The effects of pregnancy in subjects with repaired tetralogy of Fallot.

BACKGROUND: Previous reports reveal inconsistent findings of right ventricular (RV) changes following pregnancy in subjects with repaired tetralogy of Fallot (rTOF). METHODS: A two-center, retrospective cohort study which included women with rTOF who completed pregnancy that were matched to nulliparous women with rTOF by age at the time of baseline cardiac magnetic resonance (CMR), RV ejection fraction (RVEF), and indexed RV end-diastolic volume (RVEDVi). Pre-pregnancy and postpartum cardiac magnetic resonance (CMR) were analyzed and compared to sequential CMR of nulliparous subjects with rTOF. RESULTS: Thirty-six women with rTOF who completed pregnancy were matched to 72 nulliparous women with rTOF. Over a mean period of 3.1 years for the pregnancy group and 2.7 years for the comparison group, there was no significant change in the RVEDVi, RVEF, RV mass, pulmonary regurgitation severity, left ventricular (LV) volumes, LV ejection fraction (LVEF), or LV mass when comparing the baseline CMR and the follow-up CMR in either of the groups. There was a slight increase in RV indexed end-systolic volume (RVESVi) when comparing the baseline CMR and the follow-up CMR in the pregnancy group (68.93, SD 23.34 ml/m2 at baseline vs. 72.97, SD 25.24 mL/m2 at follow-up, P = .028). Using a mixed effects model for CMR parameters change over time; when adjusted for time between baseline and follow-up CMR there was no significant difference in rate of change between the pregnancy and comparison groups. CONCLUSIONS: Most ventricular remodeling parameters measured by CMR did not significantly change in subjects with rTOF who completed pregnancy or in nulliparous subjects with rTOF. In the pregnancy group, RVESVi is larger in those individuals who have undergone pregnancy without a significant change in ventricular function. These patients should be followed longitudinally to determine the long-term ventricular and clinical effects of pregnancy.

A cobalt concentration sensitive Btu-like system facilitates cobalamin uptake in Anabaena sp. PCC 7120.

Metal homeostasis is central to all forms of life, as metals are essential micronutrients with toxic effects at elevated levels. Macromolecular machines facilitate metal uptake into the cells and their intracellular level is regulated by multiple means, which can involve RNA elements and proteinaceous components. While the general principles and components for uptake and cellular content regulation of, e.g., cobalt have been identified for proteobacteria, the corresponding mechanism in other Gram-negative bacteria such as cyanobacteria remain to be established. Based on their photosynthetic activity, cyanobacteria are known to exhibit a special metal demand in comparison to other bacteria. Here, the regulation by cobalt and cobalamin as well as their uptake is described for Anabaena sp. PCC 7120, a model filamentous heterocyst-forming cyanobacterium. Anabaena contains at least three cobalamin riboswitches in its genome, for one of which the functionality is confirmed here. Moreover, two outer membrane-localized cobalamin TonB-dependent transporters, namely BtuB1 and BtuB2, were identified. BtuB2 is important for fast uptake of cobalamin under conditions with low external cobalt, whereas BtuB1 appears to function in cobalamin uptake under conditions of sufficient cobalt supply. While the general function is comparable, the specific function of the two genes differs and mutants thereof show distinct phenotypes. The uptake of cobalamin depends further on the TonB and a BtuFCD machinery, as mutants of tonB3 and btuD show reduced cobalamin uptake rates. Thus, our results provide novel information on the uptake of cobalamin and the regulation of the cellular cobalt content in cyanobacteria.

Two TonB-dependent outer membrane transporters involved in heme uptake in Anabaena sp. PCC 7120.

Low availability of micronutrients such as iron has enforced the evolution of uptake systems in all kingdoms of life. In Gram-negative bacteria, outer membrane, periplasmatic and plasma membrane localized proteins facilitate the uptake of iron-loaded chelators, which are energized by TonB proteins. The specificity of different uptake systems likely depends either on the endogenously produced siderophore or on the bioavailability of iron-chelator complexes in the environment. Hence, an uptake system for schizokinen produced by the model cyanobacterium Anabaena sp. PCC 7120 exists, while bioinformatics analysis suggests the existence of additional systems, likely for uptake of xenosiderophores. Consistently, proteins encoded by alr2153 (hutA1) and alr3242 (hutA2) are assigned as outer membrane heme transporters. Indeed, Anabaena sp. PCC 7120 can utilize external heme as an iron source. The addition of heme resulted in an induction of genes involved in heme degradation and chlorophyll a synthesis and in an increase of the chlorophyll a content. Moreover, iron starvation induced the expression of hutA1, while the addition of heme led to its repression. Remarkably, the addition of a high concentration of heme but not iron starvation resulted in hutA2 induction. Plasmid insertion mutants of both genes exhibited a reduced capacity to recover from iron starvation by heme addition, which indicates a dependence of heme uptake on functional HutA1 and HutA2 proteins. The structural model generated by bioinformatics methods is further in agreement with a role in heme uptake. Thus, we provide evidence that Anabaena sp. PCC 7120 uses a heme uptake system in parallel to other iron acquisition systems.

[Physiotherapy and sports therapeutic interventions for treatment of carpal tunnel syndrome : A systematic review]. / Physio- und sporttherapeutische Interventionen zur Behandlung eines Karpaltunnelsyndroms : Eine systematische Übersichtsarbeit.

BACKGROUND: The treatment of carpal tunnel syndrome (CTS) usually involves surgical decompression of the nerve or splinting and additional medication. Physiotherapy and sports therapy could be non-invasive and alternative treatment approaches with a simultaneous low risk of side effects. OBJECTIVE: The review systematically summarizes the current studies on the effectiveness of physiotherapy and sports therapeutic interventions for treatment of CTS and focuses on the reduction of symptoms and, as a secondary outcome, improvement of hand function. MATERIAL AND METHODS: The systematic review includes randomized controlled trials reporting on physiotherapy or sports therapy interventions published prior to February 2021 in the electronic databases PubMed, CINAHL and Web of Science. Following the guidelines of preferred reporting items for systematic reviews and meta-analyses (PRISMA) and the Cochrane Collaboration, a systematic search of the literature, data extraction and evaluation of the risk of bias using the Cochrane risk of bias tool were conducted by two independent researchers. RESULTS: Out of 461 identified studies 26 were included in the qualitative analysis. The risk of bias in the individual studies was graded as moderate to low. Potential bias might arise due to inadequate blinding of patients and study personnel in some cases as well as due to selective reporting of study results and procedures. Manual therapy proved to be faster and equally effective in reducing pain and improving function in the long term compared to surgery. Mobilization techniques, massage techniques, kinesiotaping and yoga as therapeutic interventions also showed positive effects on symptoms. CONCLUSION: For the management of mild to moderate CTS, physiotherapy and sports therapeutic interventions are characterized primarily by success after as little as 2 weeks of treatment as well as comparable success to surgery and 3 months of postoperative treatment. In addition, patients are not exposed to surgical risks. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the number 42017073839.

Cardiac MRI predictors of good long-term outcomes in patients with repaired TOF.

BACKGROUND: Risk stratification in patients with repaired tetralogy of Fallot (rTOF) have focused on poor clinical outcomes while predictors of a benign clinical course have not been characterized. OBJECTIVE: The goal of this study was to Identify cardiac magnetic resonance (CMR) markers of a good clinical course late after TOF repair. METHODS: Clinical and CMR data from the International Multicenter TOF Registry (INDICATOR) were analyzed. The primary outcome was time to the earliest occurrence of a composite of death, aborted sudden death, and sustained ventricular tachycardia (VT). The secondary outcome was time to the earliest occurrence of atrial arrhythmia, nonsustained VT, and NYHA class >II. Multinomial regression was used to identify predictors of the 3-category outcome: (a) good outcome, defined as freedom from the primary AND secondary outcomes at age 50 years; (b) poor outcome, defined as presence of the primary outcome before age 50 years; and (c) intermediate outcome, defined as not fulfilling criteria for good or poor outcomes. RESULTS: Among 1088 eligible patients, 96 had good outcome, 60 experienced poor outcome, and 932 had intermediate outcome. Patients were age 25.8±10.8 years at the time of the index CMR. Median follow-up was 5.8 years (IQR 3.0, 9.9) after CMR in event-free patients. By univariate analysis, smaller right ventricular (RV) end-systolic and end-diastolic volume index, smaller left ventricular end-systolic volume index, higher right and left ventricular ejection fraction, lower right and left ventricular mass index, and lower left ventricular mass/volume ratio were associated with good outcome. Multivariable modeling identified higher RV ejection fraction (OR 2.38 per 10% increase, P = .002) and lower RV mass index (OR 1.72, per 10 g/m2 decrease, P = .002) as independently associated with good outcome after adjusting for age at CMR. Classification and regression tree analysis identified important thresholds associated with good outcome that were specific to patients age ≥37 years at the time of CMR; these were RV ejection fraction ≥42% and RV mass index <39 g/m2. CONCLUSIONS: Adults with rTOF and no more than mild RV dysfunction combined with no significant RV hypertrophy are likely to be free from serious adverse clinical events into their sixth decade of life and may require less frequent cardiac testing.

Adaptation of the Start-Growth-Time Method for High-Throughput Biofilm Quantification.

Colony forming unit (CFU) determination by agar plating is still regarded as the gold standard for biofilm quantification despite being time- and resource-consuming. Here, we propose an adaption of the high-throughput Start-Growth-Time (SGT) method from planktonic to biofilm analysis, which indirectly quantifies CFU/mL numbers by evaluating regrowth curves of detached biofilms. For validation, the effect of dalbavancin, rifampicin and gentamicin against mature biofilms of Staphylococcus aureus and Enterococcus faecium was measured by accessing different features of the viability status of the cell, i.e., the cultivability (conventional agar plating), growth behavior (SGT) and metabolic activity (resazurin assay). SGT correlated well with the resazurin assay for all tested antibiotics, but only for gentamicin and rifampicin with conventional agar plating. Dalbavancin treatment-derived growth curves showed a compared to untreated controls significantly slower increase with reduced cell doubling times and reduced metabolic rate, but no change in CFU numbers was observed by conventional agar plating. Here, unspecific binding of dalbavancin to the biofilm interfered with the SGT methodology since the renewed release of dalbavancin during detachment of the biofilms led to an unintended antimicrobial effect. The application of the SGT method for anti-biofilm testing is therefore not suited for antibiotics which stick to the biofilm and/or to the bacterial cell wall. Importantly, the same applies for the well-established resazurin method for anti-biofilm testing. However, for antibiotics which do not bind to the biofilm as seen for gentamicin and rifampicin, the SGT method presents a much less labor-intensive method suited for high-throughput screening of anti-biofilm compounds.

Biventricular Global Function Index Is Associated With Adverse Outcomes in Repaired Tetralogy of Fallot.

INTRODUCTION: Cardiac magnetic resonance (CMR) derived biventricular global function index (BVGFI) is a new CMR parameter that integrates biventricular volumes, mass, and function using clinically available CMR parameters. The associations of BVGFI with clinical outcomes in repaired tetralogy of Fallot are unknown. METHODS: Patients with repaired tetralogy of Fallot who had a CMR before the occurrence of a composite outcome of death, resuscitated sudden death, or sustained ventricular tachycardia were studied. BVGFI was calculated as the average of right and left GFI. GFI was defined as (ventricular stroke volume×100)/(ventricular mean cavity volume + total ventricular myocardial volume). Ventricular mean cavity volume was defined as ([end-diastolic + end-systolic volume]/2). Cox multivariable regression analysis and classification and regression tree methodology were used. RESULTS: Of the 736 eligible subjects (mean age at CMR 25.4±14.5 years), with a median follow-up of 28 months, 55 subjects (7.4%) reached the composite outcome (46 deaths and 9 sustained ventricular tachycardia). Independent associations with the composite outcome were as follows: BVGFI <37 (hazard ratio, 2.52; P=0.004), right ventricular end-systolic volume index >85 mL/m2 (hazard ratio, 3.25; P<0.001), atrial tachycardia (hazard ratio, 2.03; P=0.021), and age at repair >2.5 years (hazard ratio, 3.37; P<0.001). Classification and regression tree analysis identified BVGFI as the most discriminatory CMR parameter associated with a high risk for adverse outcomes. CONCLUSIONS: BVGFI, a novel CMR-derived imaging biomarker combining biventricular volumes, mass, and function, may improve risk stratification for adverse clinical outcomes in patients with repaired tetralogy of Fallot.

Impact of pulmonary valve replacement on left ventricular rotational mechanics in repaired tetralogy of Fallot.

BACKGROUND: In repaired tetralogy of Fallot (rTOF), abnormal left ventricular (LV) rotational mechanics are associated with adverse clinical outcomes. We performed a comprehensive analysis of LV rotational mechanics in rTOF patients using cardiac magnetic resonance (CMR) prior to and following surgical pulmonary valve replacement (PVR). METHODS: In this single center retrospective study, we identified rTOF patients who (1) had both a CMR ≤ 1 year before PVR and ≤ 5 years after PVR, (2) had no other intervening procedure between CMRs, (3) had a body surface area > 1.0 m2 at CMR, and (4) had images suitable for feature tracking analysis. These subjects were matched to healthy age- and sex-matched control subjects. CMR feature tracking analysis was performed on a ventricular short-axis stack of balanced steady-state free precession images. Measurements included LV basal and apical rotation, twist, torsion, peak systolic rates of rotation and torsion, and timing of events. Associations with LV torsion were assessed. RESULTS: A total of 60 rTOF patients (23.6 ± 7.9 years, 52% male) and 30 healthy control subjects (20.8 ± 3.1 years, 50% male) were included. Compared with healthy controls, rTOF patients had lower apical and basal rotation, twist, torsion, and systolic rotation rates, and these parameters peaked earlier in systole. The only parameters that were correlated with LV torsion were right ventricular (RV) end-systolic volume (r = - 0.28, p = 0.029) and RV ejection fraction (r = 0.26, p = 0.044). At a median of 1.0 year (IQR 0.5-1.7) following PVR, there was no significant change in LV rotational parameters versus pre-PVR despite reductions in RV volumes, RV mass, pulmonary regurgitation, and RV outflow tract obstruction. CONCLUSION: In this comprehensive study of CMR-derived LV rotational mechanics in rTOF patients, rotation, twist, and torsion were diminished compared to controls and did not improve at a median of 1 year after PVR despite favorable RV remodeling.

The impact of pulmonary valve replacement on pregnancy outcomes in women with tetralogy of Fallot.

BACKGROUND: Pregnant women with repaired tetralogy of Fallot (rTOF) are at increased risk of adverse outcomes. Although pre-pregnancy pulmonary valve replacement (PVR) may be considered in some women to attenuate risk, published data to support this practice are lacking. Our objective was to explore the impact of pre-pregnancy PVR on pregnancy outcomes in rTOF. METHODS: Women with rTOF and cardiovascular magnetic resonance imaging (CMR) before and after pregnancy were included if CMR studies were completed within 3 years of pregnancy. Subjects were compared according to presence (+) or absence (-) of PVR at pre-pregnancy CMR. Pregnancy outcomes (cardiovascular, obstetric, and fetal/neonatal) were documented. RESULTS: Of the 29 study women identified, 7 were PVR+ and 22 were PVR-. Post-pregnancy, the PVR- group demonstrated interval increase in indexed right ventricular end-diastolic volumes (RVEDVi) (157 ± 28 versus 166 ± 33 ml/m2, p = 0.003) and end-systolic volumes (RVESVi) (82 ± 17 versus 89 ± 20 ml/m2, p = 0.003) as compared with pre-pregnancy, but no significant change in RV ejection fraction, RV mass, or left ventricular measurements. In the PVR+ group, there were no interval changes in RV measurements pre-versus post pregnancy. Interval rate of change in RVESVi of PVR- exceeded PVR+ women (+3.7 ± 5.0 versus -2.2 ± 5.0 ml/m2/year, p = 0.03). Pregnancy outcomes did not differ in PVR+ versus PVR- women. CONCLUSIONS: Pregnancy outcomes did not differ according to PVR status in our cohort. While RV volumes remained unchanged in PVR+ women, interval RV dilation was observed in PVR- women. Additional study of a larger population with longer follow-up may further inform clinical practice regarding pre-pregnancy PVR.

Improved neck posture and reduced neck muscle activity when using a novel camera based workstation for manual precision inspection tasks.

PURPOSE: This study investigates the effects of the usage of a novel camera system compared to a conventional lens system for manual precision tasks. Utilizing the novel camera system aims to improve neck posture, reduce neck muscle tension and thereby minimize the risk of neck pain. METHODS: Camera and lens systems were compared by assessing the craniovertebral angle (CVA), electromyographic activity of the M.trapezius and perceived exertion. 16 healthy participants (n = 8 female, 24 ± 2 years; n = 8 male, 30 ± 5 years) performed manual precision tasks in a cross-over design using both systems in sitting and standing positions. RESULTS: Analyses showed that using the camera system improved the CVA in sitting [28.4° (22.8°-33.9°) to 42.5° (38.9°-46.1°); p < 0.01] and decreased the M.trapezius activity in standing [13.1% (7.7%-18.6%) to 8.65% (5.49%-11.81%)]. Additionally, overall and neck specific perceived exertion decreased when using the camera system in standing. CONCLUSIONS: The camera system may prevent neck pain in workers performing manual precision tasks in sitting and standing postures.

Influences of Neck and/or Wrist Pain on Hand Grip Strength of Industrial Quality Proofing Workers.

BACKGROUND: The aim of this study was to analyze the interaction between neck and/or wrist pain and hand grip strength (HGS) and to investigate factors (age, sex, neck disorders, and carpal tunnel syndrome) influencing the HGS of industrial quality proofing workers (N = 145). METHODS: Standardized questionnaires [Neck Disability Index (NDI), Boston Carpal Tunnel Questionnaire] were used to evaluate existing neck and/or wrist pain. HGS measurements were performed in different wrist positions. RESULTS: Significant differences between participants with and without neck pain were found in different wrist positions, in neutral wrist position right [without neck pain (n = 48) 46.34 (43.39 - 49.30); with neck pain (n = 97) 38.46 (36.20 - 40.72), F (1,144)  = 16.82, p < 0.001, ŋ p 2 = 0.11] and left [without neck pain 44.06 (41.19 - 46.94); with neck pain 37.36 (35.13 - 39.58), F (1,144)  = 12.70, p < 0.001, ŋ p 2 = 0.08]. A significant difference between participants with and without wrist pain was found for neutral wrist position right [without wrist pain (n = 105) 42.53 (40.37 - 44.70); with wrist pain (n = 40) 37.24 (33.56 - 40.91), F (1,144)  = 6.41, p = 0.01, ŋ p 2 = 0.04]. Regression analysis showed significant results especially for steps two (age and weight, NDI) and three (age and weight, NDI, Boston Carpal Tunnel Questionnaire) for neutral position right (R2 = 0.355, R2 = 0.357, respectively). CONCLUSION: Neck pain has an impact on HGS but should be evaluated in consideration of age and sex.

Impact of Pregnancy on Ventricular Strain in Women with Repaired Tetralogy of Fallot.

Increasing numbers of women with repaired tetralogy of Fallot (rTOF) are reaching reproductive age and seek counseling regarding their cardiovascular risks related to pregnancy. Therefore, the aim of this study was to characterize changes in left ventricular (LV) strain in women with rTOF during pregnancy and in the postpartum period. Seventeen pregnancies in women with rTOF were included (mean age at repair = 3.2 years ± 5.5 years; mean age at delivery = 32.7 ± 4 years). Echocardiograms from three time periods were analyzed; baseline (prior to conception or in the first trimester), third trimester, and 4-6 weeks postpartum. Sixty-five percent of the patients had at least mild pulmonary regurgitation. Eight patients (47%) had undergone at least one pulmonary valve replacement. There were no changes in LV ejection fraction (EF) or circumferential strain across the three time periods. Significant differences were present in longitudinal strain within the three time points (p = 0.01). Postpartum strain decreased in magnitude compared to the third trimester value (- 17.7 ± 4.1 vs. - 21 ± 5, p-value = 0.003) but was not different when compared to baseline strain (- 17.7 ± 4.1 vs. - 19.4 ± 3.4; p-value = 0.15). In conclusion, in women with rTOF, changes in longitudinal strain were observed during pregnancy with a return to baseline after delivery; EF did not change. These findings provide evidence that pregnancy does not adversely impact LV mechanics in the short term in this potentially vulnerable patient population.

Transcatheter Pulmonary Valve Performance During Pregnancy and the Postpartum Period.

Increasing numbers of women with congenital heart disease are undergoing pregnancy after transcatheter pulmonary valve replacement (TPVR). We present the course of 9 pregnancies in 7 women with TPVR, noting pre-pregnancy, antepartum, and postpartum gradients, as well as maternal cardiac, obstetric, and neonatal outcomes. (Level of Difficulty: Intermediate.).

Association of Pallidal Neurostimulation and Outcome Predictors With X-linked Dystonia Parkinsonism.

Importance: Anecdotal evidence suggests that deep brain stimulation (DBS) of the internal globus pallidus (GPi) is effective in ameliorating dystonia in X-linked dystonia parkinsonism (XDP), a disease that is usually refractive to medical therapy. Objective: To determine the efficacy of GPi-DBS in a cohort of patients with XDP in a prospective study and identify predictors of postoperative outcomes. Design, Setting, and Participants: This observational prospective cohort study enrolled patients in February 2013 and was completed in December 2014. The patients were followed up for up to 46 months. Patients from the Philippines were treated in a single center in Lübeck, Germany and followed up in the Philippines. Sixteen men with XDP (mean [SD] age, 40.9 [7.3] years; disease duration, 1-6 years) from the Philippines with predominant dystonia were selected. Exposures: All patients underwent bilateral GPi-DBS in Lübeck, Germany. Main Outcomes and Measures: Clinical assessment included the motor parts of the Burke-Fahn-Marsden scale (BFMDRS-M) and the Unified Parkinson's Disease Rating Scale (UPDRS-III). T1-based basal ganglia volumetry was performed and correlated with postoperative outcomes. Results: The study participants included 16 Filipino men (mean age, 40.9 years). Masked video ratings revealed significant improvements of dystonia severity 1 week (-55%; range, -94% to 59%; P < .01) and 6 months (-59%; range, -100% to 22%; P < .001) after surgery. The UDPRS-III score also improved, albeit to a lesser extent (-19%; range, -54% to 95%; and -27%; range, -70% to 124%; respectively). Unmasked long-term follow-up confirmed the continued efficacy of GPi-DBS up to 46 months after surgery. Important secondary end points improved, including activities of daily living, pain severity, weight, and quality of life. Caudate atrophy was a predictor of a less beneficial outcome (r = 0.817, P = .004). Conclusions and Relevance: Internal globus pallidus DBS had a positive association in XDP with predominant dystonia (the primary end point) and contributed to an improved quality of life (the secondary end point). The response to DBS occurred within 1 week. Given the inverse correlation of postoperative benefit and caudate atrophy, GPi-DBS should be considered early during the disease course. Close international collaboration, training, and funding from multiple sources enabled the sustainable follow-up of patients with XDP in the Philippines.

The role of mutations in COL6A3 in isolated dystonia.

Specific mutations in COL6A3 have recently been reported as the cause of isolated recessive dystonia, which is a rare movement disorder. In all patients, at least one mutation was located in Exons 41 and 42. In an attempt to replicate these findings, we assessed by direct sequencing the frequency of rare variants in Exons 41 and 42 of COL6A3 in 955 patients with isolated or combined dystonia or with another movement disorder with dystonic features. We identified nine heterozygous carriers of rare variants including five different missense mutations and an extremely rare synonymous variant. In these nine patients, we sequenced the remaining 41 coding exons of COL6A3 to test for a second mutation in the compound heterozygous state. In only one of them, a second rare variant was identified (Thr732Met + Pro3082Arg). Of note, this patient had been diagnosed with Parkinson´s disease (with dystonic posturing) due to homozygous PINK1 mutations. The COL6A3 mutations clearly did not segregate with the disease in the four affected siblings of this family. Further, there was no indication for a disease-modifying effect of the COL6A3 mutations since disease severity or age at onset did not correlate with the number of COL6A3 mutated alleles in this family. In conjunction with the relatively high frequency of homozygous carriers of reported mutations in publically available databases, our data call a causal role for variants in COL6A3 in isolated dystonia into question.

Chimeric antigen receptor (CAR)-engineered T cells redirected against hepatitis C virus (HCV) E2 glycoprotein.

OBJECTIVE: The recent availability of novel antiviral drugs has raised new hope for a more effective treatment of hepatitis C virus (HCV) infection and its severe sequelae. However, in the case of non-responding or relapsing patients, alternative strategies are needed. To this end we have used chimeric antigen receptors (CARs), a very promising approach recently used in several clinical trials to redirect primary human T cells against different tumours. In particular, we designed the first CARs against HCV targeting the HCV/E2 glycoprotein (HCV/E2). DESIGN: Anti-HCV/E2 CARs were composed of single-chain variable fragments (scFvs) obtained from a broadly cross-reactive and cross-neutralising human monoclonal antibody (mAb), e137, fused to the intracellular signalling motif of the costimulatory CD28 molecule and the CD3ζ domain. Activity of CAR-grafted T cells was evaluated in vitro against HCV/E2-transfected cells as well as hepatocytes infected with cell culture-derived HCV (HCVcc). RESULTS: In this proof-of-concept study, retrovirus-transduced human T cells expressing anti-HCV/E2 CARs were endowed with specific antigen recognition accompanied by degranulation and secretion of proinflammatory and antiviral cytokines, such as interferon γ, interleukin 2 and tumour necrosis factor α. Moreover, CAR-grafted T cells were capable of lysing target cells of both hepatic and non-hepatic origin expressing on their surface the HCV/E2 glycoproteins of the most clinically relevant genotypes, including 1a, 1b, 2a, 3a, 4 and 5. Finally, and more importantly, they were capable of lysing HCVcc-infected hepatocytes. CONCLUSIONS: Clearance of HCV-infected cells is a major therapeutic goal in chronic HCV infection, and adoptive transfer of anti-HCV/E2 CARs-grafted T cells represents a promising new therapeutic tool.

Qualitative Characteristics of Depression in Parkinson's Patients and Controls.

BACKGROUND: Depression is common in Parkinson's disease (PD); in light of typical PD pathology it may differ phenomenologically from depression in the general population. OBJECTIVE: To assess depressive symptoms in PD patients and control groups and compare symptom profiles. METHODS: After postal screening of 10,000 citizens of Lübeck, 642 participants were examined and the Beck Depression Inventory (BDI) was sufficiently answered by 477 subjects. Based on motor examinations, we distinguished PD patients, Healthy Controls (HC, no motor impairment), and Disease Controls (DC, motor impairment other than PD). RESULTS: The sample comprised 331 men and 311 women, aged 65 ± 8 years. Out of the overall sample, 198 (41.5%) had a BDI score ≥9. BDI results above 9 points occurred in 34.5% of HC, 50.3% of DC, and 42.4% of PD patients. Compared to the control groups (HC, DC) the PD patients endorsed more "dissatisfaction" and "loss of appetite" but less "feelings of guilt," "self-hate," and "loss of libido." CONCLUSION: Depressive symptoms are more frequent in PD patients compared to HC but not DC. Interestingly, the distribution of individual symptoms of the BDI differs between groups with an emphasis on loss of pleasure/enjoyment in the PD group, a symptom typically considered to be dopaminergically transmitted.

A population-based study on combined markers for early Parkinson's disease.

The prerequisite for an earlier diagnosis of Parkinson's disease (PD) are markers that are both sensitive and specific for clinically definite PD and its prediagnosic phases. Promising candidates include enlarged hyperechogenicity of the substantia nigra (SN+) on transcranial sonography (TCS) and hyposmia. However, despite good sensitivity and specificity, both markers have yet failed to yield reliable predictions. We pursue the possibility of combined use in an ongoing population-based cohort. Subjects were recruited from 10,000 inhabitants of Luebeck/Germany aged 50 to 79 years and additional PD patients from our outpatient clinic. After neurological examination, 715 subjects were grouped into clinically definite PD (n = 106), possible prediagnostic PD (ppPD; n = 73), and a control group subdivided into healthy individuals (n = 283) and controls with diseases other than PD (n = 253). Subjects underwent TCS and smell testing. Sensitivity and specificity of SN+ and hyposmia were good for PD; however, positive predictive values (PPV) of both SN+ (5.2%) and olfaction (2.5%) were low. At least one positive/both positive markers were present in 33%/1% of healthy controls, 33%/2% of diseased controls, 62%/7% of ppPD, and 94%/51% of PD. When combining SN+ and hyposmia, PPV increased to 17.6%, with a sensitivity of 51% and a specificity of 98%. Both SN+ and hyposmia offer good enrichment towards PD and ppPD, are stable against other diseases, and the combination of markers highly increases specificity. However, if the combination of SN+ and hyposmia were used as criterion for PD diagnosis, almost half of clinically definite PD and more than 90% of ppPD would have been missed.

Patients with Parkinson׳s disease are less affected than healthy persons by relevant response-unrelated features in visual search.

Patients with Parkinson׳s disease (PD) respond more readily than healthy controls to irrelevant stimuli that contain task-relevant, response-priming features. This behavior may reflect oversensitivity to response-relevant features of irrelevant stimuli or failure to select relevant stimuli. To decide between these alternatives, we investigated in a "contingent-capture" paradigm whether PD patients are also oversensitive to task-relevant features that do not prime responses. PD patients and healthy controls had to report the orientation of bars in target color, presented among bars of other colors. Critically, target arrays were preceded by arrays of rings, all gray except one which might be the target color and might be presented at the same position as the upcoming target. Replicating earlier results from young healthy participants (Eimer, Kiss, Press, & Sauter, 2009), signal rings in target color induced an N2pc component over contralateral visual cortex and some positivity at anterior sites (d-P200), both indicative of attentional capture. Correspondingly, signals in target color facilitated correct responding to upcoming targets presented at the same location and impeded correct responses otherwise. Patients with PD had diminished N2pc, lacked the frontal focus of d-P200, and their responses tended to be less affected than healthy participants' by signal position. Thus PD patients appeared less affected than healthy persons by stimuli with relevant features. This outcome is compatible with the notion that PD patients have poorer internal representations of what is relevant in a given task.