Hypertension and heart disease are associated with development of brain atrophy in multiple sclerosis: a 5-year longitudinal study.

BACKGROUND: Cardiovascular diseases (CVDs) are more frequent in multiple sclerosis (MS) patients when compared to controls. In particular, CVDs are linked with higher accumulation of lesions and advanced brain atrophy. OBJECTIVE: To investigate whether CVDs contribute to accelerated lesion accumulation and brain atrophy over 5 years in patients with MS. METHODS: 194 MS patients and 43 controls without neurologic disease were followed for 5 years. Full physical, neurological evaluation, and structured questionnaire investigating CVD and risk factors (hypertension, hyperlipidemia, heart disease, smoking, diabetes, obesity/overweight) were collected using interview-based questionnaire and further cross-reference with electronic medical records. Lesion and brain atrophy outcomes were assessed with 3T MRI. ANCOVA adjusted for age, gender, and disease duration were used accordingly. False discovery rate correction was performed using Benjamini-Hochberg correction. RESULTS: Patients with diagnosis of heart disease showed higher white matter and whole brain volume loss compared to those without (-4.2% vs. -0.7%, P = 0.01 and -3.4% vs. -1.6%, P = 0.01, respectively). The percentage lateral ventricle volume change in MS patients with hypertension was higher compared to non-hypertensive patients (24.5% vs. 14.1%, P = 0.05). Hyperlipidemia, smoking, and obesity/overweight were not associated with progression of MRI-derived outcomes. CVDs did not contribute to larger lesion volume accrual over the 5-year period. The presence of CVDs was not associated with MRI-derived changes in the controls. CONCLUSIONS: Hypertension and heart disease contribute to advanced brain atrophy in MS patients. CVDs did not contribute to additional lesion accrual. CVD comorbidities in MS patients may contribute to neurodegenerative tissue injury that can be detected with brain MRI.

Accuracy of ultrasonography in the assessment of liver fat compared with MRI.

AIM: To investigate the accuracy of ultrasonography in the assessment of hepatic steatosis using magnetic resonance imaging (MRI) as standard of reference and to explore the influence of additional hepatic iron overload. MATERIAL AND METHODS: A total of 2,783 volunteers (1,442 women, 1,341 men; mean age, 52.3±13.8 years) underwent confounder-corrected chemical-shift-encoded MRI of the liver at 1.5 T. Proton-density fat fraction (PDFF) and transverse relaxation rate (R2*) were calculated to estimate hepatic steatosis and liver iron overload, respectively. In addition, the presence of hepatic steatosis was assessed by B-mode ultrasonography. The sensitivity, specificity, and accuracy of hepatic ultrasonography were determined for different degrees of hepatic steatosis and different amounts of liver iron. RESULTS: MRI revealed hepatic steatosis in 40% of participants (n=1,112), which was mild in 68.9% (n=766), moderate in 26.7% (n=297), and severe in 4.4% (n=49) of patients. Ultrasonography detected hepatic steatosis in 37.8% (n=1,052), corresponding to 74.5% sensitivity and 86.6% specificity. The sensitivity of ultrasound increased with the amount of hepatic fat present and was 65.1%, 95%, and 96% for low, moderate, and high fat content; whereas the specificity was constantly high at 86.6%. The diagnostic accuracy of ultrasound for detection of hepatic steatosis did not vary significantly with the amount of liver iron present. CONCLUSION: Ultrasonography is an excellent tool to assess hepatic steatosis in the clinical setting with some limitations in patients with a low liver fat content. The detection of hepatic steatosis by ultrasonography is not influenced by liver iron.

Extended interval dosing of natalizumab in multiple sclerosis.

BACKGROUND: Natalizumab (NTZ), a monoclonal antibody to human α4ß1/ß7 integrin, is an effective therapy for multiple sclerosis (MS), albeit associated with progressive multifocal leukoencephalopathy (PML). Clinicians have been extending the dose of infusions with a hypothesis of reducing PML risk. The aim of the study is to evaluate the clinical consequences of reducing NTZ frequency of infusion up to 8 weeks 5 days. METHODS: A retrospective chart review in 9 MS centres was performed in order to identify patients treated with extended interval dosing (EID) regimens of NTZ. Patients were stratified into 3 groups based on EID NTZ treatment schedule in individual centres: early extended dosing (EED; n=249) every 4 weeks 3 days to 6 weeks 6 days; late extended dosing (LED; n=274) every 7 weeks to 8 weeks 5 days; variable extended dosing (n=382) alternating between EED and LED. These groups were compared with patients on standard interval dosing (SID; n=1093) every 4 weeks. RESULTS: 17% of patients on SID had new T2 lesions compared with 14% in EID (p=0.02); 7% of patients had enhancing T1 lesions in SID compared with 9% in EID (p=0.08); annualised relapse rate was 0.14 in the SID group, and 0.09 in the EID group. No evidence of clinical or radiographic disease activity was observed in 62% of SID and 61% of EID patients (p=0.83). No cases of PML were observed in EID group compared with 4 cases in SID cohort. CONCLUSIONS: Dosing intervals up to 8 weeks 5 days did not diminish effectiveness of NTZ therapy. Further monitoring is ongoing to evaluate if the risk of PML is reduced in patients on EID.

New Approaches to Measuring Sticky Molecules: Improvement of Instrumental Response Times Using Active Passivation.

A novel method has been developed to improve sampling system response times for nominally "sticky" molecules such as HNO3 and NH3. The method reported here makes use of active, continuous passivation, where the instrument interfaces are continuously exposed to 0.01-1 ppm of fluorinated acidic or basic surfactants. To reduce HNO3 response times, perfluoroheptanoic acid and perfluorobutanesulfonic acid vapors are evaluated as passivation species. 1H,1H-perfluorooctylamine is used to improve NH3 response times. The resulting time responses using the perfluoroalkanoic acids are on the order of 0.4-0.7 s for a 75% quantitative recovery of HNO3, and 1-5 s for 90% recovery. Similar response time improvements are seen in detection of NH3 using perfluorooctylamine (<1 s for a 75% recovery, ∼ 2 s for 90% recovery). This generally applicable methodology significantly improves the capability of eddy covariance flux and real-time plume-based measurements of highly polar molecules that have historically been hampered by slow response times due to adsorption on sampling system surfaces. The utility of this approach is demonstrated by field measurements of HNO3 eddy covariance fluxes in a central U.S. prairie.

A cost-effectiveness analysis of trametinib plus dabrafenib as first-line therapy for metastatic BRAF V600-mutated melanoma in the Swiss setting.

BACKGROUND: The treatment of patients with metastatic melanomas that harbour BRAF V600E or V600K mutations with trametinib plus dabrafenib appears to be superior to treatment with vemurafenib alone. This treatment regimen is likely to become available in Switzerland in the near future. OBJECTIVES: To determine the cost-effectiveness of trametinib plus dabrafenib. METHODS: A Markov cohort simulation was conducted to model the clinical course of typical patients with metastatic melanoma. Information on response rates, clinical condition and follow-up treatments were derived and transition probabilities estimated based on the results of a clinical trial that compared treatment with trametinib plus dabrafenib vs. vemurafenib alone. RESULTS: Treatment with trametinib plus dabrafenib was estimated to cost an additional CHF199 647 (Swiss francs) on average and yield a gain of 0·52 quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio of CHF385 603 per QALY. Probabilistic sensitivity analyses showed that a willingness-to-pay threshold of CHF100 000 per QALY would not be reached at the current US price of trametinib. CONCLUSIONS: The introduction of trametinib in Switzerland at US market prices for the treatment of metastatic BRAF V600-mutated melanoma with trametinib plus dabrafenib is unlikely to be cost-effective compared with vemurafenib monotherapy. A reduction in the total price of the combination therapy is required to achieve an acceptable cost-effectiveness ratio for this clinically promising treatment.

Vehicle emissions of radical precursors and related species observed in the 2009 SHARP campaign.

UNLABELLED: The 2009 Study of Houston Atmospheric Radical Precursors (SHARP) field campaign had several components that yielded information on the primary vehicular emissions of formaldehyde (HCHO) and nitrous acid (HONO), in addition to many other species. Analysis of HONO measurements at the Moody Tower site in Houston, TX, yielded emission ratios of HONO to the vehicle exhaust tracer species NOx and CO of 14 pptv/ppbv and 2.3 pptv/ppbv, somewhat smaller than recently published results from the Galleria site, although evidence is presented that the Moody Tower values should be upper limits to the true ratios of directly emitted HONO, and are consistent with ratios used in current standard emissions models. Several other Moody Tower emission ratios are presented, in particular a value for HCHO/CO of 2.4 pptv/ppbv. Considering only estimates of random errors, this would be significantly lower than a previous value, though the small sample size and possible systematic differences should be taken into account. Emission factors for CO, NOx, and HCHO, as well as various volatile organic compounds (VOCs), were derived from mobile laboratory measurements both in the Washburn Tunnel and in on-road exhaust plume observations. These two sets of results and others reported in the literature all agree well, and are substantially larger than the CO, NOx, and HCHO emission factors derived from the emission ratios reported from the Galleria site. IMPLICATIONS: Emission factors for the species measured in the various components of the 2009 SHARP campaign in Houston, TX, including HCHO, HONO, CO, CO2, nitrogen oxides, and VOCs, are needed to support regional air quality monitoring. Components of the SHARP campaign measured these species in several different ways, each with their own potential for systematic errors and differences in vehicle fleets sampled. Comparisons between data sets suggest that differences in sampling place and time may result in quite different emission factors, while also showing that different vehicle mixes can yield surprisingly similar emission factors.

[We cannot care alone: volunteers in dementia care at Nürnberg General Hospital]. / "We cannot care alone" : Ehrenamtliche Demenzbegleiter am Klinikum Nürnberg.

BACKGROUND: People with dementia have specific care needs especially in an acute care setting. Professionals in clinical routine have limited capacities in meeting the needs of dementia patients as far as communication, interaction and orientation are concerned. AIMS: For 2 years, the Department of Internal Medicine and Geriatrics at Nürnberg General Hospital has hosted volunteers in dementia care who accompany and visit people with dementia during their acute care stay. We present the organization of the volunteer training program, training content, and preliminary evaluation results. METHODS: We chose a mixed methods approach for research and evaluation. Baseline data, motivational profile of volunteers, paper and pencil data on attitudes, skills and knowledge before and after training were assessed. RESULTS: Preliminary results show a positive effect on attitudes, skills, and knowledge after volunteer training. Volunteers and professionals need continual support and education to enable volunteers to act as an integrative part of the acute geriatric care team. CONCLUSION: The admission to an acute care setting is often frightening and confusing for dementia patients. Trained volunteers have the potential to make the hospital stay more pleasant for people with dementia.

VT ablation based on CT imaging substrate visualization: results from a large cohort of ischemic and non-ischemic cardiomyopathy patients.

INTRODUCTION: The eradication of ventricular tachycardia (VT) isthmus sites constitutes the minimal procedural endpoint for VT ablation procedures. Contemporary high-resolution computed tomography (CT) imaging, in combination with computer-assisted analysis and segmentation of CT data, facilitates targeted elimination of VT isthmi. In this context, inHEART offers digitally rendered three-dimensional (3D) cardiac models which allow preoperative planning for VT ablations in ischemic and non-ischemic cardiomyopathies. To date, almost no data have been collected to compare the outcomes of VT ablations utilizing inHEART with those of traditional ablation approaches. METHODS: The presented data are derived from a retrospective analysis of n = 108 patients, with one cohort undergoing VT ablation aided by late-enhancement CT and subsequent analysis and segmentation by inHEART, while the other cohort received ablation through conventional methods like substrate mapping and activation mapping. The ablations were executed utilizing a 3D mapping system (Carto3), with the mapping generated via the CARTO® PENTARAY™ NAV catheter and subsequently merged with the inHEART model, if available. RESULTS: Results showed more successful outcome of ablations for the inHEART group with lower VT recurrence (27% vs. 42%, p < 0.06). Subsequent analyses revealed that patients with ischemic cardiomyopathies appeared to derive a significant benefit from inHEART-assisted VT ablation procedures, with a higher rate of successful ablation (p = 0.05). CONCLUSION: Our findings indicate that inHEART-guided ablation is associated with reduced VT recurrence compared to conventional procedures. This suggests that employing advanced imaging and computational modeling in VT ablation may be valuable for VT recurrences.

Simple diameter measurement as predictor of liver volume and liver parenchymal disease.

To investigate the accuracy of liver diameters for estimation of liver size and to evaluate their application as tool for assessment of parenchymal liver disease. In the course of a population-based study, (SHIP) one thousand nine hundred thirty-nine volunteers underwent magnetic resonance imaging (MRI) of the liver including 3D gradient echo MRI sequences. Maximum liver diameters were measured in cranio-caudal (CC), anterior-posterior (AP), medial-lateral (ML) orientation. Diameters were compared with true liver volume assessed by liver segmentation. Additionally, age-dependent reference values for diameters were defined. Finally, accuracy of liver diameters was assessed to discriminate volunteers with healthy livers and participants with parenchymal changes, measured by MRI and laboratory. Reference values of liver diameters within the healthy population (n = 886) were defined as follows (mean ± standard deviation, confidence interval CI in cm): CC 17.2 ± 2, CI 13.6/21.2; AP 15.8 ± 1.9, CI 12.6/19.8; ML 19.7 ± 2.3, CI 15.8/24.6. There was a poor correlation using linear regression between liver diameter and true liver volume; CC 0.393, AP 0.359; ML 0.137. The AP direction shows the best correlation to discriminate between healthy and pathologic liver changes; AUC 0.78; p < 0.001, CC AUC 0.53; p < 0.001 and ML AUC 0.52; p = 0.008. Measurement of liver diameter, especially in the anterior-posterior direction is a simple option to detect chronic liver disease but less suitable for prediction of liver volume.

Reliability and accuracy of straightforward measurements for liver volume determination in ultrasound and computed tomography compared to real volumetry.

To evaluate the suitability of volume index measurement (VI) by either ultrasound (US) or computed tomography (CT) for the assessment of liver volume. Fifty-nine patients, 21 women, with a mean age of 66.8 ± 12.6 years underwent US of the liver followed immediately by abdominal CT. In US and CT imaging dorsoventral, mediolateral and craniocaudal liver diameters in their maximum extensions were assessed by two observers. VI was calculated by multiplication of the diameters divided by a constant (3.6). The liver volume determined by a manual segmentation in CT ("true liver volume") served as gold standard. True liver volume and calculated VI determined by US and CT were compared using Bland-Altman analysis. Mean differences of VI between observers were - 34.7% (- 90.1%; 20.7%) for the US-based and 1.1% (- 16.1%; 18.2%) for the CT-based technique, respectively. Liver volumes determined by semi-automated segmentation, US-based VI and CT-based VI, were as follows: 1.500 ± 347cm3; 863 ± 371cm3; 1.509 ± 432cm3. Results showed a great discrepancy between US-based VI and true liver volume with a mean bias of 58.3 ± 66.9%, and high agreement between CT-based VI and true liver volume with a low mean difference of 4.4 ± 28.3%. Volume index based on CT diameters is a reliable, fast and simple approach for estimating liver volume and can therefore be recommended for clinical practice. The usage of US-based volume index for assessment of liver volume should not be used due to its low accuracy of US in measurement of liver diameters.

Induction of IgG by lipid A in the newborn mouse.

IgG of paternal allotype first becomes detectable in the serum of (BALB/c x C57BL/6)F(1) mice between day 12 and 14 after birth and reaches adult levels at an age of 5 wk. Since in mice there is a transfer of maternal IgG molecules through the placenta and via milk, F(1) heterozygous at the allotype locus were used and the concentrations of IgG with paternal allotype were measured. This was done by a sensitive method capable of detecting IgG concentrations as low as 5 x 10(-4) of normal adult serum levels. It is based on the quantitative inhibition of allotype-specific facilitation of hemolysis. When lipid A or Salmonella bacteria were injected into neonatal mice, a stimulation of IgG synthesis was observed. Thus IgG levels were enhanced 10-30-fold compared to the nontreated mice. No increase in IgG levels was obtained in adult mice after treatment with lipid A. Whether the newborns were injected at birth, on day 2, 4, or 7, IgG was first demonstrable in the treated mice at an age of 6-11 days. The increase in IgG levels was not paralleled by a demonstrable antibody activity against lipid A, SRBC, and LPS. Thus the bulk of newly induced IgG is probably a statistical distribution of different specificities.

Induction of IgG in young nude mice by lipid A or thymus grafts.

Postnatal serum concentrations of IgG2a of paternal allotype, measured in congenitally thymusless nude mice, increase with kinetics and titers comparable to their normal congeneic counterparts. Lipid A, the mitogenic part of LPS, stimulates IgG synthesis in nude mice when it is given 7 days after birth. IgG concentrations at 15 days of age are 6- to 8-fold higher than in untreated control nudes; this is considerably lower, however, than in normal mice, which show up to 45-fold higher IgG2ab levels after lipid A treatment. A thymus graft from nearly congeneic donors of the same age, transplanted at 4 days after birth, also stimulates long-lasting IgG synthesis in the nude recipients. If the grafted nudes are injected with lipid A 3 days later, IgG synthesis is further stimulated 8- to 16-fold. The data are discussed in relation to the thymus dependency of IgG production and the conditions for lipid A stimulation.

Disability Improvement Is Associated with Less Brain Atrophy Development in Multiple Sclerosis.

BACKGROUND AND PURPOSE: It is unknown whether deceleration of brain atrophy is associated with disability improvement in patients with MS. Our aim was to investigate whether patients with MS with disability improvement develop less brain atrophy compared with those who progress in disability or remain stable. MATERIALS AND METHODS: We followed 980 patients with MS for a mean of 4.8 ± 2.4 years. Subjects were divided into 3 groups: progress in disability (n = 241, 24.6%), disability improvement (n = 101, 10.3%), and stable (n = 638, 65.1%) at follow-up. Disability improvement and progress in disability were defined on the basis of the Expanded Disability Status Scale score change using standardized guidelines. Stable was defined as nonoccurrence of progress in disability or disability improvement. Normalized whole-brain volume was calculated using SIENAX on 3D T1WI, whereas the lateral ventricle was measured using NeuroSTREAM on 2D-T2-FLAIR images. The percentage brain volume change and percentage lateral ventricle volume change were calculated using SIENA and NeuroSTREAM, respectively. Differences among groups were investigated using ANCOVA, adjusted for age at first MR imaging, race, T2 lesion volume, and corresponding baseline structural volume and the Expanded Disability Status Scale. RESULTS: At first MR imaging, there were no differences among progress in disability, disability improvement, and the stable groups in whole-brain volume (P = .71) or lateral ventricle volume (P = .74). During follow-up, patients with disability improvement had the lowest annualized percentage lateral ventricle volume change (1.6% ± 2.7%) followed by patients who were stable (2.1% ± 3.7%) and had progress in disability (4.1% ± 5.5%), respectively (P < .001). The annualized percentage brain volume change values were -0.7% ± 0.7% for disability improvement, -0.8% ± 0.7% for stable, and -1.1% ± 1.1% for progress in disability (P = .001). CONCLUSIONS: Patients with MS who improve in their clinical disability develop less brain atrophy across time compared with those who progress.

Comparison of sequential and high-pitch-spiral coronary CT-angiography: image quality and radiation exposure.

New protocols for coronary computed tomography angiography (CCTA) could lower the radiation dose for patients but influence the image quality. To compare image quality and radiation exposure in step-and-shoot CCTA and high-pitch spiral CCTA. Fifty-nine pairs of patients matched for weight, height, sex and heart rate were included in this study (74 m, 44 f, average age 60 years, age range 29-94 years). Step-and-shoot CCTA and high-pitch spiral CCTA was performed on a third generation dual-source CT in equally sized patient groups. The signal-to-noise ratio (SNR) in the ascending aorta and the coronary arteries were determined for each dataset. Image quality was rated using a five-point scale. We used the t-test for paired samples to compare SNR and effective dose, and the Wilcoxon test to compare image quality scores. Mean effective dose for the step-and-shoot protocol (4.15 ± 3.07 mSv) was significantly higher in comparison to the high-pitch spiral protocol (1.2 ± 0.69 mSv; p < 0.0001). Mean SNR was higher with the step-and-shoot protocol compared to the high-pitch spiral protocol in the aorta, in the left main and peripheral coronary arteries (p < 0.01), in the proximal right coronary artery (p = 0.027). Image quality scores were significantly better for the step-and-shoot protocol (p = 0.0003). Step-and-shoot CCTA has significantly better SNR and overall image quality compared to high-pitch spiral CCTA, but with a mean effective dose more than thrice as high.

Evaluation of Leptomeningeal Contrast Enhancement Using Pre-and Postcontrast Subtraction 3D-FLAIR Imaging in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Leptomeningeal contrast enhancement is found in patients with multiple sclerosis, though reported rates have varied. The use of 3D-fluid-attenuated inversion recovery pre- and postcontrast subtraction imaging may more accurately determine the frequency of leptomeningeal contrast enhancement. The purpose of this study was to investigate the frequency of leptomeningeal contrast enhancement using the pre- and postcontrast subtraction approach and to evaluate 3 different methods of assessing the presence of leptomeningeal contrast enhancement. MATERIALS AND METHODS: We enrolled 258 consecutive patients with MS (212 with relapsing-remitting MS, 32 with secondary-progressive MS, and 14 with clinically isolated syndrome) who underwent both pre- and 10-minute postcontrast 3D-FLAIR sequences after a single dose of gadolinium injection on 3T MR imaging. The analysis included leptomeningeal contrast-enhancement evaluation on 3D-FLAIR postcontrast images in native space (method A), on pre- and postcontrast 3D-FLAIR images in native space (method B), and on pre-/postcontrast 3D-FLAIR coregistered and subtracted images (method C, used as the criterion standard). RESULTS: In total, 51 (19.7%) patients with MS showed the presence of leptomeningeal contrast enhancement using method A; 39 (15.1%), using method B; and 39 (15.1%), using method C (P = .002). Compared with method C as the criterion standard, method A showed 89.8% sensitivity and 92.7% specificity, while method B showed 84.6% sensitivity and 97.3% specificity (P < .001) at the patient level. Reproducibility was the highest using method C (κ agreement, r = 088, P < .001). The mean time to analyze the 3D-FLAIR images was significantly lower with method C compared with methods A and B (P < .001). CONCLUSIONS: 3D-FLAIR postcontrast imaging offers a sensitive method for detecting leptomeningeal contrast enhancement in patients with MS. However, the use of subtraction imaging helped avoid false-positive cases, decreased reading time, and increased the accuracy of leptomeningeal contrast-enhancement foci detection in a clinical routine.

Brain Atrophy Is Associated with Disability Progression in Patients with MS followed in a Clinical Routine.

BACKGROUND AND PURPOSE: The assessment of brain atrophy in a clinical routine is not performed routinely in multiple sclerosis. Our aim was to determine the feasibility of brain atrophy measurement and its association with disability progression in patients with MS followed in a clinical routine for 5 years. MATERIALS AND METHODS: A total of 1815 subjects, 1514 with MS and 137 with clinically isolated syndrome and 164 healthy individuals, were collected retrospectively. Of 11,794 MR imaging brain scans included in the analysis, 8423 MRIs were performed on a 3T, and 3371 MRIs, on a 1.5T scanner. All patients underwent 3D T1WI and T2-FLAIR examinations at all time points of the study. Whole-brain volume changes were measured by percentage brain volume change/normalized brain volume change using SIENA/SIENAX on 3D T1WI and percentage lateral ventricle volume change using NeuroSTREAM on T2-FLAIR. RESULTS: Percentage brain volume change failed in 36.7% of the subjects; percentage normalized brain volume change, in 19.2%; and percentage lateral ventricle volume change, in 3.3% because of protocol changes, poor scan quality, artifacts, and anatomic variations. Annualized brain volume changes were significantly different between those with MS and healthy individuals for percentage brain volume change (P < .001), percentage normalized brain volume change (P = .002), and percentage lateral ventricle volume change (P = .01). In patients with MS, mixed-effects model analysis showed that disability progression was associated with a 21.9% annualized decrease in percentage brain volume change (P < .001) and normalized brain volume (P = .002) and a 33% increase in lateral ventricle volume (P = .004). CONCLUSIONS: All brain volume measures differentiated MS and healthy individuals and were associated with disability progression, but the lateral ventricle volume assessment was the most feasible.

[Strategies for the avoidance and treatment of complications during pacemaker implantation]. / Strategien zur Vermeidung und Behandlung von Komplikationen der Herzschrittmacherimplantation.

The implantation of a pacemaker is the therapy of choice for symptomatic bradyarrhythmias. The perioperative complication rate is low. This article gives an overview on possible complications, their avoidance and treatment.