An integrated mechanical degradation model to explore the mechanical response of a bioresorbable polymeric scaffold.

Simulation of bioresorbable medical devices is hindered by the limitations of current material models. Useful simulations require that both the short- and long-term response must be considered; existing models are not physically-based and provide limited insight to guide performance improvements. This study presents an integrated degradation framework which couples a physically-based degradation model, which predicts changes in both crystallinity (Xc) and molecular weight (Mn), with the results of a micromechanical model, which predicts the effective properties of the semicrystalline polymer. This degradation framework is used to simulate the deployment of a bioresorbable PLLA (Poly (L-lactide) stent into a mock vessel and the subsequent mechanical response during degradation under different diffusion boundary conditions representing neointimal growth. A workflow is established in a commercial finite element code that couples both the immediate and long-term responses. Clinically relevant lumen loss is reported and used to compare different responses and the effect of neo-intimal tissue regrowth post-implantation on degradation and on the mechanical response is assessed. In addition, the effects of possible changes in Xc, which could occur during processing and stent deployment, are explored.

User-centered development process of an operating interface to couple a robotic glove with a virtual environment to optimize hand rehabilitation following a stroke.

Introduction: Task-specific neurorehabilitation is crucial to optimize hand recovery shortly after a stroke, but intensive neurorehabilitation remains limited in resource-constrained healthcare systems. This has led to a growing interest in the use of robotic gloves as an adjunct intervention to intensify hand-specific neurorehabilitation. This study aims to develop and assess the usability of an operating interface supporting such a technology coupled with a virtual environment through a user-centered design approach. Methods: Fourteen participants with hand hemiparesis following a stroke were invited to don the robotic glove before browsing through the operating interface and its functionalities, and perform two mobility exercises in a virtual environment. Feedback was collected for improving technology usability. Participants completed the System Usability Scale and ABILHAND questionnaires and their recommendations were gathered and prioritized in a Pugh Matrix. Results: The System Usability Scale (SUS) score for the operating interface was excellent (M = 87.0 SD = 11.6). A total of 74 recommendations to improve the user interface, calibration process, and exercise usability were identified. Conclusion: The application of a full cycle of user-centred design approach confirms the high level of usability of the system which is perceived by end users as acceptable and useful for intensifying neurorehabilitation.

Preoperative radiographic and clinical factors associated with the visualization of intraoperative cerebrospinal fluid during endoscopic transsphenoidal resection of pituitary adenomas.

BACKGROUND: Intraoperative visualization of cerebrospinal fluid (CSF) during endoscopic endonasal resection of skull base tumors is the most common factor contributing to the development of postoperative CSF leaks. No previous studies have solely evaluated preoperative factors contributing to intraoperative CSF visualization. The purpose of this study was to identify preoperative factors predictive of intraoperative CSF visualization. METHODS: Retrospective review of patients who underwent transsphenoidal resection of pituitary adenomas was conducted. Clinical and radiographic variables were compared for those who had CSF visualized to those who did not. Nominal logistic regression models were built to determine predictive variables. RESULTS: Two hundred and sixty patients were included in the study. All significant demographic and radiographic variables on univariate analysis were included in multivariate analysis. Two multivariate models were built, as tumor height and supraclinoid extension were collinear. The first model, which considered tumor height, found that extension into the third ventricle carried a 4.60-fold greater risk of CSF visualization (P = 0.005). Increasing tumor height showed a stepwise, linear increase in risk; tumors >3 cm carried a 19.02-fold greater risk of CSF visualization (P = 0.003). The second model, which considered supraclinoid tumor extension, demonstrated that extension into the third ventricle carried a 4.38-fold increase in risk for CSF visualization (P = 0.010). Supraclinoid extension showed a stepwise, linear increase in intraoperative CSF risk; tumors with >2 cm of extension carried a 9.26-fold increase in risk (P = 0.017). CONCLUSION: Our findings demonstrate that tumor height, extension into the third ventricle, and extension above the clinoids are predictive of intraoperative CSF visualization.

An exploration of BCI performance variations in people with amyotrophic lateral sclerosis using longitudinal EEG data.

OBJECTIVE: Brain-computer interface (BCI) technology enables people to use direct measures of brain activity for communication and control. The National Center for Adaptive Neurotechnologies and Helen Hayes Hospital are studying long-term independent home use of P300-based BCIs by people with amyotrophic lateral sclerosis (ALS). This BCI use takes place without technical oversight, and users can encounter substantial variation in their day-to-day BCI performance. The purpose of this study is to identify and evaluate features in the electroencephalogram (EEG) that correlate with successful BCI performance during home use with the goal of improving BCI for people with neuromuscular disorders. APPROACH: Nine people with ALS used a P300-based BCI at home over several months for communication and computer control. Sessions from a routine calibration task were categorized as successful ([Formula: see text]70%) or unsuccessful (<70%) BCI performance. The correlation of temporal and spectral EEG features with BCI performance was then evaluated. MAIN RESULTS: BCI performance was positively correlated with an increase in alpha-band (8-14 Hz) activity at locations PO8, P3, Pz, and P4; and beta-band (15-30 Hz) activity at occipital locations. In addition, performance was significantly positively correlated with a positive deflection in EEG amplitude around 220 ms at frontal mid-line locations (i.e. Fz and Cz). BCI performance was negatively correlated with delta-band (1-3 Hz) activity recorded from occipital locations. SIGNIFICANCE: These results highlight the variability found in the EEG and describe EEG features that correlate with successful BCI performance during day-to-day use of a P300-based BCI by people with ALS. These results should inform studies focused on improved BCI reliability for people with neuromuscular disorders.

Long-Term Survival After Transformation of an Adrenocorticotropic Hormone-Secreting Pituitary Macroadenoma to a Silent Corticotroph Pituitary Carcinoma.

BACKGROUND: Pituitary carcinomas are rare and aggressive neoplasms that despite current treatment regimens continue to have a poor prognosis. Adrenocorticotrophic hormone pituitary tumors have been shown to alter their clinical manifestations with conversion to Cushing disease and silent types. CASE DESCRIPTION: The purpose of this paper is to present the first documented case of an adrenocorticotrophic hormone-secreting pituitary adenoma with Cushing disease that differentiated into a silent corticotroph pituitary carcinoma with metastases to distant sites in the central nervous system. CONCLUSIONS: This patient was later treated with radiotherapy, temozolomide, and bevacizumab, with 8 years of progression-free survival.

Predictors of Nasoseptal Flap Use After Endoscopic Transsphenoidal Pituitary Mass Resection.

OBJECTIVE: The pedicled nasoseptal flap (NSF) is the widely accepted reconstructive technique of choice for repair of larger skull base defects after endoscopic endonasal approaches. There is a dearth of literature examining the decision-making process regarding flap harvest. The objective of this study is to evaluate preoperative characteristics that predict the use of NSF reconstruction after endoscopic transsphenoidal resection of pituitary tumors. METHODS: In this retrospective case control study, demographic, clinical, imaging, and procedural details were gathered on all patients undergoing endoscopic transsphenoidal pituitary adenoma resection at a single academic center since January 2009. Characteristics were compared for patients receiving an NSF and those not undergoing NSF repair. A multivariate model that best predicted the use of an NSF was built and a risk score was developed. RESULTS: Two hundred thirty-eight patients were included, and 39 underwent NSF placement. Tumor size and anatomic characteristics were the predominant factors that significantly differed between cases and controls. Patients with transsellar tumor extension had 6.3 higher odds of requiring NSF, each millimeter increase in tumor height on coronal T1 magnetic resonance imaging increased the odds of NSF use by 1.2. The flap risk score (FRS) is calculated by adding tumor height (mm) to 6 if there is transsellar extension. At an FRS of >35, the FRS is 87% specific and 85% sensitive for flap placement. CONCLUSIONS: Preoperative imaging characteristics can predict NSF use. The FRS can be applied by surgical teams and referring physicians to determine which patients are more likely to undergo NSF repair.

Structural Characterisation Reveals Mechanism of IL-13-Neutralising Monoclonal Antibody Tralokinumab as Inhibition of Binding to IL-13Rα1 and IL-13Rα2.

Interleukin (IL)-13 is a pleiotropic T helper type 2 cytokine frequently associated with asthma and atopic dermatitis. IL-13-mediated signalling is initiated by binding to IL-13Rα1, which then recruits IL-4Rα to form a heterodimeric receptor complex. IL-13 also binds to IL-13Rα2, considered as either a decoy or a key mediator of fibrosis. IL-13-neutralising antibodies act by preventing IL-13 binding to IL-13Rα1, IL-4Rα and/or IL-13Rα2. Tralokinumab (CAT-354) is an IL-13-neutralising human IgG4 monoclonal antibody that has shown clinical benefit in patients with asthma. To decipher how tralokinumab inhibits the effects of IL-13, we determined the structure of tralokinumab Fab in complex with human IL-13 to 2 Å resolution. The structure analysis reveals that tralokinumab prevents IL-13 from binding to both IL-13Rα1 and IL-13Rα2. This is supported by biochemical ligand-receptor interaction assay data. The tralokinumab epitope is mainly composed of residues in helices D and A of IL-13. It is mostly light chain complementarity-determining regions that are driving paratope interactions; the variable light complementarity-determining region 2 plays a key role by providing residue contacts for a network of hydrogen bonds and a salt bridge in the core of binding. The key residues within the paratope contributing to binding were identified as Asp50, Asp51, Ser30 and Lys31. This study demonstrates that tralokinumab prevents the IL-13 pharmacodynamic effect by binding to IL-13 helices A and D, thus preventing IL-13 from interacting with IL-13Rα1 and IL-13Rα2.

BCI in practice.

Brain-computer interfaces are systems that use signals recorded from the brain to enable communication and control applications for individuals who have impaired function. This technology has developed to the point that it is now being used by individuals who can actually benefit from it. However, there are several outstanding issues that prevent widespread use. These include the ease of obtaining high-quality recordings by home users, the speed, and accuracy of current devices and adapting applications to the needs of the user. In this chapter, we discuss some of these unsolved issues.

Women's experiences of menopause in an online MS cohort: A case series.

BACKGROUND: Many women with multiple sclerosis (MS) are postmenopausal. Previously reported findings from an online MS cohort suggested that earlier, surgical menopause may be associated with higher patient-reported MS severity scores. OBJECTIVE: To explore experiences of menopause in a series of MS women responding to a reproductive survey from an online research platform, PatientsLikeMe (PLM). METHODS: The free-text responses from a detailed reproductive history survey deployed to PLM members were analyzed using grounded theory approach. RESULTS: Of the 208 free text responses, 127 responses related to menopause. Five themes emerged: (1) perimenopausal onset of MS symptoms, (2) overlap of MS and menopausal symptoms, (3) MS exacerbations and pseudo-exacerbations triggered by hot flashes, (4) escalation of disease course after menopause, including increasing fatigue, cognitive disturbance, and other symptoms; and (5) effect of HRT on MS symptoms. Some women reported no effects of menopause or HRT. CONCLUSION: Given an aging population and a median age of individuals currently living with MS very close to menopausal age in many cohorts, there is a pressing need to understand the impact of menopause on MS course. Qualitative responses in this study illustrated several specific themes that require quantitative testing in clinic-based cohorts.

The role of oral hygiene in head and neck cancer: results from International Head and Neck Cancer Epidemiology (INHANCE) consortium.

BACKGROUND: Poor oral hygiene has been proposed to contribute to head and neck cancer (HNC) risk, although causality and independency of some indicators are uncertain. This study investigates the relationship of five oral hygiene indicators with incident HNCs. METHODS: In a pooled analysis of 8925 HNC cases and 12 527 controls from 13 studies participating in the International Head and Neck Cancer Epidemiology Consortium, comparable data on good oral hygiene indicators were harmonized. These included: no denture wear, no gum disease (or bleeding), <5 missing teeth, tooth brushing at least daily, and visiting a dentist ≥once a year. Logistic regression was used to estimate the effects of each oral hygiene indicator and cumulative score on HNC risk, adjusting for tobacco smoking and alcohol consumption. RESULTS: Inverse associations with any HNC, in the hypothesized direction, were observed for <5 missing teeth [odds ratio (OR) = 0.78; 95% confidence interval (CI) 0.74, 0.82], annual dentist visit (OR = 0.82; 95% CI 0.78, 0.87), daily tooth brushing (OR = 0.83, 95% CI 0.79, 0.88), and no gum disease (OR = 0.94; 95% CI 0.89, 0.99), and no association was observed for wearing dentures. These associations were relatively consistent across specific cancer sites, especially for tooth brushing and dentist visits. The population attributable fraction for ≤ 2 out of 5 good oral hygiene indicators was 8.9% (95% CI 3.3%, 14%) for oral cavity cancer. CONCLUSION: Good oral hygiene, as characterized by few missing teeth, annual dentist visits, and daily tooth brushing, may modestly reduce the risk of HNC.

Sustained weight loss in patients treated with mifepristone for Cushing's syndrome: a follow-up analysis of the SEISMIC study and long-term extension.

BACKGROUND: Overweight and obesity are common among patients with Cushing's syndrome (CS) and may persist in some patients even after ostensibly curative surgery, contributing to cardiometabolic dysfunction and increased cardiovascular risk. Mifepristone, a selective glucocorticoid receptor antagonist, was effective in controlling hyperglycemia in a 24-week trial of adults (N = 50) with endogenous CS and associated type 2 diabetes mellitus/impaired glucose tolerance or hypertension who had failed or were not candidates for surgery (SEISMIC, Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome). This analysis examines long-term weight change among patients who received mifepristone in SEISMIC and enrolled in a long-term safety extension (LTE) study. METHODS: Patients completing the 24-week SEISMIC study and subsequent 6-week off-drug safety evaluation were invited to enroll in the LTE study. Mifepristone doses at the end of SEISMIC were the LTE starting doses. Body weight measures were reviewed at baseline and week 24 of SEISMIC and at LTE month 6, 12, 18, 24, and final visit (last observation collected during the LTE study). RESULTS: Of the 30 patients enrolled in the LTE, evaluable weight data were available for 29 (20/29 female; mean age of 44.7 ± 11.2 years). These patients received mifepristone for a median of 29.2 months (range 8.4-41.9). Mean ± SD weight from SEISMIC baseline to LTE final visit decreased by 10.3 ± 16.3 kg (mean 105.4 ± 34.3 kg to 95.1 ± 32.9 kg), a 9.3 % decrease from baseline weight (P = 0.0008). Of the 29 LTE patients, 18 (62.1 %) lost ≥ 5 % of body weight by the end of the initial 24-week treatment period; this ≥5 % weight loss persisted in 83.3 % (15/18) at LTE final visit. Ten patients (34.5 %) lost ≥ 10 % of initial body weight by week 24 of SEISMIC, which persisted in 80 % at LTE final visit. No new safety signals were detected with long-term mifepristone use. CONCLUSION: Clinically meaningful weight loss achieved during a 24-week study of mifepristone for CS persisted for two additional years in patients who remained on therapy. Long-term treatment with mifepristone appears to have a beneficial effect on weight in patients with endogenous CS. TRIAL REGISTRATION: NCT00569582 (SEISMIC); NCT00936741 (Long-Term Extension).

Patients report worse MS symptoms after menopause: findings from an online cohort.

BACKGROUND: Many women with multiple sclerosis (MS) are postmenopausal, yet the impact of menopause on MS symptoms is unknown. OBJECTIVE: To investigate patient-reported impact of menopause in a large online research platform, PatientsLikeMe (PLM). METHODS: A detailed reproductive history survey was deployed to PLM members, and responses were linked to PLM׳s prospectively collected patient-reported severity score (MS Rating Scale, MSRS). The MSRS has previously shown good correlation with physician-derived EDSS scores. RESULTS: Of the 513 respondents, 55% were postmenopausal; 54% of these reported induced menopause. Median age at natural menopause was 51. Surgical menopause occurred at an earlier age (p<0.001) and was associated with more hormone replacement therapy use (p=0.02) than natural menopause. Postmenopausal status, surgical menopause, and earlier age at menopause were all associated with worse MSRS scores (p≤0.01) in regressions adjusting for age, disease type and duration. CONCLUSION: Postmenopausal patients in this study reported worse MS disease severity. Further, this study highlights a utility for online research platforms, which allow for rapid generation of hypotheses that then require validation in clinical settings.

Dietary intake of flavonoids and oesophageal and gastric cancer: incidence and survival in the United States of America (USA).

BACKGROUND: Flavonoids, polyphenolic compounds concentrated in fruits and vegetables, have experimentally demonstrated chemopreventive effects against oesophageal and gastric cancer. Few epidemiologic studies have examined flavonoid intake and incidence of these cancers, and none have considered survival. METHODS: In this USA multicentre population-based study, case participants (diagnosed during 1993-1995 with oesophageal adenocarcinoma (OEA, n=274), gastric cardia adenocarcinoma (GCA, n=248), oesophageal squamous cell carcinoma (OES, n=191), and other gastric adenocarcinoma (OGA, n=341)) and frequency-matched controls (n=662) were interviewed. Food frequency questionnaire responses were linked with USDA Flavonoid Databases and available literature for six flavonoid classes and lignans. Case participants were followed until 2000 for vital status. Multivariable-adjusted odds ratios (ORs) and hazard ratios (HRs) (95% confidence intervals (CIs)) were estimated, comparing highest with lowest intake quartiles, using polytomous logistic and proportional hazards regressions, respectively. RESULTS: Little or no consistent association was found for total flavonoid intake (main population sources: black tea, orange/grapefruit juice, and wine) and incidence or survival for any tumour type. Intake of anthocyanidins, common in wine and fruit juice, was associated with a 57% reduction in the risk of incident OEA (OR=0.43, 95% CI=0.29-0.66) and OES (OR=0.43, 95% CI=0.26-0.70). The ORs for isoflavones, for which coffee was the main source, were increased for all tumours, except OES. Anthocyanidins were associated with decreased risk of mortality for GCA (HR=0.63, 95% CI=0.42-0.95) and modestly for OEA (HR=0.87, 95% CI=0.60-1.26), but CIs were wide. CONCLUSIONS: Our findings, if confirmed, suggest that increased dietary anthocyanidin intake may reduce incidence and improve survival for these cancers.

Multiscale modeling of trabecular bone marrow: understanding the micromechanical environment of mesenchymal stem cells during osteoporosis.

Mechanical loading directs the differentiation of mesenchymal stem cells (MSCs) in vitro and it has been hypothesized that the mechanical environment plays a role in directing the cellular fate of MSCs in vivo. However, the complex multicellular composition of trabecular bone marrow means that the precise nature of mechanical stimulation that MSCs experience in their native environment is not fully understood. In this study, we developed a multiscale model that discretely represents the cellular constituents of trabecular bone marrow and applied this model to characterize mechanical stimulation of MCSs in vivo.We predicted that cell-level strains in certain locations of the trabecular marrow microenvironment were greater in magnitude (maximum e12»24,000 le) than levels that have been found to result in osteogenic differentiation of MSCs in vitro (>8000 le),which may indicate that the native mechanical environment of MSCs could direct cellular fate in vivo. The results also showed that cell­cell adhesions could play an important role in mediating mechanical stimulation within the MSC population in vivo. The model was applied to investigate how changes that occur during osteoporosis affected mechanical stimulation in the cellular microenvironment of trabecular bone marrow. Specifically,a reduced bone volume (BV) resulted in an overall increase in bone deformation, leading to greater cell-level mechanical stimulation in trabecular bone marrow (maximume12»48,000 le). An increased marrow adipocyte content resulted in slightly lower levels of stimulation within the adjacent cell population due to a shielding effect caused by the more compliant behavior of adipocytes (maximum e12»41,000 le). Despite this reduction, stimulation levels in trabecular bone marrow during osteoporosis remained much higher than those predicted to occur under healthy conditions. It was found that compensatory mechanobiological responses that occur during osteoporosis, such as increased trabecular stiffness and axial alignment of trabeculae, would be effective in returning MSC stimulation in trabecular marrow to normal levels. These results have provided novel insight into the mechanical stimulation of the trabecular marrow MSC population in both healthy and osteoporotic bone, and could inform the design three dimensional(3D) in vitro bioreactor strategies techniques, which seek to emulate physiological conditions.

Bone cell mechanosensation of fluid flow stimulation: a fluid-structure interaction model characterising the role integrin attachments and primary cilia.

Load-induced fluid flow acts as an important biophysical signal for bone cell mechanotransduction in vivo, where the mechanical environment is thought to be monitored by integrin and primary cilia mechanoreceptors on the cell body. However, precisely how integrin- and primary cilia-based mechanosensors interact with the surrounding fluid flow stimulus and ultimately contribute to the biochemical response of bone cells within either the in vitro or in vivo environment remains poorly understood. In this study, we developed fluid-structure interaction models to characterise the deformation of integrin- and primary cilia-based mechanosensors in bone cells under fluid flow stimulation. Under in vitro fluid flow stimulation, these models predicted that integrin attachments on the cell-substrate interface were highly stimulated ε(eq) > 200,000 µÎµ, while the presence of a primary cilium on the cell also resulted in significant strain amplifications, arising at the ciliary base. As such, these mechanosensors likely play a role in mediating bone mechanotransduction in vitro. Under in vivo fluid flow stimulation, integrin attachments along the canalicular wall were highly stimulated and likely play a role in mediating cellular responses in vivo. The role of the primary cilium as a flow sensor in vivo depended upon its configuration within the lacunar cavity. Specifically, our results showed that a short free-standing primary cilium could not effectively fulfil a flow sensing role in vivo. However, a primary cilium that discretely attaches the lacunar wall can be highly stimulated, due to hydrodynamic pressure in the lacunocanalicular system and, as such, could play a role in mediating bone mechanotransduction in vivo.

Cell morphology and focal adhesion location alters internal cell stress.

Extracellular mechanical cues have been shown to have a profound effect on osteogenic cell behaviour. However, it is not known precisely how these cues alter intracellular mechanics to initiate changes in cell behaviour. In this study, a combination of in vitro culture of MC3T3-E1 cells and finite-element modelling was used to investigate the effects of passive differences in substrate stiffness on intracellular mechanics. Cells on collagen-based substrates were classified based on the presence of cell processes and the dimensions of various cellular features were quantified. Focal adhesion (FA) density was quantified from immunohistochemical staining, while cell and substrate stiffnesses were measured using a live-cell atomic force microscope. Computational models of cell morphologies were developed using an applied contraction of the cell body to simulate active cell contraction. The results showed that FA density is directly related to cell morphology, while the effect of substrate stiffness on internal cell tension was modulated by both cell morphology and FA density, as investigated by varying the number of adhesion sites present in each morphological model. We propose that the cells desire to achieve a homeostatic stress state may play a role in osteogenic cell differentiation in response to extracellular mechanical cues.

Use of glucosamine and chondroitin supplements and risk of colorectal cancer.

PURPOSE: Glucosamine and chondroitin are non-vitamin, non-mineral supplements which have anti-inflammatory properties. These supplements are typically used for joint pain and osteoarthritis and are commonly taken as either glucosamine alone or glucosamine plus chondroitin. An exploratory analysis conducted within the VITamins And Lifestyle (VITAL) study observed any use of glucosamine and chondroitin to be associated with reduced risk of colorectal cancer (CRC) after 5 years of follow-up. METHODS: With two additional years of follow-up, we have studied these associations in greater depth, including associations by frequency/duration of use and by formulation, and have evaluated whether observed associations are modified by factors associated with inflammation. Participants include 75,137 western Washington residents aged 50-76 who completed the mailed VITAL questionnaire between 2000 and 2002. Use of glucosamine and chondroitin was ascertained by questions about supplement use during the 10-year period prior to baseline, and participants were followed for CRC through 2008 (n = 557). Cox regression was used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). RESULTS: Persons reporting use of glucosamine + chondroitin on 4+ days/week for 3+ years had a non-statistically significant 45 % lower CRC risk than non-users (HR: 0.55; 95 % CI 0.30-1.01; p-trend: 0.16). This association varied by body mass index (p-interaction: 0.006), with inverse association observed among the overweight/obese (p-trend: 0.02), but not among the underweight/normal weight. Use of glucosamine alone was not significantly associated with CRC risk. CONCLUSIONS: There is great need to identify safe and effective cancer preventive strategies, suggesting that glucosamine and chondroitin may merit further attention as a potential chemopreventive agent.

A fluid-structure interaction model to characterize bone cell stimulation in parallel-plate flow chamber systems.

Bone continuously adapts its internal structure to accommodate the functional demands of its mechanical environment and strain-induced flow of interstitial fluid is believed to be the primary mediator of mechanical stimuli to bone cells in vivo. In vitro investigations have shown that bone cells produce important biochemical signals in response to fluid flow applied using parallel-plate flow chamber (PPFC) systems. However, the exact mechanical stimulus experienced by the cells within these systems remains unclear. To fully understand this behaviour represents a most challenging multi-physics problem involving the interaction between deformable cellular structures and adjacent fluid flows. In this study, we use a fluid-structure interaction computational approach to investigate the nature of the mechanical stimulus being applied to a single osteoblast cell under fluid flow within a PPFC system. The analysis decouples the contribution of pressure and shear stress on cellular deformation and for the first time highlights that cell strain under flow is dominated by the pressure in the PPFC system rather than the applied shear stress. Furthermore, it was found that strains imparted on the cell membrane were relatively low whereas significant strain amplification occurred at the cell-substrate interface. These results suggest that strain transfer through focal attachments at the base of the cell are the primary mediators of mechanical signals to the cell under flow in a PPFC system. Such information is vital in order to correctly interpret biological responses of bone cells under in vitro stimulation and elucidate the mechanisms associated with mechanotransduction in vivo.

A new therapeutic approach in the medical treatment of Cushing's syndrome: glucocorticoid receptor blockade with mifepristone.

OBJECTIVE: Cushing's syndrome (CS) is a serious endocrine disorder caused by prolonged exposure to high cortisol levels. Initial treatment of this condition is dependent upon the cause, but is generally surgical. For patients whose hypercortisolism is not cured by surgery, medical therapy is often required. Drugs that have typically been used for CS medical therapy act by decreasing cortisol levels. Mifepristone is a glucocorticoid receptor antagonist now available for use in patients with CS. Unlike other agents, mifepristone does not decrease cortisol levels, but directly antagonizes its effects. Our objective is to review the pharmacology and clinical use of this novel agent and to discuss detailed guidance on the management of CS patients treated with mifepristone. METHODS: We review the literature regarding mifepristone use in CS and recently published clinical trial data. Detailed information related to clinical assessment of mifepristone use, potential drug interactions, drug initiation and dose titration, and monitoring of drug tolerability are provided. RESULTS: Clinical trial data have shown that mifepristone improves glycemic control and blood pressure, causes weight loss and a decrease in waist circumference, lessens depression, and improves overall wellbeing. However, adverse effects include adrenal insufficiency, hypokalemia, and endometrial thickening with vaginal bleeding. These findings are supported by the earlier literature case reports. CONCLUSION: This article provides a review of the pharmacology and clinical use of mifepristone in Cushing's syndrome, as well as detailed guidance on the management of patients treated with this novel agent.