Macrophage Migration Inhibitory Factor Promotes Thromboinflammation and Predicts Fast Progression of Aortic Stenosis.

BACKGROUND: Aortic stenosis (AS) is driven by progressive inflammatory and fibrocalcific processes regulated by circulating inflammatory and valve resident endothelial and interstitial cells. The impact of platelets, platelet-derived mediators, and platelet-monocyte interactions on the acceleration of local valvular inflammation and mineralization is presently unknown. METHODS: We prospectively enrolled 475 consecutive patients with severe symptomatic AS undergoing aortic valve replacement. Clinical workup included repetitive echocardiography, analysis of platelets, monocytes, chemokine profiling, aortic valve tissue samples for immunohistochemistry, and gene expression analysis. RESULTS: The patients were classified as fast-progressive AS by the median ∆Vmax of 0.45 m/s per year determined by echocardiography. Immunohistological aortic valve analysis revealed enhanced cellularity in fast-progressive AS (slow- versus fast-progressive AS; median [interquartile range], 247 [142.3-504] versus 717.5 [360.5-1234]; P<0.001) with less calcification (calcification area, mm2: 33.74 [27.82-41.86] versus 20.54 [13.52-33.41]; P<0.001). MIF (macrophage migration inhibitory factor)-associated gene expression was significantly enhanced in fast-progressive AS accompanied by significantly elevated MIF plasma levels (mean±SEM; 6877±379.1 versus 9959±749.1; P<0.001), increased platelet activation, and decreased intracellular MIF expression indicating enhanced MIF release upon platelet activation (CD62P, %: median [interquartile range], 16.8 [11.58-23.8] versus 20.55 [12.48-32.28], P=0.005; MIF, %: 4.85 [1.48-9.75] versus 2.3 [0.78-5.9], P<0.001). Regression analysis confirmed that MIF-associated biomarkers are strongly associated with an accelerated course of AS. CONCLUSIONS: Our findings suggest a key role for platelet-derived MIF and its interplay with circulating and valve resident monocytes/macrophages in local and systemic thromboinflammation during accelerated AS. MIF-based biomarkers predict an accelerated course of AS and represent a novel pharmacological target to attenuate progression of AS.

New approach for detection of LDL-hypercholesterolemia in the pediatric population: The Fr1dolin-Trial in Lower Saxony, Germany.

BACKGROUND AND AIMS: Lipid disorders are often detected very late, particularly in affected young children. We evaluated the feasibility of a screening for LDL-hypercholesterolemia (highLDL) among toddlers and preschoolers. METHODS: Population-based screening has been offered to all children (2-6 years) living in the State of Lower Saxony, Germany, with capillary blood sampling for detection of elevated LDL-cholesterol (LDL-C ≥ 135 mg/dL). Positive results were confirmed by a second measurement. Follow-up in specialized centers, including disease specific counselling and extended diagnostics, as well as evaluation of psychological distress of the parents, is carried out longitudinally. RESULTS: Up to March 2018, 5656 children have participated in the screening program. 5069/5656 children have completed the screening for highLDL (52.0% boys; median age: 4.0 years [Interquartile range, IQR 3.0-5.1]; mother age: 35 years [IQR 31-38]; father's age: 37 years; [IQR 33-42]). HighLDL was identified in 112 children (2.2%; 40.2% boys; LDL-C 157.6 ±â€¯29.5 mg/dL, mean ±â€¯SD). In the total cohort, parents stated in 40.9% of the cases a positive family history for hyperlipidemia and in 29.9% a premature cardiovascular event. Children with highLDL had more often both risk factors in their family history; however, in 37% of them none of these factors were reported. CONCLUSIONS: The first results of the screening program showed its feasibility and revealed high prevalence of highLDL in the general population. Furthermore, a large proportion of families of affected children were not aware about their lipid disorders.

Mitral Valve Endocarditis due to Lactobacillus.

Lactobacillus species are Gram-positive, facultative anaerobic, rod-shaped bacteria. They belong to the lactic acid bacteria group and are also known as a usual part of the normal flora of the gastrointestinal tract as well as of the urinary and genital tracts. They are an infrequent human pathogen but can induce several infections such as bacteremia and infectious endocarditis. We report the case of an 81-year-old woman with Lactobacillus bacteremia and mitral valve endocarditis as well as splenic abscesses.

Galectin-3 is associated with left ventricular reverse remodeling and outcome after percutaneous mitral valve repair.

BACKGROUND: Plasma Galectin-3 is a marker of myocardial inflammation and fibrosis, was associated with left ventricular (LV) reverse remodeling after conventional surgical mitral valve repair (MVR) and predicted clinical events in patients undergoing transcatheter aortic valve replacement (TAVR). We aimed to evaluate the association between pre-interventional Galectin-3 levels and (1) reverse LV remodeling and (2) major adverse cardiovascular events (MACE) in patients undergoing percutaneous MVR. METHODS: Forty-four consecutive patients (median age 79 years, LV ejection fraction 39.5 ±â€¯11.4%, 91% in NYHA functional class ≥III) with symptomatic moderate to severe mitral regurgitation undergoing percutaneous MVR were prospectively included. Plasma Galectin-3 levels were measured before the procedure. Echocardiographic and clinical assessment was performed at baseline and after 3 months. LV reverse remodeling was prospectively defined as a ≥10% increase in global longitudinal strain. MACE included death, myocardial infarction, heart failure related rehospitalization and stroke and was assessed after a mean follow-up time of 2 years. RESULTS: 72.7% of the patients showed LV reverse remodeling. Pre-interventional Galectin-3 < 10 ng/ml was an independent predictor of LV reverse remodeling (OR 10.3, 95% CI 1.2-83.9, p = 0.036). 25 patients (56.8%) experienced a MACE. Patients with Galectin-3 levels ≥ 10 ng/ml had significantly more MACE than patients with Galectin-3 levels < 10 ng/ml (100% vs. 45.5%, p = 0.003). Diabetes independently predicted MACE (HR 3.1, 95% CI 1.0-9.4, p = 0.049); Galectin-3 ≥ 10 ng/ml was of borderline significance (HR 2.2, 95% CI 0.9-5.4, p = 0.088). CONCLUSIONS: Pre-interventional plasma Galectin-3 levels are associated with LV reverse remodeling and with clinical outcome after percutaneous MVR.

Screening for Type 1 Diabetes Risk in Newborns: The Freder1k Pilot Study in Saxony.

An increased risk for type 1 diabetes can be identified using genetic and immune markers. The Freder1k study introduces genetic testing for type 1 diabetes risk within the context of the newborn screening in order to identify newborns with a high risk to develop type 1 diabetes for follow-up testing of early stage type 1 diabetes and for primary prevention trials. Consent for research-based genetic testing of type 1 diabetes risk is obtained with newborn screening. Increased risk is assessed using three single nucleotide polymorphisms for HLA DRB1*03 (DR3), HLA DRB1*04 (DR4), HLA DQB1*0302 (DQ8) alleles, and defined as 1. an HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype or 2. an HLA DR4-DQ8 haplotype and a first-degree family history of type 1 diabetes. Families of infants with increased risk are asked to participate in follow-up visits at infant age 6 months, 2 years, and 4 years for autoantibody testing and early diagnosis of type 1 diabetes. After 8 months, the screening rate has reached 181 per week, with 63% coverage of newborns within Freder1k-clinics and 24% of all registered births in Saxony. Of 4178 screened, 2.6% were identified to have an increased risk, and around 80% of eligible infants were recruited to follow-up. Psychological assessment of eligible families is ongoing with none of 31 families demonstrating signs of excessive burden associated with knowledge of type 1 diabetes risk. This pilot study has shown that it is feasible to perform genetic risk testing for childhood disease within the context of newborn screening programs.

Psychological well-being and independent living of young adults with childhood-onset craniopharyngioma.

AIM: To assess the psychological well-being and social integration of adults with craniopharyngioma diagnosed in childhood. METHOD: A cross-sectional study of a nationwide cohort of young adults with craniopharyngioma in Germany was performed. A structured questionnaire covered the sociodemographic, clinical data, and subjective effects of the condition on social integration. Psychological well-being was assessed using the Hospital Anxiety and Depression Scale (HADS). Results were compared to young adults with type 1 diabetes mellitus (T1DM). RESULTS: The study included 59 participants (29 females, 30 males; mean age 25y 2mo [SD 5y 10mo]), mean age at first surgery 10y 2mo [SD 3y 7mo]. Compared to the T1DM group, significantly more young people with craniopharyngioma aged 25 to 35 years lived at their parents' homes (craniopharyngioma 43.34%; T1DM 13.7%; χ2 =4.14, p=0.049), and fewer lived in a relationship (craniopharyngioma 8.69%; T1DM 54.7%; χ2 =15.74, p<0.001). The HADS revealed a score for depression above the cut-off in 20.69 per cent of young adults with craniopharyngioma and in 6 per cent of young adults with T1DM (χ2 =13.42, p<0.001). INTERPRETATION: Young adults with craniopharyngioma reported subjective disadvantages in professional and social integration. Further, they presented with reduced well-being and increased depression rates. Better psychosocial support and self-management education might reduce the long-term burden of the disease.

Mesonephric adenocarcinoma of the vagina : Diagnosis and multimodal treatment of a rare tumor and analysis of worldwide experience.

BACKGROUND: Mesonephric adenocarcinoma of the vagina is an extremely rare tumor of the female genital tract, with only a few cases reported so far worldwide. Consequently, there is no established standard treatment and limited knowledge about the prognosis and biologic behavior of vaginal mesonephric adenocarcinoma. METHODS: This report documents a new case of vaginal mesonephric adenocarcinoma diagnosed in a 54-year-old woman, and analyzes this in the context of all previously published cases. RESULTS: MRI demonstrated that the 2.5 × 1.8 cm tumor of the vaginal wall was invading urethra and bladder. Following surgical excision, histologic analysis determined mesonephric adenocarcinoma of the vagina, stage pT2 R1. In order to avoid the mutilating extended surgery which would be required to reach R0 and considerable impairment of quality of life, adjuvant radiochemotherapy was administered with external radiation and brachytherapy, including 5 cycles of cisplatin (40 mg/m²) for radiosensitization. After 4 years of continuous oncologic follow-up, the patient is alive and clinically free of disease. CONCLUSION: In this case it was shown that adjuvant radiochemotherapy with radiation and brachytherapy was effective to manage the surgical R1 situation and maintain the patient's life quality. More published cases reports are needed to gradually substantiate optimal treatment strategies.

The Human Tau Interactome: Binding to the Ribonucleoproteome, and Impaired Binding of the Proline-to-Leucine Mutant at Position 301 (P301L) to Chaperones and the Proteasome.

The tau protein is central to the etiology of several neurodegenerative diseases, including Alzheimer's disease, a subset of frontotemporal dementias, progressive supranuclear palsy and dementia following traumatic brain injury, yet the proteins it interacts with have not been studied using a systematic discovery approach. Here we employed mild in vivo crosslinking, isobaric labeling, and tandem mass spectrometry to characterize molecular interactions of human tau in a neuroblastoma cell model. The study revealed a robust association of tau with the ribonucleoproteome, including major protein complexes involved in RNA processing and translation, and documented binding of tau to several heat shock proteins, the proteasome and microtubule-associated proteins. Follow-up experiments determined the relative contribution of cellular RNA to the tau interactome and mapped interactions to N- or C-terminal tau domains. We further document that expression of P301L mutant tau disrupts interactions of the C-terminal half of tau with heat shock proteins and the proteasome. The data are consistent with a model whereby a higher propensity of P301L mutant tau to aggregate may reflect a perturbation of its chaperone-assisted stabilization and proteasome-dependent degradation. Finally, using a global proteomics approach, we show that heterologous expression of a tau construct that lacks the C-terminal domain, including the microtubule binding domain, does not cause a discernible shift of the proteome except for a significant direct correlation of steady-state levels of tau and cystatin B.

Clinical and histopathological features of patients with systemic sclerosis undergoing endomyocardial biopsy.

BACKGROUND: Cardiac involvement in systemic sclerosis (SSc) is associated with a variable phenotype including heart failure, arrhythmias and pulmonary hypertension. The aim of the present study was to evaluate clinical characteristics, histopathological findings and outcome of patients with SSc and a clinical phenotype suggesting cardiac involvement. METHODS AND RESULTS: 25 patients with SSc and clinical signs of cardiac involvement were included between June 2007 and December 2010. They underwent routine clinical work-up including laboratory testing, echocardiography, left and right heart catheterization, holter recordings and endomyocardial biopsy. Primary endpoint (EP) was defined as the combination of cardiovascular death, arrhythmic endpoints (defined as appropriate discharge of implantable cardioverter defibrillator (ICD)) or rehospitalization due to heart failure. The majority of patients presented with slightly impaired left ventricular function (mean LVEF 54.1±9.0%, determined by echocardiography). Endomyocardial biopsies detected cardiac fibrosis in all patients with a variable area percentage of 8% to 32%. Cardiac inflammation was diagnosed as follows: No inflammation in 3.8%, isolated inflammatory cells in 38.5%, a few foci of inflammation in 30.8%, several foci of inflammation in 15.4%, and pronounced inflammation in 7.7% of patients. During follow up (FU) (22.5 months), seven (28%) patients reached the primary EP. Patients with subsequent events showed a higher degree of fibrosis and inflammation in the myocardium by trend. While patients with an inflammation grade 0 or 1 showed an event rate of 18.2%, the subgroup of patients with an inflammation grade 2 presented with an event rate of 25% versus an event rate of 50% in the subgroup of patients with an inflammation grade 3 and 4, respectively (p=0.193). Furthermore, the subgroup of patients with fibrosis grade 1 showed an event rate of 11%, patients with fibrosis grade 2 and 3 presented with an event rate of 33% and 42% respectively (p = 0.160). CONCLUSIONS: Patients with SSc and clinical signs of cardiac involvement presented with mildly impaired LVEF. Prognosis was poor with an event rate of 28% within 22.5 months FU and was associated with the degree of cardiac inflammation and fibrosis.

Cardiac magnetic resonance imaging in patients undergoing percutaneous mitral valve repair with the MitraClip system.

BACKGROUND: Percutaneous mitral valve repair (MVR) with the MitraClip(®) system in patients with mitral regurgitation (MR) is known to reduce symptoms and to improve cardiac morphology and function. MitraClip has been approved for cardiac magnetic resonance imaging (MRI). To date, however, no systematic analysis exists on cardiac MRI in patients undergoing the MitraClip procedure. OBJECTIVE: The aim of this study was to (1) prove feasibility and robustness of cardiac MRI and (2) visualize effects of the procedure on cardiac morphology and function by cardiac MRI. METHODS: 27 consecutive patients (age 77.5 ± 7.6 years) with symptomatic moderate to severe MR undergoing the MitraClip(®) procedure were prospectively included. Cardiac MRI at 1.5 T was performed before and at 3 months after intervention. Cardiac morphology and function were evaluated using steady-state free precession (SSFP) cine sequences by assessment of left ventricular enddiastolic and endsystolic diameters (LVEDD, LVESD) and volumes (EDV, ESV), ejection fraction (LVEF) and stroke volume (SV), diameter of mitral annulus, and myocardial mass (MM). Planimetry of the left atrium (LA) was performed in identical slices in a four-chamber view. RESULTS: Around the clip an extinction artifact was observed which did not disturb the evaluation of cardiac morphology and function. At follow-up, we observed significant decreases of LVEDD (58.0 to 53.3 mm, p < 0.0001), EDV (167 to 159 mL, p = 0.0006) and ESV (101 to 89 mL, p < 0.0001), diameter of mitral annulus (41.4 to 37.9 mm, p < 0.0001), myocardial mass (148.4 to 144.5 g, p = 0.0004) and LA size (40.2 to 37.6 cm(2), p < 0.0001). LVEF improved (43.3 to 46.7 %, p = 0.0041). CONCLUSIONS: Cardiac MRI is feasible and robust in patients with MitraClips. The clinical benefit of a successful MitraClip intervention is paralleled by significant improvements of cardiac morphology and function which can be monitored and validated using MRI in clinical follow-up examinations.

Gremlin-1 identifies fibrosis and predicts adverse outcome in patients with heart failure undergoing endomyocardial biopsy.

BACKGROUND: Gremlin-1 (Grem1), an antagonist of bone morphogenetic proteins, is involved in fibrotic tissue formation in kidney and lung. The impact of myocardial Grem1 expression is unknown. We investigated the prognostic value of Grem1 expression in 214 consecutive patients with nonischemic heart failure (HF) undergoing endomyocardial biopsy. METHODS: In all patients, the following risk factors were assessed: Grem1 expression (semiquantitative score scheme ranging from 1 to 4), presence of inflammatory markers, detection of viral genome, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), New York Heart Association functional class (NYHA), troponin I, and B-type natriuretic peptide. Degree of myocardial fibrosis was defined as an index. Study end point was a combination of all-cause death and HF-related rehospitalization within 3 years of follow-up. RESULTS: Grem1 expression significantly correlated with the degree of myocardial fibrosis (correlation coefficient r = 0.619; P < .0001). Patients with the highest Grem1 expression (score 4) showed the most severely impaired LVEF and highest LVEDD (P < .0001 and P = .030, respectively, for comparison of semiquantitative scores). During follow-up, 33 patients (15.4%) reached the study end point. Grem1 expression and NYHA ≥II were independent predictors of the end point (Grem1: hazard ratio [HR] 7.5, 95% confidence interval [CI] 1.8-32.2; P = .006; NYHA ≥II: HR 2.0, 95% CI 1.0-4.1; P = .048). CONCLUSIONS: Grem1 correlates with the degree of myocardial fibrosis and left ventricular dysfunction and is an independent predictor of adverse outcome in patients with nonischemic HF.

Risk profiles and antithrombotic treatment of patients newly diagnosed with atrial fibrillation at risk of stroke: perspectives from the international, observational, prospective GARFIELD registry.

BACKGROUND: Limited data are available on the characteristics, clinical management, and outcomes of patients with atrial fibrillation at risk of stroke, from a worldwide perspective. The aim of this study was to describe the baseline characteristics and initial therapeutic management of patients with non-valvular atrial fibrillation across the spectrum of sites at which these patients are treated. METHODS AND FINDINGS: The Global Anticoagulant Registry in the FIELD (GARFIELD) is an observational study of patients newly diagnosed with non-valvular atrial fibrillation. Enrollment into Cohort 1 (of 5) took place between December 2009 and October 2011 at 540 sites in 19 countries in Europe, Asia-Pacific, Central/South America, and Canada. Investigator sites are representative of the distribution of atrial fibrillation care settings in each country. Cohort 1 comprised 10,614 adults (≥18 years) diagnosed with non-valvular atrial fibrillation within the previous 6 weeks, with ≥1 investigator-defined stroke risk factor (not limited to those in existing risk-stratification schemes), and regardless of therapy. Data collected at baseline included demographics, medical history, care setting, nature of atrial fibrillation, and treatments initiated at diagnosis. The mean (SD) age of the population was 70.2 (11.2) years; 43.2% were women. Mean±SD CHADS2 score was 1.9±1.2, and 57.2% had a score ≥2. Mean CHA2DS2-VASc score was 3.2±1.6, and 8,957 (84.4%) had a score ≥2. Overall, 38.0% of patients with a CHADS2 score ≥2 did not receive anticoagulant therapy, whereas 42.5% of those at low risk (score 0) received anticoagulant therapy. CONCLUSIONS: These contemporary observational worldwide data on non-valvular atrial fibrillation, collected at the end of the vitamin K antagonist-only era, indicate that these drugs are frequently not being used according to stroke risk scores and guidelines, with overuse in patients at low risk and underuse in those at high risk of stroke. TRIAL REGISTRATION: ClinicalTrials.gov TRI08888.

Thrombolysis is an appropriate treatment in lead-associated infective endocarditis with giant vegetations located on the right atrial lead.

CD endocarditis is a potentially lethal complication after implantation of permanent pacemakers or implantable cardioverter-defibrillators. Complete extraction of the hardware along with antibiotic treatment is the standard therapy. However, there is no standard procedure in the treatment of lead-associated infective endocarditis with large thrombotic vegetations. The authors present the case of a 60-year-old patient with a large vegetation located on the right atrial lead. Due to a high surgical and thrombembolic risk, especially of acute massive pulmonary embolism, the patient received recombinant tissue plasminogen activator to dissolve the thrombus under echocardiographic monitoring. The thrombotic masses were substantially reduced after thrombolysis. Therefore, standard transvenous extraction of the leads could be performed and high risk cardiac re-operation could be avoided.

Influence of the distal femoral resection angle on the principal stresses in ceramic total knee components.

PURPOSE: A certain failure mode using a newly developed cemented ceramic femoral component in total knee replacement was observed in clinical application, i.e. fracture of the femoral component during intraoperative impaction. This may be caused by unintentional deflection of the saw blades during cutting with consecutive higher resection angle of the distal femur than desired, leading to bending of the femoral component during implantation. A finite-element-analysis was carried out to simulate implantation of the femoral component and to evaluate the influence of distal femur preparation on implant stress. SCOPE: We developed and validated a numerical model of the ceramic femoral component including a contact formulation which allowed calculating the principal stresses of the implant during implantation onto the resected femur. The analysis considered different anterior and posterior resection angles with a total of 17 variations. By increasing the femoral resection angle in the finite-element-model it could be shown that a deviation of three degrees from the intended resection angle can cause critical stress amounts during implantation. CONCLUSIONS: When implanting the ceramic component in total knee arthroplasty, the femoral resection angles should be prepared very precisely, in particular anterior saw blade deflection has to be avoided. The implant manufacturer increased implant safety through an additional resection template. Moreover, the impaction of the ceramic femoral component during cementing was not further recommended by using a hammer.

Psychological distress is associated with vision-related but not with generic quality of life in patients with visual field defects after cerebral lesions.

Considerably diminished quality of life (QoL) is observed in patients with visual field defects after lesions affecting the visual pathway. But little is known to what extent vision-and health-related QoL impairments are associated with psychological distress. In 24 patients with chronic visual field defects (mean age=56.17±12.36) the National Eye Institute-visual functioning questionnaire (NEI-VFQ) for vision-related QoL, the Short Form Health Survey-36 (SF-36) for generic QoL and the revised Symptom-Checklist (SCL-90-R) were administered. Cases with clinically relevant SCL-90-R symptoms were defined. Demographic, QoL and visual field parameters were correlated with SCL-90-R scales. About 40% of the investigated patients met the criteria for the definition of psychiatric caseness. 8/12 NEI-VFQ scales correlated significantly with SCL-90-R phobic anxiety (r-range -0.41 to -0.64, P<0.05), 5/12 NEI-VFQ scales correlated with SCL-90-R interpersonal sensitivity (-0.43 to -0.50), and 3/12 with SCL-90-R depression (-0.51 to -0.57) and obsessive-compulsiveness (-0.41 to -0.43). In contrast, only 1/8 SF-36 scales correlated significantly with SCL-90-R depression, phobic anxiety and interpersonal sensitivity (-0.41 to -0.54). No substantial correlations were observed between visual field parameters and SCL-90-R scales. Significant correlations of SCL-90-R with NEI-VFQ but not with SF-36 suggest that self-rated psychological distress is the result of diminished vision-related QoL as a consequence of visual field loss. The extent of visual field loss itself did not influence the rating of psychological distress directly, since SCL-90-R symptoms were only reported when diminished vision-related QoL was present. Patients with reduced vision-related QoL due to persisting visual field defects should therefore be offered additional neuropsychological rehabilitation and supportive psychotherapeutic interventions even years after the lesion.

International longitudinal registry of patients with atrial fibrillation at risk of stroke: Global Anticoagulant Registry in the FIELD (GARFIELD).

BACKGROUND: Atrial fibrillation (AF) is associated with high rates of morbidity and mortality. Patients with AF carry a fivefold increased risk of stroke and the risk of death from AF-related stroke is doubled. Current management is often inadequate, leaving patients at risk for a potentially fatal or disabling event. The purpose of the GARFIELD registry is to evaluate the management and outcomes of patients with newly diagnosed non-valvular AF at risk for stroke. DESIGN: The GARFIELD registry is an observational, multicenter, prospective study of patients with newly diagnosed AF and one or more additional risk factors for stroke. The aim is to enroll 55,000 patients at >1,000 centers in 50 countries. Enrollment will take place in five independent, sequential, prospective cohorts. An additional retrospective validation cohort of 5,000 patients with established AF and at least one additional risk factor for stroke will be conducted in parallel with cohort one. The study started in December 2009, with a planned recruitment period of 4 years and a minimum of 2-year follow-up for each patient. SUMMARY: The GARFIELD registry will provide valuable insights into the clinical management and related outcomes of AF patients throughout many regions of the world and across the spectrum of healthcare systems. By capturing data from unselected patients treated in everyday practice, the registry has the potential to identify best practices as well as deficiencies in available treatment options for specific patient populations and to describe how therapeutic strategies, patient care, and outcomes will evolve over time.

Subjective and objective outcome measures of computer-based vision restoration training.

OBJECTIVE: To determine the relationship of objective and subjective outcome measures of Vision Restoration Training (VRT) for visual field recovery in partially blind patients. This is of interest because the patient's subjective improvement cannot be inferred from objective changes in visual field charts. DESIGN: Nineteen patients with visual system lesions underwent visual field tests (objective measure) before and after six months of VRT. Subjective outcome was determined by pre- and post-training interviews (open narration, questions on activities of daily living, ratings). Interview content was quantified by determining the response frequency for relevant content categories. Drawings of perceived visual field size were used as a subjective topographical measure. Subjective training results were compared to objective visual field size (perimetry). RESULTS: Visual field size increased significantly over the training period. Patients' subjective evaluations depended on the size and location of regained areas, but also on specific evaluation of safe navigation, mobility, reading, and communication. Patients with objective increase of visual field size also reported subjective improvements in daily life. CONCLUSIONS: Computer-based training can improve visual field size as well as subjective visual performance. The patients' subjective experience should be included in treatment evaluation to ensure the meaningfulness of training beyond perimetric measures.

Junctional adhesion molecule A expressed on human CD34+ cells promotes adhesion on vascular wall and differentiation into endothelial progenitor cells.

OBJECTIVE: To investigate the role of junctional adhesion molecule A (JAM-A) on adhesion and differentiation of human CD34(+) cells into endothelial progenitor cells. METHODS AND RESULTS: Tissue healing and vascular regeneration is a multistep process requiring firm adhesion of circulating progenitor cells to the vascular wall and their further differentiation into endothelial cells. The role of JAM-A in platelet-mediated adhesion of progenitor cells was investigated by adhesion assays in vitro and with the help of intravital fluorescence microscopy in mice. Preincubation of human CD34(+) progenitor cells with soluble JAM-A-Fc (sJAM-A-Fc) resulted in significantly decreased adhesion over immobilized platelets or inflammatory endothelium under high shear stress in vitro and after carotid ligation in vivo or ischemia/reperfusion injury in the microcirculation of mice. Human CD34(+) cells express JAM-A, as defined by flow cytometry and Western blot analysis. JAM-A mediates differentiation of CD34(+) cells to endothelial progenitor cells and facilitates CD34(+) cell-induced reendothelialization in vitro. Pretreatment of human CD34(+) cells with sJAM-A-Fc resulted in increased neointima formation 3 weeks after endothelial denudation in the carotid arteries of nonobese diabetic/severe combined immunodeficient mice. CONCLUSIONS: These results indicate that the expression of JAM-A on CD34(+) cells mediates adhesion to the vascular wall after injury and differentiation into endothelial progenitor cells, a mechanism potentially involved in vascular regeneration. Human CD34(+) cells express JAM-A, mediating their interaction with platelets and endothelial cells. Specifically, JAM-A expressed on human CD34(+) progenitor cells regulates their adhesion over immobilized platelets or inflammatory endothelium under high shear stress in vitro and after carotid ligation in vivo or ischemia/reperfusion injury in the microcirculation of mice. Moreover, it mediates differentiation of CD34(+) cells to endothelial progenitor cells and facilitates reendothelialization.