[Oncologic aspects in treatment of pathologic fractures]. / Onkologische Aspekte der Behandlung pathologischer Frakturen.

BACKGROUND: Pathological fractures are not only incisive events for tumor patients often with the need of surgical treatment but also often represent a relevant challenge in the overall concept of oncological treatment. OBJECTIVE: The aim of this article is to illustrate the necessity of a pre-interventional interdisciplinary consideration of disease-specific and patient-specific characteristics. MATERIAL AND METHODS: A literature search and evaluation of existing guidelines were carried out including the keywords "bone metastases" and "pathological fractures" with respect to the oncological and radiotherapeutic treatment. RESULTS: An essential classification of the surgical and other needs for treatment is carried out by the identification of the underlying disease and dissemination situation. For tumor-related pathological fractures a palliative treatment situation is present in most cases. Nevertheless, a possible oligometastasis and an increasing number of effective systemic treatment methods must be taken into consideration when planning the surgical treatment. In addition to the therapeutic emergency indications in spinal compression or symptomatic hypercalcemia, both additive radiotherapy and supplementary pharmaceutical osteoprotection have to be addressed in this context. Radiotherapy in particular represents an effective alternative option for symptom and tumor control. CONCLUSION: The work-up of the multifaceted oncological treatment concept represents an interdisciplinary challenge, which ideally defines the further treatment procedure, including fracture treatment, in an interdisciplinary tumor board within an overall oncological concept.

Comparison of contrast-enhanced videofluoroscopy to unenhanced dynamic MRI in minor patients following surgical correction of velopharyngeal dysfunction.

OBJECTIVES: To compare dynamic magnetic resonance imaging (MRI) with videofluoroscopy (VFS) regarding image quality and assessment of gap size between soft palate (SP) and posterior pharyngeal wall (PPW) in children and adolescents following surgical correction of velopharyngeal dysfunction (VPD). METHODS: Twenty-one patients undergoing unenhanced 3-T MRI and contrast-enhanced VFS were included in this IRB-approved prospective study. The MRI scan protocol comprised refocused gradient-echo sequences in transverse and sagittal planes during speech, with TE 1.97 ms, TR 3.95 ms, flip angle 8°, matrix size 128 × 128, and 5-mm slice thickness. Radial k-space sampling and sliding window reconstruction were used to achieve an image acquisition rate of 28 frames per second (fps). VFS with 30 fps was similarly performed in both planes. Closure of the velopharyngeal port during phonation was evaluated by two experienced radiologists. RESULTS: Eleven (52.4%) patients displayed a complete closure, whereas ten (47.6%) patients showed a post-operative gap during speech. VFS and MRI equally identified the cases with persistent or recurrent VPD. Differences in SP-PPW distance between VFS (3.9 ± 1.6 mm) and MRI (4.1 ± 1.5 mm) were not statistically significant (p = 0.5). The subjective overall image quality of MRI was rated inferior (p < 0.001) compared with VFS, with almost perfect inter-rater agreement (κ = 0.90). The presence of susceptibility artifacts did not limit anatomical measurements. CONCLUSION: Dynamic MRI is equally reliable as VFS to assess persistent or recurrent inadequate velum closure in patients following surgical treatment of VPD. KEY POINTS: • Unenhanced 3-T dynamic MRI and contrast-enhanced videofluoroscopy are equally useful for the identification of patients with incomplete velopharyngeal closure during speech. • MRI using refocused gradient-echo acquisition with radial k-space sampling and sliding window reconstruction generates diagnostic images with 28 frames per second. • MRI can offer a radiation-free alternative to currently established videofluoroscopy for young patients.

Dual-energy CT in patients with abdominal malignant lymphoma: impact of noise-optimised virtual monoenergetic imaging on objective and subjective image quality.

AIM: To investigate the impact of noise-optimised virtual monoenergetic imaging (VMI+) reconstructions on quantitative and qualitative image parameters in patients with malignant lymphoma at dual-energy computed tomography (DECT) examinations of the abdomen. MATERIALS AND METHODS: Thirty-five consecutive patients (mean age, 53.8±18.6 years; range, 21-82 years) with histologically proven malignant lymphoma of the abdomen were included retrospectively. Images were post-processed with standard linear blending (M_0.6), traditional VMI, and VMI+ technique at energy levels ranging from 40 to 100 keV in 10 keV increments. Signal-to-noise (SNR) and contrast-to-noise ratios (CNR) were objectively measured in lymphoma lesions. Image quality, lesion delineation, and image noise were rated subjectively by three blinded observers using five-point Likert scales. RESULTS: Quantitative image quality parameters peaked at 40-keV VMI+ (SNR, 15.77±7.74; CNR, 18.27±8.04) with significant differences compared to standard linearly blended M_0.6 (SNR, 7.96±3.26; CNR, 13.55±3.47) and all traditional VMI series (p<0.001). Qualitative image quality assessment revealed significantly superior ratings for image quality at 60-keV VMI+ (median, 5) in comparison with all other image series (p<0.001). Assessment of lesion delineation showed the highest rating scores for 40-keV VMI+ series (median, 5), while lowest subjective image noise was found for 100-keV VMI+ reconstructions (median, 5). CONCLUSION: Low-keV VMI+ reconstructions led to improved image quality and lesion delineation of malignant lymphoma lesions compared to standard image reconstruction and traditional VMI at abdominal DECT examinations.

Validating Baboon Ex Vivo and In Vivo Radiation-Related Gene Expression with Corresponding Human Data.

The research for high-throughput diagnostic tests for victims of radio/nuclear incidents remains ongoing. In this context, we have previously identified candidate genes that predict risk of late-occurring hematologic acute radiation syndrome (HARS) in a baboon model. The goal of the current study was to validate these genes after radiation exposure in humans. We also examined ex vivo relative to in vivo measurements in both species and describe dose-response relationships. Eighteen baboons were irradiated in vivo to simulate different patterns of partial- or total-body irradiation (TBI), corresponding to an equivalent dose of 2.5 or 5 Sv. Human in vivo blood samples were obtained from patients exposed to different dose ranges: diagnostic computerized tomography (CT; 0.004-0.018 Sv); radiotherapy for prostate cancer (0.25-0.3 Sv); and TBI of leukemia patients (2 × 1.5 or 2 × 2 Sv, five patients each). Peripheral whole blood of another five baboons and human samples from five healthy donors were cultivated ex vivo and irradiated with 0-4 Sv. RNA was isolated pairwise before and 24 h after irradiation and converted into cDNA. Gene expression of six promising candidate genes found previously by us in a baboon model ( WNT3, POU2AF1, CCR7, ARG2, CD177, WLS), as well as three genes commonly used in ex vivo whole blood experiments ( FDXR, PCNA, DDB2) was measured using qRT-PCR. We confirmed the six baboon candidate genes in leukemia patients. However, expression for the candidate gene FDXR showed an inverse relationship, as it was downregulated in baboons and upregulated in human samples. Comparisons among the in vivo and ex vivo experiments revealed the same pattern in both species and indicated peripheral blood cells to represent the radiation-responsive targets causing WNT3 and POU2AF1 gene expression changes. CCR7, ARG2, CD177 and WLS appeared to be altered due to radiation-responsive targets other than the whole blood cells. Linear dose-response relationships of FDXR, WNT3 and POU2AF1 using human ex vivo samples corresponded with human in vivo samples, suggesting that ex vivo models for in vivo dose estimates can be used over a wide dose range (0.001-5 Sv for POU2AF1). In summary, we validated six baboon candidate genes in humans, but the FDXR measurements underscored the importance of independent assessments even when candidates from animal models have striking gene sequence homology to humans. Since whole blood cells represented the same radiation-responsive targets for FDXR, WNT3 and POU2AF1 gene expression changes, ex vivo cell culture models can be utilized for in vivo dose estimates over a dose range covering up to 3.5 log scales. These findings might be a step forward in the development of a gene expression-based high-throughput diagnostic test for populations involved in large-scale radio/nuclear incidents.

Reprint of Pharmacological and molecular characterization of the positive allosteric modulators of metabotropic glutamate receptor 2.

The metabotropic glutamate receptor 2 (mGlu2) plays an important role in the presynaptic control of glutamate release and several mGlu2 positive allosteric modulators (PAMs) have been under assessment for their potential as antipsychotics. The binding mode of mGlu2 PAMs is better characterized in functional terms while few data are available on the relationship between allosteric and orthosteric binding sites. Pharmacological studies characterizing binding and effects of two different chemical series of mGlu2 PAMs are therefore carried out here using the radiolabeled mGlu2 agonist 3[H]-LY354740 and mGlu2 PAM 3[H]-2,2,2-TEMPS. A multidimensional approach to the PAM mechanism of action shows that mGlu2 PAMs increase the affinity of 3[H]-LY354740 for the orthosteric site of mGlu2 as well as the number of 3[H]-LY354740 binding sites. 3[H]-2,2,2-TEMPS binding is also enhanced by the presence of LY354740. New residues in the allosteric rat mGlu2 binding pocket are identified to be crucial for the PAMs ligand binding, among these Tyr3.40 and Asn5.46. Also of remark, in the described experimental conditions S731A (Ser5.42) residue is important only for the mGlu2 PAM LY487379 and not for the compound PAM-1: an example of the structural differences among these mGlu2 PAMs. This study provides a summary of the information generated in the past decade on mGlu2 PAMs adding a detailed molecular investigation of PAM binding mode. Differences among mGlu2 PAM compounds are discussed as well as the mGlu2 regions interacting with mGlu2 PAM and NAM agents and residues driving mGlu2 PAM selectivity. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.

Intra-individual comparison of CAIPIRINHA VIBE technique with conventional VIBE sequences in contrast-enhanced MRI of focal liver lesions.

PURPOSE: To evaluate the impact of controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA) volume interpolated breath-hold examination (VIBE) magnetic resonance imaging (MRI) technique on image quality, reader confidence, and inter-observer agreement for the assessment of focal liver lesions in comparison with the standard VIBE approach. MATERIAL AND METHODS: In this IRB-approved intra-individual comparison study, abdominal arterial and portal-venous contrast-enhanced MRI studies were retrospectively analyzed in 38 patients with malignant liver lesions. Each patient underwent both CAIPIRINHA and conventional VIBE 3T MRI within 3 months, showing stable disease. Images were evaluated using 5-point rating scales by two blinded radiologists with more than 20 and 5 years of experience in MRI, respectively. Readers scored dignity of liver lesions and assessed which liver segments were affected by malignancy (ranging from 1=definitely benign/not affected to 5=definitely malignant/affected by malignancy). Readers also rated overall image quality, sharpness of intrahepatic veins, and diagnostic confidence (ranging from 1=poor to 5=excellent). RESULTS: Reviewers achieved a higher inter-observer reliability using CAIPIRINHA when they reported which liver segments were affected by malignancy compared to traditional VIBE series (κ=0.62 and 0.54, respectively, p<0.05). Similarly, CAIPIRINHA showed a slightly higher inter-rater agreement for the dignity of focal liver lesions versus the standard VIBE images (κ=0.50 and 0.49, respectively, p<0.05). CAIPIRINHA series also scored higher in comparison to standard VIBE sequences (mean scores: image quality, 4.2 and 3.5; sharpness of intrahepatic vessels, 3.8 and 3.2, respectively, p<0.05) for both reviewers and allowed for higher subjective diagnostic confidence (ratings, 3.8 and 3.2, respectively, p<0.05). CONCLUSION: Compared to the standard VIBE approach, CAIPIRINHA VIBE technique provides improved image quality and sharpness of intrahepatic veins, as well as higher diagnostic confidence. Additionally, this technique allows for higher inter-observer agreement when reporting focal liver lesions for both dignity and allocation.

Pharmacological and molecular characterization of the positive allosteric modulators of metabotropic glutamate receptor 2.

The metabotropic glutamate receptor 2 (mGlu2) plays an important role in the presynaptic control of glutamate release and several mGlu2 positive allosteric modulators (PAMs) have been under assessment for their potential as antipsychotics. The binding mode of mGlu2 PAMs is better characterized in functional terms while few data are available on the relationship between allosteric and orthosteric binding sites. Pharmacological studies characterizing binding and effects of two different chemical series of mGlu2 PAMs are therefore carried out here using the radiolabeled mGlu2 agonist 3[H]-LY354740 and mGlu2 PAM 3[H]-2,2,2-TEMPS. A multidimensional approach to the PAM mechanism of action shows that mGlu2 PAMs increase the affinity of 3[H]-LY354740 for the orthosteric site of mGlu2 as well as the number of 3[H]-LY354740 binding sites. 3[H]-2,2,2-TEMPS binding is also enhanced by the presence of LY354740. New residues in the allosteric rat mGlu2 binding pocket are identified to be crucial for the PAMs ligand binding, among these Tyr3.40 and Asn5.46. Also of remark, in the described experimental conditions S731A (Ser5.42) residue is important only for the mGlu2 PAM LY487379 and not for the compound PAM-1: an example of the structural differences among these mGlu2 PAMs. This study provides a summary of the information generated in the past decade on mGlu2 PAMs adding a detailed molecular investigation of PAM binding mode. Differences among mGlu2 PAM compounds are discussed as well as the mGlu2 regions interacting with mGlu2 PAM and NAM agents and residues driving mGlu2 PAM selectivity.

Comorbidity of respiratory and cardiovascular diseases among the elderly residing close to mine dumps in South Africa: A cross-sectional study.

BACKGROUND: Pollution arising from mine dumps in South Africa (SA) has been a source of concern to nearby communities. OBJECTIVES: To investigate whether comorbidity of respiratory and cardiovascular diseases among elderly persons (≥55 years) was associated with proximity to mine dumps. METHODS: Elderly persons in communities 1 - 2 km (exposed) and ≥5 km (unexposed) from five preselected mine dumps in Gauteng and North West provinces in SA were included in a cross-sectional study. RESULTS: Exposed elderly persons had a significantly higher prevalence of cardiovascular and respiratory diseases than those who were unexposed. Multiple logistic regression analysis indicated that living close to mine dumps was significantly associated with asthma + hyper- tension (odds ratio (OR) 1.67; 95% confidence interval (CI) 1.22 - 2.28), asthma + pneumonia (OR 1.86; 95% CI 1.14 - 3.04), emphysema + arrhythmia (OR 1.38; 95% CI 1.07 - 1.77), emphysema + myocardial infarction (OR 2.01; 95% CI 1.73 - 2.54), emphysema + pneumonia (OR 3.36; 95% CI 1.41 - 7.98), hypertension + myocardial infarction (OR 1.60; 95% CI 1.04 - 2.44) and hypertension + pneumonia (OR 1.34; 95% CI 1.05 - 1.93). CONCLUSION: Detrimental associations between comorbidity of the health outcomes and proximity to mine dumps were observed among the elderly in SA.

Advanced Modeled Iterative Reconstruction in Low-Tube-Voltage Contrast-Enhanced Neck CT: Evaluation of Objective and Subjective Image Quality.

BACKGROUND AND PURPOSE: Dose-saving techniques in neck CT cause increased image noise that can be counteracted by iterative reconstruction. Our aim was to evaluate the image quality of advanced modeled iterative reconstruction (ADMIRE) in contrast-enhanced low-tube-voltage neck CT. MATERIALS AND METHODS: Sixty-one patients underwent 90-kV(peak) neck CT by using third-generation 192-section dual-source CT. Image series were reconstructed with standard filtered back-projection and ADMIRE strength levels 1, 3, and 5. Attenuation and noise of the sternocleidomastoid muscle, internal jugular vein, submandibular gland, tongue, subscapularis muscle, and cervical fat were measured. Signal-to-noise and contrast-to-noise ratios were calculated. Two radiologists assessed image noise, image contrast, delineation of smaller structures, and overall diagnostic acceptability. Interobserver agreement was calculated. RESULTS: Image noise was significantly reduced by using ADMIRE compared with filtered back-projection with the lowest noise observed in ADMIRE 5 (filtered back-projection, 9.4 ± 2.4 Hounsfield units [HU]; ADMIRE 1, 8.3 ± 2.8 HU; ADMIRE 3, 6.7 ± 2.0 HU; ADMIRE 5, 5.4 ± 1.7 HU; all, P < .001). Sternocleidomastoid SNR and internal jugular vein-sternocleidomastoid contrast-to-noise ratios were significantly higher for ADMIRE with the best results in ADMIRE 5 (all, P < .001). Subjective image quality and image contrast of ADMIRE 3 and 5 were consistently rated better than those for filtered back-projection and ADMIRE 1 (all, P < .001). Image noise was rated highest for ADMIRE 5 (all, P < .005). Delineation of smaller structures was voted higher in all ADMIRE strength levels compared with filtered back-projection (P < .001). Global interobserver agreement was good (0.75). CONCLUSIONS: Contrast-enhanced 90-kVp neck CT is feasible, and ADMIRE 5 shows superior objective image quality compared with filtered back-projection. ADMIRE 3 and 5 show the best subjective image quality.

Evaluation of image quality and dose reduction of 80 kVp neck computed tomography in patients with suspected peritonsillar abscess.

AIM: To evaluate neck computed tomography (CT) with a reduced tube voltage of 80 kVp in patients with suspected peritonsillar abscess (PTA) regarding objective and subjective image quality, and the potential for dose reduction. MATERIALS AND METHODS: Forty-seven patients with clinically suspected PTA were retrospectively analysed. Patients were examined using dual-source CT in dual-energy mode. The objective and subjective image quality of 80 kVp images were compared with linearly blended 120 kVp images (M_0.3; 30% of 80 kV, 70% of 140 kV spectrum). Attenuation of abscess rim enhancement, central necrosis, and several other anatomical landmarks were measured. The signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and rim-to-abscess CNR (raCNR) were calculated. Radiation dose was assessed as size-specific dose estimates (SSDE). Subjective image quality was assessed according to the European guidelines on quality criteria for CT. Interobserver agreement was calculated using the intraclass correlation coefficient (ICC). RESULTS: Attenuation of inflamed soft tissue (141.7 ± 16.3 versus 93.7 ± 9.3 HU, p < 0.001), CNR (9.6 ± 4.8 versus 5.6 ± 3.8, p = 0.001), raCNR (14.3 ± 5.9 versus 12.4 ± 4.4, p = 0.02), and subjective image sharpness (3.6 ± 0.6 versus 2.8 ± 0.7, p < 0.001) were significantly increased in the 80 kVp compared to 120 kVp, whereas subjective and objective image noise were significantly increased with 80 kVp acquisition (p < 0.001). Overall interobserver agreement was almost perfect (ICC, 0.87). Calculated SSDE of 80 kVp acquisition was decreased by 49.7% compared to 120 kVp (10.58 ± 0.76 versus 21.04 ± 1.43 mGy, p < 0.001). CONCLUSION: Low-tube-voltage 80 kVp neck CT provides increased enhancement of soft-tissue inflammation, CNR, raCNR, and improved abscess delineation in patients with PTA compared to standard 120 kVp acquisition while resulting in a significant reduction of radiation exposure.

Seventy kilovolt ultra-low dose CT of the paranasal sinus: first clinical results.

AIM: To evaluate the diagnostic image quality and radiation dose of low-dose 70 kV computed tomography (CT) of the paranasal sinus in comparison to 100 and 120 kV CT. MATERIALS AND METHODS: CT of the paranasal sinus was performed in 127 patients divided into three groups using different tube voltages and currents (70 kV/75 mAs, ultra-low dose protocol, n = 44; 100 kV/40 mAs, standard low-dose protocol, n = 42; 120 kV/40 mAs, standard protocol, n = 41). CT dose index (CTDIvol), dose-length product (DLP), attenuation, image noise and signal-to-noise ratio (SNR) were compared between the groups using Wilcoxon-Mann-Whitney U-test. Subjective diagnostic image quality was compared by using a five-point scale (1 = non-diagnostic, 5 = excellent, read by two readers in consensus) and Cohen's weighted kappa analysis for interobserver agreement. RESULTS: Radiation dose was significantly lower with 70 kV acquisition than 100 and 120 kV (DLP: 31 versus 52 versus 82 mGy·cm; CTDI 2.33 versus 3.95 versus 6.31 mGy, all p < 0.05). Mean SNR (70 kV: 0.37; 100 kV: 0.21; 120 kV: 0.13; p < 0.05) and organ attenuation increased significantly with lower voltages. All examinations showed diagnostic image quality. Subjective diagnostic image quality was higher with standard protocols than the 70 kV protocol (120 kV: 5.0; 100 kV: 4.5; 70 kV: 3.5, p < 0.05) without significant differences with substantial interobserver agreement (κ > 0.59). CONCLUSION: The ultra-low dose (70 kV) CT imaging of the paranasal sinus allowed for significant dose reduction by 61% and an increased attenuation of organ structures in comparison to standard acquisition while maintaining diagnostic image quality with a slight reduction in subjective image quality.

Non-linear image blending improves visualization of head and neck primary squamous cell carcinoma compared to linear blending in dual-energy CT.

AIM: To compare non-linear and linear image-blending post-processing techniques in dual-energy CT (DECT) of primary head and neck squamous cell carcinoma (SCC) regarding subjective and objective image quality. MATERIALS AND METHODS: Head and neck DECT studies from 69 patients (48 male, 21 female; mean age 62.3 years) were retrospectively evaluated. All tumour lesions were histologically confirmed SCC. Linearly blended 80/140 kVp images series with varying weighting factors of 0.3 (M_0.3), 0.6 and 0.8 were compared with non-linearly blended images. Attenuation of tumour lesion, various soft-tissue structures, the internal jugular vein, and image noise were measured, tumour signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. Overall image quality, delineation of tumour lesion, image sharpness, and noise level were rated individually by three radiologists using five-point Likert scales. Interobserver agreement was calculated using intraclass correlation coefficient (ICC). RESULTS: Enhancement of tumour lesions (non-linear, 137.5 ± 20.1 HU; M_0.3, 92.7 ± 14.4 HU; M_0.6, 110 ± 15.4 HU; M_0.8, 123 ± 18.2 HU), CNR (non-linear, 12 ± 8; M_0.3, 4 ± 4.7; M_0.6, 7.5 ± 5.5; M_0.8, 8 ± 5.5), subjective overall image quality and tumour delineation were significantly increased (all p < 0.001) with the non-linear blending technique compared to all investigated linear blending weighting factors. Overall interobserver agreement was substantial (ICC 0.70; 95% CI: 0.66-0.73). CONCLUSION: Post-processing of DECT using a non-linear blending technique provides improved objective and subjective image quality of head and neck SCC compared to linearly blended images series.

Low-tube-voltage 80-kVp neck CT: evaluation of diagnostic accuracy and interobserver agreement.

BACKGROUND AND PURPOSE: Low-tube-voltage acquisition has been shown to facilitate substantial dose savings for neck CT with similar image contrast compared with standard 120-kVp acquisition. However, its potential for the detection of neck pathologies is uncertain. Our aim was to evaluate the effects of low-tube-voltage 80-kV(peak) acquisitions for neck CT on diagnostic accuracy and interobserver agreement. MATERIALS AND METHODS: Three radiologists individually analyzed 80-kVp and linearly blended 120-kVp image series of 170 patients with a variety of pathologies who underwent dual-energy neck CT. Reviewers were unblinded to the clinical indication for CT but were otherwise blinded to any other data or images and were asked to state a final main diagnosis. Findings were compared with medical record charts, CT reports, and pathology results. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for each observer. Interobserver agreement was evaluated by using intraclass correlation coefficients. RESULTS: Diagnoses were grouped as squamous cell carcinoma-related (n = 107, presence/absence of primary/recurrent squamous cell carcinoma), lymphoma-related (n = 40, presence/absence of primary/recurrent lymphoma), and benign (n = 23, eg, abscess). Cumulative sensitivity, specificity, positive predictive value, and negative predictive value for 80-kVp and blended 120-kVp images were 94.8%, 93.0%, 95.9%, and 91.1%, respectively. Results were also consistently high for squamous cell carcinoma-related (94.8%/95.3%, 89.1%/89.1%, 94.3%/94.4%, 90.1%/91.0%) and lymphoma-related (95.0%, 100.0%, 100.0%, 95.2%) 80-kVp/120-kVp image series. Global interobserver agreement was almost perfect (intraclass correlation coefficient, 0.82, 0.80; 95% CI, 0.76-0.74, 0.86-0.85). Calculated dose-length product was reduced by 48% with 80-kVp acquisitions compared with the standard 120-kVp scans (135.5 versus 282.2 mGy × cm). CONCLUSIONS: Low-tube-voltage 80-kVp CT of the neck provides sufficient image quality with high diagnostic accuracy in routine clinical practice and has the potential to substantially decrease radiation exposure.

Acute intracranial hemorrhage in CT: benefits of sinogram-affirmed iterative reconstruction techniques.

BACKGROUND AND PURPOSE: Acute intracranial hemorrhage represents a severe and time critical pathology that requires precise and quick diagnosis, mainly by performing a CT scan. The purpose of this study was to compare image quality and intracranial hemorrhage conspicuity in brain CT with sinogram-affirmed iterative reconstruction and filtered back-projection reconstruction techniques at standard (340 mAs) and low-dose tube current levels (260 mAs). MATERIALS AND METHODS: A total of 94 consecutive patients with intracranial hemorrhage received CT scans either with standard or low-dose protocol by random assignment. Group 1 (n=54; mean age, 64 ± 20 years) received CT at 340 mAs, and group 2 (n=40; mean age, 57 ± 23 years) received CT at 260 mAs. Images of both groups were reconstructed with filtered back-projection reconstruction and 5 iterative strengths (S1-S5) and ranked blind by 2 radiologists for image quality and intracranial hemorrhage on a 5-point scale. Image noise, SNR, dose-length product (mGycm), and mean effective dose (mSv) were calculated. RESULTS: In both groups, image quality and intracranial hemorrhage conspicuity were rated subjectively with an excellent/good image quality. A higher strength of sinogram-affirmed iterative reconstruction showed an increase in image quality with a difference to filtered back-projection reconstruction (P < .05). Subjective rating showed the best score of image quality and intracranial hemorrhage conspicuity achieved through S3/S4-5. Objective analysis of image quality showed in an increase of SNR with a higher strength of sinogram-affirmed iterative reconstruction. Patients in group 2 (mean: 744 mGycm/1.71 mSv) were exposed to a significantly lower dose than those in group 1 (mean: 1045 mGycm/2.40 mSv, P < .01). CONCLUSIONS: S3 provides better image quality and visualization of intracranial hemorrhage in brain CT at 260 mAs. Dose reduction by almost one-third is possible without significant loss in diagnostic quality.

Modification of the secondary structure of angiotensin II by substitution of hydrogen with Cs cations: an experimental and theoretical study.

MALDI mass spectrometry in combination with post-source decay (PSD) analysis is a fast and easy to apply method for peptide sequencing. In this study, the PSD technique was used to investigate the influence of the adaption of one, two, and three caesium cations to angiotensin II in the gas phase. The PSD spectra of caesium-aggregated angiotensin II show far less fragmentation in comparison to the protonated one. In the case of singly (doubly) Cs(+) substituted angiotensin II, the PSD mass spectrum shows only fragments with one (two) Cs cation(s). These results are interpreted in terms of additional interactions of the caesium cation(s) with the peptide. In order to investigate this suggestion, the molecular structures were calculated with semi-empirical molecular dynamic (MD) simulations and further optimized at the quantum chemical level (BP86, SVP) of theory. On the one hand, secondary structures of Cs(+) substituted angiotensin II are more compact than the structure of protonated angiotensin II, indicating electrostatic interactions of the Cs cations and the heterocyclic structures. Moreover, oxyphilic interactions of the cations with the oxygen atoms of the peptide backbone also contribute as further van-der-Waals interactions of the Cs(+) substituted angiotensin II. These interactions are able to explain its higher stability due to reduced dissociation in comparison to the protonated angiotensin II. On the other hand, most MD simulations of doubly and triply Cs(+) substituted angiotensin II show a formation of a [2 Cs] cluster, surrounded by the peptide molecule. The formation of this cluster would explain the lack of singly Cs(+) substituted fragments in the PSD mass spectrum of doubly Cs(+) substituted angiotensin II.

Structural determinants of allosteric antagonism at metabotropic glutamate receptor 2: mechanistic studies with new potent negative allosteric modulators.

BACKGROUND AND PURPOSE: Altered glutamatergic neurotransmission is linked to several neurological and psychiatric disorders. Metabotropic glutamate receptor 2 (mGlu2) plays an important role on the presynaptic control of glutamate release and negative allosteric modulators (NAMs) acting on mGlu2/3 receptors are under assessment for their potential as antidepressants, neurogenics and cognitive enhancers. Two new potent mGlu2/3 NAMs, RO4988546 and RO5488608, are described in this study and the allosteric binding site in the transmembrane (TM) domain of mGlu2 is characterized. EXPERIMENTAL APPROACH: Site directed mutagenesis, functional measurements and ß2-adrenoceptor-based modelling of mGlu2 were employed to identify important molecular determinants of two new potent mGlu2/3 NAMs. KEY RESULTS: RO4988546 and RO5488608 affected both [³H]-LY354740 agonist binding at the orthosteric site and the binding of a tritiated positive allosteric modulator (³H-PAM), indicating that NAMs and PAMs could have overlapping binding sites in the mGlu2 TM domain. We identified eight residues in the allosteric binding pocket that are crucial for non-competitive antagonism of agonist-dependent activation of mGlu2 and directly interact with the NAMs: Arg³·²8, Arg³·²9, Phe³·³6, His(E2.52) , Leu5·4³, Trp6·48, Phe6·55 and Val7·4³. The mGlu2 specific residue His(E2.52) is likely to be involved in selectivity and residues located in the outer part of the binding pocket are more important for [³H]-LY354740 agonist binding inhibition, which is independent of the highly conserved Trp6·48 residue. CONCLUSIONS AND IMPLICATIONS: This is the first complete molecular investigation of the allosteric binding pocket of mGlu2 and Group II mGluRs and provides new information on what determines mGlu2 NAMs selective interactions and effects.

Increased micronuclei and bulky DNA adducts in cord blood after maternal exposures to traffic-related air pollution.

Exposure to traffic-related air pollution in urban environment is common and has been associated with adverse human health effects. In utero exposures that result in DNA damage may affect health later in life. Early effects of maternal and in utero exposures to traffic-related air pollution were assessed through the use of validated biomarkers in blood cells from mother-newborn pairs. A cross-sectional biomonitoring study with healthy pregnant women living in the Greater Copenhagen area, Denmark, was conducted. Bulky DNA adducts and micronuclei (MN) were measured in blood from 75 women and 69 umbilical cords, concurrently collected at the time of planned Caesarean section. Modeled residential traffic density, a proxy measure of traffic-related air pollution exposures, was validated by indoor levels of nitrogen dioxide and polycyclic aromatic hydrocarbons in 42 non-smoking homes. DNA adduct levels were similar and positively correlated in maternal and cord blood (1.40 vs. 1.37 n/10(8) nucleotides; r=0.99; p<0.01). Maternal MN frequencies were significantly associated with age (p<0.01), and higher than those of the newborns (7.0 vs. 3.2 MN per 1000 binucleated cells). Adduct levels were highest among mother-newborn pairs who lived near medium-traffic-density (>400-2500 vehicle km/24h; p<0.01) places. MN frequencies among newborns from women who lived at high-traffic-density homes (>2500 vehicle km/24h) were significantly increased (p=0.02). This trend remained after adjusting for potential confounders and effect modifiers. For the first time increased bulky DNA adducts and MN in cord blood after maternal exposures to traffic-related air pollution are found, demonstrating that these transplacental environmental exposures induce DNA damage in newborns. Given that increased DNA damage early in life indicate an increased risk for adverse health effects later in life, these findings justify intervention of pregnant women.

Matrix-assisted laser desorption/ionization by using femtosecond laser pulses in the near-infrared wavelength regime.

We observe a substantial matrix-assisted laser desorption/ionization (MALDI) signal when irradiating femtosecond laser pulses in the near-infrared spectral range centered around 800 nm and using standard MALDI matrices with absorption bands in the ultraviolet (UV) regime. The laser pulse energy dependence of this novel phenomenon is investigated in comparison with MALDI with near-UV laser pulses. Our observations show that multiphoton absorption/ionization could be a major issue among the MALDI processes when the sample is irradiated with ultra-short laser pulses.

Influence of cooking and heating fuel use on 1-59 month old mortality in South Africa.

OBJECTIVES: To determine the association between the combustion of wood, animal dung, coal and paraffin (polluting fuels) for cooking and heating and 1-59 month old mortality in South Africa, whilst adjusting for a number of confounders. METHODS: Data from 3,556 children (142 deaths) living in 2,828 households were extracted from the 1998 South African Demographic and Health Survey (SADHS) database. The SADHS was the first national health survey conducted across the entire country and provided the opportunity to examine the prevalence and determinants of various morbidity and mortality outcomes in a representative national population. RESULTS: The results suggest that exposure to cooking and heating smoke from polluting fuels is significantly associated with 1-59 month mortality, after controlling for mother's age at birth, water source, asset index and household crowdedness (RR=1.95; 95% CI=1.04, 3.68). CONCLUSIONS: Although there is potential for residual confounding despite adjustment, the better documented evidence on outdoor air pollution and mortality suggest this association may be real. As nearly half of households in South Africa still rely on polluting fuels and women of childbearing age perform most cooking tasks, the attributable risk arising from this association, if confirmed, could be substantial. It is trusted that more detailed analytical intervention studies will scrutinise these results in order to develop integrated intervention programmes to reduce children's exposure to air pollution emanating from cooking and heating fuels.