Secondary organ fistulation after thoracic endovascular aortic repair.

This manuscript describes the mechanisms behind aorto-oesophageal fistulation (AOF) and aortobronchial/pulmonary (ABPF) fistulation after TEVAR, reports the therapeutical approaches and defines recommendations how to prevent these complications in the future.

Mechanisms of symptomatic spinal cord ischemia after TEVAR: insights from the European Registry of Endovascular Aortic Repair Complications (EuREC).

PURPOSE: To test the hypothesis that simultaneous closure of at least 2 independent vascular territories supplying the spinal cord and/or prolonged hypotension may be associated with symptomatic spinal cord ischemia (SCI) after thoracic endovascular aortic repair (TEVAR). METHODS: A pattern matching algorithm was used to develop a risk model for symptomatic SCI using a prospective 63-patient single-center cohort to test the positive predictive value (PPV) of prolonged intraoperative hypotension and/or simultaneous closure of at least 2 of 4 the vascular territories supplying the spinal cord (left subclavian, intercostal, lumbar, and hypogastric arteries). This risk model was then applied to data extracted from the multicenter European Registry on Endovascular Aortic Repair Complications (EuREC). Between 2002 and 2010, the 19 centers participating in EuREC reported 38 (1.7%) cases of symptomatic spinal cord ischemia among the 2235 patients in the database. RESULTS: In the single-center cohort, direct correlations were seen between the occurrence of symptomatic SCI and both prolonged intraoperative hypotension (PPV 1.00, 95% CI 0.22 to 1.00, p=0.04) and simultaneous closure of at least 2 independent spinal cord vascular territories (PPV 0.67, 95% CI 0.24 to 0.91, p=0.005). Previous closure of a single vascular territory was not associated with an increased risk of symptomatic spinal cord ischemia (PPV 0.07, 95% CI 0.01 to 0.16, p=0.56). The combination of prolonged hypotension and simultaneous closure of at least 2 territories exhibited the strongest association (PPV 0.75, 95% CI 0.38 to 0.75, p<0.0001). Applying the model to the entire EuREC cohort found an almost perfect agreement between the predicted and observed risk factors (kappa 0.77, 95% CI 0.65 to 0.90). CONCLUSION: Extensive coverage of intercostal arteries alone by a thoracic stent-graft is not associated with symptomatic SCI; however, simultaneous closure of at least 2 vascular territories supplying the spinal cord is highly relevant, especially in combination with prolonged intraoperative hypotension. As such, these results further emphasize the need to preserve the left subclavian artery during TEVAR.

A single TCR alpha-chain with dominant peptide recognition in the allorestricted HER2/neu-specific T cell repertoire.

T cells can recognize tumor cells specifically by their TCR and the transfer of TCR-engineered T cells is a promising novel tool in anticancer therapies. We isolated and characterized four allorestricted TCRs with specificity for the HER2/neu-derived peptide 369 (HER2(369)) demonstrating high peptide specificity. PBMCs transduced with especially one TCR, HER2-1, mediated specific tumor reactivity after TCR optimization suggesting that this TCR represents a potential candidate for targeting HER2 by TCR-transduced effector cells. Another TCR showed high-peptide specificity without tumor reactivity. However, the TCR alpha-chain of this TCR specifically recognized HER2(369) not only in combination with the original beta-chain but also with four other beta-chains of the same variable family deriving from TCRs with diverse specificities. Pairing with one beta-chain derived from another HER2(369)-specific TCR potentiated the chimeric TCRs in regard to functional avidity, CD8 independency, and tumor reactivity. Although the frequency of such TCR single chains with dominant peptide recognition is currently unknown, they may represent interesting tools for TCR optimization resulting in enhanced functionality when paired to novel partner chains. However, undirected mispairing with novel partner chains may also result in enhanced cross-reactivity and self-reactivity. These results may have an important impact on the further design of strategies for adoptive transfer using TCR-transduced T cells.

CMV-specific TCR-transgenic T cells for immunotherapy.

Reactivation of CMV can cause severe disease after allogeneic hemopoietic stem cell transplantation. Adoptive T cell therapy was successfully used for patients who had received transplants from CMV-positive donors. However, patients with transplants from CMV-negative donors are at highest risk, and an adoptive therapy is missing because CMV-specific T cells are not available from such donors. To address this problem, we used retroviral transfer of CMV-specific TCR genes. We generated CMV-specific T cell clones of several HLA restrictions recognizing the endogenously processed Ag pp65. The genes of four TCRs were cloned and transferred to primary T cells from CMV-negative donors. These CMV-TCR-transgenic T cells displayed a broad spectrum of important effector functions (secretion of IFN-gamma and IL-2, cytotoxicity, proliferation) in response to endogenously processed pp65 and could be enriched and expanded by strictly Ag-specific stimulation. Expansion of engineered T cells was accompanied by an increase in specific effector functions, indicating that the transferred specificity is stable and fully functional. Hence, we expect these CMV-TCR-transgenic T cells to be effective in controlling acute CMV disease and establishing an antiviral memory.

[ADHD in adults: identifying, experiencing, comprehending]. / ADHS im Erwachsenenalter: Erkennen, Erleben und Verstehen.

In former times ADHD was seen as a children`s disease, nowadays it is assured, that 4 % of adults suffer from ADHD. By today`s state of research there are a lot of factors of influence according to the biopsychosocial model. For the development of mentalization and ability of reflexion, difficult early relationships, mistreatment or other traumatisations are characteristically relevant. In this paper the authors want to point to the interaction and the correlation of neurobiological, psychodynamic and psychosocial influences and to discuss the multifactorial development of this disease pattern. By the use of a multidimensional approach there could be additional therapeutic possibilities considering the patient individually and integrated.

Formin-like 1 (FMNL1) is regulated by N-terminal myristoylation and induces polarized membrane blebbing.

The formin protein formin-like 1 (FMNL1) is highly restrictedly expressed in hematopoietic lineage-derived cells and has been previously identified as a tumor-associated antigen. However, function and regulation of FMNL1 are not well defined. We have identified a novel splice variant (FMNL1gamma) containing an intron retention at the C terminus affecting the diaphanous autoinhibitory domain (DAD). FMNL1gamma is specifically located at the cell membrane and cortex in diverse cell lines. Similar localization of FMNL1 was observed for a mutant lacking the DAD domain (FMNL1DeltaDAD), indicating that deregulation of autoinhibition is effective in FMNL1gamma. Expression of both FMNL1gamma and FMNL1DeltaDAD induces polarized nonapoptotic blebbing that is dependent on N-terminal myristoylation of FMNL1 but independent of Src and ROCK activity. Thus, our results describe N-myristoylation as a regulative mechanism of FMNL1 responsible for membrane trafficking potentially involved in a diversity of polarized processes of hematopoietic lineage-derived cells.

Adipocyte fatty acid binding protein during refeeding of female patients with anorexia nervosa.

BACKGROUND: Adipocyte fatty acid binding protein (A-FABP) has been suggested to play an important role in fat metabolism linking obesity and the metabolic syndrome. Increasing A-FABP plasma levels were observed during greatest weight loss after bariatric surgery suggesting that A-FABP may indicate changes in fat mass in dynamic situations. AIM OF THE STUDY: As there are no data on weight gain, we investigated the effect of refeeding anorexic patients on body composition and A-FABP plasma levels. METHODS: Parameters of glucose and lipid metabolism as well as plasma levels of leptin and A-FABP were prospectively assessed in 16 female patients with anorexia nervosa during inpatient weight restoration. Body composition was determined by multifrequency body impedance analysis. RESULTS: After 28 days, fat mass increased from 4.4 +/- 2.5 kg at baseline to 5.5 +/- 2.2 kg (P < 0.01), constituting 40% of total weight gain. Conversely, A-FABP concentrations decreased from 32.56 +/- 35.59 ng/ml at baseline to 21.27 +/- 13.68 ng/ml (P < 0.05), which corresponds to a significant decrease in the proportion of A-FABP per kilogram fat mass from 7.86 +/- 5.23 to 4.09 +/- 2.12 ng/ml/kg (P

Heterogeneity of traumatic injury of the tricuspid valve: a report of four cases.

Tricuspid valve injury causing severe tricuspid regurgitation is the most common cardiac complication following blunt chest trauma. We present four cases with different clinical presentations that included pleural effusion, arrhythmias, cyanosis, peripheral edema and dyspnea, with varying onset of symptoms. Echocardiographic evaluation and intraoperative findings in these patients revealed a broad spectrum of injury to the tricuspid valve including papillary muscle and chordal rupture, chordal elongation and leaflet perforation. Because surgical treatment is required in most patients and since the diagnosis is often delayed, we believe that early echocardiographic evaluation is required in all patients with blunt chest trauma, in particular if clinical symptoms of right heart failure are present.

STAT3 mRNA and protein expression in colorectal cancer: effects on STAT3-inducible targets linked to cell survival and proliferation.

AIMS: To evaluate mRNA and protein expression of signal transducers and activators of transcription (STAT)3 in colorectal carcinomas (CRCs) and to define the association of STAT3 activity with the STAT3-inducible targets cyclin D1, survivin, Bcl-xl and Mcl-1. MATERIALS AND METHODS: Matching serial sections of normal colonic epithelium and invasive CRCs (n = 32) were subjected to quantitative reverse transcriptase polymerase chain reaction specific to STAT3, cyclin D1, survivin, Bcl-xl and Mcl-1, as well as immunohistochemistry. For STAT3 immunohistochemistry, two antibodies, recognising unphosphorylated (UP-) and phosphorylated (tyr705, P-) STAT3 were used. Ki-67 (MIB-1) staining was included as a proliferation marker. RESULTS: Compared with normal colonic epithelium, UP-STAT3 and P-STAT3 (p = 0.023 and 0.006) protein expression and expression of its associated targets cyclin D1, survivin and Bcl-xl were significantly (all p<0.001) increased in carcinoma. In carcinomas, STAT3 (p = 0.019) and Bcl-xl (p = 0.001) mRNAs were correlated with lymph node status. Moreover, nuclear P-STAT3 protein expression (active state) was associated with the expression of its target genes Bcl-xl (p = 0.038) and survivin (p = 0.01) as well as with Ki-67 (p = 0.017). By contrast, cytoplasmic UP-STAT was significantly linked to Bcl-xl mRNA (p = 0.024) and protein (p = 0.001) as well as to cytoplasmic survivin protein expression (p = 0.019). CONCLUSION: Both inactive (UP-STAT3) and active (P-STAT3) STAT3 proteins are markedly increased in invasive CRCs. This is associated with Bcl-xl and survivin induction, increased proliferation and lymph node metastasis. This study therefore provides the basis for further examination of the prognostic or predictive value of these molecular markers in CRC.

Motor dysfunction in patients with liver cirrhosis: impairment of handwriting.

Motor dysfunction is an important clinical finding in patients with liver cirrhosis and mild forms of hepatic encephalopathy. The mechanisms and clinical appearance of motor impairment in patients with liver cirrhosis are not completely understood. We studied fine motor control in forty four patients with advanced liver cirrhosis (excluding those with hepatic encephalopathy grade II) and 48 healthy controls using a kinematic analysis of standardized handwriting tests. We analysed parameters of velocity, the ability to coordinate and the level of automatisation of handwriting movements. Furthermore, we studied the association between impairment of handwriting and clinical neuro-psychiatric symptoms. As compared with control subjects, patients showed a statistically significant reduction of movement peak velocity in all handwriting tasks as well as a substantial increase of number of velocity inversions per stroke. Using a z-score based assessment we found impairment of handwriting in fourteen out of forty four patients (31.8 %). The deterioration of handwriting was associated with clinical symptoms of motor dysfunction, such as bradykinesia, adiadochokinesia, dysmetria of upper extremities and gait ataxia. This is the first study that quantitatively investigates impairment of handwriting in patients with liver cirrhosis. Our findings suggest the application of kinematic analysis of handwriting for diagnostics of motor dysfunction in patients with mild forms of hepatic encephalopathy.

Diagnostic value of fine motor deficits in patients with low-grade hepatic encephalopathy.

AIM: The role of motor dysfunction in early diagnosis of low-grade hepatic encephalopathy remains uncertain. We performed a pilot study to comparatively investigate the kinematic characteristics of small and large rapid alternating movements in patients with liver cirrhosis and low-grade hepatic encephalopathy. METHODS: A kinematic analysis of alternating handwriting (7.5 mm) and large drawing movements (DM, 175 mm) was performed in 30 patients with liver cirrhosis (no hepatic encephalopathy: n = 10; minimal hepatic encephalopathy: n = 9; grade I hepatic encephalopathy: n = 11; healthy controls: n = 12). The correlation between kinematic parameters, clinical neuro-psychiatric symptoms of cerebral dysfunction and the grade of encephalopathy was investigated. RESULTS: Both movement types, handwriting and drawing, were significantly slower in cirrhotic patients. In contrast to large DM, the deterioration of handwriting movements significantly correlated with the increase of symptoms of motor dysfunction and differentiated significantly within the group of cirrhosis patients corresponding to the degree of hepatic encephalopathy. CONCLUSION: The deterioration of fine motor control is an important symptom of low-grade hepatic encephalopathy. The kinematic analysis of handwriting allows the quantitative analysis of alterations of motor function and is a possible tool for diagnostics and monitoring of motor dysfunction in patients with low-grade hepatic encephalopathy.

New insights regarding the incidence, presentation and treatment options of aorto-oesophageal fistulation after thoracic endovascular aortic repair: the European Registry of Endovascular Aortic Repair Complications.

OBJECTIVES: To review the incidence, clinical presentation, definite management and 1-year outcome in patients with aorto-oesophageal fistulation (AOF) following thoracic endovascular aortic repair (TEVAR). METHODS: International multicentre registry (European Registry of Endovascular Aortic Repair Complications) between 2001 and 2011 with a total caseload of 2387 TEVAR procedures (17 centres). RESULTS: Thirty-six patients with a median age of 69 years (IQR 56-75), 25% females and 9 patients (19%) following previous aortic surgery were identified. The incidence of AOF in the entire cohort after TEVAR in the study period was 1.5%. The primary underlying aortic pathology for TEVAR was atherosclerotic aneurysm formation in 53% of patients and the median time to development of AOF was 90 days (IQR 30-150). Leading clinical symptoms were fever of unknown origin in 29 (81%), haematemesis in 19 (53%) and shock in 8 (22%) patients. Diagnosis could be confirmed via computed tomography in 92% of the cases with the leading sign of a new mediastinal mass in 28 (78%) patients. A conservative approach resulted in a 100% 1-year mortality, and 1-year survival for an oesophageal stenting-only approach was 17%. Survival after isolated oesophagectomy was 43%. The highest 1-year survival rate (46%) could be achieved via an aggressive treatment including radical oesophagectomy and aortic replacement [relative risk increase 1.73 95% confidence interval (CI) 1.03-2.92]. The survival advantage of this aggressive treatment modality could be confirmed in bootstrap analysis (95% CI 1.11-3.33). CONCLUSIONS: The development of AOF is a rare but lethal complication after TEVAR, being associated with the need for emergency TEVAR as well as mediastinal haematoma formation. The only durable and successful approach to cure the disease is radical oesophagectomy and extensive aortic reconstruction. These findings may serve as a decision-making tool for physicians treating these complex patients.

A fully synthetic human Fab antibody library based on fixed VH/VL framework pairings with favorable biophysical properties.

This report describes the design, generation and testing of Ylanthia, a fully synthetic human Fab antibody library with 1.3E+11 clones. Ylanthia comprises 36 fixed immunoglobulin (Ig) variable heavy (VH)/variable light (VL) chain pairs, which cover a broad range of canonical complementarity-determining region (CDR) structures. The variable Ig heavy and Ig light (VH/VL) chain pairs were selected for biophysical characteristics favorable to manufacturing and development. The selection process included multiple parameters, e.g., assessment of protein expression yield, thermal stability and aggregation propensity in fragment antigen binding (Fab) and IgG1 formats, and relative Fab display rate on phage. The framework regions are fixed and the diversified CDRs were designed based on a systematic analysis of a large set of rearranged human antibody sequences. Care was taken to minimize the occurrence of potential posttranslational modification sites within the CDRs. Phage selection was performed against various antigens and unique antibodies with excellent biophysical properties were isolated. Our results confirm that quality can be built into an antibody library by prudent selection of unmodified, fully human VH/VL pairs as scaffolds.

Endovascular and conventional treatment of thoracic aortic aneurysms: a comparison of costs.

BACKGROUND: The purpose of this study is to compare costs of conventional surgical therapy with costs of endovascular stent-graft placement in patients with thoracic aortic aneurysms. METHODS: Fifteen patients undergoing either conventional surgical therapy or endovascular stent-graft placement of thoracic aortic aneurysms were analyzed. A catalog of costs was then created for both procedures and this catalog was applied individually to each patient. RESULTS: Total costs of the service provision of endovascular stent-graft placement including anesthesia were 38.220.98 euros considering 1.7 stent-grafts per patient and including 5900.00 euros (Euros) for days of care. In conventional surgical therapy, adding the costs of the service provision of left heart catheterization, conventional surgical therapy including anesthesia, as well as intraoperative echocardiography a sum of 19.534.12 euros was calculated. Days of care accounted for 31.230.00 euros and total costs of 50.764.12 euros were calculated. The difference between total costs of the two procedures was 12.543.14 euros. CONCLUSIONS: Costs of endovascular stent-graft placement in patients with thoracic aortic aneurysms compare favorably with conventional surgical therapy, revealing a cost benefit of 24.7%. Higher procedural costs are outweighed by a lower number of days of care. Nevertheless, aneurysm-related secondary endovascular or surgical procedures may balance the benefit of endovascular therapy. Which strategy to choose, conventional or endovascular, should remain to be based on age, comorbidity, and technical feasibility.

Allorestricted T cells with specificity for the FMNL1-derived peptide PP2 have potent antitumor activity against hematologic and other malignancies.

Cell-based immunotherapy in settings of allogeneic stem cell transplantation or donor leukocyte infusion has curative potential, especially in hematologic malignancies. However, this approach is severely restricted due to graft-versus-host disease (GvHD). This limitation may be overcome if target antigens are molecularly defined and effector cells are specifically selected. We chose formin-related protein in leukocytes 1 (FMNL1) as a target antigen after intensive investigation of its expression profile at the mRNA and protein levels. Here, we confirm restricted expression in peripheral blood mononuclear cells (PBMCs) from healthy donors but also observe overexpression in different leukemias and aberrant expression in transformed cell lines derived from solid tumors. We isolated allorestricted T-cell clones expressing a single defined TCR recognizing a particular HLA-A2-presented peptide derived from FMNL1. This T-cell clone showed potent antitumor activity against lymphoma and renal cell carcinoma cell lines, Epstein-Barr virus (EBV)-transformed B cells, and primary tumor samples derived from patients with chronic lymphocytic leukemia (CLL), whereas nontransformed cells with the exception of activated B cells were only marginally recognized. Allorestricted TCRs with specificity for naturally presented FMNL1-derived epitopes may represent promising reagents for the development of adoptive therapies in lymphoma and other malignant diseases.