Endosomal egress and intercellular transmission of hepatic ApoE-containing lipoproteins and its exploitation by the hepatitis C virus.

Liver-generated plasma Apolipoprotein E (ApoE)-containing lipoproteins (LPs) (ApoE-LPs) play central roles in lipid transport and metabolism. Perturbations of ApoE can result in several metabolic disorders and ApoE genotypes have been associated with multiple diseases. ApoE is synthesized at the endoplasmic reticulum and transported to the Golgi apparatus for LP assembly; however, the ApoE-LPs transport pathway from there to the plasma membrane is largely unknown. Here, we established an integrative imaging approach based on a fully functional fluorescently tagged ApoE. We found that newly synthesized ApoE-LPs accumulate in CD63-positive endosomes of hepatocytes. In addition, we observed the co-egress of ApoE-LPs and CD63-positive intraluminal vesicles (ILVs), which are precursors of extracellular vesicles (EVs), along the late endosomal trafficking route in a microtubule-dependent manner. A fraction of ApoE-LPs associated with CD63-positive EVs appears to be co-transmitted from cell to cell. Given the important role of ApoE in viral infections, we employed as well-studied model the hepatitis C virus (HCV) and found that the viral replicase component nonstructural protein 5A (NS5A) is enriched in ApoE-containing ILVs. Interaction between NS5A and ApoE is required for the efficient release of ILVs containing HCV RNA. These vesicles are transported along the endosomal ApoE egress pathway. Taken together, our data argue for endosomal egress and transmission of hepatic ApoE-LPs, a pathway that is hijacked by HCV. Given the more general role of EV-mediated cell-to-cell communication, these insights provide new starting points for research into the pathophysiology of ApoE-related metabolic and infection-related disorders.

Predictive factors of surgery in metastatic colorectal cancer: a retrospective cohort study.

INTRODUCTION: Current management of metastatic colorectal cancer is based on neoadjuvant chemotherapy. Few studies have reported on surgery procedures in patients with metastatic colorectal cancer. The objective of this study was to describe our institutional experience with emergency surgery performed in patients with metastatic colorectal cancer during chemotherapy. PATIENTS AND METHODS: This was a retrospective cohort study including adult patients of ≤80 years with a metastatic colorectal cancer between 2017 and 2020 and undergoing surgery during chemotherapy. Statistical analyses were based on Kaplan-Meier's curve and Cox proportional hazard model. The surgery statistical risk during chemotherapy was studied through all tumor and patient's characteristics. Multivariable logistic regression models were used to identify predictive factors of emergency surgery in these patients. RESULTS: Seventy-two cases were identified and 60% patients undergone an emergency surgery. By Kaplan-Meier's analyses, intestinal surgery was much more frequent and early in patients who have severe stenosis (either blocking or only permeable using a gastroscope) at the time of diagnosis. Patients with severe malignant stenosis presented a 6.28 time higher surgery risk (p < .0001). The median time between admission and surgery was 54 days in patients with severe stenosis who were operated. CONCLUSION: The degree of colorectal tumor stenosis measured by endoscopy was a risk factor for emergency surgery in patients with metastatic colorectal cancer during neoadjuvant chemotherapy. In this group of patients presenting low survival outcomes, further studies are needed to define the place of preventive surgery, avoiding emergency surgery and morbidity in such fragile patients.

Effect of short-term smoking & L-arginine on coronary endothelial function assessed by cardiac magnetic resonance cold pressor testing: a pilot study.

BACKGROUND: The effect of smoking on coronary vasomotion has been investigated in the past with various imaging techniques in both short- and long-term smokers. Additionally, coronary vasomotion has been shown to be normalized in long-term smokers by L-Arginine acting as a substrate for NO synthase, revealing the coronary endothelium as the major site of abnormal vasomotor response. Aim of the prospective cohort study was to investigate coronary vasomotion of young healthy short-term smokers via magnetic resonance cold pressor test with and without the administration of L-Arginine and compare obtained results with the ones from nonsmokers. METHODS: Myocardial blood flow (MBF) was quantified with first-pass perfusion MRI on a 1.5 T scanner in healthy short-term smokers (N = 10, age: 25.0 ± 2.8 years, 5.0 ± 2.9 pack years) and nonsmokers (N = 10, age: 34.3 ± 13.6) both at rest and during cold pressor test (CPT). Smokers underwent an additional examination after administration of L-Arginine within a median of 7 days of the naïve examination. RESULTS: MBF at rest turned out to be 0.77 ± 0.30 (smokers with no L-Arginine; mean ± standard deviation), 0.66 ± 0.21 (smokers L-Arginine) and 0.84 ± 0.08 (nonsmokers). Values under CPT were 1.21 ± 0.42 (smokers no L-Arginine), 1.09 ± 0.35 (smokers L-Arginine) and 1.63 ± 0.33 (nonsmokers). In all groups, MBF was significantly increased under CPT compared to the corresponding rest examination (p < 0.05 in all cases). Additionally, MBF under CPT was significantly different between the smokers and the nonsmokers (p = 0.002). MBF at rest was significantly different between the smokers when L-Arginine was given and the nonsmokers (p = 0.035). CONCLUSION: Short-term smokers showed a reduced response to cold both with and without the administration of L-Arginine. However, absolute MBF values under CPT were lower compared to nonsmokers independently of L-Arginine administration.

[Interventional management of secondary retentions after thoracic and abdominal trauma]. / Interventionelle Versorgung sekundärer Verhalte nach thorakalem und abdominellem Trauma.

BACKGROUND: Percutaneous treatment of secondary thoracic and abdominal retention formations after blunt or penetrating trauma now represents a standard interventional radiological procedure. Various supportive imaging procedures are available, whereby computed tomography is mostly the treatment of choice due to the high diagnostic sensitivity. OBJECTIVE: Based on clinical examples this review article gives an overview of the state of the art minimally invasive interventional treatment of secondary posttraumatic retention formations of the thorax and abdomen. The indications and contraindications are illustrated and typical techniques and access routes are described. MATERIAL AND METHODS: Besides the general introduction and technical part, the article is divided into the anatomical compartments thorax and abdomen and frequently asked questions are dealt with. CONCLUSION: After the study of this article you should have got to know and understand the indications for a minimally invasive approach, the possible techniques and necessary materials as well as the indications and contraindications.

Synthesis of a Molecule with Five Different Adjacent Pnictogens.

The first molecular compound with all five pnictogens was obtained by a multi-step reaction. Lithiation of the (bisamido)diazadiarsetidine (tBuNAs)2 (tBuNH)2 in aliphatic solvents leads to the dimeric metallated species [(tBuNAs)2 (tBuNLi)2 ]2 (12 ). Upon reactions with AsCl3 , SbCl3 and BiCl3 the polycyclic compounds [(tBuNAs)2 (tBuN)2 ]PnCl (Pn=As (2), Sb (3), Bi (4)) can be obtained. Conversion of 2-4 with [tBu2 SbP(tBu)Li(OEt2 )]2 leads to the remarkable interpnictogens [(tBuNAs)2 (tBuN)2 ]PnP(tBu)SbtBu2 (Pn=As (5), Sb (6), Bi (7)), whereby 7 is the first example of a molecule containing all five Group 15 elements. The compound with adjacent AsNBiPSb-chains is surprisingly stable and does not show high sensibility against light as the labile Bi-P bond might suggest.

Childhood Adversity, Proximal Stressors and PTSD Among People with Severe Mental Illness: An Exploratory Study.

The purpose of this exploratory study is to: (1) assess prevalence of childhood adversities and posttraumatic stress disorder (PTSD); (2) assess their association, and; (3) explore whether proximal sources of stress affect this relationship and/or have an association with PTSD among people with severe and persistent psychological disorders. Using data from 141 respondents, we assess the extent to which individuals in this population experienced 17 PTSD symptoms, various correlates to probable PTSD, and the most relevant of these factors in a multivariate logistic regression. Overall, 27% of the participants met study criteria for probable PTSD and each symptom was reported by at least 18% of the sample. Multivariate logistic regression models indicated that interpersonal conflict and being a victim of a crime were significantly related to probable PTSD. We discuss these findings in relation to treatment and course of disease for people suffering from severe and persistent mental illness experiencing a traumatic event.

Fully automated quantification of biventricular volumes and function in cardiovascular magnetic resonance: applicability to clinical routine settings.

BACKGROUND: Cardiovascular magnetic resonance (CMR) represents the clinical gold standard for the assessment of biventricular morphology and function. Since manual post-processing is time-consuming and prone to observer variability, efforts have been directed towards automated volumetric quantification. In this study, we sought to validate the accuracy of a novel approach providing fully automated quantification of biventricular volumes and function in a "real-world" clinical setting. METHODS: Three-hundred CMR examinations were randomly selected from the local data base. Fully automated quantification of left ventricular (LV) mass, LV and right ventricular (RV) end-diastolic and end-systolic volumes (EDV/ESV), stroke volume (SV) and ejection fraction (EF) were performed overnight using commercially available software (suiteHEART®, Neosoft, Pewaukee, Wisconsin, USA). Parameters were compared to manual assessments (QMass®, Medis Medical Imaging Systems, Leiden, Netherlands). Sub-group analyses were further performed according to image quality, scanner field strength, the presence of implanted aortic valves and repaired Tetralogy of Fallot (ToF). RESULTS: Biventricular automated segmentation was feasible in all 300 cases. Overall agreement between fully automated and manually derived LV parameters was good (LV-EF: intra-class correlation coefficient [ICC] 0.95; bias - 2.5% [SD 5.9%]), whilst RV agreement was lower (RV-EF: ICC 0.72; bias 5.8% [SD 9.6%]). Lowest agreement was observed in case of severely altered anatomy, e.g. marked RV dilation but normal LV dimensions in repaired ToF (LV parameters ICC 0.73-0.91; RV parameters ICC 0.41-0.94) and/or reduced image quality (LV parameters ICC 0.86-0.95; RV parameters ICC 0.56-0.91), which was more common on 3.0 T than on 1.5 T. CONCLUSIONS: Fully automated assessments of biventricular morphology and function is robust and accurate in a clinical routine setting with good image quality and can be performed without any user interaction. However, in case of demanding anatomy (e.g. repaired ToF, severe LV hypertrophy) or reduced image quality, quality check and manual re-contouring are still required.

Magnetic resonance cold pressor test to investigate potential endothelial dysfunction in patients suffering from type 1 diabetes.

BACKGROUND: In its course, diabetes impairs microvascular function through endothelial dysfunction. As the response of myocardial perfusion to sympathetic stimulation through cold is modulated by endothelium-related factors, an incipient endothelial dysfunction might be observed noninvasively by investigation of myocardial perfusion with a cold pressor test (CPT). This approach has been used in clinical MRI previously. PURPOSE: To assess endothelial function of patients suffering from type 1 diabetes by MR CPT. STUDY TYPE: Prospective cohort study. SUBJECTS: Twenty type 1 diabetics and 20 healthy volunteers. FIELD STRENGTH/SEQUENCE: 3T, dynamic contrast enhanced perfusion (steady-state free precession). ASSESSMENT: Absolute quantitative myocardial perfusion values at rest and under CPT. STATISTICAL TESTS: Kolmogorov-Smirnov test to determine normal distribution of the results. T-test for independent samples. RESULTS: Patients' mean myocardial perfusion was 0.68 cc/g/min at rest and 0.80 cc/g/min during CPT, respective values of 0.81 cc/g/min and 1.36 cc/g/min were found in healthy volunteers. Perfusion values differed significantly for CPT (P < 0.01) but not for resting conditions (P = 0.06). DATA CONCLUSION: This study demonstrated that endothelial function might be impaired in type 1 diabetes patients. This fosters the thesis that endothelial function may serve as an early biomarker for coronary artery disease in patients with type 1 diabetes while these patients are still clinically asymptomatic. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;48:1595-1601.

Absence of DNA double-strand breaks in human peripheral blood mononuclear cells after 3 Tesla magnetic resonance imaging assessed by γH2AX flow cytometry.

OBJECTIVES: Magnetic resonance imaging (MRI) is regarded as a non-harming and non-invasive imaging modality with high tissue contrast and almost no side effects. Compared to other cross-sectional imaging modalities, MRI does not use ionising radiation. Recently, however, strong magnetic fields as applied in clinical MRI scanners have been suspected to induce DNA double-strand breaks in human lymphocytes. METHODS: In this study we investigated the impact of 3-T cardiac MRI examinations on the induction of DNA double-strand breaks in peripheral mononuclear cells by γH2AX staining and flow cytometry analysis. The study cohort consisted of 73 healthy non-smoking volunteers with 36 volunteers undergoing CMRI and 37 controls without intervention. Differences between the two cohorts were analysed by a mixed linear model with repeated measures. RESULTS: Both cohorts showed a significant increase in the γH2AX signal from baseline to post-procedure of 6.7 % (SD 7.18 %) and 7.8 % (SD 6.61 %), respectively. However, the difference between the two groups was not significant. CONCLUSION: Based on our study, γH2AX flow cytometry shows no evidence that 3-T MRI examinations as used in cardiac scans impair DNA integrity in peripheral mononuclear cells. KEY POINTS: • No evidence for DNA double-strand breaks after cardiac MRI. • Prospective study underlines safe use of MRI with regard to DNA damage. • Controlled trial involving both genders investigating DNA DSBs after 3-T MRI.

Diagnosing ARVC in Pediatric Patients Applying the Revised Task Force Criteria: Importance of Imaging, 12-Lead ECG, and Genetics.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a potentially lethal disease that is well described in adults. In pediatric patients, however, identification of patients at risk of adverse events of ARVC remains a challenge. We aimed to determine which criteria of the revised Task Force Criteria (rTFC), alone or combined, have an impact on diagnosis of ARVC when compared to disease-specific genetic mutations in pediatric patients ≤ 18 years. Between September 2010 and December 2013, 48 consecutive young patients ≤ 18 years of age (mean 14, range of 12.9-15.1 years) underwent contrast-enhanced magnetic resonance imaging (CMR), genetic testing, and comprehensive clinical work-up for ARVC criteria to test for clinically suspected ARVC. As specified by the rTFC, patients were grouped into four categories: "definite," "borderline," "possible," and "none" ARVC. Of the 48 patients, 12 were found to have gene mutations of either the desmoplakin (9/12) or plakophilin (3/12) locus. According to rTFC 12/48 patients were considered as "definite" ARVC (25%), while 10/12 (83.3%) had an ARVC-specific gene mutation. Of the remaining 36 patients, 6 (12.5%) were grouped as "borderline" ARVC, 7 (14.6%) as "possible" ARVC (including the remaining two genetic mutations), and 22 (45.8%) as "none" ARVC, respectively. Statistical analysis of ARVC criteria in patients diagnosed with "definite" ARVC revealed high prevalence of positive findings by imaging (CMR and echocardiography) and positive genetics. The positive predictive value to detect "definite" ARVC by genotyping was 83.3%, while the negative predictive value was 94%. Logistic regression analyses for different criteria combinations revealed that imaging modalities (echo and CMR combined) and abnormalities of 12-lead ECG were significant markers (p < 0.01). Positive results of endomyocardial biopsies or arrhythmia on ECG or Holter as defined by the rTFC were not significant in this analysis. The rTFC for ARVC should be used with caution in children and adolescents suspected for ARVC. 12-Lead ECG and imaging modalities (CMR and echo) were of major value, positive results should prompt genetic testing.

Targeted endomyocardial biopsy guided by real-time cardiovascular magnetic resonance.

BACKGROUND: Endomyocardial biopsies (EMB) are an important diagnostic tool for myocarditis and other infiltrative cardiac diseases. Routinely, biopsies are obtained under fluoroscopic guidance with a substantial radiation burden. Despite procedural success, there is a large sampling error caused by missing the affected myocardium. Therefore, multiple (>6) biopsies are taken in the clinical setting. In cardiovascular magnetic resonance (CMR), late gadolinium enhancement (LGE) depicts areas of affected myocardium in myocarditis or in other infiltrative cardiomyopathies. Thus, targeted biopsy under real-time CMR image guidance might reduce the problem of sampling error. METHODS: Seven minipigs of the Goettingen strain underwent radiofrequency ablation in the left ventricle. At least two focal lesions were induced on the lateral wall in five and the apex in two animals. Each ablation lesion was created by two consecutive 30 sec ablations (max. 30 W, temperature 60-64 °C). Biopsies were taken immediately after lesion induction using a commercially available 7 F conventional bioptome under fluoroscopic guidance at the ablation site. Afterwards the animals underwent CMR and lesion visualization by LGE at 3T. The lesions were then targeted and biopsied under CMR-guidance using a MR-conditional bioptome guided by a steerable catheter. Interactive real-time (RT) visualization of the intervention on an in-room monitor was based on radial FLASH with nonlinear inverse reconstruction (NLINV) at a temporal resolution of 42 ms. All samples underwent a standard histological evaluation. RESULTS: Radiofrequency ablation was successful in all animals. Fluoroscopy-guided biopsies were performed with a success rate of 6/6 minipigs - resulting in a nonlethal pericardial effusion in one animal. Visualization of radiofrequency lesions by CMR was successful in 7/7 minipig, i.e. at least one lesion was clearly visible. Localization and tracking of the catheters and the bioptome using interactive control of the imaging plane was achieved in 6/6 MP; however in the animal with a large pericardial effusion after EMB under fluoroscopy no further EMB was attempted for safety reasons. Biopsies under interactive RT-CMR guidance were successfully performed in 5/6 animals, in one animal the bioptome reached the lesion, however the forceps did not cut out a sample. Specimens obtained under CMR guidance contained part of the lesion in 6/15 (40%) myocardial specimens and in 4/5 (80%) animals in which samples were achieved. Conventional biopsies revealed ablation lesions in 4/17 (23.5%) specimens in 3/6 minipigs (50%). CONCLUSION: Focal lesions induced by radiofrequency ablation in a minipig model are a useful tool for CMR-guided biopsy studies. In contrast to fluoroscopy, CMR provides excellent visualization of lesions. Interactive real-time CMR allows excellent passive tracking of the instruments and EMB provides significantly superior sampling accuracy compared to fluoroscopy-guided biopsies. Nonetheless, further improvements of MR-compatible bioptomes and guiding catheters are essential before applying this method in a clinical setting.

See the unseen: Mesorectal lymph node metastases in prostate cancer.

BACKGROUND: Our study is the first evaluation of nodal metastatic prostate cancer (PCa) to mesorectal lymph nodes (MLN) detected by (68) Ga-PSMA-PET/CT. METHODS: We retrospectively analyzed 76 consecutive PCa patients who underwent (68) Ga-PSMA-PET/CT: 61 PCa patients with biochemical recurrence (BCR) after curative treatment and 15 high-risk PCa before primary therapy. We assessed PET-positive MLN, which are indicative for PCa. RESULTS: We detected PET-positive lesions for PCa in (68) Ga-PSMA-PET/CT in 66 of 76 (87%) patients. Nodal disease was imaged in 47 of 66 (71%) patients. Indicative mesorectal nodal lesions for PCa were detected in 12 of 76 (15.8%) patients. The median number of PET-positive MLN was one per patient. Seven of twelve patients had recurrent PCa after radical prostatectomy with a median PSA value of 1.84 ng/ml (range 0.31-13). Five of twelve patients had untreated first diagnosed high-risk PCa with median PSA value of 90 ng/ml (range 4.6-93) at PET/CT, respectively. For all PET positive MLN a morphological correlate was found in CT (shortest diameter median 4 mm [range 4-21]; longest diameter median 7.5 mm [range 5-25]). After PET/CT, four patients with recurrent PCa received hormonal therapy, one patient was treated with directed radiation therapy of MLN, one patient received chemotherapy, and one patient was treated with pelvic lymph node dissection. Three high-risk PCa patients received hormonal therapy, and two patients were treated with adjuvant hormonal therapy after radical prostatectomy. CONCLUSIONS: Detection and exact location of nodal metastasis for PCa is crucial for the choice of treatment and the patient's prognosis. (68) Ga-PSMA-PET/CT seems to improve the detection of nodal metastasis in PCa, especially concerning mesorectal lymph nodes.

Loss of Schwann cell plasticity in chronic inflammatory demyelinating polyneuropathy (CIDP).

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is often associated with chronic disability, which can be accounted to incomplete regeneration of injured axons. We hypothesized that Schwann cell support for regenerating axons may be altered in CIDP, which may account for the poor clinical recovery seen in many patients. METHODS: We exposed human and rodent Schwann cells to sera from CIDP patients and controls. In a model of chronic nerve denervation, we transplanted these conditioned Schwann cells intraneurally and assessed their capacity to support axonal regeneration by electrophysiology and morphometry. RESULTS: CIDP-conditioned Schwann cells were less growth supportive for regenerating axons as compared to Schwann cells exposed to control sera. The loss of Schwann cell support was associated with lower levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) in CIDP sera and correlated with altered expression of c-Jun and p57kip2 in Schwann cells. The inactivation of these regulatory factors resulted in an altered expression of neurotrophins including BDNF, GDNF, and NGF in CIDP-conditioned Schwann cells in vitro. CONCLUSIONS: Our study provides evidence that pro-regenerative functions of Schwann cells are affected in CIDP. It thereby offers a possible explanation for the clinical observation that in many CIDP patients recovery is incomplete despite sufficient immunosuppressive treatment.

A model-based reconstruction technique for quantitative myocardial perfusion imaging.

PURPOSE: To reduce saturation effects in the arterial input function (AIF) estimation of quantitative myocardial first-pass saturation recovery perfusion imaging by employing a model-based reconstruction. THEORY AND METHODS: Imaging was performed with a saturation recovery prepared radial FLASH sequence. A model-based reconstruction was applied for reconstruction. By exploiting prior knowledge about the relaxation process, an image series with different saturation recovery times was reconstructed. By evaluating images with an effective saturation time of approximately 3 ms, saturation effects in the AIF determination were reduced. In a volunteer study, this approach was compared with a standard prebolus technique. RESULTS: In comparison to the low-dose injection of a prebolus acquisition, saturation effects were further reduced in the AIFs determined using the model-based approach. These effects, which were clearly visible for all six volunteers, were reflected in a statistically significant difference of up to 20% in the absolute perfusion values. CONCLUSION: The application of model-based reconstruction algorithms in quantitative myocardial perfusion imaging promises a significant improvement of the AIF determination. In addition to greatly reducing saturation effects that occur even for the prebolus methods, only a single bolus has to be applied. Magn Reson Med 76:880-887, 2016. © 2015 Wiley Periodicals, Inc.

Biphasic 68Ga-PSMA-HBED-CC-PET/CT in patients with recurrent and high-risk prostate carcinoma.

PURPOSE: Binding of (68)Ga-PSMA-HBED-CC ((68)Ga-PSMA) at prostate cancer (PC) cells increases over time. A biphasic protocol may help separating benign from tumor lesions. The aim of this study was the retrospective evaluation of a diagnostic incremental value of a dual-time point (biphasic) (68)Ga-PSMA-PET/CT in patients with prostate cancer. METHODS: Retrospective analysis of 35 consecutive patients (49-78 years, median 71) with newly diagnosed PC (12/35) or recurrence of PC (23/35). PET/CT (Gemini TF16, Philips) was acquired 1 h and 3 h p. i. of 140-392 MBq (300 MBq median) (68)Ga-PSMA, followed by a diagnostic contrast CT. PET findings were correlated with histology or unequivocal CT findings. Semiquantitative PET data (SUVmax, SUV mean) were acquired and target-to-background-ratios (T/B-ratio) were calculated for benign and malign lesions for both time points. Size of lymph nodes (LN) on diagnostic CT was recorded. Statistical analysis was performed for assessment of significant changes of semiquantitative PET-parameters over time and for correlation of size and uptake of lymph nodes. RESULTS: One hundred and four lesions were evaluated. Sixty lesions were referenced by histology or unequivocal CT findings, including eight (13.3 %) histopathologically benign lymph nodes, 12 (20 %) histopathologically lymph node metastases, 12 (20 %) primary tumors, three (5 %) local recurrences, and 25 (41.7 %) bone metastases. Forty-four lesions were axillary LN with normal CT-appearance. Benign lesions had significantly lower SUVmax and T/B-ratios compared with malignant findings. Malign lesions showed a significant increase of both parameters over time compared to benign findings. There was no correlation between LN size and SUVmax. The sensitivity, specificity, the positive predictive value and negative predictive value of PET/CT regarding pelvic LN was 94 %, 99 %, 89 %, and 99.5 %, respectively. CONCLUSIONS: In contrast to benign tissues, the uptake of proven tumor lesions increases on (68)Ga-PSMA-PET/CT over time. A biphasic PET-study may lead to a better detection of tumor lesions in unequivocal findings.

Disease Burden Among Individuals with Severe Mental Illness in a Community Setting.

This study examines the prevalence of comorbid physical health conditions within a community sample of individuals with severe mental illness (SMI), compares them to a matched national sample without SMI, and identifies which comorbidities create the greatest disease burden for those with SMI. Self-reported health status, co-morbid medical conditions and perceived disease burden were collected from 203 adults with SMI. Prevalence of chronic health conditions was compared to a propensity-matched sample without SMI from the National Comorbidity Survey-Replication (NCS-R). Compared to NCS-R sample without SMI, our sample with SMI had a higher prevalence of seven out of nine categories of chronic health conditions. Chronic pain and headaches, as well as the number of chronic conditions, were associated with increased disease burden for individuals with SMI. Further investigation of possible interventions, including effective pain management, is needed to improve the health status of this population.

Paclitaxel inhibits mRNA transport in axons.

Paclitaxel is an integral component of solid tumor treatment. This chemotherapeutic agent provokes an often irreversible peripheral sensory neuropathy with pathological features of distal axonal degeneration. Current pathological concepts assume that polymerization of axonal microtubules and mitochondrial dysfunction contributes to the development of paclitaxel-induced peripheral neuropathy. The relationship, however, between microtubule stabilization, mitotoxicity and axonal degeneration is still not completely understood. To explore the function of axonal mitochondria we treated transgenic mice that harbor cyan fluorescent protein (CFP)-labeled neuronal mitochondria with repeated doses of paclitaxel and assessed neuropathic changes by nerve conduction and histological studies. In addition, mitochondrial content and morphology was determined by ex vivo imaging of axons containing CFP-labeled mitochondria. Using quantitative RT-PCR and fluorescence-labeled mRNA we determined axonal mRNA transport of nuclear encoded mitochondrial proteins. Prolonged treatment with high doses of paclitaxel-induced a predominant sensory neuropathy in mice. Although mitochondrial velocity in axons per se was not altered, we observed significant changes in mitochondrial morphology, suggesting that paclitaxel treatment impairs the dynamics of axonal mitochondria. These changes were caused by decreased levels of nuclear encoded mRNA, including the mitochondrial fusion/fission machinery. Moreover, impaired axonal mRNA transport in vitro resulted in mitochondrial dysfunction and subsequent axonal degeneration. Taken together, our experiments provide evidence that disrupted axonal transport of nuclear derived mRNA plays a crucial role in the pathogenesis of paclitaxel-induced sensory neuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP): change of serum IgG dimer levels during treatment with intravenous immunoglobulins.

BACKGROUND: Intravenous immunoglobulin (IVIg) is an effective treatment in chronic inflammatory demyelinating polyneuropathy (CIDP). In most patients, the optimal IVIg dose and regime is unknown. Polyvalent immunoglobulin (Ig) G form idiotypic/anti-idiotypic antibody pairs in serum and IVIg preparations. We determined IgG dimer levels before and after IVIg treatment in CIDP patients with the aim to explore their utility to serve as a surrogate marker for treatment response. METHODS: IgG was purified from serum of five controls without treatment, as well as from serum of 16 CIDP patients, two patients with Miller Fisher syndrome (MFS), and one patient with myasthenia gravis before and after treatment with IVIg. IgG dimer levels were determined by size exclusion chromatography. IgG dimer formation was correlated with clinical response to IVIg treatment in CIDP. Re-monomerized IgG dimer fractions were analyzed for immunoreactivity against peripheral nerve tissue. RESULTS: IgG dimer levels were significantly higher in post- compared to pre-IVIg infusion samples. Low post-treatment IgG dimer levels in CIDP patients were associated with clinical worsening during IVIg treatment. Re-monomerized IgG dimer fractions from CIDP patients showed immunoreactivity against peripheral nerve tissue, whereas similarly treated samples from MFS patients showed immunoreactivity against GQ1b. CONCLUSION: Assessment of IgG dimer levels could be a novel approach to monitor CIDP patients during IVIg treatment, but further studies in larger cohorts are warranted to explore their utility to serve as a potential therapeutic biomarker for IVIg treatment response in CIDP.

Diagnostic value of preoperative CT scan to stratify colon cancer for neoadjuvant therapy.

BACKGROUND AND OBJECTIVE: Neoadjuvant therapy could improve oncological outcome of patients suffering from colon cancer. An accurate staging method is needed to define suitable patients. The aim of this retrospective study was to validate the value of CT for identifying patients with local advanced (T3/4) or nodal-positive colon cancer. METHODS AND MATERIAL: Preoperative abdominal CT scans of 210 patients with colon cancer were evaluated by two radiologists independently for the T stage and N stage. Results were compared to pathology. Patients were stratified according to the guidelines for rectal cancer into patients with low risk (T0/1/2 and N0) or high risk (T3/4 or N+). RESULTS: Inter-observer correlation was high with over 90 %. Overall sensitivity T stage was 93.0 % and for N stage 76.9 %. Using CT scan to identify local advanced (T3/4 or N+) tumors, the consensus sensitivity was 94.9 %, the specificity 53.6 %, the positive predictive value (PPV) 92.8 %, and the negative predictive value (NPV) 62.5 %. CONCLUSION: Computer tomography represents an effective tool for identifying patients with colon cancer suitable for neoadjuvant therapy according to the guidelines for rectal cancer.

SElf-gated Non-Contrast-Enhanced FUnctional Lung imaging (SENCEFUL) using a quasi-random fast low-angle shot (FLASH) sequence and proton MRI.

Obtaining functional information on the human lung is of tremendous interest in the characterization of lung defects and pathologies. However, pulmonary ventilation and perfusion maps usually require contrast agents and the application of electrocardiogram (ECG) triggering and breath holds to generate datasets free of motion artifacts. This work demonstrates the possibility of obtaining highly resolved perfusion-weighted and ventilation-weighted images of the human lung using proton MRI and the SElf-gated Non-Contrast-Enhanced FUnctional Lung imaging (SENCEFUL) technique. The SENCEFUL technique utilizes a two-dimensional fast low-angle shot (FLASH) sequence with quasi-random sampling of phase-encoding (PE) steps for data acquisition. After every readout, a short additional acquisition of the non-phase-encoded direct current (DC) signal necessary for self-gating was added. By sorting the quasi-randomly acquired data according to respiratory and cardiac phase derived from the DC signal, datasets of representative respiratory and cardiac cycles could be accurately reconstructed. By application of the Fourier transform along the temporal dimension, functional maps (perfusion and ventilation) were obtained. These maps were compared with dynamic contrast-enhanced (DCE, perfusion) as well as standard Fourier decomposition (FD, ventilation) reference datasets. All datasets were additionally scored by two experienced radiologists to quantify image quality. In addition, one initial patient examination using SENCEFUL was performed. Functional images of healthy volunteers and a patient diagnosed with hypoplasia of the left pulmonary artery and left-sided pulmonary fibrosis were successfully obtained. Perfusion-weighted images corresponded well to DCE-MRI data; ventilation-weighted images offered a significantly better depiction of the lung periphery compared with standard FD. Furthermore, the SENCEFUL technique hints at a potential clinical relevance by successfully detecting a perfusion defect in the patient scan. It can be concluded that SENCEFUL enables highly resolved ventilation- and perfusion-weighted maps of the human lung to be obtained using proton MRI, and might be interesting for further clinical evaluation.