MRI monitoring of cartilage repair in the knee: a review

Various treatment options for deep cartilage defects are presently available. The efficacy of bone marrow stimulation with microfracture, of mosaicplasty and of various autologous chondrocyte implantation (ACI) techniques has been subject to numerous studies recently. Magnetic resonance imaging (MRI) has gained a major role in the assessment of cartilage repair. The introduction of high-field MRI to clinical routine makes high resolution and three-dimensional imaging readily available. New quantitative MRI techniques that directly visualize the molecular structure of cartilage may further advance our understanding of cartilage repair. The clinical evaluation of cartilage repair tissue is a complex issue, and MR imaging will become increasingly important both in research and in clinical routine. This article reviews the clinical aspects of microfracture, mosaicplasty, and ACI and reports the recent technical advances that have improved MRI of cartilage. Morphological evaluation methods are recommended for each of the respective techniques. Finally, an overview of T2 mapping and delayed gadolinium-enhanced MR imaging of cartilage in cartilage repair is provided.

Advanced morphological and biochemical magnetic resonance imaging of cartilage repair procedures in the knee joint at 3 Tesla

Morphological and biochemical magnetic resonance imaging (MRI) is due to high field MR systems, advanced coil technology, and sophisticated sequence protocols capable of visualizing articular cartilage in vivo with high resolution in clinical applicable scan time. Several conventional two-dimensional (2D) and three-dimensional (3D) approaches show changes in cartilage structure. Furthermore newer isotropic 3D sequences show great promise in improving cartilage imaging and additionally in diagnosing surrounding pathologies within the knee joint. Functional MR approaches are additionally able to provide a specific measure of the composition of cartilage. Cartilage physiology and ultra-structure can be determined, changes in cartilage macromolecules can be detected, and cartilage repair tissue can thus be assessed and potentially differentiated. In cartilage defects and following nonsurgical and surgical cartilage repair, morphological MRI provides the basis for diagnosis and follow-up evaluation, whereas biochemical MRI provides a deeper insight into the composition of cartilage and cartilage repair tissue. A combination of both, together with clinical evaluation, may represent a desirable multimodal approach in the future, also available in routine clinical use.

[Cerebral vasculitis]

Cerebral vasculitis is a rare disease with a potentially harmful or even fatal outcome that often affects young adults. Primary autoimmune mediated disease can be distinguished from secondary vasculitis associated to infectious disorders, connective tissue diseases, malignancies or toxic drug effects. Pathomechanisms lead to destruction of the vessel wall and consecutive hemorrhagic or ischemic brain lesions. Beyond these mechanisms direct autoimmune mediated neurotoxicity is postulated. Clinical presentation is highly variable with potentially fluctuating signs and symptoms. Besides multifocal deficits from disseminated CNS involvement, diffuse encephalopathy or psychosis may result from diffuse CNS affection. For systemic vasculitis with CNS involvement, affection of joints, skin and organs may facilitate the diagnostic evaluation. CNS affection in systemic diseases is highly variable and may even precede systemic manifestation. The diagnostic work-up includes clinical evaluation, analysis of autoantibodies, MRI, digital subtraction angiography and biopsy of the affected tissue in doubtful cases. Standard therapy are corticosteroids often combined with immunosuppressants such as azathioprine, methotrexate or mycophenolate mofetil in chronic disease or cyclophosphamid in acute disorder. When therapy can be initiated timely, prognosis of cerebral vasculitis is usually favourable.

S-Adenosylmethionine for osteoarthritis of the knee or hip

BACKGROUND: Osteoarthritis is the most common form of joint disease and the leading cause of pain and disability in the elderly. S-Adenosylmethionine may be a viable treatment option but the evidence about its effectiveness and safety is equivocal. OBJECTIVES: We set out to compare S-Adenosylmethionine (SAMe) with placebo or no specific intervention in terms of effects on pain and function and safety outcomes in patients with knee or hip osteoarthritis. SEARCH STRATEGY: We searched CENTRAL, MEDLINE, EMBASE, CINAHL and PEDro up to 5 August 2008, checked conference proceedings and reference lists, and contacted authors. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared SAMe at any dosage and in any formulation with placebo or no intervention in patients with osteoarthritis of the knee or hip. DATA COLLECTION AND ANALYSIS: Two independent authors extracted data using standardised forms. We contacted investigators to obtain missing outcome information. We calculated standardised mean differences (SMDs) for pain and function, and relative risks for safety outcomes. We combined trials using inverse-variance random-effects meta-analysis. MAIN RESULTS: Four trials including 656 patients were included in the systematic review, all compared SAMe with placebo. The methodological quality and the quality of reporting were poor. For pain, the analysis indicated a small SMD of -0.17 (95% CI -0.34 to 0.01), corresponding to a difference in pain scores between SAMe and placebo of 0.4 cm on a 10 cm VAS, with no between trial heterogeneity (I(2) = 0). For function, the analysis suggested a SMD of 0.02 (95% CI -0.68 to 0.71) with a moderate degree of between-trial heterogeneity (I2 = 54%). The meta-analyses of the number of patients experiencing any adverse event, and withdrawals or drop-outs due to adverse events, resulted in relative risks of 1.27 (95% CI 0.94 to 1.71) and 0.94 (95% CI 0.48 to 1.86), respectively, but confidence intervals were wide and tests for overall effect were not significant. No trial provided information concerning the occurrence of serious adverse events. AUTHORS' CONCLUSIONS: The current systematic review is inconclusive, hampered by the inclusion of mainly small trials of questionable quality. The effects of SAMe on both pain and function may be potentially clinically relevant and, although effects are expected to be small, deserve further clinical evaluation in adequately sized randomised, parallel-group trials in patients with knee or hip osteoarthritis. Meanwhile, routine use of SAMe should not be advised.

Protective autophagy is involved in resistance towards MET inhibitors in human gastric adenocarcinoma cells

MET, also known as hepatocyte growth factor receptor (HGFR), is a receptor tyrosine kinase with an important role, both in normal cellular function as well as in oncogenesis. In many cancer types, abnormal activation of MET is related to poor prognosis and various strategies to inhibit its function, including small molecule inhibitors, are currently in preclinical and clinical evaluation. Autophagy, a self-digesting recycling mechanism with cytoprotective functions, is induced by cellular stress. This process is also induced upon cytotoxic drug treatment of cancer cells and partially allows these cells to escape cell death. Thus, since autophagy protects different tumor cells from chemotherapy-induced cell death, current clinical trials aim at combining autophagy inhibitors with different cancer treatments. We found that in a gastric adenocarcinoma cell line GTL-16, where MET activity is deregulated due to receptor overexpression, two different MET inhibitors PHA665752 and EMD1214063 lead to cell death paralleled by the induction of autophagy. A combined treatment of MET inhibitors together with the autophagy inhibitor 3-MA or genetically impairing autophagy by knocking down the key autophagy gene ATG7 further decreased cell viability of gastric cancer cells. In general, we observed the induction of cytoprotective autophagy in MET expressing cells upon MET inhibition and a combination of MET and autophagy inhibition resulted in significantly decreased cell viability in gastric cancer cells.

Pulmonary Disease due to Mycobacterium tuberculosis in a Horse: Zoonotic Concerns and Limitations of Antemortem Testing.

A case of pulmonary tuberculosis caused by Mycobacterium tuberculosis was diagnosed in a horse. Clinical evaluation performed prior to euthanasia did not suggest tuberculosis, but postmortem examination provided pathological and bacteriological evidence of mycobacteriosis. In the lungs, multiple tuberculoid granulomas communicating with the bronchiolar lumen, pleural effusion, and a granulomatous lymphadenitis involving mediastinal and tracheobronchial lymph nodes were found. Serologic response to M. tuberculosis antigens was detected in the infected horse, but not in the group of 42 potentially exposed animals (18 horses, 14 alpacas, 6 donkeys, and 4 dogs) which showed no signs of disease. Diagnosis of tuberculosis in live horses remains extremely difficult. Four of 20 animal handlers at the farm were positive for tuberculous infection upon follow-up testing by interferon-gamma release assay, indicating a possibility of interspecies transmission of M. tuberculosis.

ARMin III – arm therapy exoskeleton with an ergonomic shoulder actuation

Rehabilitation robots have become important tools in stroke rehabilitation. Compared to manual arm training, robot-supported training can be more intensive, of longer duration and more repetitive. Therefore, robots have the potential to improve the rehabilitation process in stroke patients. Whereas a majority of previous work in upper limb rehabilitation robotics has focused on end-effector-based robots, a shift towards exoskeleton robots is taking place because they offer a better guidance of the human arm, especially for movements with a large range of motion. However, the implementation of an exoskeleton device introduces the challenge of reproducing the motion of the human shoulder, which is one of the most complex joints of the body. Thus, this paper starts with describing a simplified model of the human shoulder. On the basis of that model, a new ergonomic shoulder actuation principle that provides motion of the humerus head is proposed, and its implementation in the ARMin III arm therapy robot is described. The focus lies on the mechanics and actuation principle. The ARMin III robot provides three actuated degrees of freedom for the shoulder and one for the elbow joint. An additional module provides actuated lower arm pro/supination and wrist flexion/extension. Five ARMin III devices have been manufactured and they are currently undergoing clinical evaluation in hospitals in Switzerland and in the United States.

Self-Reported Psychotic-Like Experiences Are a Poor Estimate of Clinician-Rated Attenuated and Frank Delusions and Hallucinations

Background: One reason for the decision to delay the introduction of an Attenuated Psychosis Syndrome in the main text of the fifth edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders was the concern that attenuated psychotic symptoms (APS) might in fact be common features in adolescents and young adults from the general population of no psychopathological significance in themselves. This concern was based on reports of high prevalence rates of psychotic-like experiences (PLEs) in the general population and the assumption that PLEs are a good estimate of APS. Although the criterion validity of self-reported PLEs had already been studied with respect to clinician-rated psychotic symptoms and found insufficient, it had been argued that PLEs might in fact be more comparable with mild, subclinical expressions of psychotic symptoms and, therefore, with APS. The present paper is the first to specifically study this assumption. Sampling and Methods: The sample consisted of 123 persons seeking help at a service for the early detection of psychosis, of whom 54 had an at-risk mental state or psychosis, 55 had a nonpsychotic mental disorder and 14 had no full-blown mental disorder. PLEs were assessed with the Peters Delusion Inventory and the revised Launay-Slade Hallucination Scale, and psychotic symptoms and APS were assessed with the Structured Interview for Prodromal Syndromes. Results: At a level of agreement between the presence of any PLE (in 98.4% of patients) and any APS (in 40.7%) just exceeding chance (κ = 0.022), the criterion validity of PLEs for APS was insufficient. Even if additional qualifiers (high agreement or distress, preoccupation and conviction) were considered, PLEs (in 52.8%) still tended to significantly overestimate APS, and agreement was only fair (κ = 0.340). Furthermore, the group effect on PLE prevalence was, at most, moderate (Cramer's V ≤ 0.382). Conclusions: The prevalence of APS cannot be deduced from studies of PLEs. Thus, the high population prevalence rate of PLEs does not allow the conclusion that APS are common features of no pathological significance and would lack clinical validity as an Attenuated Psychosis Syndrome in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition. Rather, the population prevalence rate of APS has to be assumed to be largely unknown at present but is likely lower than indicated by epidemiological studies of PLEs. Therefore, dedicated studies are warranted, in which APS are assessed in a way that equates to their clinical evaluation.

Localization of Epileptogenic Zone on Pre-surgical Intracranial EEG Recordings: Toward a Validation of Quantitative Signal Analysis Approaches

In patients diagnosed with pharmaco-resistant epilepsy, cerebral areas responsible for seizure generation can be defined by performing implantation of intracranial electrodes. The identification of the epileptogenic zone (EZ) is based on visual inspection of the intracranial electroencephalogram (IEEG) performed by highly qualified neurophysiologists. New computer-based quantitative EEG analyses have been developed in collaboration with the signal analysis community to expedite EZ detection. The aim of the present report is to compare different signal analysis approaches developed in four different European laboratories working in close collaboration with four European Epilepsy Centers. Computer-based signal analysis methods were retrospectively applied to IEEG recordings performed in four patients undergoing pre-surgical exploration of pharmaco-resistant epilepsy. The four methods elaborated by the different teams to identify the EZ are based either on frequency analysis, on nonlinear signal analysis, on connectivity measures or on statistical parametric mapping of epileptogenicity indices. All methods converge on the identification of EZ in patients that present with fast activity at seizure onset. When traditional visual inspection was not successful in detecting EZ on IEEG, the different signal analysis methods produced highly discordant results. Quantitative analysis of IEEG recordings complement clinical evaluation by contributing to the study of epileptogenic networks during seizures. We demonstrate that the degree of sensitivity of different computer-based methods to detect the EZ in respect to visual EEG inspection depends on the specific seizure pattern.

Alignment between learning needs and learning goals of Mini-CEX in clerkships

Background: Defining learning goals (LG) in alignment with learning needs (LN) is one of the key purposes of formative workplace-based assessment, but studies about this topic are scarce. Summary of Work: We analysed quantitatively and qualitatively how often trainer-student pairs identified the same LN during Mini Clinical Evaluation Exercises (Mini-CEX) in clerkships and to what degree those LNs were in line with the recorded LGs. Multilevel logistic regression models were used to predict LGs by identified LNs, controlling for context variables. Summary of Results: 512 trainers and 165 students conducted 1783 Mini-CEX (98% completion rate). Concordantly, trainer-student pairs most often identified LNs in the domains ‘clinical reasoning’ (23% of 1167 complete forms), ‘organisation / efficiency’ (20%) and ‘physical examination’ (20%). At least one ‘defined’ LG was noted on 313 student forms (18% of 1710), with a total of 446 LGs. Of these, the most frequent LGs were ‘physical examination’ (49% of 446 LGs) and ‘history taking’ (21%); corresponding LNs as well as context variables (e.g. clinic size) were found to be predictors of these LGs. Discussion and Conclusions: Although trainer-student pairs often agreed in their identified LNs, many assessments did not result in an aligned LG or a LG at all. Interventions are needed to enhance the proportion of (aligned) LGs in Mini-CEX in order to tap into its full potential not only as a ‘diagnostic’ but also as an ‘educational tool’. Take-home messages: The sparseness of LGs, their dependency on context variables and their partial non-alignment with students’ LNs raise the question of how the effectiveness of Mini-CEX can be further enhanced.

Horizontal head titubation in infants with Joubert syndrome: a new finding

AIM Head thrusts are well documented in Joubert syndrome and ocular motor apraxia. We provide a detailed clinical characterization of head titubation in 13 young children with Joubert syndrome. METHOD Detailed characterization of head titubation was assessed by targeted clinical evaluation and/or analysis of videos. RESULTS In 12 of 13 children (eight males, five females; median age 6y, range 2mo-15y) head titubation was first recognized in the first 2 months of age and decreased in severity until spontaneous resolution. In all children, the head titubation was horizontal, high frequency (~3Hz), had small amplitude (5-10°), was never present during sleep, and did not interfere with the neurodevelopment during infancy. In the majority of children, emotion, anxiety, and tiredness were worsening factors for head titubation. INTERPRETATION Head titubation is a benign, early presentation of Joubert syndrome. Head titubation in hypotonic infants should prompt a careful search for Joubert syndrome. Awareness of its occurrence in Joubert syndrome may avoid unnecessary investigations.

Ombitasvir (ABT-267), a novel NS5A inhibitor for the treatment of hepatitis C

INTRODUCTION: Chronic hepatitis C infection is a global disease with 160 million people infected worldwide. Until recently, therapy was characterized by long duration, suboptimal success rates and significant adverse drug reactions. The development of direct-acting antivirals initiated a dramatic change in the treatment of hepatitis C. AREAS COVERED: This review covers the development of the novel NS5A inhibitor ombitasvir (ABT-267) and its clinical evaluation in Phase I to III trials as monotherapy and in combination with the NS3/4A inhibitor ABT-450/r and the non-nucleoside NS5B inhibitor dasabuvir (ABT-333) ± ribavirin. EXPERT OPINION: Ombitasvir (ABT-267) is a potent inhibitor of the hepatitis C virus protein NS5A, has favorable pharmacokinetic characteristics and is active in the picomolar range against genotype 1 - 6. In patients with genotype 1 and 4, 12-week combination treatment with ombitasvir, dasabuvir and ABT-450/r plus ribavirin was highly effective and resulted in 12-week sustained virological response rates higher than 95% in treatment-naöve and treatment-experienced patients. In liver transplant recipients with genotype 1 hepatitis C, success rates in the same range can be expected after 24 weeks of treatment according to preliminary trial results. Genotype 1a patients with compensated cirrhosis who were prior nonresponders benefit from a treatment duration of 24 weeks.

Infarction Distribution Pattern in Acute Stroke May Predict the Extent of Leptomeningeal Collaterals.

OBJECTIVE The aim of this study was to evaluate whether the distribution pattern of early ischemic changes in the initial MRI allows a practical method for estimating leptomeningeal collateralization in acute ischemic stroke (AIS). METHODS Seventy-four patients with AIS underwent MRI followed by conventional angiogram and mechanical thrombectomy. Diffusion restriction in Diffusion weighted imaging (DWI) and correlated T2-hyperintensity of the infarct were retrospectively analyzed and subdivided in accordance with Alberta Stroke Program Early CT score (ASPECTS). Patients were angiographically graded in collateralization groups according to the method of Higashida, and dichotomized in 2 groups: 29 subjects with collateralization grade 3 or 4 (well-collateralized group) and 45 subjects with grade 1 or 2 (poorly-collateralized group). Individual ASPECTS areas were compared among the groups. RESULTS Means for overall DWI-ASPECTS were 6.34 vs. 4.51 (well vs. poorly collateralized groups respectively), and for T2-ASPECTS 9.34 vs 8.96. A significant difference between groups was found for DWI-ASPECTS (p<0.001), but not for T2-ASPECTS (p = 0.088). Regarding the individual areas, only insula, M1-M4 and M6 showed significantly fewer infarctions in the well-collateralized group (p-values <0.001 to 0.015). 89% of patients in the well-collateralized group showed 0-2 infarctions in these six areas (44.8% with 0 infarctions), while 59.9% patients of the poor-collateralized group showed 3-6 infarctions. CONCLUSION Patients with poor leptomeningeal collateralization show more infarcts on the initial MRI, particularly in the ASPECTS areas M1 to M4, M6 and insula. Therefore DWI abnormalities in these areas may be a surrogate marker for poor leptomeningeal collaterals and may be useful for estimation of the collateral status in routine clinical evaluation.

Transiente Globale Amnesie versus Transiente Ischämische Attacke – Klinik und Schlaganfallrisiko

Transient global amnesia versus transient ischaemic attack: clinical presentation and cerebral vascular accident risk Transient global amnesia is an acute, benign, isolated and temporarily limited disturbance of memory, that can occur repeatedly but shows no increased risk of cardiovascular events or stroke in particular. Therefore, patients with the typical clinical presentation and a normal brain magnetic resonance-scan require neither further diagnostic nor therapeutic interventions. Since the differential diagnosis of transient global amnesia is wide, and transient ischaemic attacks can present similarly, a careful clinical evaluation and neuroimaging is recommended. In any case of doubt further diagnostic steps according to stroke workup should be initiated. In contrast, a transient ischaemic attack represents a neurological emergency where clinical and diagnostic evaluation must be introduced fast. The rapid establishment of therapeutic and secondary preventive measures decreases the clearly elevated stroke risk and prevents disability.

Stem cell mobilization chemotherapy with gemcitabine is effective and safe in myeloma patients with bortezomib-induced neurotoxicity.

Vinorelbine chemotherapy with granulocyte-colony stimulating factor (G-CSF) stimulation is a widely applied non-myelosuppressive mobilization regimen in Switzerland for myeloma patients, but its neurotoxic potential limits its use in patients with bortezomib-induced polyneuropathy. In this single-center study, we alternatively evaluated safety and effectiveness of gemcitabine chemotherapy with G-CSF for mobilization of autologous stem cells. Between March 2012 and February 2013, all bortezomib-pretreated myeloma patients planned to undergo first-line high-dose melphalan chemotherapy received a single dose of 1250 mg/m(2) gemcitabine, with G-CSF started on day 4. The 24 patients in this study had received a median of four cycles of bortezomib-dexamethason-based induction. Bortezomib-related polyneuropathy was identified in 21 patients (88%) by clinical evaluation and a standardized questionnaire. Administration of gemcitabine mobilization did not induce new or aggravate pre-existing neuropathy. Stem cell mobilization was successful in all 24 patients, with a single day of apheresis being sufficient in 19 patients (78%). The median yield was 9.51 × 10(6) CD34+ cells/kg. Stem collection could be accomplished at day 8 in 67%. Our data suggest that single-dose gemcitabine together with G-CSF is an effective mobilization regimen in myeloma patients and a safe alternative non-myelosuppressive mobilization chemotherapy for myeloma patients with bortezomib-induced polyneuropathy.