Τετάρτη, 22 Νοεμβρίου 2017

Leveraging Mega-trends in Medicine Today to Enhance Patient Care in Radiology Tomorrow

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Publication date: Available online 22 November 2017
Source:Academic Radiology
Author(s): Andrew B. Rosenkrantz




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Selecting Cases for Resident Interpretation to Enhance the Teaching Experience

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Publication date: Available online 22 November 2017
Source:Academic Radiology
Author(s): Ronald L. Eisenberg




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Performance of Ultrafast DCE-MRI for Diagnosis of Prostate Cancer

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Publication date: Available online 20 November 2017
Source:Academic Radiology
Author(s): Aritrick Chatterjee, Dianning He, Xiaobing Fan, Shiyang Wang, Teodora Szasz, Ambereen Yousuf, Federico Pineda, Tatjana Antic, Melvy Mathew, Gregory S. Karczmar, Aytekin Oto
Rationale and ObjectivesThis study aimed to test high temporal resolution dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for different zones of the prostate and evaluate its performance in the diagnosis of prostate cancer (PCa). Determine whether the addition of ultrafast DCE-MRI improves the performance of multiparametric MRI.Materials and MethodsPatients (n = 20) with pathologically confirmed PCa underwent preoperative 3T MRI with T2-weighted, diffusion-weighted, and high temporal resolution (~2.2 seconds) DCE-MRI using gadoterate meglumine (Guerbet, Bloomington, IN) without an endorectal coil. DCE-MRI data were analyzed by fitting signal intensity with an empirical mathematical model to obtain parameters: percent signal enhancement, enhancement rate (α), washout rate (β), initial enhancement slope, and enhancement start time along with apparent diffusion coefficient (ADC) and T2 values. Regions of interests were placed on sites of prostatectomy verified malignancy (n = 46) and normal tissue (n = 71) from different zones.ResultsCancer (α = 6.45 ± 4.71 s−1, β = 0.067 ± 0.042 s−1, slope = 3.78 ± 1.90 s−1) showed significantly (P < .05) faster signal enhancement and washout rates than normal tissue (α = 3.0 ± 2.1 s−1, β = 0.034 ± 0.050 s−1, slope = 1.9 ± 1.4 s−1), but showed similar percentage signal enhancement and enhancement start time. Receiver operating characteristic analysis showed area under the curve for DCE parameters was comparable to ADC and T2 in the peripheral (DCE 0.67–0.82, ADC 0.80, T2 0.89) and transition zones (DCE 0.61–0.72, ADC 0.69, T2 0.75), but higher in the central zone (DCE 0.79–0.88, ADC 0.45, T2 0.45) and anterior fibromuscular stroma (DCE 0.86–0.89, ADC 0.35, T2 0.12). Importantly, combining DCE with ADC and T2 increased area under the curve by ~30%, further improving the diagnostic accuracy of PCa detection.ConclusionQuantitative parameters from empirical mathematical model fits to ultrafast DCE-MRI improve diagnosis of PCa. DCE-MRI with higher temporal resolution may capture clinically useful information for PCa diagnosis that would be missed by low temporal resolution DCE-MRI. This new information could improve the performance of multiparametric MRI in PCa detection.



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Sonographic Criteria Predictive of Malignant Thyroid Nodules

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Publication date: Available online 16 November 2017
Source:Academic Radiology
Author(s): Carlos Miguel Oliveira, Rui Alves Costa, Miguel Patrício, Amélia Estêvão, Bruno Graça, Filipe Caseiro-Alves
Rationale and ObjectivesThe objective of this study was to evaluate the ultrasound features of thyroid nodules and their association with malignancy, focusing on establishing feature-oriented ultrasound criteria to determine proper management of a thyroid nodule.Materials and MethodsA sample of 379 thyroid nodules were biopsied (from a total of 357 patients aged 59.8 ± 14.8 years) and 300 were included in the final study (271 benign nodules and 29 malignant ones). Ultrasound features were recorded for each nodule: size, echogenicity, homogeneity, contours, shape, texture, peripheral halo, calcifications, and the presence of adenopathy. Statistical analysis of the data was performed using the Mann-Whitney U test and chi-square test. The sensitivity and the specificity of variables seen to have a statistically significant association with the malignancy of nodules were assessed and a logistic regression was performed.ResultsA taller-than-wide shape, an ill-defined contour, the presence of a halo, microcalcifications, and adenopathy were found to have a statistically significant relationship (P < 0.05) with malignancy, although with a low sensitivity and a high specificity. The presence of at least one suspicious feature yields great sensitivity (89.7%) in detecting malignant disease.ConclusionsThe ultrasound features of thyroid nodules alone do not allow the radiologist to make a confident diagnosis regarding the malignancy of a nodule without performing a biopsy. However, a nodule showing a taller-than-wide shape, microcalcifications, a peripheral halo, an ill-defined contour, or associated adenopathy should be considered for cytology.



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Shear Wave Elastography (SWE) for Monitoring of Treatment of Tendinopathies

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Publication date: Available online 16 November 2017
Source:Academic Radiology
Author(s): Timm Dirrichs, Valentin Quack, Matthias Gatz, Markus Tingart, Björn Rath, Marcel Betsch, Christiane K. Kuhl, Simone Schrading
Rationale and ObjectivesWe aimed to investigate the diagnostic accuracy with which shear wave elastography (SWE) can be used to monitor response to treatment of tendinopathies, and to compare it to conventional ultrasound (US)-imaging methods (B-mode US (B-US) and power Doppler US (PD-US)).Materials and MethodsA prospective Institutional Review Board-approved longitudinal study on 35 patients with 47 symptomatic tendons (17 Achilles-, 15 patellar-, and 15 humeral-epicondylar) who underwent standardized multimodal US and standardized clinical assessment before and after 6 months of treatment (tailored stretching exercise, sport break, and local Polidocanol) was carried out. All US studies were performed by radiologists blinded to the clinical symptoms on both tendon sides to avoid biased interpretations, by B-US, PD-US, and SWE, conducted in the same order, using a high-resolution linear 15 MHz probe (Aixplorer). Orthopedic surgeons who were in turn blinded to US imaging results used established orthopedic scores (Victorian Institute of Sports Assessment questionnaire for Achilles, Victorian Institute of Sports Assessment questionnaire for patellar tendons, and Disability Arm Shoulder Hand scoring system) to rate presence, degree, and possible resolution of symptoms. We analyzed the diagnostic accuracy with which the different US imaging methods were able to detect symptomatic tendons at baseline as well as treatment effects, with orthopedic scores serving as reference standard.ResultsB-US, PD-US, and SWE detected symptomatic tendons with a sensitivity of 66% (31 of 47), 72% (34 of 47), and 87.5% (41 of 47), respectively. Positive predictive value was 0.67 for B-US, 0.87 for PD-US, and 1 for SWE. After treatment, clinical scores improved in 68% (32 of 47) of tendons. Treatment effects were observable by B-US, PD-US, and SWE with a sensitivity of 3.1% (1 of 32), 28.1% (9 of 32), and 81.3% (26 of 32), respectively. B-US was false-positive in 68.8% (20 of 32), PD-US in 46.9% (15 of 32), and SWE in 12.5% (4 of 32) (SWE). Clinical scores and B-US, PD-US, and SWE findings correlated poorly (r = 0.24), moderately (r = 0.59), and strongly (r = 0.80).ConclusionUnlike B-US or PD-US, SWE is able to depict processes associated with tendon healing and may be a useful tool to monitor treatment effects.



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The Current State of Radiology Call Assistant Triage Programs Among US Radiology Residency Programs

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Publication date: Available online 22 November 2017
Source:Academic Radiology
Author(s): Jennifer Shaffer Ngo, Charles M. Maxfield, Gary R. Schooler
Rationale and ObjectivesGiven increasing volume and workflow interruptions in radiology, we sought to identify and characterize radiology call assistant triage (RCAT) programs among US radiology residency programs.Materials and MethodsA survey was created using Qualtrics survey software and emailed to all members of the Association of Program Directors in Radiology listserv. A total of 296 active members belong to this listserv, including program directors and assistant program directors. The survey included questions about the existence and specifics of a call triage assistant program.ResultsData were obtained from 88 active members of the Association of Program Directors in Radiology (30% response rate). Of those, 20 programs (23%) have an RCAT program. Triage assistant staffing includes nonmedical or clerical staff (60%), medical students (30%), first-year radiology residents (5%), and technologists (5%). All respondents with RCAT programs report satisfaction with their program and plan to continue. A significant majority (75%) have no plans to change, whereas the remaining 25% are considering program expansion and pay increases. Among residency programs without RCAT programs, none reported termination of their triage program. The most common reasons for not having triage assistants include cost, lack of awareness, differing opinions on utility, and the presence of 24/7 attending coverage.ConclusionTwenty US radiology residency programs report having an RCAT program. All report satisfaction with their program despite different staffing models. RCAT programs may represent an effective measure in limiting interruptions and potentially decreasing interpretative errors made by residents on call.



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Extreme widening of asymmetric giant cystic Virchow-Robin spaces



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Effect of Age on High T1 Signal Intensity of the Dentate Nucleus and Globus Pallidus in a Large Population Exposed to Gadodiamide.

Objective: The purpose of this study was to assess the effect of age and number of previous injections of gadodiamide on the signal intensity of unenhanced T1-weighted (T1w) images of the dentate nucleus and globus pallidus in a large population. Materials and Methods: A large, single-center retrospective population survey was designed and received institutional review board approval. Between January 2014 and December 2014, T1w signal intensity ratios were obtained from a large population of 2500 consecutive enhanced brain magnetic resonance imaging (MRI) scans. Of these, 1906 MRI scans of patients not previously exposed to any gadolinium (Gd)-based contrast agent were used as control group and were compared with 892 MRI scans of patients with documented prior exposure to intravenous gadodiamide. A quantitative study was conducted to assess the T1w signal intensity of dentate nucleus-to-pons (Dn/Po) and globus pallidus-to-thalamus (Gp/Th) ratios. Multiple regression analysis was used to test the effect of age, time delay, and number of previous Gd-based contrast agent injections as predictor variables of T1w signal intensity ratios. Results: In the Gd-exposed patients, multivariate regression analysis showed age ([beta] = -0.285; P

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Effect of Age on High T1 Signal Intensity of the Dentate Nucleus and Globus Pallidus in a Large Population Exposed to Gadodiamide.

Objective: The purpose of this study was to assess the effect of age and number of previous injections of gadodiamide on the signal intensity of unenhanced T1-weighted (T1w) images of the dentate nucleus and globus pallidus in a large population. Materials and Methods: A large, single-center retrospective population survey was designed and received institutional review board approval. Between January 2014 and December 2014, T1w signal intensity ratios were obtained from a large population of 2500 consecutive enhanced brain magnetic resonance imaging (MRI) scans. Of these, 1906 MRI scans of patients not previously exposed to any gadolinium (Gd)-based contrast agent were used as control group and were compared with 892 MRI scans of patients with documented prior exposure to intravenous gadodiamide. A quantitative study was conducted to assess the T1w signal intensity of dentate nucleus-to-pons (Dn/Po) and globus pallidus-to-thalamus (Gp/Th) ratios. Multiple regression analysis was used to test the effect of age, time delay, and number of previous Gd-based contrast agent injections as predictor variables of T1w signal intensity ratios. Results: In the Gd-exposed patients, multivariate regression analysis showed age ([beta] = -0.285; P

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Editorial Board

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Publication date: November 2017
Source:Radiotherapy and Oncology, Volume 125, Issue 2





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Contents

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Publication date: November 2017
Source:Radiotherapy and Oncology, Volume 125, Issue 2





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Global impact of radiotherapy in oncology: Saving one million lives by 2035

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Publication date: November 2017
Source:Radiotherapy and Oncology, Volume 125, Issue 2
Author(s): Yolande Lievens, Mary Gospodarowicz, Surbhi Grover, David Jaffray, Danielle Rodin, Julie Torode, Mei Ling Yap, Eduardo Zubizarreta




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Added diagnostic value of respiratory-gated 4D 18F–FDG PET/CT in the detection of liver lesions: a multicenter study

Abstract

Purpose

The aim of the present study was to evaluate the added diagnostic value of respiratory-gated 4D18F–FDG PET/CT in liver lesion detection and characterization in a European multicenter retrospective study.

Methods

Fifty-six oncological patients (29 males and 27 females, mean age, 61.2 ± 11.2 years) from five European centers, submitted to standard 3D–PET/CT and liver 4D–PET/CT were retrospectively evaluated. Based on visual analysis, liver PET/CT findings were scored as positive, negative, or equivocal both in 3D and 4D PET/CT. The impact of 4D–PET/CT on the confidence in classifying liver lesions was assessed. PET/CT findings were compared to histology and clinical follow-up as standard reference and diagnostic accuracy was calculated for both techniques. At semi-quantitative analysis, SUVmax was calculated for each detected lesion in 3D and 4D–PET/CT.

Results

Overall, 72 liver lesions were considered for the analysis. Based on visual analysis in 3D–PET/CT, 32/72 (44.4%) lesions were considered positive, 21/72 (29.2%) negative, and 19/72 (26.4%) equivocal, while in 4D–PET/CT 48/72 (66.7%) lesions were defined positive, 23/72 (31.9%) negative, and 1/72 (1.4%) equivocal. 4D–PET/CT findings increased the confidence in lesion definition in 37/72 lesions (51.4%). Considering 3D equivocal lesions as positive, sensitivity, specificity, and accuracy were 88.9, 70.0, and 83.1%, respectively, while the same figures were 67.7, 90.0, and 73.8% if 3D equivocal findings were included as negative. 4D–PET/CT sensitivity, specificity, and accuracy were 97.8, 90.0, and 95.4%, respectively, considering equivocal lesions as positive and 95.6, 90.0, and 93.8% considering equivocal lesions as negative. The SUVmax of the liver lesions in 4D–PET (mean ± SD, 6.9 ± 3.2) was significantly higher (p < 0.001) than SUVmax in 3D–PET (mean ± SD, 5.2 ± 2.3).

Conclusions

Respiratory-gated PET/CT technique is a valuable clinical tool in diagnosing liver lesions, reducing 3D undetermined findings, improving diagnostic accuracy, and confidence in reporting. 4D–PET/CT also improved the quantification of SUVmax of liver lesions.



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Metabolic activity by 18 F–FDG-PET/CT is predictive of early response after nivolumab in previously treated NSCLC

Abstract

Background

Nivolumab, an anti-programmed death-1 (PD-1) antibody, is administered in patients with previously treated non-small cell lung cancer. However, little is known about the established biomarker predicting the efficacy of nivolumab. Here, we conducted a preliminary study to investigate whether 18F–FDG-PET/CT could predict the therapeutic response of nivolumab at the early phase.

Methods

Twenty-four patients were enrolled in this study. 18F–FDG-PET/CT was carried out before and 1 month after nivolumab therapy. SUVmax, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were calculated. Immunohistochemical analysis of PD-L1 expression and tumour-infiltrating lymphocytes was conducted.

Results

Among all patients, a partial metabolic response to nivolumab was observed in 29% on SUVmax, 25% on MTV, and 33% on TLG, whereas seven (29%) patients achieved a partial response (PR) based on RECIST v1.1. The predictive probability of PR (100% vs. 29%, p = 0.021) and progressive disease (100% vs. 22.2%, p = 0.002) at 1 month after nivolumab initiation was significantly higher in 18F–FDG on PET/CT than in CT scans. Multivariate analysis confirmed that 18F–FDG uptake after administration of nivolumab was an independent prognostic factor. PD-L1 expression and nivolumab plasma concentration could not precisely predict the early therapeutic efficacy of nivolumab.

Conclusion

Metabolic response by 18F–FDG was effective in predicting efficacy and survival at 1 month after nivolumab treatment.



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Prognostic value of lymph node-to-primary tumor standardized uptake value ratio in endometrioid endometrial carcinoma

Abstract

Purpose

To determine whether the relative metabolic activity of pelvic or para-aortic LN compared with that of primary tumor measured by preoperative [18F]FDG PET/CT scan has prognostic value in patients with endometrioid endometrial carcinoma.

Methods

We retrospectively reviewed patients with endometrioid endometrial carcinoma who underwent preoperative [18F]FDG PET/CT scans. Prognostic values of PET/CT-derived metabolic variables such as maximum standardized uptake value (SUV) of the primary endometrial carcinoma (SUVTumor) and LN (SUVLN), and the LN-to-endometrial carcinoma SUV ratio (SUVLN / SUVTumor) were assessed.

Results

Clinico-pathological data, imaging data, and treatment results were reviewed for 107 eligible patients. Median post-surgical follow-up was 23 months (range, 6–60), and 7 (6.5%) patients experienced recurrence. Regression analysis showed that SUVLN / SUVTumor (P < 0.001), SUVLN (P = 0.003), International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.006), and tumor grade (P = 0.011) were risk factors of recurrence. Multivariate regression analysis revealed that FIGO stage (P = 0.034) was the independent risk factor of recurrence. SUVLN / SUVTumor showed significant correlation with FIGO stage (P < 0.001), LN metastasis (P < 0.001), lymphovascular space invasion (P < 0.001), recurrence (P = 0.001), tumor grade (P < 0.001), and deep myometrial invasion of tumor (P = 0.022). Patient groups categorized by SUVLN / SUVTumor showed significant difference in progression-free survival (Log-rank test, P = 0.001).

Conclusions

Preoperative SUVLN / SUVTumor measured by [18F]FDG PET/CT was significantly associated with recurrence, and may become a novel prognostic factor in patients with endometrioid endometrial carcinoma.



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Targeting angiogenesis for radioimmunotherapy with a 177 Lu-labeled antibody

Abstract

Purpose

Increased angiogenesis is a marker of aggressiveness in many cancers. Targeted radionuclide therapy of these cancers with angiogenesis-targeting agents may curtail this increased blood vessel formation and slow the growth of tumors, both primary and metastatic. CD105, or endoglin, has a primary role in angiogenesis in a number of cancers, making this a widely applicable target for targeted radioimmunotherapy.

Methods

The anti-CD105 antibody, TRC105 (TRACON Pharmaceuticals), was conjugated with DTPA for radiolabeling with 177Lu (t 1/2 6.65 days). Balb/c mice were implanted with 4T1 mammary carcinoma cells, and five study groups were used: 177Lu only, TRC105 only, 177Lu-DTPA-IgG (a nonspecific antibody), 177Lu-DTPA-TRC105 low-dose, and 177Lu-DTPA-TRC105 high-dose. Toxicity of the agent was monitored by body weight measurements and analysis of blood markers. Biodistribution studies of 177Lu-DTPA-TRC105 were also performed at 1 and 7 days after injection. Ex vivo histology studies of various tissues were conducted at 1, 7, and 30 days after injection of high-dose 177Lu-DTPA-TRC105.

Results

Biodistribution studies indicated steady uptake of 177Lu-DTPA-TRC105 in 4T1 tumors between 1 and 7 days after injection (14.3 ± 2.3%ID/g and 11.6 ± 6.1%ID/g, respectively; n = 3) and gradual clearance from other organs. Significant inhibition of tumor growth was observed in the high-dose group, with a corresponding significant increase in survival (p < 0.001, all groups). In most study groups (all except the nonspecific IgG group), the body weights of the mice did not decrease by more than 10%, indicating the safety of the injected agents. Serum alanine transaminase levels remained nearly constant indicating no damage to the liver (a primary clearance organ of the agent), and this was confirmed by ex vivo histological analyses.

Conclusion

177Lu-DTPA-TRC105, when administered at a sufficient dose, is able to curtail tumor growth and provide a significant survival benefit without off-target toxicity. Thus, this targeted agent could be used in combination with other treatment options to slow tumor growth allowing the other agents to be more effective.



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Comment on “Comparison of CT and PET/CT for biopsy guidance in oncological patients”



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18F-FDG-PET detects complete response to PD1-therapy in melanoma patients two weeks after therapy start

Abstract

Purpose

The aim of the study was to evaluate if 18F-FDG-PET has the potential to detect complete responders to PD1-therapy in patients with unresectable metastasized melanoma two weeks after therapy initiation.

Methods

Between September 2014 and May 2016, ten patients (four females; 65 ± 12 y) received a whole-body 18F-FDG-PET/MRI examination at three time points: Before therapy start (t0, base-line), two weeks (t1, study examination) and three months after treatment initiation (t2, reference standard). Therapy response was assessed with PET response criteria in solid tumors (PERCIST). Time to progression and overall survival (OS) were obtained for all patients.

Results

Three patients with partial metabolic response in PET at t1 turned out to have complete response at t2. No tumor relapse was observed in those patients so far (observation period: 265, 511 and 728 days, respectively). At t2, progressive metabolic disease (PMD) was seen in six patients from whom four showed PMD and two showed stable metabolic disease (SMD) at t1. OS in patients with PMD at t2 varied between 148 and 814 days. SMD at both t1 and t2 was seen in one patient, tumor progress was observed after 308 days.

Conclusion

Our study indicates that whole-body 18F-FDG-PET might be able to reliably identify complete responders to PD1-therapy as early as two weeks after therapy initiation in stage IV melanoma patients. This might help to shorten therapy regimes and avoid unnecessary side effects in the future.



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Improving quality of life in patients with pancreatic neuroendocrine tumor following peptide receptor radionuclide therapy assessed by EORTC QLQ-C30

Abstract

Introduction

Neuroendocrine tumors (NETs) have proven to be appropriate neoplasms for peptide receptor radionuclide therapy (PRRT), as the majority of these slow-growing malignancies overexpress somatostatin receptors. The aim of this study was to evaluate changes in quality of life (QoL) of patients with P-NET following PRRT.

Methods

Sixty-eight patients with P-NET (31 female, mean age 61.4 y) underwent PRRT: 12 with NET of grade 1, 40 of grade 2, 8 of grade 3 (grade non-available n = 8). Prior to treatment, 39 patients showed ECOG 0, 26 patients ECOG 1, and three patients ECOG 2. Clinical assessment included evaluation of QoL and symptom changes using a standardized questionnaire (EORTC QLQ-C30) and was performed at baseline and every three months following each therapy cycle up to 12 months. Primary analysis compared QoL at baseline and after the fourth treatment cycle (N = 53).

Results

Up to four treatment cycles PRRT were performed for each patient. The median cumulative administered activity was 28.2 GBq. Primary analysis revealed that compared to baseline QoL was significantly improved revealing increased global health status (p = 0.008) and social functioning (p = 0.049) at the end of the study. Furthermore, fatigue and appetite loss showed a significant improvement after the last PRRT cycle (fatigue: p = 0.029, appetite loss p = 0.015). Sub-analyses showed that QoL was improved revealing increased global health status (3 months after first, second, and third treatment cycle p = 0.048, p = 0.002, and p < 0.001, respectively), emotional functioning (3 months after first-third cycle p = 0.003, p = 0.049, and p = 0.001, respectively) and social functioning (3 months after the first and second p < 0.001, and after the third cycle p = 0.015, respectively). Furthermore, some symptoms were significantly alleviated compared with baseline: fatigue (after first-third cycle p = 0.026, p = 0.050, and p = 0.008, respectively), nausea and vomiting (after first and second cycle p = 0.006 and p = 0.001, respectively), dyspnea (after third cycle p = 0.025), appetite loss (after first-third cycle p = 0.010, p = 0.001, and p = 0.009, respectively), constipation (after first-third cycle p = 0.050, p = 0.003, and p = 0.060, respectively).

Conclusion

PRRT is an effective treatment of P-NET improving QoL of patients in terms of increasing global health and mitigation of physical complaints.



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Targeted alpha therapy of mCRPC: Dosimetry estimate of 213 Bismuth-PSMA-617

Abstract

Purpose

PSMA-617 is a small molecule targeting the prostate-specific membrane antigen (PSMA). In this work, we estimate the radiation dosimetry for this ligand labeled with the alpha-emitter 213Bi.

Methods

Three patients with metastatic prostate cancer underwent PET scans 0.1 h, 1 h, 2 h, 3 h, 4 h and 5 h after injection of 68Ga-PSMA-617. Source organs were kidneys, liver, spleen, salivary glands, bladder, red marrow and representative tumor lesions. The imaging nuclide 68Ga was extrapolated to the half-life of 213Bi. The residence times of 213Bi were forwarded to the instable daughter nuclides. OLINDA was used for dosimetry calculation. Results are discussed in comparison to literature data for 225Ac-PSMA-617.

Results

Assuming a relative biological effectiveness of 5 for alpha radiation, the dosimetry estimate revealed equivalent doses of mean 8.1 Sv RBE5/GBq for salivary glands, 8.1 Sv RBE5/GBq for kidneys and 0.52 Sv RBE5/GBq for red marrow. Liver (1.2 Sv RBE5/GBq), spleen (1.4 Sv RBE5/GBq), bladder (0.28 Sv RBE5/GBq) and other organs (0.26 SvRBE5/GBq) were not dose-limiting. The effective dose is 0.56 Sv RBE5/GBq. Tumor lesions were in the range 3.2–9.0 SvRBE5/GBq (median 7.6 SvRBE5/GBq). Kidneys would limit the cumulative treatment activity to 3.7 GBq; red marrow might limit the maximum single fraction to 2 GBq. Despite promising results, the therapeutic index was inferior compared to 225Ac-PSMA-617.

Conclusions

Dosimetry of 213Bi-PSMA-617 is in a range traditionally considered reasonable for clinical application. Nevertheless, compared to 225Ac-PSMA-617, it suffers from higher perfusion-dependent off-target radiation and a longer biological half-life of PSMA-617 in dose-limiting organs than the physical half-life of 213Bi, rendering this nuclide as a second choice radiolabel for targeted alpha therapy of prostate cancer.



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Clinical impact of PSMA-based 18 F–DCFBC PET/CT imaging in patients with biochemically recurrent prostate cancer after primary local therapy

Abstract

Purpose

The purpose of our study was to assess 18F–DCFBC PET/CT, a PSMA targeted PET agent, for lesion detection and clinical management of biochemical relapse in prostate cancer patients after primary treatment.

Methods

This is a prospective IRB-approved study of 68 patients with documented biochemical recurrence after primary local therapy consisting of radical prostatectomy (n = 50), post radiation therapy (n = 9) or both (n = 9), with negative conventional imaging. All 68 patients underwent whole-body 18F–DCFBC PET/CT, and 62 also underwent mpMRI within one month. Lesion detection with 18F–DCFBC was correlated with mpMRI findings and pre-scan PSA levels. The impact of 18F–DCFBC PET/CT on clinical management and treatment decisions was established after 6 months' patient clinical follow-up.

Results

Forty-one patients (60.3%) showed at least one positive 18F–DCFBC lesion, for a total of 79 lesions, 30 in the prostate bed, 39 in lymph nodes, and ten in distant sites. Tumor recurrence was confirmed by either biopsy (13/41 pts), serial CT/MRI (8/41) or clinical follow-up (15/41); there was no confirmation in five patients, who continue to be observed. The 18F–DCFBC and mpMRI findings were concordant in 39 lesions (49.4%), and discordant in 40 lesions (50.6%); the majority (n = 32/40) of the latter occurring because the recurrence was located outside the mpMRI field of view. 18F–DCFBC PET positivity rates correlated with PSA values and 15%, 46%, 83%, and 77% were seen in patients with PSA values <0.5, 0.5 to <1.0, 1.0 to <2.0, and ≥2.0 ng/mL, respectively. The optimal cut-off PSA value to predict a positive 18F–DCFBC scan was 0.78 ng/mL (AUC = 0.764). A change in clinical management occurred in 51.2% (21/41) of patients with a positive 18F–DCFBC result, generally characterized by starting a new treatment in 19 patients or changing the treatment plan in two patients.

Conclusions

18F–DCFBC detects recurrences in 60.3% of a population of patients with biochemical recurrence, but results are dependent on PSA levels. Above a threshold PSA value of 0.78 ng/mL, 18F–DCFBC was able to identify recurrence with high reliability. Positive 18F–DCFBC PET imaging led clinicians to change treatment strategy in 51.2% of patients.



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From fixed activities to personalized treatments in radionuclide therapy: lost in translation?



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18F–FDG PET/CT in solitary plasmacytoma: metabolic behavior and progression to multiple myeloma

Abstract

Purpose

Solitary plasmacytoma (SP) is a rare plasma-cell neoplasm, which can develop both in skeletal and/or soft tissue and frequently progresses to multiple myeloma (MM). Our aim was to study the metabolic behavior of SP and the role of 18F–FDG-PET/CT in predicting progression to MM.

Materials and methods

Sixty-two patients with SP who underwent 18F–FDG-PET/CT before any treatment were included. PET images were qualitatively and semiquantitatively analyzed by measuring the maximum standardized uptake value body weight (SUVbw), lean body mass (SUVlbm), body surface area (SUVbsa), metabolic tumor volume (MTV), total lesion glycolysis (TLG) and compared with age, sex, site of primary disease, and tumor size.

Results

Fifty-one patients had positive 18F–FDG-PET/CT (average SUVbw was 8.3 ± 4.7; SUVlbm 5.8 ± 2.6; SUVbsa 2 ± 1; MTV 45.4 ± 37; TLG 227 ± 114); the remaining 11 were not 18F–FDG-avid. Tumor size was significantly higher in patients avid lesions compared to FDG not avid; no other features are associated with FDG-avidity. Progression to MM occurred in 29 patients with an average of 18.3 months; MM was more likely to develop in patients with bone plasmacytoma and in patients with 18F–FDG avid lesion. Time to transformation in MM (TTMM) was significantly shorter in patients with osseous SP, in 18F–FDG avid lesion, for SUVlbm > 5.2 and SUVbsa > 1.7.

Conclusions

18F–FDG pathological uptake in SP occurred in most cases, being independently associated with tumor size. PET/CT seemed to be correlated to a higher risk of transformation in MM, in particular for 18F–FDG avid plasmacytoma and SBP. Among semiquantitative features, SUVlbm > 5.2 and SUVbsa > 1.7 were significantly correlated with TTMM.



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Diagnostic and prognostic value of 18F-FDG PET/CT in recurrent germinal tumor carcinoma

Abstract

Aim

The aim of this bicentric retrospective study was to assess the diagnostic performance, the prognostic value, the incremental prognostic value and the impact on therapeutic management of 18F-FDG PET/CT in patients with suspected recurrent germinal cell testicular carcinoma (GCT).

Materials and methods

From the databases of two centers including 31,500 18F-FDG PET/CT oncological studies, 114 patients affected by GCT were evaluated in a retrospective study. All 114 patients underwent 18F-FDG PET/CT for suspected recurrent disease. Diagnostic performance of visually interpreted 18F-FDG PET/CT and potential impact on the treatment decision were assessed using histology (17 patients), other diagnostic imaging modalities (i.e., contrast enhanced CT in 89 patients and MRI in 15) and clinical follow-up (114 patients) as reference. Progression-free survival (PFS) and overall survival (OS) rates were computed by means of Kaplan-Meier survival analysis. The progression rate (Hazard Ratio-HR) was determined using univariate Cox regression analysis by considering various clinical variables.

Results

Recurrent GCT was confirmed in 47 of 52 patients with pathological 18F-FDG PET/CT findings, by means of histology in 18 patients and by other diagnostic imaging modalities/follow-up in 29. Sensitivity, specificity, accuracy, positive and negative likelihood ratio (LR+ and LR-, respectively), pre-test Odds-ratio and post-test Odds-ratio of 18FDG PET/CT were 86.8%, 90.2%, 88.4%, 8.85, 0.14, 0.85, 8.85, respectively.18F-FDG PET/CT impacted significantly on therapeutic management in 26/114 (23%) cases (from palliative to curative in 12 patients, from "wait and watch" to new chemotherapy in six patients and the "wait-and-watch" approach in eight patients with unremarkable findings). At 2 and 5-year follow-up, PFS was significantly longer in patients with a negative than a pathological 18F-FDG PET/CT scan (98% and 95% vs 48% and 38%, respectively; p = 0.02). An unremarkable scan was associated also with a longer OS (98% after 2 years and 95% after 5 years, p = 0.02). At univariate Cox regression analysis, a pathological 18F-FDG PET/CT scan was associated with an increased risk of disease progression (HR = 24.3, CI 95% 14.1-40.6; p = 0.03) and lower OS (HR = 17.3 CI 95% 4,9-77; p < 0.001). Its prognostic value was confirmed also if tested against advanced disease at diagnosis and rising Human Chorionic Gonadotropin Beta (HCGB) or Alpha-Fetoprotein (AFP) (HR = 7.3 for STAGE III-PET+, p = 0.03; HR = 14.3 elevated HCGB-PET+, p = 0.02; HR 10.7 elevated AFP-PET+, p = 0.01) At multivariate analysis, only a pathological 18F-FDG PET/CT scan and advanced disease in terms of TNM staging were predictors of disease progression and OS. 18F-FDG PET/CT showed incremental value over other variables both in predicting PFS (chi-square from 24 to 40, p < 0.001) and OS (chi-square from 32 to 38, p = 0.003).

Conclusion

18F-FDG PET/CT has a very good diagnostic performance in patients with suspected recurrent GCT and has an important prognostic value in assessing the rate of PFS and OS. Furthermore, 18F-FDG PET/CT impacted the therapeutic regimen in 23% of patients, thus providing a significant impact in the restaging process.



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Comparison of 18 F-FDG PET/MRI and MRI for pre-therapeutic tumor staging of patients with primary cancer of the uterine cervix

Abstract

Purpose

The aim of the present study was to assess and compare the diagnostic performance of integrated PET/MRI and MRI alone for local tumor evaluation and whole-body tumor staging of primary cervical cancers. In addition, the corresponding impact on further patient management of the two imaging modalities was assessed.

Methods

A total of 53 consecutive patients with histopathological verification of a primary cervical cancer were prospectively enrolled for a whole-body 18F-FDG PET/MRI examination. Two experienced physicians analyzed the MRI data, in consensus, followed by a second reading session of the PET/MRI datasets. The readers were asked to perform a dedicated TNM staging in accordance with the 7th edition of the AJCC staging manual. Subsequently, the results of MRI and PET/MRI were discussed in a simulated interdisciplinary tumor board and therapeutic decisions based on both imaging modalities were recorded. Results from histopathology and cross-sectional imaging follow-up served as the reference standard.

Results

PET/MRI allowed for a correct determination of the T stage in 45/53 (85%) cases, while MRI alone enabled a correct identification of the tumor stage in 46/53 (87%) cases. In 24 of the 53 patients, lymph node metastases were present. For the detection of nodal-positive patients, sensitivity, specificity and accuracy of PET/MRI were 83%, 90% and 87%, respectively. The respective values for MRI alone were 71%, 83% and 77%. In addition, PET/MRI showed higher values for the detection of distant metastases than MRI alone (sensitivity: 87% vs. 67%, specificity: 92% vs. 90%, diagnostic accuracy: 91% vs. 83%). Among the patients with discrepant staging results in the two imaging modalities, PET/MRI enabled correct treatment recommendations for a higher number (n = 9) of patients than MRI alone (n = 3).

Conclusion

The present results demonstrate the successful application of integrated PET/MRI imaging for whole-body tumor staging of cervical cancer patients, enabling improved treatment planning when compared to MRI alone.



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Heat shock protein (hsp70) in brown trout epidermis after sudden temperature rise

So far, hsp70 has not yet been studied in the fish skin. This organ has a potential as an indicator organ and we investigate whether hsp70 could be used as a biomarker. In this study, we examined whether and how the epidermis reacts to a temperature rise . Brown trout , Salmo trutta fario, were exposed to higher temperature for 2 h and were allowed to recover subsequently. Samples were taken from controls, after heat shock , as well as after 24 and 48 h of recovery. The occurrence of hsp70 in trout skin was examined by Western blot. The amount of hsp70 was higher after 2-h heat shock and was rising until the end of the experiment. Immunocytochemically, hsp70 was detected in epidermal filament cells. After 2-h heat shock , hsp70 was predominantly located in the nucleus. At this lime, light and electron microscopy revealed several features known to occur under a variety of stressors. Ultrastructurally, the appearance of compact filament aggregates in pavement cells was remarkable. After 24 h of recovery, filament compaction was lacking and after 48 h aspects of regeneration were obvious. However, an increased amount of apoptotic cells in the epidermis was prominent at this time only.

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Antibiotics, Vol. 6, Pages 29: Activity In Vitro of Clotrimazole against Canine Methicillin-Resistant and Susceptible Staphylococcus pseudintermedius

Antibiotics, Vol. 6, Pages 29: Activity In Vitro of Clotrimazole against Canine Methicillin-Resistant and Susceptible Staphylococcus pseudintermedius

Antibiotics doi: 10.3390/antibiotics6040029

Authors: Sian-Marie Frosini Ross Bond

Emergence of multidrug-resistance in Staphylococcus pseudintermedius (SP) has increased interest in topical therapy as an alternative to systemic antibiotics in canine pyoderma. The antifungal imidazole, clotrimazole, is contained in numerous licensed canine ear preparations. Its in vitro activity against SP has not been evaluated, although previous studies have shown that the related imidazole, miconazole, has significant anti-staphylococcal efficacy. We therefore determined minimum inhibitory concentrations (MICs) of clotrimazole amongst 50 SP isolates (25 methicillin-resistant [MR]SP and susceptible [MS]SP) collected from dogs in Germany during 2010–2011 using an agar dilution method (CLSI VET01-A4). MICs amongst MRSP and MSSP were comparable (MIC50 and MIC90 = 1mg/L for both groups, p = 0.317); overall, 49 isolates had MIC = 1 mg/L and one had MIC = 0.5 mg/L. The relatively low MICs obtained in this study are likely to be exceeded by topical therapy and thus further clinical evaluation of clotrimazole use in canine superficial pyoderma and otitis externa caused by MRSP and MSSP is now warranted.



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International Bullous Diseases Group - Consensus on Diagnostic Criteria for Epidermolysis Bullosa Acquisita

Summary

Background

Epidermolysis bullosa acquisita (EBA) is a complex autoimmune bullous disease disease with variable clinical presentations and multiple possible diagnostic tests making an international consensus on diagnosis of EBA needed.

Objectives

To obtain an international consensus on the clinical and diagnostic criteria for EBA.

Methods

The international bullous diseases group (IBDG) met three times to discuss the clinical and diagnostic criteria for EBA. For the final voting exercise, 22 experts from 14 different countries voted on 50 different items. When more than 30% disagreed with a proposal, a discussion was held and revoting occurred.

Results

48/50 proposals achieved consensus after discussion. This included 9 diagnostic criteria that are summarized in a flow chart. The IBDG was unable to determine one procedure which would be applicable worldwide.

Limitations

Differential diagnosis of bullous systemic lupus erythematosus has not been addressed.

Conclusion

This first international consensus conference established generally agreed upon clinical and laboratory criteria defining the clinical classification and diagnostic testing for EBA. Holding these voting exercises in person with the possibility of discussion prior to voting has advantages in reaching consensus over Delphi exercises with remote voting.

This article is protected by copyright. All rights reserved.



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Adam Kay: Mirth partner

bmj;359/nov22_1/j5227/FAF1faDuncan SmithBiographyAdam Kay, 37, is a doctor who left medicine to become a comedy performer and scriptwriter—interests he combined in This is Going to Hurt, a book about...
recent?d=yIl2AUoC8zA recent?d=dnMXMwOfBR0 recent?i=-AiTj5WKbq0:3YqJeMWg4eY:V_sGLiP recent?d=qj6IDK7rITs recent?i=-AiTj5WKbq0:3YqJeMWg4eY:gIN9vFw recent?d=l6gmwiTKsz0 recent?d=7Q72WNTAKBA recent?i=-AiTj5WKbq0:3YqJeMWg4eY:F7zBnMy recent?i=-AiTj5WKbq0:3YqJeMWg4eY:-BTjWOF


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Janet McLelland

bmj;359/nov21_10/j5270/FAF1faJanet McLelland (“Jan”) grew up in Newcastle. She was a research fellow at the Royal Postgraduate Medical School, where she completed her MD thesis, “Studies Relating to...
recent?d=yIl2AUoC8zA recent?d=dnMXMwOfBR0 recent?i=ZMexnG4TUPc:AznlAzIOW4M:V_sGLiP recent?d=qj6IDK7rITs recent?i=ZMexnG4TUPc:AznlAzIOW4M:gIN9vFw recent?d=l6gmwiTKsz0 recent?d=7Q72WNTAKBA recent?i=ZMexnG4TUPc:AznlAzIOW4M:F7zBnMy recent?i=ZMexnG4TUPc:AznlAzIOW4M:-BTjWOF


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Robert Cleghorn Robb

bmj;359/nov21_9/j5289/FAF1faRobert Cleghorn Robb was born in Newmains, Lanarkshire, Scotland. He was educated locally and studied medicine at the University of Glasgow. After qualifying in 1946, he...
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Pathological Roles of Neutrophil-Mediated Inflammation in Asthma and Its Potential for Therapy as a Target

Asthma is a chronic inflammatory disease that undermines the airways. It is caused by dysfunction of various types of cells, as well as cellular components, and is characterized by recruitment of inflammatory cells, bronchial hyperreactivity, mucus production, and airway remodelling and narrowing. It has commonly been considered that airway inflammation is caused by the Th2 immune response, or eosinophilia, which is a hallmark of bronchial asthma pathogenesis. Some patients display a neutrophil-dominant presentation and are characterized with low (or even absent) Th2 cytokines. In recent years, increasing evidence has also suggested that neutrophils play a key role in the development of certain subtypes of asthma. This review discusses neutrophils in asthma and potentially related targeted therapies.

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SERINC as a Restriction Factor to Inhibit Viral Infectivity and the Interaction with HIV

The serine incorporator 5 (SERINC5) is a recently discovered restriction factor that inhibits viral infectivity by preventing fusion. Retroviruses have developed strategies to counteract the action of SERINC5, such as the expression of proteins like negative regulatory factor (Nef), S2, and glycosylated Gag (glycoGag). These accessory proteins downregulate SERINC5 from the plasma membrane for subsequent degradation in the lysosomes. The observed variability in the action of SERINC5 suggests the participation of other elements like the envelope glycoprotein (Env) that modulates susceptibility of the virus towards SERINC5. The exact mechanism by which SERINC5 inhibits viral fusion has not yet been determined, although it has been proposed that it increases the sensitivity of the Env by exposing regions which are recognized by neutralizing antibodies. More studies are needed to understand the role of SERINC5 and to assess its utility as a therapeutic strategy.

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Diagnosis and Treatment of Esophageal Granular Cell Tumor: A Case Report and Review of the Literature

Gastrointestinal granular cell tumors are uncommon. The most common site of gastrointestinal granular cell tumor (GCT) is esophagus. We report a case of esophageal GCT incidentally diagnosed by endoscopy. The lesion was evaluated by endoscopic ultrasonography and resected using the endoscopic technique without complication.

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Skin Hyperpigmentation as the Presenting Symptom of Subacute Combined Degeneration of the Spinal Cord

Vitamin B12 deficiency results in hematological, neurological, and rarely dermatological complications. Subacute combined degeneration of the cord is one of the neurological complications, and usually the presenting symptom is paresthesia. Herein, we report a case of a 46-year-old man with subacute combined degeneration presenting with knuckle hyperpigmentation.

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Methanol Extract of Holarrhena antidysenterica Inhibits the Growth of Human Oral Squamous Cell Carcinoma Cells and Osteoclastogenesis of Bone Marrow Macrophages

Oral squamous cell carcinoma (OSCC) frequently invades mandibular bone, and outcomes for treatment with surgical resection are typically poor, ultimately resulting in death. Holarrhena antidysenterica L. (Apocynaceae), distributed throughout Sri Lanka and India, has been used as a folk remedy to treat various diseases. Treatment with methanol extract of H. antidysenterica bark (HABE) inhibited cell viability and BrdU incorporation and induced apoptotic cell death in Ca9-22 gingival and HSC-3 tongue SCC cells. Flow cytometric analysis indicated that HABE treatment preferentially induces apoptotic cell death via increasing the sub-G1 peak in Ca9-22 cells and cell cycle arrest at the G1 phase in HSC-3 cells. HABE treatment in the presence of zVAD-fmk, a pan-caspase inhibitor, rescued cell viabilities in both OSCC cell lines. The ratio of Bax to Bcl-2 increased with reductions in the Bcl-2 protein expression, and the activation of caspase 3 and subsequent cleavage of PARP was detected in HABE-treated Ca9-22 and HSC-3 cells. Furthermore, HABE treatment at noncytotoxic concentrations inhibited osteoclast formation in RANKL-stimulated bone marrow macrophages. Taken together, HABE possesses the inhibitory activity on the growth of OSCC cells and antiosteoclastogenic activity. Therefore, HABE may be a promising alternative and complementary agent for preventing and treating OSCC.

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Cognitive Impact of Deep Brain Stimulation on Parkinson’s Disease Patients

Subthalamic nucleus (STN) or globus pallidus interna (GPi) deep brain stimulation (DBS) is considered a robust therapeutic tool in the treatment of Parkinson’s disease (PD) patients, although it has been reported to potentially cause cognitive decline in some cases. We here provide an in-depth and critical review of the current literature regarding cognition after DBS in PD, summarizing the available data on the impact of STN and GPi DBS as monotherapies and also comparative data across these two therapies on 7 cognitive domains. We provide evidence that, in appropriately screened PD patients, worsening of one or more cognitive functions is rare and subtle after DBS, without negative impact on quality of life, and that there is very little data supporting that STN DBS has a worse cognitive outcome than GPi DBS.

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Anti-Interleukin-22-Neutralizing Antibody Attenuates Angiotensin II-Induced Cardiac Hypertrophy in Mice

Background. Interleukin- (IL-) 22 is considered a proinflammatory cytokine. Recent evidence has demonstrated that it plays a role in cardiovascular diseases. In the recent study, we investigate whether IL-22 is involved in cardiac hypertrophy. Methods. Angiotensin II was used to build hypertrophy model and the IL-22 and IL-22 receptor 1 (IL-22R1) levels in heart tissue were measured. In addition, angiotensin II-treated mice received an injection of anti-IL-22-neutralizing antibody (nAb) to investigate the effects of IL-22 nAb on myocardial hypertrophy, cardiac function, and cardiac fibrosis; the activation of the signaling pathway and the prohypertrophic inflammatory cytokine mRNA levels was detected. Furthermore, the effect of IL-22 nAb on angiotensin II-induced hypertrophy in vitro was also determined. Results. IL-22 and IL-22R1 levels were significantly increased after angiotensin II infusion. Anti-IL-22 nAb significantly alleviated the severity of hypertrophy, prevented systolic and diastolic abnormalities, reduced cardiac fibrosis, STAT3 and ERK phosphorylation, and downregulated the mRNA expression of IL-17, IL-6, IL-1β, IFN-γ, and TNF-α. In addition, IL-22 nAb attenuated angiotensin II-induced hypertrophy in H9C2 cells. Conclusion. Our data demonstrated that neutralization of IL-22 alleviated angiotensin II-induced cardiac hypertrophy. The downregulation of IL-22 may be a novel therapeutic strategy to prevent cardiac hypertrophy.

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JCDD, Vol. 4, Pages 20: Growth and Morphogenesis during Early Heart Development in Amniotes

JCDD, Vol. 4, Pages 20: Growth and Morphogenesis during Early Heart Development in Amniotes

Journal of Cardiovascular Development and Disease doi: 10.3390/jcdd4040020

Authors: Kenzo Ivanovitch Isaac Esteban Miguel Torres

In this review, we will focus on the growth and morphogenesis of the developing heart, an aspect of cardiovascular development to which Antoon Moorman and colleagues have extensively contributed. Over the last decades, genetic studies and characterization of regionally regulated gene programs have provided abundant novel insights into heart development essential to understand the basis of congenital heart disease. Heart morphogenesis, however, is inherently a complex and dynamic three-dimensional process and we are far from understanding its cellular basis. Here, we discuss recent advances in studying heart morphogenesis and regionalization under the light of the pioneering work of Moorman and colleagues, which allowed the reinterpretation of regional gene expression patterns under a new morphogenetic framework. Two aspects of early heart formation will be discussed in particular: (1) the initial formation of the heart tube and (2) the formation of the cardiac chambers by the ballooning process. Finally, we emphasize that in addition to analyses based on fixed samples, new approaches including clonal analysis, single-cell sequencing, live-imaging and quantitative analysis of the data generated will likely lead to novel insights in understanding early heart tube regionalization and morphogenesis in the near future.



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IJMS, Vol. 18, Pages 2487: Fast Detection of a BRCA2 Large Genomic Duplication by Next Generation Sequencing as a Single Procedure: A Case Report

IJMS, Vol. 18, Pages 2487: Fast Detection of a BRCA2 Large Genomic Duplication by Next Generation Sequencing as a Single Procedure: A Case Report

International Journal of Molecular Sciences doi: 10.3390/ijms18112487

Authors:Marcella NunziatoFlavio StarnoneBarbara LombardoMatilde PensabeneCaterina CondelloFrancesco VerdescaChiara CarlomagnoSabino De PlacidoLucio PastoreFrancesco SalvatoreValeria D’Argenio

The aim of this study was to verify the reliability of a next generation sequencing (NGS)-based method as a strategy to detect all possible BRCA mutations, including large genomic rearrangements. Genomic DNA was obtained from a peripheral blood sample provided by a patient from Southern Italy with early onset breast cancer and a family history of diverse cancers. BRCA molecular analysis was performed by NGS, and sequence data were analyzed using two software packages. Comparative genomic hybridization (CGH) array was used as confirmatory method. A novel large duplication, involving exons 4–26, of BRCA2 was directly detected in the patient by NGS workflow including quantitative analysis of copy number variants. The duplication observed was also found by CGH array, thus confirming its extent. Large genomic rearrangements can affect the BRCA1/2 genes, and thus contribute to germline predisposition to familial breast and ovarian cancers. The frequency of these mutations could be underestimated because of technical limitations of several routinely used molecular analysis, while their evaluation should be included also in these molecular testing. The NGS-based strategy described herein is an effective procedure to screen for all kinds of BRCA mutations.



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Chirurgie maligner hormonaktiver neuroendokriner Pankreastumoren



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Kalorimetricheskoe izuchenie perekhoda spiral'-klubok v DNK pri vzaimodeistvii s ionami Cu2+

Using the method of differential scanning calorimetry, the DNA helix-coil transition was studied in solutions (10(-3) M Na+, 10(-3) M tris HCl, pH 7.0) containing divalent copper ions at relative metal ion concentrations (Mt2+/PDNA) ranging from 0.2 to 20. Dependences of the melting temperature and enthalpy on relative ion concentration were determined. An aggregation of Cu(2+) + DNA complexes in the range of average ion concentration was established. It is shown that the melting enthalpy of "units" increases with copper ion concentration. The data obtained were compared with values determined by UV-spectroscopy. Association constants for Cu2+ binding to DNA were defined by the ligand theory.

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Strukturnye i fiziko-khimicheskie kharakteristiki DNK iz tkaneǐ zhivotnykh, podvergavshikhsia dlitel'nomu khronicheskomu oblucheniiu v zone chernobylia

The properties of animal DNAs exposed to prolonged irradiation in the Chernobyl zone, have been studied by the methods of viscometry, thermal denaturation, IR-spectroscopy, and electrophoresis. High content of low-molecular fractions have been observed in the preparations of DNA from liver and spleen, their quantities increasing with age and generation of animals. This effect is especially strong in DNA from liver. Low-molecular fraction of DNA is shown to be enriched with G-C pairs and to consist of the following four fractions: 1) approximately 500 base pairs (B.p.), 2) approximately 1.5 divided by 2 thousand B.p., 3) approximately 4 divided by 5 thousand B.p. and 4) a mixture of approximately 20 thousand B.p. fragments. Further, it has been observed that the DNA preparations from the tissues of experimental animals contain about ten times higher contents of Fe, Zn, Se and other elements as compared to the control preparations.

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Izuchenie metodami IK- i Ramanovskoǐ spektroskopii vzaimodeǐstviia DNK s ionami medi

DNA with Cu2+ ions in solution and films is studied by IR and Raman spectroscopy at different relative humidities (R.H. = 51 divided by 98%). DNA complexed with Cu2+ ions is shown to transit to the double-helix conformation, passing A-form, the water content per nucleotide (n) being essentially larger: 12 for Cu2+/P = 0.4 (n = 8 for DNA without ions). Cu2+ decrease the biopolymer hydration at R.H. 50-76% interactions with Cu2+ are stated to depend on the hydration degree of macromolecules. The analysis of the absorption band shifts of Raman spectra evidences the changes in the base torsion angle around the glycoside bond to the values characteristic of the syn-conformation and the interaction both with phosphates and nitrogen bases.

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Active biomonitoring with brown trout and rainbow trout in diluted sewage plant effluents

Brown trout Salmo trutta populations of numerous Swiss rivers are declining. Sewage plant effluents are discussed as a possible cause. To investigate the influence of sewage plant effluents , brown trout as well as rainbow trout Oncorhynchus mykiss were exposed to 10% diluted waste water over a period of 12 months. The effects were compared to those on trout kept in commercial tap water. The mortality rate was low and no pathogenic bacteria or viruses were recorded in exposed and tap-water animals. Parasitological examination revealed a mild infestation with Gryodactylus sp. in all groups. Macroscopically and histologically, only minor changes in gills, skin, and kidney of exposed animals were found when compared to fish kept in tap water. Degenerative and inflammatory reactions in the liver of exposed animals were the most prominent findings. Several brown trout caught in the River Langete showed marked proliferative, degenerative and inflammatory lesions of gills, liver, and kidney. The results do not suggest that waste-water effects would explain the decrease of fish populations. However, it is conceivable that the effluents in combination with other factors in the river enhance the development of changes. (C) 1999 The Fisheries Society of the British Isles.

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Intersex in feral brown trout from Swiss midland rivers

The incidence of intersex in feral populations of brown trout Salmo trutta in Switzerland is reported. The affected brown trout showed spermatogenic activity in ovarian tissue. (c) 2005 The Fisheries Society of the British Isles.

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Waste water management plant effluents cause cellular alterations in the skin of brown trout

To assess the impact of a sewage plant on fish, brown trout Salmo trutta were kept in two cages for 55 days in a moderately polluted river upstream of a sewage plant . In one of the cages, undiluted treated waste water of the sewage plant (WWE) was added at an average concentration of 5%, whereas the other cage received river water (R) only, A high mortality occurred in the WWE group. In comparison to control trout held in tap water , the skin structure and ultrastructure were altered clearly in both groups exposed to river water , including necrosis, apoptosis, decreased number of mucous cells, decrease in epidermal thickness, invasion of leucocytes, extension of melanocytes into the epidermis, being gradually more prominent in the WWE group. The most obvious difference between the two exposed groups was found in structure, size and electron density of the secretory vesicles of the filament cells. This and the observed vacuolation of Golgi saccules are indicative for disturbances in the secretory pathway of the filament cells. Certain toxins were suspected to cause the decompaction of myelin sheaths demonstrated in both groups. Reasons for the rather minor overall differences between the exposed groups are discussed, The extremely high mortality rate in the WWE group supports the importance of reducing the load of pollutants in the effluent of the waste - water management plant . (C) 1997 The Fisheries Society of the British Isles.

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Lectin-histochemistry of rainbow trout (Oncorhynchus mykiss) gill and skin

In order to characterize the glycoconjugate residues in skin and gills of the adult rainbow trout, the binding pattern of five biotinylated lectins with different carbohydrate specificities was examined. In the skin, mucous cells revealed binding sites for PNA and SBA; filament-containing cells were additionally labelled with Con A. However, the basal cell layer showed no reaction. In the gill, subpopulations of mucous cells reacted with Con A, PNA, SBA and UEA-I. This broader spectrum of glycoconjugates in gill mucous cells compared with the epidermal mucous cells could point to the additional function of gill mucus in ion and osmoregulation. Lectin binding sites were less common in the respiratory epithelial cells of the secondary lamellae than in those of the primary lamellae. Chloride cells revealed mannose, galactose and fucose residues. Immature chloride cells, as indicated by a comparison with Na+/K+ ATPase immunolabelling, reacted with Con A; subpopulations of them reacted with PNA, SBA and UEA-I. The results form the basis for further investigations in which these cell populations can be analysed under different environmental conditions

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Gesucht: Indikatoren für die Qualität von Fliessgewässern. Ein Beispiel zur Schaffung von Synergien zwischen Forschung und Lehre



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How disposable diapers can improve measurements of tumour growth

Catching cancer early can make all the difference for successful treatment. A common screening practice measures tumour growth with X-ray computed tomography (CT), which takes a series of cross-section images of the body. Before they are used in...

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Women prefer annual mammograms to bi-annual screening

Women prefer to get their mammograms every year, instead of every two years, according to a new study being presented next week at the annual meeting of the Radiological Society of North America (RSNA). "Women understand that yearly mammograms have been...

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Researchers discover specific tumour environment that triggers cells to metastasise

A team of bioengineers and bioinformaticians at the University of California San Diego have discovered how the environment surrounding a tumour can trigger metastatic behaviour in cancer cells. Specifically, when tumour cells are confined in a dense...

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Chemo brain starts during cancer's progression, not just after chemotherapy

The memory and thinking problems experienced by cancer survivors, known as "chemo brain" or "chemo fog," are not just the result of chemotherapy treatment, they may start as tumours form and develop, suggests a Baycrest-led study. Researchers found that...

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New study points the way to therapy for rare cancer that targets the young

After years of rigorous research, a team of scientists has identified the genetic engine that drives a rare form of liver cancer. The findings offer prime targets for drugs to treat the usually lethal disease, fibrolamellar hepatocellular carcinoma...

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People willing to trade treatment efficacy for reduced side effects in cancer therapies

When choosing their preferred treatment, people with chronic lymphocytic leukaemia (CLL) place the highest value on medicines that deliver the longest progression-free survival, but are willing to swap some drug efficacy for a reduced risk of serious...

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Down-top nanofabrication of binary (CdO)x (ZnO)1-x nanoparticles and their antibacterial activity

26_sep_2017_figure_590.jpg



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Testosterone elevates expression of tenascin-R and oligomannosidic carbohydrates in developing male zebra finches

The song system of zebra finches is a model for studying the influence of steroids on neural connectivity and behavior during development, To investigate the molecular mechanisms underlying the song-related and gonadal hormone-regulated development of neural activity, we have chosen to investigate the expression of recognition molecules in the brain nuclei associated with motor control of song production, Here we show that testosterone accelerates expression of the predominantly oligodendroglia-, but also neuron-associated extracellular matrix glycoprotein tenascin-R and the oligomannosidic carbohydrate L3 during the third and seventh posthatching week in the higher vocal center (HVC) and robust nucleus of the archistriatum (RA), but not in other brain regions, The results suggest that recognition molecules and associated carbohydrate structures can be regulated by testosterone and that an increased expression of these molecules correlates with testosterone -induced modifications of song behavior. (C) 1996 Wiley-Liss, Inc.

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Exogenous testosterone alters expression pattern of cell recognition molecules in brains of juvenal zebra finches

WE assessed spatio-temporal expression of tenascin and janusin by immunocytochemistry in testosterone -treated zebra finches and in untreated controls. These cell recognition molecules and components of the extracellular matrix mediate neurone-glia interactions, which are crucial for differentiation of ordered neural structures. We describe boundaries for the spatio-temporal expression of cell recognition molecules that highly correlate with the song motor centres as defined by combined neuroanatomical and ethological studies on song vocalization. The expression of janusin is accelerated by exogenous testosterone .

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Naturschutz in der Lehre der Allgemeinen Ökologie an der Universität Bern



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Regenbogenforelle und Zebrabärbling, zwei Modelle für verlängerte Toxizitätstests: Relative Empfindlichkeit, Art- und Organspezifität in der cytopathologischen Reaktion von Leber und Darm auf Atrazin

In order to elucidate cytopathological alterations in hepatic and intestinal cells, immature rainbow trout (Oncorhynchus mykiss) were exposed for five weeks to 10, 20, 40, and 160 micrograms/l of the herbicide atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine; model 1). For comparison, ultrastructural changes in female zebra fish (Brachydanio rerio) liver were studied after exposure to 100, 1,000 and 10,000 micrograms/l atrazine for three months (exposure from egg stage to sexual maturation; model 2). Neither epithelial nor glandular cells in the gastrointestinal tract of rainbow trout reveal cytological modifications following exposure to atrazine. In contrast, hepatocytes of rainbow trout and zebra fish clearly display dose-dependent and species-specific cytopathological effects at 40 and 1000 micrograms/l, respectively. In rainbow trout (model 1), rough endoplasmic reticulum (RER) appears of particular diagnostic value for the effects of atrazine, since it already shows a full spectrum of cytological alterations after 40 micrograms/l, and since in cells without RER modifications no further cytopathological symptoms can be revealed. At 40 micrograms/l atrazine, further changes include disturbance of the intracellular compartmentation, increased heterogeneity of mitochondria (longitudinally arranged cristae, branching, size), formation of myelinated bodies as well as immigration of macrophages and granulocytes along the biliary system and the space of Disse. The separation of peripheral storage areas from the central organelle-containing cytoplasm is no longer evident at 80 micrograms/l, and the phagocytic activity of invading macrophages is drastically increased. Following exposure to 160 micrograms/l atrazine, additional pathological changes comprise clubshaped deformation of mitochondria, formation of myelinated bodies in the intermembranous space of mitochondria, increase of degranulated ER cisternae and lysosomes, as well as perisinusoidal accumulation of lipid droplets. Deformation of the nuclear envelope, elevated mitotic activity and an increased number of nuclei with two or more nucleoli indicate interactions between atrazine and the nucleus. In the liver of female zebra fish (model 2), atrazine-induced alterations are limited to increased parenchymal variability, disturbance of the intracellular compartmentation, partial RER fractionation and vesiculation, club-shaped deformation of mitochondria and an increase in the number of lysosomes, myelinated bodies and invading macrophages at 1000 micrograms/l atrazine. After three months at 10,000 micrograms/l, mortality of zebra fish is increased to 100%. According to cytopathological alterations of hepatocytes following long-term exposure, susceptibility of the test model rainbow trout to atrazine appears higher than that of the model zebra fish.

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Armut in Basel – Sozialräumliche Ausrichtung des niederschwelligen Hilfsangebots

Zusammenfassung Die Exkursion “Armut in Basel – sozialräumliche Ausrichtung des niederschwelligen Hilfsangebots” gibt einen Einblick in den Alltag Armutsbetroffener in Basel. Armutsbetroffene, Einkommensschwache oder Randständige sind Menschen, die am oder unter dem Existenzminimum leben, das gesellschaftliche Netz weitgehend verloren haben und häufig aufgrund von Arbeitslosigkeit keine geregelte Tagesstruktur aufweisen. Neben einer theoretischen Einführung werden zentrale niederschwellige Institutionen besucht, welche unterschiedliche Angebote für Armutsbetroffene bereitstellen. Die leichte Zugänglichkeit und damit Inanspruchnahme von Leistungen ist eine wichtige Eigenschaft der Niederschwelligkeit. Die Exkursion “Armut in Basel – sozialräumliche Ausrichtung des niederschwelligen Hilfsangebots”gibt einen Einblick in den Alltag Armutsbetroffener in Basel. Armutsbetroffene, Einkommensschwacheoder Randständige sind Menschen, die am oder unter dem Existenzminimum leben,das gesellschaftliche Netz weitgehend verloren haben und häufig aufgrund von Arbeitslosigkeitkeine geregelte Tagesstruktur aufweisen. Neben einer theoretischen Einführung werden zentraleniederschwellige Institutionen besucht, welche unterschiedliche Angebote für Armutsbetroffenebereitstellen. Die leichte Zugänglichkeit und damit Inanspruchnahme von Leistungen ist einewichtige Eigenschaft der Niederschwelligkeit.

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Grenzüberschreitende Zusammenarbeit in der Region Basel - Institutionen und Infrastrukturprojekte im Dreiländereck

Grenzregionen erfordern eine grenzüberschreitende Zusammenarbeit.Umden Aktionsradius der im Grenzgebiet wohnenden Menschen nicht einzuschränken bzw. deren Arbeits- und Freizeitmobilität zu erhöhen, ist grenzüberschreitende Zusammenarbeit unabdingbar. Infrastrukturprojekte und Institutionen sollen den Aufbau grenzüberschreitender Aktivitäten fördern und so die gesellschaftliche und wirtschaftliche Attraktivität der Region erhöhen. Die Exkursion zeigt ausgewählte Institutionen und Projekte der Dreilandregion am Oberrhein, welche die Zusammenarbeit fördern und damit den Weg zu einem trinationalen Lebensraum bereiten. Sie leisten einen Beitrag zum Zusammenwachsen der angrenzenden Gemeinden und Bezirke der drei Länder Schweiz, Deutschland und Frankreich. Grenzregionen erfordern eine grenzüberschreitende Zusammenarbeit.Umden Aktionsradius derim Grenzgebiet wohnenden Menschen nicht einzuschränken bzw. deren Arbeits- und Freizeitmobilitätzu erhöhen, ist grenzüberschreitende Zusammenarbeit unabdingbar. Infrastrukturprojekteund Institutionen sollen den Aufbau grenzüberschreitender Aktivitäten fördern und so die gesellschaftlicheund wirtschaftliche Attraktivität der Region erhöhen. Die Exkursion zeigt ausgewählteInstitutionen und Projekte der Dreilandregion am Oberrhein, welche die Zusammenarbeit fördernund damit den Weg zu einem trinationalen Lebensraum bereiten. Sie leisten einen Beitragzum Zusammenwachsen der angrenzenden Gemeinden und Bezirke der drei Länder Schweiz,Deutschland und Frankreich.

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Das Life Sciences-Cluster in der trinationalen Region Basel - Auszüge aus einer Befragungs- und GIS-gestützten Studie

Zusammenfassung Cluster, d. h. Ballungen von Unternehmen und Organisationen derselben Branche, scheinen Wettbewerbsvorteile zu schaffen und Regionen zu stärken. Daher besitzt der Begriff heute vor allem in Politik und Wirtschaftsförderung einen grossen Stellenwert, obwohl er in der wissenschaftlichen Debatte kontrovers diskutiert wird. Dieser Artikel zeigt Auszüge aus einer Survey- und GIS-basierten Studie zum Life Sciences-Cluster in der trinationalen Region Basel, in der mögliche Prozesse und Wirkungen der Unternehmensballung empirisch untersucht werden. Im Folgenden stehen die Analyse der Branchen- und Unternehmensstruktur des Clusters, seine räumliche Struktur, das Zugehörigkeitsgefühl der Unternehmen zum Cluster sowie eine Standortanalyse der grenzüberschreitenden Region Basel als Wirtschaftsraum im Fokus. Die Studie konnte besonders innerhalb der Kantone Basel-Stadt und Basel-Landschaft eine deutliche Clusterbildung zeigen. Dabei sind alle Branchen der Life Sciences, mit Fokus auf der Pharmazie, sowie Unternehmen von allen Stufen der Wertschöpfungskette vor Ort ansässig. Das Zugehörigkeitsgefühl zum Cluster variierte branchenspezifisch und war innerhalb der Biotechnologie und Pharmazie am stärksten ausgeprägt. Als Wirtschaftsstandort wurde die Region Basel insgesamt positiv bewertet. Von den sechs untersuchten Einflussgrössen wurden die wirtschaftsnahe Infrastruktur, die Verkehrsinfrastruktur und der Wohn- und Freizeitwert deutlich häufiger positiv bewertet als die staatlichen Rahmenbedingungen, die Verfügbarkeit von Arbeitskräften und der Marktzugang in der Region Basel. Zusammenfassung Cluster, d. h. Ballungen von Unternehmen und Organisationen derselben Branche, scheinenWettbewerbsvorteile zu schaffen und Regionen zu stärken. Daher besitzt der Begriff heute vor allemin Politik und Wirtschaftsförderung einen grossen Stellenwert, obwohl er in der wissenschaftlichenDebatte kontrovers diskutiert wird. Dieser Artikel zeigt Auszüge aus einer Survey- undGIS-basierten Studie zum Life Sciences-Cluster in der trinationalen Region Basel, in der möglicheProzesse und Wirkungen der Unternehmensballung empirisch untersucht werden. Im Folgendenstehen die Analyse der Branchen- und Unternehmensstruktur des Clusters, seine räumliche Struktur,das Zugehörigkeitsgefühl der Unternehmen zum Cluster sowie eine Standortanalyse dergrenzüberschreitenden Region Basel als Wirtschaftsraum im Fokus. Die Studie konnte besondersinnerhalb der Kantone Basel-Stadt und Basel-Landschaft eine deutliche Clusterbildung zeigen.Dabei sind alle Branchen der Life Sciences, mit Fokus auf der Pharmazie, sowie Unternehmen vonallen Stufen der Wertschöpfungskette vor Ort ansässig. Das Zugehörigkeitsgefühl zum Cluster variiertebranchenspezifisch und war innerhalb der Biotechnologie und Pharmazie am stärkstenausgeprägt. Als Wirtschaftsstandort wurde die Region Basel insgesamt positiv bewertet. Von densechs untersuchten Einflussgrössen wurden die wirtschaftsnahe Infrastruktur, die Verkehrsinfrastrukturund der Wohn- und Freizeitwert deutlich häufiger positiv bewertet als die staatlichenRahmenbedingungen, die Verfügbarkeit von Arbeitskräften und der Marktzugang in der RegionBasel.

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Geomorphologische Exkursion in Basel – Einblick in den natürlichen quartären und anthropogenen Formenschatz zwischen dem Basler Münster und der Birsmündung

Die Kurzexkursion führt vom Basler Münster über die St. Alban-Vorstadt bis zum Birsköpfli. Je nach Wahl der angegebenen Varianten dauert die Exkursion zu Fuss zwischen zwei und vier Stunden. Das Ziel der Exkursion ist es, den SchülerInnen die wichtigsten geomorphologischen Formen und die dafür verantwortlichen Prozesse im urbanen Gelände näher zu bringen. Nebst dem natürlichen Formenschatz, welcher im Raum Basel mehrheitlich durch die Fluvialdynamik im Quartär geprägt wurde, weist die Exkursion auch auf das geländeformbildende Einwirken des Menschen während den vergangenen 2’000 Jahren hin. Der Artikel enthält zudem zu den meisten der neun Haltepunkte Ideen für Teilnehmer-aktivierende Aufträge, mit welchen die Überblicksexkursion abwechslungsreich und dialogartig gestaltet werden kann.

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Die Beurteilung der TSH-Suppression mit einem TSH-Assay der 3. Generation: diagnostische und therapeutische Konsequenzen

We measured basal and TRH-stimulated TSH values with a 3rd generation assay in patients under suppressive thyroxine (T4) therapy for thyroid carcinoma or goiter and in patients with overt hyperthyroidism. All hyperthyroid patients had undetectable basal TSH levels ( 0.05 mU/l could be measured in 42% of group A and 100% of group B (= subtotal TSH suppression). Many of these TSH values measured by a 3rd generation assay are in the undetectable range for most of the commercially available 2nd generation assays (> 0.10 mU/l). Conclusion: TSH assay of the 3rd generation decisively improves the diagnosis of hyperthyroidism and probably also borderline hyperthyroidism. Against the background of increased risk of osteoporosis and cardiac function disorders as a result of suppressive T4 treatment, our results suggest the following practical therapeutic guidelines: total TSH suppression with the risk of iatrogenic hyperthyroidism should be confined to high risk patients (eg with metastatic thyroid cancer). Where the risk is low, however (thyroid cancer with favourable prognosis, goiter, goiter prophylaxis), only subtotal TSH suppression is indicated.

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Prediction of metabolism-induced hepatotoxicity on three-dimensional hepatic cell culture and enzyme microarrays

Abstract

Human liver contains various oxidative and conjugative enzymes that can convert nontoxic parent compounds to toxic metabolites or, conversely, toxic parent compounds to nontoxic metabolites. Unlike primary hepatocytes, which contain myriad drug-metabolizing enzymes (DMEs), but are difficult to culture and maintain physiological levels of DMEs, immortalized hepatic cell lines used in predictive toxicity assays are easy to culture, but lack the ability to metabolize compounds. To address this limitation and predict metabolism-induced hepatotoxicity in high-throughput, we developed an advanced miniaturized three-dimensional (3D) cell culture array (DataChip 2.0) and an advanced metabolizing enzyme microarray (MetaChip 2.0). The DataChip is a functionalized micropillar chip that supports the Hep3B human hepatoma cell line in a 3D microarray format. The MetaChip is a microwell chip containing immobilized DMEs found in the human liver. As a proof of concept for generating compound metabolites in situ on the chip and rapidly assessing their toxicity, 22 model compounds were dispensed into the MetaChip and sandwiched with the DataChip. The IC50 values obtained from the chip platform were correlated with rat LD50 values, human C max values, and drug-induced liver injury categories to predict adverse drug reactions in vivo. As a result, the platform had 100% sensitivity, 86% specificity, and 93% overall predictivity at optimum cutoffs of IC50 and C max values. Therefore, the DataChip/MetaChip platform could be used as a high-throughput, early stage, microscale alternative to conventional in vitro multi-well plate platforms and provide a rapid and inexpensive assessment of metabolism-induced toxicity at early phases of drug development.



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JCM, Vol. 6, Pages 107: Knee and Ankle Arthroplasty in Hemophilia

JCM, Vol. 6, Pages 107: Knee and Ankle Arthroplasty in Hemophilia

Journal of Clinical Medicine doi: 10.3390/jcm6110107

Authors: Luigi Solimeno Gianluigi Pasta

Today, major surgical procedures can be safely performed in hemophilic patients with chronic arthropathy, using available factor concentrates. In this setting, total knee replacement is considered the “gold standard”, while the use of total ankle replacement is still debated. Indeed, the unsatisfactory results obtained with the previous available design of implants did not raise enthusiasm as knee or hip replacement. Recently, the introduction of new implant designs and better reported outcomes have renewed the interest in total ankle replacement in people with hemophilia. In this review, the role of replacement surgery in the treatment of chronic hemophilic arthropathy will be described.



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ARHGEF19 interacts with BRAF to activate MAPK signaling during the tumorigenesis of non-small cell lung cancer

Abstract

Rho guanine nucleotide exchange factors (RhoGEFs) are proteins that activate Rho GTPases in response to extracellular stimuli and regulate various biologic processes. ARHGEF19, one of RhoGEFs, was reported to activate RhoA in the Wnt-PCP pathway controlling convergent extension in Xenopus gastrulation. The goal of this study was to identify the role and molecular mechanisms of ARHGEF19 in the tumorigenesis of non-small cell lung cancer (NSCLC). ARHGEF19 expression was significantly elevated in NSCLC tissues, and ARHGEF19 levels were significantly associated with lymph node status, distant metastasis and TNM stage; Patients with high ARHGEF19 levels had poor overall survival (OS) and progression-free survival (PFS). Our investigations revealed that ARHGEF19 overexpression promoted the cell proliferation, invasion and metastasis of lung cancer cells, whereas knockdown of this gene inhibited these processes. Mechanistically, ARHGEF19 activated the mitogen-activated protein kinase (MAPK) pathway in a RhoA-independent manner: ARHGEF19 interacted with BRAF and facilitated the phosphorylation of its downstream kinase MEK1/2; both the Dbl homology (DH) and Pleckstrin homology (PH) domains of ARHGEF19 were indispensable for the phosphorylation of MEK1/2. Furthermore, downregulation of miR-29b was likely responsible for the increased expression of ARHGEF19 in lung cancer tissues and, consequently, the abnormal activation of MAPK signaling. These findings suggest that ARHGEF19 upregulation, due to the low expression of miR-29 in NSCLC tissues, may play a crucial role in NSCLC tumorigenesis by activating MAPK signaling. ARHGEF19 could serve as a negative prognostic marker as well as a therapeutic target for NSCLC patients. This article is protected by copyright. All rights reserved.



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Experimental Investigation and Analysis of Dynamic Buckling of Drill String in Horizontal Well

Buckling of tubulars has been the subject of many researches in the past. However, the models in previous research always followed the same assumptions: the friction and rotation effects are ignored. The assumptions are relatively far from the reality. This paper focuses on the rotational drill string in horizontal well. The differential equation of the dynamic buckling is established considering some various factors, including friction, the drill string-borehole interaction, and rotation, and the equations of the critical load of the sinusoidal buckling and the spiral buckling are derived. Furthermore, the friction curve of the drill string and the critical load of the dynamic buckling during rotation are obtained. In addition, the influence of the rotational speed on the dynamic buckling and the axis orbit of the dynamic buckling are also gained. The results show that the critical load of the sinusoidal buckling has nothing to do with the rotational speed while the amplitude and the frequency of the dynamic buckling become larger with the increase of the rotational speed, and the dynamic buckling presents a completely different state with the development of the axial load at different speed ranges.

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Theatre Is a Valid Add-On Therapeutic Intervention for Emotional Rehabilitation of Parkinson’s Disease Patients

Conventional medical treatments of Parkinson’s disease (PD) are effective on motor disturbances but may have little impact on nonmotor symptoms, especially psychiatric ones. Thus, even when motor symptomatology improves, patients might experience deterioration in their quality of life. We have shown that 3 years of active theatre is a valid complementary intervention for PD as it significantly improves the well-being of patients in comparison to patients undergoing conventional physiotherapy. Our aim was to replicate these findings while improving the efficacy of the treatment. We ran a single-blinded pilot study lasting 15 months on 24 subjects with moderate idiopathic PD. 12 were assigned to a theatre program in which patients underwent “emotional” training. The other 12 underwent group physiotherapy. Patients were evaluated at the beginning and at the end of their treatments, using a battery of eight clinical and five neuropsychological scales. We found that the emotional theatre training improved the emotional well-being of patients, whereas physiotherapy did not. Interestingly, neither of the groups showed improvements in either motor symptoms or cognitive abilities tested by the neuropsychological battery. We confirmed that theatre therapy might be helpful in improving emotional well-being in PD.

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Sunitinib-Induced Acute Interstitial Nephritis in a Thrombocytopenic Renal Cell Cancer Patient

Sunitinib, a multitargeted tyrosine Kkinase inhibitor (TKI), is currently the standard of care for patients with metastatic renal cell carcinoma. Renal adverse events associated with sunitinib include proteinuria, renal insufficiency secondary to focal segmental glomerulosclerosis (FSGS), and thrombotic microangiopathy. We describe the second reported instance of biopsy-proven sunitinib-induced acute interstitial nephritis (AIN), in a challenging case complicated by thrombocytopenia. The case illustrates the importance of early diagnosis and intervention in ensuring long-term recovery from renal complications. Four other cases of AIN reported along with inhibition of the vascular endothelial growth factor (VEGF) by either TKI (sunitinib and sorafenib) or antibodies (bevacizumab) suggest a possible class effect. Given our experience, we recommend monitoring renal function with VEGF inhibition, and in the case of renal failure in the setting of an unclear diagnosis, we recommend prompt biopsy.

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TB Risk Perceptions among Medical Residents at a Tertiary Care Center in India

Setting. Government tertiary health care center in India. Objective. To understand the perceptions of medical residents about their risk of developing TB in the workplace. Design. Cross-sectional study in which a semistructured questionnaire which included an open-ended question to assess their main concerns regarding TB in workplace was used to collect data. Results. Out of 305 resident doctors approached, 263 (94%) completed a structured questionnaire and 200 of these responded to an open-ended question. Daily exposure to TB was reported by 141 (64%) residents, 13 (5%) reported a prior history of TB, and 175 (69%) respondents were aware of TB infection control guidelines. A majority reported concerns about acquiring TB (78%) and drug-resistant TB (88%). The key themes identified were concerns about developing drug-resistant TB (; 50%); disease and its clinical consequences (; 20%); social and professional consequences (; 19%); exposure to TB patients (; 16%); poor infection control measures (; 14%); and high workload and its health consequences (; 8%). Conclusion. Though many resident doctors were aware of TB infection control guidelines, only few expressed concern about lack of TB infection control measures. Doctors need to be convinced of the importance of these measures which should be implemented urgently.

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State-Transition-Aware Spilling Heuristic for MLC STT-RAM-Based Registers

Multilevel Cell Spin-Transfer Torque Random Access Memory (MLC STT-RAM) is a promising nonvolatile memory technology to build registers for its natural immunity to electromagnetic radiation in rad-hard space environment. Unlike traditional SRAM-based registers, MLC STT-RAM exhibits unbalanced write state transitions due to the fact that the magnetization directions of hard and soft domains cannot be flipped independently. This feature leads to nonuniform costs of write states in terms of latency and energy. However, current SRAM-targeting register allocations do not have a clear understanding of the impact of the different write state-transition costs. As a result, those approaches heuristically select variables to be spilled without considering the spilling priority imposed by MLC STT-RAM. Aiming to address this limitation, this paper proposes a state-transition-aware spilling cost minimization (SSCM) policy, to save power when MLC STT-RAM is employed in register design. Specifically, the spilling cost model is first constructed according to the linear combination of different state-transition frequencies. Directed by the proposed cost model, the compiler picks up spilling candidates to achieve lower power and higher performance. Experimental results show that the proposed SSCM technique can save energy by 19.4% and improve the lifetime by 23.2% of MLC STT-RAM-based register design.

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Hmox1 Deficiency Sensitizes Mice to Peroxynitrite Formation and Diabetic Glomerular Microvascular Injuries

Objective. Indirect evidence suggests a role for heme oxygenase-1 (HO-1) in limiting diabetic vasculopathy. The goal of this study was to assess the role of HO-1 in the development of microvascular lesions within glomeruli during diabetes mellitus using a mouse model with specific alteration of the Hmox1 gene. Approach and Results. The effects of Hmox1 haploinsufficiency were studied as a means of assessing the intrinsic contribution of HO-1 in the development of renal microvascular lesions during diabetes. Renal function and histology were analyzed 10 weeks after diabetes induction with streptozotocin. Diabetic Hmox1+/− mice showed higher levels of albuminuria and blood urea compared to their wild-type diabetic littermates. More severe glomerular microvascular lesions were also observed in the diabetic Hmox1+/− mice. This was associated with a renal increase in the expression of the oxidative stress marker, nitrotyrosine. Conclusions. Genetic Hmox1 partial deficiency is sufficient to sensitize mice to the development of diabetic glomerular microvascular lesions. HO-1 exerts antioxidant effects in the kidney during diabetes mellitus. These have protective effects on the development of glomerular endothelial injury.

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Comment on “DKA-Induced Takotsubo Cardiomyopathy in Patient with Known HOCM”



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Kinect V2 Performance Assessment in Daily-Life Gestures: Cohort Study on Healthy Subjects for a Reference Database for Automated Instrumental Evaluations on Neurological Patients

Background. The increase of sanitary costs related to poststroke rehabilitation requires new sustainable and cost-effective strategies for promoting autonomous and dehospitalized motor training. In the Riprendo@Home and Future Home for Future Communities research projects, the promising approach of introducing low-cost technologies that promote home rehabilitation is exploited. In order to provide reliable evaluation of patients, a reference database of healthy people’s performances is required and should consider variability related to healthy people performances. Methods. 78 healthy subjects performed several repetitions of daily-life gestures, the reaching movement (RM) and hand-to-mouth (HtMM) movement with both the dominant and nondominant upper limbs. Movements were recorded with a Kinect V2. A synthetic biomechanical protocol based on kinematical, dynamical, and motor control parameters was used to assess motor performance of the healthy people. The investigation was conducted by clustering participants depending on their limb dominancy (right/left), gender (male/female), and age (young/middle/senior) as sources of variability. Results. Results showed that limb dominancy has minor relevance in affecting RM and HtMM; gender has relevance in affecting the HtMM; age has major effect in affecting RM and HtMM. Conclusions. An investigation of healthy subjects’ upper limb performances during daily-life gestures was performed with the Kinect V2 sensor. Findings will be the basis for a database of normative data for neurological patients’ motor evaluation.

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