples drop out. If tumor characteristics are different between samples included and excluded from GE profiling, this can lead to bias. Therefore, we assessed whether patient and tumor characteristics differ between tumors suitable or unsuitable for generating GE profiles in breast cancer. METHODS: In a consecutive cohort of 738 breast cancer patients who received neoadjuvant chemotherapy at the Netherlands Cancer Institute, GE profiling was performed. We compared tumor characteristics and treatment outcome between patients included and excluded from GE profiling. Results were validated in an independent cohort of 812 patients treated with primary surgery. RESULTS: GE analysis could be performed in 53% of the samples. Patients with tumor GE profiles more often had high-grade tumors [odds ratio 2.57 (95%CI 1.77-3.72), p < 0.001] and were more often lymph node positive [odds ratio 1.50 (95%CI 1.03-2.19), p = 0.035] compared to the group for which GE profiling was not possible. In the validation cohort, tumors suitable for gene expression analysis were more often high grade. CONCLUSIONS: In our gene expression studies, tumors suitable for GE profiling had more often an unfavorable prognostic profile. Due to selection of samples with a high tumor percentage, we automatically select for tumors with specific features, i.e., tumors with a higher grade and lymph node involvement. It is important to be aware of this phenomenon when performing gene expression analysis in a research or clinical context.

Bilateral endoscopic totally extraperitoneal (TEP) inguinal hernia repair does not impair male fertility.

PURPOSE: Endoscopic totally extraperitoneal (TEP) hernia repair with polypropylene mesh has become a well-established technique. However, since the mesh is placed in close contact with the spermatic cord, mesh-induced inflammation may affect its structures, possibly resulting in impaired fertility. The aim of this observational prospective cohort study was to assess fertility after bilateral endoscopic TEP inguinal hernia repair in male patients. METHODS: Fifty-seven male patients (22-60 years old) with primary, reducible, bilateral inguinal hernias underwent elective bilateral endoscopic TEP hernia repair with use of polypropylene mesh. The primary outcome was testicular perfusion; secondary outcomes were testicular volume, endocrinological status, and semen quality. All patients were assessed preoperatively and 6 months postoperatively. RESULTS: Follow-up was completed in 44 patients. No statistically significant differences in measurements of testicular blood flow parameters or testicular volume were found. Postoperative LH levels were significantly higher [preoperative median 4.3 IU/L (IQR 3.4-5.3) versus postoperative median 5.0 IU/L (IQR 3.6-6.5), p = 0.03]. Levels of inhibin B were significantly lower postoperatively [preoperative median 139.0 ng/L (IQR 106.5-183.0) versus postoperative median 27.0 ng/L (IQR 88.3-170.9), p = 0.01]. No significant changes in FSH or testosterone levels were observed. There were no differences in semen quality. CONCLUSIONS: Our data suggest that bilateral endoscopic TEP hernia repair with polypropylene mesh does not impair fertility, as no differences in testicular blood flow, testicular volume, or semen quality were observed. Postoperative levels of LH and inhibin B differed significantly from preoperative measurements, yet no clinical relevance could be ascribed to these findings.

Randomized clinical trial on the effect of a multispecies probiotic on visceroperception in hypersensitive IBS patients.

BACKGROUND: Irritable bowel syndrome (IBS) is characterized by heterogeneous pathophysiology and low response to treatment. Up to 60% of IBS patients suffers from visceral hypersensitivity, which is associated with symptom severity and underlying pathophysiological mechanisms. Recently, positive effects of probiotics in IBS have been reported, but overall the response was modest. We performed a study in IBS patients, characterized by visceral hypersensitivity measured with the rectal barostat, aiming to assess the effect of 6 weeks of multispecies probiotic mix on visceral pain perception. METHODS: We conducted a randomized, placebo-controlled, double-blind trial in forty Rome III IBS patients with visceral hypersensitivity. Prior to intake, patients kept a 2-week symptom diary and underwent a rectal barostat measurement. When hypersensitivity was confirmed, participation was allowed and patients received a multispecies probiotic with in vitro proven potential beneficial effects on mechanisms contributing to visceral hypersensitivity (six different probiotic strains; 10(9)  cfu/g), or a placebo product of one sachet (5 g) per day for 6 weeks. At the end of the intervention period, visceroperception and symptoms were reassessed. KEY RESULTS: Thirty-five patients completed the trial. The percentage of patients with visceral hypersensitivity decreased significantly in the probiotic and placebo group (76.5% and 71.4%, respectively; N.S. between groups). Improvement in pain scores and mean symptom score did not differ between the probiotic and placebo group. CONCLUSIONS & INFERENCES: In this placebo-controlled trial in IBS patients with visceral hypersensitivity, no significant effect of a multispecies probiotic on viscerperception was observed. The study has been registered in the US National Library of Medicine (http://www.clinicaltrials.gov, NCT00702026).

Contrast-enhanced microCT (EPIC-µCT) ex vivo applied to the mouse and human jaw joint.

OBJECTIVES: The temporomandibular joint (TMJ) is susceptive to the development of osteoarthritis (OA). More detailed knowledge of its development is essential to improve our insight into TMJ-OA. It is imperative to have a standardized reliable three-dimensional (3D) imaging method that allows for detailed assessment of both bone and cartilage in healthy and diseased joints. We aimed to determine the applicability of a contrast-enhanced microCT (µCT) technique for ex vivo research of mouse and human TMJs. METHODS: Equilibrium partitioning of an ionic contrast agent via µCT (EPIC-µCT) was previously applied for cartilage assessment in the knee joint. The method was ex vivo, applied to the mouse TMJ and adapted for the human TMJ. RESULTS: EPIC-µCT (30-min immersion time) was applied to mouse mandibular condyles, and 3D imaging revealed an average cartilage thickness of 110 ± 16 µm. These measurements via EPIC-µCT were similar to the histomorphometric measures (113 ± 19 µm). For human healthy OA-affected TMJ samples, the protocol was adjusted to an immersion time of 1 h. 3D imaging revealed a significant thicker cartilage layer in joints with early signs of OA compared with healthy joints (414.2 ± 122.6 and 239.7 ± 50.5 µm, respectively). A subsequent significant thinner layer was found in human joints with late signs of OA (197.4 ± 159.7 µm). CONCLUSIONS: The EPIC-µCT technique is effective for the ex vivo assessment of 3D cartilage morphology in the mouse as well as human TMJ and allows bone-cartilage interaction research in TMJ-OA.

Breast cancer subtyping by immunohistochemistry and histological grade outperforms breast cancer intrinsic subtypes in predicting neoadjuvant chemotherapy response.

Intrinsic subtypes are widely accepted for the classification of breast cancer. Lacking gene expression data, surrogate classifications based on immunohistochemistry (IHC) have been proposed. A recent St. Gallen consensus meeting recommends to use this "surrogate intrinsic subtypes" for predicting adjuvant chemotherapy resistance, implying that "Surrogate Luminal A" breast cancers should only receive endocrine therapy. In this study we assessed both gene expression based intrinsic subtypes as well as surrogate intrinsic subtypes regarding their power to predict neoadjuvant chemotherapy benefit. Single institution data of 560 breast cancer patients were reviewed. Gene expression data was available for 247 patients. Subtypes were determined on the basis of IHC, Ki67, histological grade, endocrine responsiveness, and gene expression, and were correlated with chemotherapy response and recurrence-free survival. In ER+/HER2- tumors, a high histological grade was the best predictor for chemotherapy benefit, both in terms of pCR (p = 0.004) and recurrence-free survival (p = 0.002). The gene expression based and surrogate intrinsic subtype based on Ki67 had no predictive or prognostic value in ER+/HER2- tumors. Histological grade, ER, PR, and HER2 were the best predictive factors for chemotherapy response in breast cancer. We propose to continue the conventional use of these markers.

Triple-negative breast cancer: BRCAness and concordance of clinical features with BRCA1-mutation carriers.

BACKGROUND: BRCAness is defined as shared tumour characteristics between sporadic and BRCA-mutated cancers. However, how to exactly measure BRCAness and its frequency in breast cancer is not known. Assays to establish BRCAness would be extremely valuable for the clinical management of these tumours. We assessed BRCAness characteristics frequencies in a large cohort of triple-negative breast cancers (TNBCs). METHODS: As a measure of BRCAness, we determined a specific BRCA1-like pattern by array Comparative Genomic Hybridisation (aCGH), and BRCA1 promoter methylation in 377 TNBCs, obtained from 3 different patient cohorts. Clinicopathological data were available for all tumours, BRCA1-germline mutation status and chemotherapy response data were available for a subset. RESULTS: Of the tumours, 66-69% had a BRCA1-like aCGH profile and 27-37% showed BRCA1 promoter methylation. BRCA1-germline mutations and BRCA1 promoter methylation were mutually exclusive events (P=1 × 10(-5)). BRCAness was associated with younger age and grade 3 tumours. Chemotherapy response was significantly higher in BRCA1-mutated tumours, but not in tumours with BRCAness (63% (12 out of 19) vs 35% (18 out of 52) pathological complete remission rate, respectively). CONCLUSION: The majority of the TNBCs show BRCAness, and those tumours share clinicopathological characteristics with BRCA1-mutated tumours. A better characterisation of TNBC and the presence of BRCAness could have consequences for both hereditary breast cancer screening and the treatment of these tumours.

Short-term cardiovascular responses to changing task demands.

When measuring operator states the predictive power of cardiovascular and respiratory measures in relation to mental workload has been questioned. One of the main questions is to what extent do cardiovascular measures actually reflect mental workload. This question arises because good measures of mental workload should be sensitive to changes in mental effort alone and not to other influences or at least the changes associated with mental workload should be easy to isolate. In the case of cardiovascular measures, the physiological change brought on by the baroreflex is a compensatory control effect that can potentially overshadow changes in physiology due to mental effort and therefore reduce the usefulness of cardiovascular measures. However, this does not need to be the case. Despite the effects caused by the baroreflex differences in heart rate, heart rate variability and other cardiovascular measures associated with task related effort can still be found using short-term response patterns. The short-segment analysis approach described in this paper is based on a time-frequency method in which the spectral power of the cardiovascular measures in specified spectral bands is computed from small time segments, i.e. 30 s. To demonstrate the effectiveness of this technique two studies which made use of a simulation of an ambulance dispatcher's task are described, both with easy and difficult task conditions. A short-lasting increase in task demand was found to be reflected in short-lasting increases in heart rate and blood pressure in combination with corresponding decreases in heart rate variability and blood pressure variability. These effects were larger in easy task conditions than in hard conditions, likely due to a higher overall effort-level during the hard task conditions. However, the developed measures are still very sensitive to mental effort and if this brief segmentation approach is used cardiovascular measures show promise as good candidates for reflecting mental effort during the assessment of operator state.

Clinical correlates of 'BRCAness' in triple-negative breast cancer of patients receiving adjuvant chemotherapy.

BACKGROUND: We have previously reported an array comparative genomic hybridization profile that identifies triple-negative breast cancers (TNBC), with BRCA1 dysfunction and a high sensitivity to intensified dose bifunctional alkylating agents. To determine the effect of conventional-dose chemotherapy in patients with this so-called BRCA1-like profile, clinical characteristics and survival were studied in a large group of TNBC patients. PATIENTS AND METHODS: DNA was isolated and BRCA1-like status was assessed in 101 patients with early-stage TNBC receiving adjuvant cyclophosphamide-based chemotherapy. Clinical characteristics and survival were compared between BRCA1-like and non-BRCA1-like groups. Results Sixty-six tumors (65%) had a BRCA1-like profile. Patients with BRCA1-like tumors tended to be younger and had more often node-negative disease (P = 0.06 and P = 0.03, respectively). Five-year recurrence-free survival was 80% for the BRCA1-like group and 75% for the non-BRCA1-like group (P = 0.35). T stage was the only variable significantly associated with survival. CONCLUSIONS: BRCA1-like tumors share clinical features, like young age at diagnosis and similar nodal status, with breast cancers in BRCA1 mutation carriers. Their prognosis is similar to that of non-BRCA1-like tumors when conventional-dose chemotherapy is administered. TNBCs that are classified as BRCA1-like may contain a defect in homologous recombination and could, in theory, benefit from the addition of poly ADP ribose polymerase inhibitors.

Neoadjuvant chemotherapy in ER+ HER2- breast cancer: response prediction based on immunohistochemical and molecular characteristics.

A pathological complete remission (pCR) is rarely achieved by neoadjuvant chemotherapy in estrogen receptor-positive (ER+) HER2-negative (HER2-) tumors. Therefore, its use might be questionable in specific groups of this tumor type. To select which patients benefit and which could be spared neoadjuvant chemotherapy, we tested standard pathology and molecular markers in ER+ HER2- breast tumors. Pretreatment biopsies were available from 211 ER+ HER2- tumors, who had been treated with neoadjuvant chemotherapy (adriamycin/cyclophosphamide). mRNA expression data were available for 132 tumors. We determined progesterone receptor expression (PR), endocrine sensitivity, HER2 expression, histology, proliferation, and molecular subtypes. We correlated these data to chemotherapy response using pCR rates and the previously published neoadjuvant response index (NRI). PR-negative tumors (n = 65, 30.8%) and luminal B type tumors (n = 43, 20.4%) responded significantly better to chemotherapy than other tumors. These associations remained significant in multivariate analysis. However, even in the subgroup of patients with the lowest response rate, comprising tumors that had both a positive-PR expression and the luminal A subtype (n = 58, 44%), the majority of the patients had downstaging because of chemotherapy. For histology (lobular vs. ductal), endocrine sensitivity, and proliferation, no associations with chemotherapy response were observed. Gene expression array analysis resulted in 28 significant genes (FDR < 0.1). PR expression and luminal B status are associated with a better response to neoadjuvant chemotherapy. However, both markers had only weak response predictive power, and it was not possible to identify a subgroup with no or only minimal chemotherapy benefit. Therefore, the decision to refrain from neoadjuvant chemotherapy to ER+ HER2- breast tumors should not be based on predictive markers, but exclusively on estimates of prognosis.

Indicators of homologous recombination deficiency in breast cancer and association with response to neoadjuvant chemotherapy.

BACKGROUND: Tumors with homologous recombination deficiency (HRD), such as BRCA1-associated breast cancers, are not able to reliably repair DNA double-strand breaks (DSBs) and are therefore highly sensitive to both DSB-inducing chemotherapy and poly (ADP-ribose) polymerase inhibitors. We have studied markers that may indicate the presence of HRD in HER2-negative breast cancers and related them to neoadjuvant chemotherapy response. PATIENTS AND METHODS: Array comparative genomic hybridization (aCGH), BRCA1 promoter methylation, BRCA1 messenger RNA (mRNA) expression and EMSY amplification were assessed in 163 HER2-negative pretreatment biopsies from patients scheduled for neoadjuvant chemotherapy. RESULTS: Features of BRCA1 dysfunction were frequent in triple-negative (TN) tumors: a BRCA1-like aCGH pattern, promoter methylation and reduced mRNA expression were observed in, respectively, 57%, 25% and 36% of the TN tumors. In ER+ tumors, a BRCA2-like aCGH pattern and the amplification of the BRCA2 inhibiting gene EMSY were frequently observed (43% and 13%, respectively) and this BRCA2-like profile was associated with a better response to neoadjuvant chemotherapy. CONCLUSIONS: Abnormalities associated with BRCA1 inactivation are present in about half of the TN breast cancers but were not predictive of chemotherapy response. In ER+/HER2- tumors, a BRCA2-like aCGH pattern was predictive of chemotherapy response. These findings should be confirmed in independent series.

Mineral heterogeneity affects predictions of intratrabecular stress and strain.

Knowledge of the influence of mineral variations (i.e., mineral heterogeneity) on biomechanical bone behavior at the trabecular level is limited. The aim of this study is to investigate how this material property affects the intratrabecular distributions of stress and strain in human adult trabecular bone. Two different sets of finite element (FE) models of trabecular samples were constructed; tissue stiffness was either scaled to the local degree of mineralization of bone as measured with microCT (heterogeneous) or tissue stiffness was assumed to be homogeneous. The influence of intratrabecular mineral heterogeneity was analyzed by comparing both models. Interesting effects were seen regarding intratrabecular stress and strain distributions. In the homogeneous model, the highest stresses were found at the surface with a significant decrease towards the core. Higher superficial stresses could indicate a higher predicted fracture risk in the trabeculae. In the heterogeneous model this pattern was different. A significant increase in stress with increasing distance from the trabecular surface was found followed by a significant decrease towards the core. This suggests trabecular bending during a compression. In both models a decrease in strain values from surface to core was predicted, which is consistent with trabecular bending. When mineral heterogeneity was taken into account, the predicted intratrabecular patterns of stress and strain are more consistent with the expected biomechanical behavior as based on mineral variations in trabeculae. Our findings indicate that mineral heterogeneity should not be neglected when performing biomechanical studies on topics such as the (long-term or dose dependent) effects of antiresorptive treatments.

Cardiovascular state changes during performance of a simulated ambulance dispatchers' task: potential use for adaptive support.

Adaptive support has the potential to keep the operator optimally motivated, involved, and able to perform a task. In order to use such support, the operator's state has to be determined from physiological parameters and task performance measures. In an environment where the task of an ambulance dispatcher was simulated, two studies have been carried out to evaluate the feasibility of using cardiovascular measures for adaptive support. During performance of this 2-3h lasting planning task, a pattern of results is found that can be characterized by an initial increase of blood pressure and heart rate and a decrease of heart rate variability (defense reaction pattern) followed by an ongoing increase of blood pressure counteracted by a decrease in heart rate. This pattern can be explained by an augmented short-term blood pressure control (baroreflex), which is reflected in an increase of baroreflex sensitivity. Additionally, in this latter phase heart rate variability (HRV) increases as a function of time, while blood pressure variability decreases. In the two studies performed, the baroreflex pattern was consistent for all the relevant variables. In both studies there were periods with high and low workload. Effects of task load are mainly reflected in the variability measures, while in the second study, additionally, blood pressure level was higher during periods with high task demands. The conclusion of the studies is that consistent cardiovascular response patterns can be recognized during this semi-realistic planning task, where variability measures are most sensitive to task demand changes, while blood pressure and baroreflex sensitivity are most informative with respect to cardiovascular state changes. These findings can be seen as a great potential benefit for future use in adaptive support applications.

Cardiovascular and eye activity measures as indices for momentary changes in mental effort during simulated flight.

This study examines effects of momentary changes in mental effort on cardiovascular and eye activity measures. A total of 19 male pilots performed an instrument flight task. Task load was manipulated by having the pilots perform flight manoeuvres of varying complexity. Multilevel analyses demonstrated clear effects of momentary changes in mental effort on both the cardiovascular and the eye activity measures. An increase in task load resulted in an increase of heart rate and a decrease in heart rate variability, mean dwell time and fixation duration. Heart rate differentiated between resting period and task execution. Heart rate variability from short data segments provided more insight in intermediate levels of mental effort. The eye activity measures were sensitive to intermediate levels of mental effort as well. Attitude changes resulted in an increase of mean dwell time and mean fixation duration. Task analysis is required to use eye measures as valid indices of mental effort. Having indications of the effects of changing mental demands during daily work of operators is of great importance nowadays. This paper presents an approach to estimate such effects on the basis of heart rate and eye activity measures. In particular, the use of averaged short-term heart rate variability measures is a relatively new aspect.

Biomechanical effect of mineral heterogeneity in trabecular bone.

Due to daily loading, trabecular bone is subjected to deformations (i.e., strain), which lead to stress in the bone tissue. When stress and/or strain deviate from the normal range, the remodeling process leads to adaptation of the bone architecture and its degree of mineralization to effectively withstand the sustained altered loading. As the apparent mechanical properties of bone are assumed to depend on the degree and distribution of mineralization, the goal of the present study was examine the influences of mineral heterogeneity on the biomechanical properties of trabecular bone in the human mandibular condyle. For this purpose nine right condyles from human dentate mandibles were scanned and evaluated with a microCT system. Cubic regional volumes of interest were defined, and each was transformed into two different types of finite element (FE) models, one homogeneous and one heterogeneous. In the heterogeneous models the element tissue moduli were scaled to the local degree of mineralization, which was determined using microCT. Compression and shear tests were simulated to determine the apparent elastic moduli in both model types. The incorporation of mineralization variation decreased the apparent Young's and shear moduli by maximally 21% in comparison to the homogeneous models. The heterogeneous model apparent moduli correlated significantly with bone volume fraction and degree of mineralization. It was concluded that disregarding mineral heterogeneity may lead to considerable overestimation of apparent elastic moduli in FE models.

The anion exchanger Ae2 is required for enamel maturation in mouse teeth.

One of the mechanisms by which epithelial cells regulate intracellular pH is exchanging bicarbonate for Cl(-). We tested the hypothesis that in ameloblasts the anion exchanger-2 (Ae2) is involved in pH regulation during maturation stage amelogenesis. Quantitative X-ray microprobe mineral content analysis, scanning electron microscopy, histology, micro-computed tomography and Ae2 immuno-localisation analyses were applied to Ae2-deficient and wild-type mouse mandibles. Immuno-localisation of Ae2 in wild-type mouse incisors showed a very strong expression of Ae2 in the basolateral membranes of the maturation stage ameloblasts. Strikingly, zones of contiguous ameloblasts were found within the maturation stage in which Ae2 expression was extremely low as opposed to neighbouring cells. Maturation stage ameloblasts of the Ae2(a,b)(-/-) mice failed to stain for Ae2 and showed progressive disorganisation as enamel development advanced. Maturation stage enamel of the Ae2(a,b)(-/-) mice contained substantially less mineral and more protein than wild-type enamel as determined by quantitative X-ray microanalysis. Incisor enamel was more severely affected than molar enamel. Scanning electron microscopy revealed that the rod-inter-rod structures of the Ae2(a,b)(-/-) mice incisor enamel were absent. Mineral content of dentine and bone of Ae2(a,b)(-/-) mice was not significantly different from wild-type mice. The enamel from knockout mouse teeth wore down much faster than that from wild-type litter mates. Basolateral bicarbonate secretion via the anionic exchanger Ae2 is essential for mineral growth in the maturation stage enamel. The observed zonal expression of Ae2 in the maturation stage ameloblasts is in line with a model for cyclic proton secretion during maturation stage amelogenesis.

Porosity of human mandibular condylar bone.

Quantification of porosity and degree of mineralization of bone facilitates a better understanding of the possible effects of adaptive bone remodelling and the possible consequences for its mechanical properties. The present study set out first to give a three-dimensional description of the cortical canalicular network in the human mandibular condyle, in order to obtain more information about the principal directions of stresses and strains during loading. Our second aim was to determine whether the amount of remodelling was larger in the trabecular bone than in cortical bone of the condyle and to establish whether the variation in the amount of remodelling was related to the surface area of the cortical canals and trabeculae. We hypothesized that there were differences in porosity and orientation of cortical canals between various cortical regions. In addition, as greater cortical and trabecular porosities are likely to coincide with a greater surface area of cortical canals and trabeculae available for osteoblastic and osteoclastic activity, we hypothesized that this surface area would be inversely proportional to the degree of mineralization of cortical and trabecular bone, respectively. Micro-computed tomography was used to quantify porosity and mineralization in cortical and trabecular bone of ten human mandibular condyles. The cortical canals in the subchondral cortex of the condyle were orientated in the mediolateral direction, and in the anterior and posterior cortex in the superoinferior direction. Cortical porosity (average 3.5%) did not differ significantly between the cortical regions. It correlated significantly with the diameter and number of cortical canals, but not with cortical degree of mineralization. In trabecular bone (average porosity 79.3%) there was a significant negative correlation between surface area of the trabeculae and degree of mineralization; such a correlation was not found between the surface area of the cortical canals and the degree of mineralization of cortical bone. No relationship between trabecular and cortical porosity, nor between trabecular degree of mineralization and cortical degree of mineralization was found, suggesting that adaptive remodelling is independent and different between trabecular and cortical bone. We conclude (1) that the principal directions of stresses and strains are presumably directed mediolaterally in the subchondral cortex and superoinferiorly in the anterior and posterior cortex, (2) that the amount of remodelling is larger in the trabecular than in the cortical bone of the mandibular condyle; in trabecular bone variation in the amount of remodelling is related to the available surface area of the trabeculae.

Variations in mineralization affect the stress and strain distributions in cortical and trabecular bone.

The mechanical properties of bone depend largely on its degree and distribution of mineralization. The present study analyzes the effect of an inhomogeneous distribution of mineralization on the stress and strain distributions in the human mandibular condyle during static clenching. A condyle was scanned with a micro-CT scanner to create a finite element model. For every voxel the degree of mineralization (DMB) was determined from the micro-CT scan. The Young's moduli of the elements were calculated from the DMB using constant, linear, and cubic relations, respectively. Stresses, strains, and displacements in cortical and trabecular bone, as well as the condylar deformation (extension along the antero-posterion axis) and compliance were compared. Over 90% of the bone mineral was located in the cortical bone. The DMB showed large variations in both cortical bone (mean: 884, SD: 111 mg/cm(3)) and trabecular bone (mean: 738, SD: 101 mg/cm(3)). Variations of the stresses and the strains were small in cortical bone, but large in trabecular bone. In the cortical bone an inhomogeneous mineral distribution increased the stresses and the strains. In the trabecular bone, however, it decreased the stresses and increased the strains. Furthermore, the condylar compliance remained relatively constant, but the condylar deformation doubled. It was concluded that neglect of the inhomogeneity of the mineral distribution results in a large underestimation of the stresses and strains of possibly more than 50%. The stiffness of trabecular bone strongly influences the condylar deformation. Vice versa, the condylar deformation largely determines the magnitude of the strains in the trabecular bone.

Degree and distribution of mineralization in the human mandibular condyle.

The degree of mineralization of bone (DMB) in the mandibular condyle reflects the age and remodeling rate of the bone tissue. Quantification of DMB facilitates a better understanding of possible effects of adaptive remodeling on mineralization of the condyle and its possible consequences for its mechanical quality. We hypothesized differences in the degree and distribution of mineralization between trabecular and cortical bone and between various cortical regions. Microcomputed tomography was used to measure mineralization in 10 human mandibular condyles. Mean DMB was higher in cortical (1,045 mg hydroxyapatite/cm(3)) than in trabecular bone (857 mg/cm(3)) and differed significantly between cortical regions (anterior 987 mg/cm(3), posterior 1,028 mg/cm(3), subchondral 1,120 mg/cm(3)). The variation of DMB distribution was significantly larger in the anterior cortex than in the posterior and subchondral cortex, indicating a larger amount of heterogeneity of mineralization anteriorly. Within the cortical bone, DMB increased with the distance from the cortical canals to the periphery. Similarly, the DMB of trabecular bone increased with the distance from the surface of the trabeculae to their cores. It was concluded that the rate of remodeling differs between condylar trabecular and cortical bone and between cortical regions and that DMB is not randomly distributed across the bone. The difference in DMB between condylar cortical and trabecular bone suggests a large difference in Young's modulus.

Efficacy and tolerability of diclofenac potassium sachets in migraine: a randomized, double-blind, cross-over study in comparison with diclofenac potassium tablets and placebo.

A randomized, controlled, cross-over trial compared single doses of 50 mg diclofenac potassium sachets and tablets with placebo in 328 patients with migraine pain, treating 888 attacks. For the primary endpoint 24.7% of the patients were pain free at 2 h postdose with sachets, 18.5% for tablets and 11.7% for placebo. Treatment differences were significant for sachets vs. placebo (P<0.0001), tablets vs. placebo (P=0.0040) and for sachets vs. tablets (P=0.0035). The numbers needed to treat compared with placebo to achieve pain free at 2 h were 7.75 [95% confidence interval (CI) 5.46, 13.35] for sachets and 15.83 (95% CI 8.63, 96.20) for tablets. Sachets were also statistically superior to tablets for sustained headache response, sustained pain free and reduction in headache intensity within the first 2 h postdose measured on a visual analogue scale (P<0.05). Onset of analgesic effect was 15 min for sachets and 60 min for tablets. Fewer patients needed rescue medication, and there were marked improvements in accompanying symptoms and working ability with both sachets and tablets vs. placebo. No safety issues were identified. This study demonstrates that sachets offer patients suffering from migraine pain a more effective treatment with a faster onset of analgesia when compared with tablets.