Independent validation of a new reirradiation risk score (RRRS) for glioma patients predicting post-recurrence survival: A multicenter DKTK/ROG analysis

Publication date: Available online 9 February 2018
Source:Radiotherapy and Oncology
Author(s): Maximilian Niyazi, Sebastian Adeberg, David Kaul, Anne-Laure Boulesteix, Nina Bougatf, Daniel F. Fleischmann, Arne Grün, Anna Krämer, Claus Rödel, Franziska Eckert, Frank Paulsen, Kerstin A. Kessel, Stephanie E. Combs, Oliver Oehlke, Anca-Ligia Grosu, Annekatrin Seidlitz, Annika Lattermann, Mechthild Krause, Michael Baumann, Maja Guberina, Martin Stuschke, Volker Budach, Claus Belka, Jürgen Debus
Background and purposeReirradiation (reRT) is a valid option with considerable efficacy in patients with recurrent high-grade glioma, but it is still not known which patients might be optimal candidates for a second course of irradiation. This study validated a newly developed prognostic score independently in an external patient cohort.Material and methodsThe reRT risk score (RRRS) is based on a linear combination of initial histology, clinical performance status, and age derived from a multivariable model of 353 patients. This score can predict post-recurrence survival (PRS) after reRT. The validation dataset consisted of 212 patients.ResultsThe RRRS differentiates three prognostic groups. Discrimination and calibration were maintained in the validation group. Median PRS times in the development cohort for the good/intermediate/poor risk categories were 14.2, 9.1, and 5.3 months, respectively. The respective groups within the validation cohort displayed median PRS times of 13.8, 8.8, and 3.8 months, respectively. Uno's C for development data was 0.64 (CI: 0.60–0.69) and for validation data 0.63 (CI: 0.58–0.68).ConclusionsThe RRRS has been successfully validated in an independent patient cohort. This linear combination of three easily determined clinicopathological factors allows for a reliable classification of patients and may be used as stratification factor for future trials.



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Tritium and radiocarbon levels in the Rhône river delta and along the French Mediterranean coastline

Publication date: Available online 9 February 2018
Source:Journal of Environmental Radioactivity
Author(s): P. Jean-Baptiste, M. Fontugne, E. Fourré, L. Marang, C. Antonelli, S. Charmasson, F. Siclet
The Rhône is characterised by a heavy concentration of nuclear-based industries including nuclear power stations and nuclear sites housing civilian and military facilities. Here, we report the results of a four-year survey (2010–2013) of tritium and radiocarbon levels in a variety of matrices within the Rhône delta and along the French Mediterranean coastline. The aim of the study is to create a spatial reference framework of environmental levels of these two radionuclides, which are the most prevalent in radioactive effluents from nuclear power stations. Although both tritium and radiocarbon levels in the samples analysed are very low and can only be detected using ultra-sensitive analytical techniques, they clearly show the influence of the tritium and radiocarbon discharges carried by the Rhône plume along the Mediterranean coast. The tritium content of suspended matter and sediments of the Rhône is a special case, which shows elevated tritium values not seen in other French rivers with similar nuclear facilities. The north-south spatial distribution of this tritium anomaly shows that these trace values are at their highest in the upper Rhône, close to the Swiss border and upstream of Creys Malville, the northernmost nuclear power station on the Rhône. This points to a legacy of past tritium releases by the watchmaking industry. A dedicated study would be needed to clearly identify the source and the exact nature of this contamination.



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Independent validation of a new reirradiation risk score (RRRS) for glioma patients predicting post-recurrence survival: A multicenter DKTK/ROG analysis

Reirradiation (reRT) is a valid option with considerable efficacy in patients with recurrent high-grade glioma, but it is still not known which patients might be optimal candidates for a second course of irradiation. This study validated a newly developed prognostic score independently in an external patient cohort.

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MRI Findings of Adult-Onset Orbital Xanthogranulomatous Disease

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Evaluation of Leptomeningeal Contrast Enhancement Using Pre-and Postcontrast Subtraction 3D-FLAIR Imaging in Multiple Sclerosis [ADULT BRAIN]

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 ( 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.

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Dual-Energy CT in Hemorrhagic Progression of Cerebral Contusion: Overestimation of Hematoma Volumes on Standard 120-kV Images and Rectification with Virtual High-Energy Monochromatic Images after Contrast-Enhanced Whole-Body Imaging [ADULT BRAIN]

BACKGROUND AND PURPOSE:

In patients with hemorrhagic contusions, hematoma volumes are overestimated on follow-up standard 120-kV images obtained after contrast-enhanced whole-body CT. We aimed to retrospectively determine hemorrhagic progression of contusion rates on 120-kV and 190-keV images derived from dual-energy CT and the magnitude of hematoma volume overestimation.

MATERIALS AND METHODS:

We retrospectively analyzed admission and follow-up CT studies in 40 patients with hemorrhagic contusions. After annotating the contusions, we measured volumes from admission and follow-up 120-kV and 190-keV images using semiautomated 3D segmentation. Bland-Altman analysis was used for hematoma volume comparison.

RESULTS:

On 120-kV images, hemorrhagic progression of contusions was detected in 24 of the 40 patients, while only 17 patients had hemorrhagic progression of contusions on 190-keV images (P = .008). Hematoma volumes were systematically overestimated on follow-up 120-kV images (9.68 versus 8 mm³; mean difference, 1.68 mm³; standard error, 0.37; P < .001) compared with 190-keV images. There was no significant difference in volumes between admission 120-kV and 190-keV images. Mean and median percentages of overestimation were 29% (95% CI, 18–39) and 22% (quartile 3 – quartile 1 = 36.8), respectively.

CONCLUSIONS:

The 120-kV images, which are comparable with single-energy CT images, significantly overestimated the hematoma volumes, hence the rate of hemorrhagic progression of contusions, after contrast-enhanced whole-body CT. Hence, follow-up of hemorrhagic contusions should be performed on dual-energy CT, and 190-keV images should be used for the assessment of hematoma volumes.

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Improved Visualization of Cortical Lesions in Multiple Sclerosis Using 7T MP2RAGE [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Cortical lesions are common and often extensive in multiple sclerosis but are difficult to visualize by MRI, leaving important questions about their clinical implications and response to therapy unanswered. Our aim was to determine whether cortical lesions are better visualized using magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE) than T2*-weighted imaging on 7T MR imaging.

MATERIALS AND METHODS:

Brain MR imaging using T1-weighted MP2RAGE at 500-μm isotropic resolution, T2*-weighted gradient-echo, and T2*-weighted segmented echo-planar imaging sequences were collected for 13 patients with MS and 5 age-matched neurologically healthy controls on a 7T research system. One MS case underwent postmortem MR imaging including gradient-echo and MP2RAGE sequences, after which cortical lesions seen on MR imaging were assessed with immunohistochemistry.

RESULTS:

MP2RAGE detected 203 cortical lesions (median, 16 lesions/case; interquartile range, 15), compared to 92 with T2*gradient-echo (median, 7; interquartile range, 8; P < .001) and 81 with T2*EPI (median, 7; interquartile range, 5; P < .001). This increase in lesion number detected on MP2RAGE versus T2* was observed for juxtacortical, leukocortical, and intracortical lesions. Forty-three percent of all cortical lesions were identified only on MP2RAGE. White matter lesion volume correlated with total juxtacortical (r = 0.86, P < .001) and leukocortical lesion volume (r = 0.70, P < .01) but not intracortical lesion volume, suggesting that pathophysiology may differ by lesion type. Of 4 suspected lesions seen on postmortem imaging, 3 were found to be true cortical lesions while 1 represented postmortem tissue damage.

CONCLUSIONS:

A combination of MP2RAGE and T2*-weighted imaging at 7T improved detection of cortical lesions and should enable longitudinal studies to elucidate their spatiotemporal dynamics and clinical implications.

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Brain Imaging in Cases with Positive Serology for Dengue with Neurologic Symptoms: A Clinicoradiologic Correlation [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Dengue is a common arboviral disease, which uncommonly involves the brain. There has been a recent surge in dengue cases and dengue-related deaths in tropical countries. The aim of this study was to describe brain imaging findings in patients with dengue infection having neurologic symptoms.

MATERIALS AND METHODS:

Thirty-five patients with positive serology for dengue with CNS symptoms undergoing imaging of the brain were included in the study. Clinical, laboratory, and imaging parameters were assessed and correlated to poor outcome.

RESULTS:

A Glasgow Coma Scale score of ≤12 at presentation, clinical classification of severe-type dengue, and the presence of acute renal failure were associated with poor outcome. Imaging parameters associated with poor outcome were involvement of the thalami and cerebellar peduncles and the presence of diffusion restriction and hemorrhagic foci in the brain parenchyma.

CONCLUSIONS:

Although not specific, dengue infection has imaging findings that can be used to narrow down the differential list and help in prognostication.

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Iron-Insensitive Quantitative Assessment of Subcortical Gray Matter Demyelination in Multiple Sclerosis Using the Macromolecular Proton Fraction [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Fast macromolecular proton fraction mapping is a recent quantitative MR imaging method for myelin assessment. The objectives of this study were to evaluate the macromolecular proton fraction as a measure of demyelination in subcortical GM structures in multiple sclerosis and assess a potential relationship between demyelination and excess iron deposition using the macromolecular proton fraction and T2* mapping.

MATERIALS AND METHODS:

Macromolecular proton fraction and T2* maps were obtained from 12 healthy controls, 18 patients with relapsing-remitting MS, and 12 patients with secondary-progressive MS using 3T MR imaging. Parameter values in the caudate nucleus, globus pallidus, putamen, substantia nigra, and thalamus were compared between groups and correlated to clinical data.

RESULTS:

The macromolecular proton fraction in all subcortical structures and T2* in the globus pallidus, putamen, and caudate nucleus demonstrated a significant monotonic decrease from controls to patients with relapsing-remitting MS and from those with relapsing-remitting MS to patients with secondary-progressive MS. The macromolecular proton fraction in all subcortical structures significantly correlated with the Expanded Disability Status Scale and MS Functional Composite scores with absolute Pearson correlation coefficient (r) values in a range of 0.4–0.6. Significant correlations (r = –0.4 to –0.6) were also identified between the macromolecular proton fraction and the 9-Hole Peg Test, indicating a potential relationship with nigrostriatal pathway damage. Among T2* values, weak significant correlations with clinical variables were found only in the putamen. The macromolecular proton fraction did not correlate with T2* in any of the studied anatomic structures.

CONCLUSIONS:

The macromolecular proton fraction provides an iron-insensitive measure of demyelination. Myelin loss in subcortical GM structures in MS is unrelated to excess iron deposition. Subcortical GM demyelination is more closely associated with the disease phenotype and disability than iron overload.

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Endovascular Thrombectomy in Wake-Up Stroke and Stroke with Unknown Symptom Onset [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Mechanical thrombectomy in acute ischemic stroke within 6 hours of symptom onset is effective and safe. However, in many patients, information on the beginning of symptoms is not available. Patients can be divided into those with wake-up stroke and daytime-unwitnessed stroke. Evidence on outcome and complications after mechanical thrombectomy in wake-up stroke and daytime-unwitnessed stroke is rare. A potential beneficial effect of mechanical thrombectomy in selected patients with wake-up stroke or daytime-unwitnessed stroke is suspected.

MATERIALS AND METHODS:

We analyzed 1073 patients with anterior circulation stroke undergoing mechanical thrombectomy between 2010 and 2016. Patients with wake-up stroke and daytime-unwitnessed stroke were compared with controls receiving mechanical thrombectomy as the standard of care. We assessed good functional outcome (mRS ≤ 2 at 3 months), mortality rates, and frequencies of symptomatic intracranial hemorrhage. Subgroup analyses tried to detect influences of patient selection via further imaging modalities (MR imaging, CTP; wake-up stroke [advanced], daytime-unwitnessed stroke [advanced]) on outcome and safety.

RESULTS:

There was no significant difference in good functional outcome between patients with wake-up stroke and controls (35.9% versus 38.3%, P = .625). Outcome in patients with daytime-unwitnessed stroke was inferior compared with controls (27.3%, P = .007). Groups did not differ in all-cause mortality at day 90 (P = .224) and the rate of symptomatic intracranial hemorrhage (P = .292). Advanced imaging improved the frequency of good functional outcome (non-wake-up stroke [advanced] versus wake-up stroke [advanced]: OR, 2.92; 95% CI, 1.32–6.45; non-daytime-unwitnessed stroke [advanced] versus daytime-unwitnessed stroke [advanced]: OR, 2.09; 95% CI, 1.03–4.25) with an additional reduction in all-cause mortality (non-daytime-unwitnessed stroke [advanced] versus daytime-unwitnessed stroke [advanced]: OR, 0.42; 95% CI, 0.20–0.88).

CONCLUSIONS:

Mechanical thrombectomy in selected patients with wake-up stroke allows a good functional outcome comparable with that of controls. Outcome after mechanical thrombectomy in daytime-unwitnessed stroke seems to be inferior compared with that in controls. Advanced imaging modalities may increase the frequency of good functional outcome in both patients with wake-up stroke and daytime-unwitnessed stroke.

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Post-contrast acute kidney injury – Part 1: Definition, clinical features, incidence, role of contrast medium and risk factors

Abstract

Purpose

The Contrast Media Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) has updated its 2011 guidelines on the prevention of post-contrast acute kidney injury (PC-AKI). The results of the literature review and the recommendations based on it, which were used to prepare the new guidelines, are presented in two papers.

Areas covered in part 1

Topics reviewed include the terminology used, the best way to measure eGFR, the definition of PC-AKI, and the risk factors for PC-AKI, including whether the risk with intravenous and intra-arterial contrast medium differs.

Key Points

• PC-AKI is the preferred term for renal function deterioration after contrast medium.

• PC-AKI has many possible causes.

• The risk of AKI caused by intravascular contrast medium has been overstated.

• Important patient risk factors for PC-AKI are CKD and dehydration.

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Determination of glomerular filtration rate (GFR) from fractional renal accumulation of iodinated contrast material: a convenient and rapid single-kidney CT-GFR technique

Abstract

Objectives

To develop a convenient and rapid single-kidney CT-GFR technique.

Methods

One hundred and twelve patients referred for multiphasic renal CT and 99mTc-DTPA renal dynamic imaging Gates-GFR measurement were prospectively included and randomly divided into two groups of 56 patients each: the training group and the validation group. On the basis of the nephrographic phase images, the fractional renal accumulation (FRA) was calculated and correlated with the Gates-GFR in the training group. From this correlation a formula was derived for single-kidney CT-GFR calculation, which was validated by a paired t test and linear regression analysis with the single-kidney Gates-GFR in the validation group.

Results

In the training group, the FRA (x-axis) correlated well (r = 0.95, p < 0.001) with single-kidney Gates-GFR (y-axis), producing a regression equation of y = 1665x + 1.5 for single-kidney CT-GFR calculation. In the validation group, the difference between the methods of single-kidney GFR measurements was 0.38 ± 5.57 mL/min (p = 0.471); the regression line is identical to the diagonal (intercept = 0 and slope = 1) (p = 0.727 and p = 0.473, respectively), with a standard deviation of residuals of 5.56 mL/min.

Conclusion

A convenient and rapid single-kidney CT-GFR technique was presented and validated in this investigation.

Key Points

• The new CT-GFR method takes about 2.5 min of patient time.

• The CT-GFR method demonstrated identical results to the Gates-GFR method.

• The CT-GFR method is based on the fractional renal accumulation of iodinated CM.

• The CT-GFR method is achieved without additional radiation dose to the patient.

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RFA versus robotic partial nephrectomy for T1a renal cell carcinoma: a propensity score-matched comparison of mid-term outcome

Abstract

Objective

To compare oncological and functional mid-term outcomes following robotic partial nephrectomy (RPN) and radiofrequency ablation (RFA) for treating T1a renal cell carcinoma (RCC) using propensity score-matching.

Methods

Between December 2008–April 2016, 63 patients from each treatment group were propensity score-matched for age, sex, American Society of Anesthesiologists score, tumour size, tumour laterality, tumour histology, R.E.N.A.L. nephrometry score and preoperative estimated glomerular filtration rate (eGFR). Post-treatment follow-up periods for RPN and RFA ranged from 1–90 months (median, 24.6) and 1–65 months (21), respectively. Tumour location, percentage of eGFR preservation and 2-year recurrence-free survival rate were compared between groups.

Results

Exophytic and endophytic RCC occurred in 73.0 % (46/63) and 27.0 % (17/63) of the RPN group, and 52.4 % (33/63) and 47.6 % (30/63) of the RFA group, respectively (p=0.017). There was 91.7 % preservation of eGFR in the RPN group and 86.8 % in the RFA group (p=0.088). Two-year recurrence-free survival rate was 100 % in the RPN and 95.2 % in the RFA group (p=0.029).

Conclusions

RPN provides a higher recurrence-free survival rate than RFA. However, RFA is a better treatment option for an endophytic or recurrent RCC that is difficult to treat with RPN.

Key Points

• RPN provides a higher recurrence-free survival rate than RFA.

• Unlike RPN, repeat RFA is easy to perform for recurrent RCC.

• Endophytic RCC could be better treated with RFA.

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Coronary CT angiography in patients with atrial fibrillation: Standard-dose and low-dose imaging with a high-resolution whole-heart CT scanner

Abstract

Objective

To compare image quality, observer confidence, radiation exposure in the standard-dose (SD-CCTA) and low-dose (LD-CCTA) protocols of coronary CT angiography (CCTA) in patients with atrial fibrillation (AF).

Material and methods

CCTA was performed in 303 patients using a CT scanner with 16-cm coverage (111 scans during sinus rhythm (SR); 192 during AF). LD-CCTA was used in 218 patients; SD-CCTA in 85 patients suspected of having coronary artery disease (CAD). Image quality and observer confidence were evaluated on 5-point scales. Radiation doses were recorded.

Results

Image quality was superior in the SD-CCTA compared to the LD-CCTA (SR 1.45±0.40; AF 1.72±0.46; vs. SR 1.83±0.48; AF 1.92±0.50; p < 0.001). Observers were more confident with SD-CCTA than with LD-CCTA (SR 1.38±0.33; AF 1.61±0.43; vs. SR 1.70±0.45; AF 1.82±0.50; p < 0.001). Radiation doses in AF were significantly higher than in the SR (LD-CCTA, 1.68±0.71 mSv; SD-CCTA, 3.72±1.95 mSv; vs. LD-CCTA, 1.3 ±0.52 mSv; SD-CCTA, 2.67±1.47 mSv; p < 0.001).

Conclusion

Using a low-dose protocol in AF, radiation exposure can be decreased by 50 % at the expense of 20 % impaired image quality. A low-dose CCTA protocol can be considered in young patients, whereas the standard-dose protocol is recommended for older patients and those suspected of having CAD.

Key Points

• Whole-heart CT allows visualization of the coronary arteries in atrial fibrillation.

• Low-dose CT decreases radiation exposure by 50%, image quality by 20%.

• Standard-dose CT seems advantageous when concomitant coronary artery disease is suspected.

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Magnetic resonance post-contrast vascular hyperintensities at 3 T: a new highly sensitive sign of vascular occlusion in acute ischaemic stroke

Abstract

Background

Magnetic resonance imaging (MRI) is the diagnostic cornerstone for precisely identifying acute ischaemic strokes and locating vascular occlusions, especially since mechanical thrombectomy has become a reference treatment. We observed that a post-contrast three-dimensional turbo-spin-echo T1-weighted sequence showed striking post-contrast vascular hyperintensities (PCVH) in ischaemic territories. We aimed to evaluate the prevalence and the meaning of this finding.

Methods

This retrospective single centre study included 130 consecutive patients admitted for acute ischaemic stroke with a 3-T MRI performed in the first 12 h of symptom onset from September 2014 through September 2016. Two neuroradiologists blinded to clinical data analysed the first MRI assessments. The association between PCVH and clinical, radiological and follow-up findings was assessed, as well as inter- and intra-observer agreements.

Results

Of 130 patients, 105 (81%) had PCVH in the ischaemic territory. PCVH were associated with the presence of thrombus on susceptibility weighted imaging (p < 0.0001) and vascular occlusions on MR angiography (p < 0.0001). All patients with a visible thrombus had PCVH closely surrounding the clot. PCVH were associated with higher initial (p < 0.01) and follow-up (p < 0.01) National Institutes of Health Stroke Scale score, and higher mRS score (p < 0.05). Thrombectomy was the reference treatment for all patients with arterial occlusions. Inter- and intra-observer agreements for the detection of PCVH were excellent (κ = 0.95 and κ = 0.91, respectively).

Conclusions

PCVH during acute strokes are a striking sensitive and reproducible tool for diagnosing and locating vascular occlusions. It may help triage patients who can benefit from thrombectomy.

Key points

• Post-contrast vascular hyperintensities (PCVH) are a sensitive MR finding in acute stroke

• PCVH are strongly associated with the presence and location of arterial occlusions

• Inter- and intra-observer agreements for the detection of PCVH are excellent

• PCVH are visible even in the case of significant motion artefacts

• PCVH may help triage patients who can benefit from mechanical thrombectomy

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What are the predictors of clinical success after percutaneous vertebroplasty for osteoporotic vertebral fractures?

Abstract

Objectives

Osteoporotic vertebral fractures are responsible for acute pain and disability that may persist for more than 2 months. We wanted to identify predicting factors for mid-term outcome after vertebroplasty.

Methods

We included consecutive patients who underwent vertebroplasty for fragility fractures with persistent and intense pain between January 2014–June 2016. Outcome was assessed by an independent clinician after 1 month using a standardized questionnaire. Patients were classified as having either a favorable or a poor outcome. Presence of an intravertebral cleft and bone oedema mean signal intensity was assessed by an independent radiologist blinded to the clinical data. Pre-intervention clinical or radiological factors were analysed as predictors for outcome.

Results

In the 78 included patients (females 71%, age 75 ± 8.3 years), 61.5% had a favourable outcome. When vertebroplasty was performed within 2 months after fracture, the outcome was favourable in 19 patients (39.6%) and poor in five (16.7%; estimate for favourable outcome: OR = 4.1, 95% CI 1.2–13.8, p = 0.021). Absence of intravertebral cleft on pre-intervention imaging was also a predictor of favourable outcome (OR = 3.7, 95% CI 1.2–11.8, p = 0.024). On pre-intervention MRI, vertebral body oedema intensity signal did not influence the outcome.

Conclusions

In patients with persistent and intense pain after an osteoporotic vertebral fracture, early intervention and absence of intravertebral cleft were predictors of favourable outcome at 1 month after vertebroplasty.

Key Points

• Performing vertebroplasty within 2 months following a fragility fracture increases success rate.

• Presence of an intravertebral cleft at baseline is a predictor of poor mid-term outcome.

• A pre-intervention MRI should be performed to ascertain the indication of vertebroplasty.

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Table of Contents

Publication date: March 2018
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, Volume 125, Issue 3





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Society Page

Publication date: March 2018
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, Volume 125, Issue 3





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Information for Readers

Publication date: March 2018
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, Volume 125, Issue 3





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Editorial Board

Publication date: March 2018
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, Volume 125, Issue 3





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mDixon-based texture analysis of an intraosseous lipoma: a case report and current review for the dental clinician

Publication date: March 2018
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, Volume 125, Issue 3
Author(s): Kyung Mi Lee, Hyug-Gi Kim, Yeon-Hee Lee, Eui Jong Kim
An intraosseous lipoma is a rare histologic variant of lipoma, accounting for only 0.1% of all primary bone tumors. This may not be the actual incidence because most of these lesions are frequently asymptomatic, but imaging modalities, such as computed tomography or magnetic resonance imaging (MRI) seem to have increased the detection rate. Lipoma occasionally undergoes osseous metaplasia and becomes an osseous lipoma. Although there are numerous papers discussing intraosseous lipoma and some authors have tried to differentiate lipomas from osseous lipomas, there is still a great deal of confusion with regard to characteristic radiologic features and the use of terms. Use of the mDixon sequence in MRI could be an effective, noninvasive method of lesion detection and differential diagnosis. Texture analysis is a useful technique for capturing intratumoral characteristics. We report what is possibly the first use of the mDixon MRI sequence in the measurement of tumoral texture in a case of the extremely rare inferior nasal turbinate intraosseous lipoma in a 58-year-old female. We conclude that mDixon and texture analysis are helpful methods for differentiating intraosseous lipomas from other masses and confirming the benign characteristics of lipoma. Our review of head and neck intraosseous lipoma could be of particular interest to head and neck surgeons and dental clinicians.



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Impact of intracranial artery calcification on cerebral hemodynamic changes

Abstract

Purpose

Intracranial artery calcification (IAC) has been demonstrated to be correlated with ischemic stroke, cognitive decline, and other vascular events by accumulating evidences from both Western and Asian populations. The proposed study aimed to investigate its potential mechanisms by evaluating the blood flow velocity and pulsatility index (PI) of cerebral arteries.

Methods

Consecutive ischemic stroke patients admitted to the Prince of Wales Hospital were recruited after excluding those with atrial fibrillation or poor temporal window. Quantitative measurements of IAC severity were assessed on brain CT scans. Transcranial Doppler (TCD) ultrasonography was performed to evaluate the blood flow velocity of the middle cerebral artery (MCA) and vertebral-basilar artery (VBA).

Results

In total, 318 patients were analyzed. Spearman's correlation analysis demonstrated both high MCA systolic flow velocity and high MCA PI were correlated with IAC Agatston score, p < 0.001 individually. Similar correlation was also found between IAC Agatston score and high VBA velocity/high VBA PI, p ≤ 0.001 individually. Multiple logistic regression analysis showed IAC Agatston score was an independent risk factor for high MCA velocity (OR 1.533; 95% CI 1.235–1.903), high VBA velocity (OR 1.964; 95% CI 1.381–2.794), and high VBA PI (OR 1.200; 95% CI 1.016–1.418), respectively.

Conclusion

Heavier IAC might cause generalized artery flow velocity changes and increased pulsatility index, which may indicate high resistance within cerebrovasculature.

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Incidental pulmonary embolism in suspected stroke patients undergoing carotid CT angiography

Abstract

Purpose

The purpose of this study was to investigate the prevalence of incidental pulmonary embolism (IPE) in suspected stroke patients receiving carotid computed tomography angiography (CTA) and its characteristics.

Materials and methods

A total of 4873 cases receiving carotid CTA between January 2013 and December 2016 were retrospectively reassessed by one radiologist. Patients with previous or suspected PE were excluded. The remaining prior contrast-enhanced carotid CTA studies were regarded as a "potentially incidental" IPE when a filling defect was found in one or more pulmonary arteries and subjected to the other two thoracic radiologists independently for reviewing and assessing for characteristics of the IPE and the image quality of the PE. The differences were noted between inpatients and outpatients in prevalence of IPE. Characteristics of the patients with IPE were also studied in terms of gender, age, as well as clinical indication.

Results

The prevalence of IPE among these suspected stroke patients was 0.8% on carotid CT angiography, and 24 (96%) of all IPEs had not been previously diagnosed by the original reporting radiologists. Most of the IPEs were at the lobar or segmental levels, single and in right upper lobe of pulmonary arteries. In most of the cases, the reviewing radiologists judged the contrast bolus as good. The outpatient group had a lower percentage of patients with IPE when compared with the inpatient counterpart (p = 0.024). The prevalence of IPE in patients with suspected stroke was higher with the increasing of age (p = 0.013).

Conclusions

IPE can occur in suspected stroke patients on carotid CT angiography, and most of them have been previously neglected in clinical practice. Radiologists should check the higher pulmonary arterial vasculature carefully on the contrast-enhanced carotid CTA scans.

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Quantitative Analysis of Conebeam CT for Delineating Stents in Stent-Assisted Coil Embolization.

Quantitative Analysis of Conebeam CT for Delineating Stents in Stent-Assisted Coil Embolization.

AJNR Am J Neuroradiol. 2018 Feb 01;:

Authors: Kuriyama T, Sakai N, Beppu M, Sakai C, Imamura H, Masago K, Katakami N, Isoda H

Abstract
BACKGROUND AND PURPOSE: Innovative techniques and device-related advances have improved the outcomes of neuroendovascular treatment. 3D imaging has previously used 2 × 2 binning, but 1 × 1 binning has recently been made available. The aim of this study was to evaluate the quantitative ability of conebeam CT for stent delineation and to investigate its effectiveness in the clinical environment.
MATERIALS AND METHODS: Four acquisition groups of 3D MIP images acquired using conebeam CT with varying conditions (acquisition time, 10 or 20 seconds and binning, 1 × 1 or 2 × 2) were compared. Two methods of analysis were performed, a phantom study and an analysis of 28 randomly selected patients. The phantom study assessed the contrast-to-noise ratio and full width at half maximum values in conebeam CT images of intracranial stent struts. In the clinical subjects, we assessed contrast-to-noise ratio, full width at half maximum, and dose-area product.
RESULTS: In the phantom study, the contrast-to-noise ratio was not considerably different between 10- and 20-second acquisition times at equivalent binning settings. Additionally, the contrast-to-noise ratio at equivalent acquisition times did not differ considerably by binning setting. For the full width at half maximum results, equivalent acquisition times differed significantly by binning setting. In the clinical analyses, the 10-second/1 × 1 group (versus 20 second/2 × 2) showed a higher contrast-to-noise ratio (P < .05) and a dose-area product reduced by approximately 70% (P < .05), but the difference in full width at half maximum was not significant (P = .20).
CONCLUSIONS: For stent-assisted coil embolization, quantitative assessment of conebeam CT showed that 10 second/1 × 1 was equivalent to 20 second/2 × 2 for imaging deployed intracranial stents. Furthermore, the 10-second/1 × 1 settings resulted in a much smaller DAP.

PMID: 29419404 [PubMed - as supplied by publisher]

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Neuroradiology Fellowship Case Requirements Need Reform.

Neuroradiology Fellowship Case Requirements Need Reform.

AJNR Am J Neuroradiol. 2018 Feb 01;:

Authors: Pfeifer CM

PMID: 29419403 [PubMed - as supplied by publisher]

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Deep Learning in Neuroradiology.

Deep Learning in Neuroradiology.

AJNR Am J Neuroradiol. 2018 Feb 01;:

Authors: Zaharchuk G, Gong E, Wintermark M, Rubin D, Langlotz CP

Abstract
Deep learning is a form of machine learning using a convolutional neural network architecture that shows tremendous promise for imaging applications. It is increasingly being adapted from its original demonstration in computer vision applications to medical imaging. Because of the high volume and wealth of multimodal imaging information acquired in typical studies, neuroradiology is poised to be an early adopter of deep learning. Compelling deep learning research applications have been demonstrated, and their use is likely to grow rapidly. This review article describes the reasons, outlines the basic methods used to train and test deep learning models, and presents a brief overview of current and potential clinical applications with an emphasis on how they are likely to change future neuroradiology practice. Facility with these methods among neuroimaging researchers and clinicians will be important to channel and harness the vast potential of this new method.

PMID: 29419402 [PubMed - as supplied by publisher]

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Optimization of DARTEL Settings for the Detection of Alzheimer Disease.

Optimization of DARTEL Settings for the Detection of Alzheimer Disease.

AJNR Am J Neuroradiol. 2018 Feb 01;:

Authors: Komatsu J, Matsunari I, Samuraki M, Shima K, Noguchi-Shinohara M, Sakai K, Hamaguchi T, Ono K, Matsuda H, Yamada M

Abstract
BACKGROUND AND PURPOSE: Although Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL) has been introduced as an alternative to conventional voxel-based morphometry, there are scant data available regarding the optimal image-processing settings. The aim of this study was to optimize image-processing and ROI settings for the diagnosis of Alzheimer disease using DARTEL.
MATERIALS AND METHODS: Between May 2002 and August 2014, we selected 158 patients with Alzheimer disease and 198 age-matched healthy subjects; 158 healthy subjects served as the control group against the patients with Alzheimer disease, and the remaining 40 served as the healthy data base. Structural MR images were obtained in all the participants and were processed using DARTEL-based voxel-based morphometry with a variety of settings. These included modulated or nonmodulated, nonsmoothed or smoothed settings with a 4-, 8-, 12-, 16-, or 20-mm kernel size. A z score was calculated for each ROI, and univariate and multivariate logistic regression analyses were performed to determine the optimal ROI settings for each dataset. The optimal settings were defined as those demonstrating the highest χ2 test statistics in the multivariate logistic regression analyses. Finally, using the optimal settings, we obtained receiver operating characteristic curves. The models were verified using 10-fold cross-validation.
RESULTS: The optimal settings were obtained using the hippocampus and precuneus as ROIs without modulation and smoothing. The average area under the curve was 0.845 (95% confidence interval, 0.788-0.902).
CONCLUSIONS: We recommend using the precuneus and hippocampus as ROIs without modulation and smoothing for DARTEL-based voxel-based morphometry as a tool for diagnosing Alzheimer disease.

PMID: 29419401 [PubMed - as supplied by publisher]

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High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-Weighted MR Images: Comparison between Gadobutrol and Linear Gadolinium-Based Contrast Agents.

High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-Weighted MR Images: Comparison between Gadobutrol and Linear Gadolinium-Based Contrast Agents.

AJNR Am J Neuroradiol. 2018 Feb 01;:

Authors: Moser FG, Watterson CT, Weiss S, Austin M, Mirocha J, Prasad R, Wang J

Abstract
BACKGROUND AND PURPOSE: In view of the recent observations that gadolinium deposits in brain tissue after intravenous injection, our aim of this study was to compare signal changes in the globus pallidus and dentate nucleus on unenhanced T1-weighted MR images in patients receiving serial doses of gadobutrol, a macrocyclic gadolinium-based contrast agent, with those seen in patients receiving linear gadolinium-based contrast agents.
MATERIALS AND METHODS: This was a retrospective analysis of on-site patients with brain tumors. Fifty-nine patients received only gadobutrol, and 60 patients received only linear gadolinium-based contrast agents. Linear gadolinium-based contrast agents included gadoversetamide, gadobenate dimeglumine, and gadodiamide. T1 signal intensity in the globus pallidus, dentate nucleus, and pons was measured on the precontrast portions of patients' first and seventh brain MRIs. Ratios of signal intensity comparing the globus pallidus with the pons (globus pallidus/pons) and dentate nucleus with the pons (dentate nucleus/pons) were calculated. Changes in the above signal intensity ratios were compared within the gadobutrol and linear agent groups, as well as between groups.
RESULTS: The dentate nucleus/pons signal ratio increased in the linear gadolinium-based contrast agent group (t = 4.215, P < .001), while no significant increase was seen in the gadobutrol group (t = -1.422, P = .08). The globus pallidus/pons ratios followed similarly, with an increase in the linear gadolinium-based contrast agent group (t = 2.931, P < .0001) and no significant change in those receiving gadobutrol (t = 0.684, P = .25).
CONCLUSIONS: Successive doses of gadobutrol do not result in T1 shortening compared with changes seen in linear gadolinium-based contrast agents.

PMID: 29419400 [PubMed - as supplied by publisher]

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Spinal Angiogram: A Treacherous Criterion Standard….

Spinal Angiogram: A Treacherous Criterion Standard….

AJNR Am J Neuroradiol. 2018 Feb 01;:

Authors: Clarençon F, Shotar E, Boch AL, Rolla-Bigliani C, Al Raasi A, Grabli D, Vicart S, Sourour NA, Chiras J

PMID: 29419399 [PubMed - as supplied by publisher]

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Substantia Nigra Free Water Increases Longitudinally in Parkinson Disease.

Substantia Nigra Free Water Increases Longitudinally in Parkinson Disease.

AJNR Am J Neuroradiol. 2018 Feb 01;:

Authors: Guttuso T, Bergsland N, Hagemeier J, Lichter DG, Pasternak O, Zivadinov R

Abstract
BACKGROUND AND PURPOSE: Free water in the posterior substantia nigra obtained from a bi-tensor diffusion MR imaging model has been shown to significantly increase over 1- and 4-year periods in patients with early-stage idiopathic Parkinson disease compared with healthy controls, which suggests that posterior substantia nigra free water may be an idiopathic Parkinson disease progression biomarker. Due to the known temporal posterior-to-anterior substantia nigra degeneration in idiopathic Parkinson disease, we assessed longitudinal changes in free water in both the posterior and anterior substantia nigra in patients with later-stage idiopathic Parkinson disease and age-matched healthy controls for comparison.
MATERIALS AND METHODS: Nineteen subjects with idiopathic Parkinson disease and 19 age-matched healthy control subjects were assessed on the same 3T MR imaging scanner at baseline and after approximately 3 years.
RESULTS: Baseline mean idiopathic Parkinson disease duration was 7.1 years. Both anterior and posterior substantia nigra free water showed significant intergroup differences at baseline (P < .001 and P = .014, respectively, idiopathic Parkinson disease versus healthy controls); however, only anterior substantia nigra free water showed significant longitudinal group × time interaction increases (P = .021, idiopathic Parkinson disease versus healthy controls). There were no significant longitudinal group × time interaction differences found for conventional diffusion tensor imaging or free water-corrected DTI assessments in either the anterior or posterior substantia nigra.
CONCLUSIONS: Results from this study provide further evidence supporting substantia nigra free water as a promising disease-progression biomarker in idiopathic Parkinson disease that may help to identify disease-modifying therapies if used in future clinical trials. Our novel finding of longitudinal increases in anterior but not posterior substantia nigra free water is potentially a result of the much longer disease duration of our cohort compared with previously studied cohorts and the known posterior-to-anterior substantia nigra degeneration that occurs over time in idiopathic Parkinson disease.

PMID: 29419398 [PubMed - as supplied by publisher]

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Randomised controlled trial using a theory-based m-health intervention to improve physical activity and sleep health in adults: the Synergy Study protocol

Introduction

There is a need to reduce physical inactivity and poor sleep health in the adult population to decrease chronic disease rates and the associated burden. Given the high prevalence of these risk behaviours, effective interventions with potential for wide reach are warranted.

Methods and analysis

The aim of this two-arm RCT will be to test the effect of a three month personalised mobile app intervention on two main outcomes: minutes of moderate-to-vigorous-intensity physical activity and overall sleep quality. In addition, between-group changes in health-related quality of life and mental health status will be assessed as secondary outcomes. The pre-specified mediators and moderators include social cognitive factors, the neighbourhood environment, health (BMI, depression, anxiety, stress), sociodemographic factors (age, gender, education) and app usage. Assessments will be conducted after three months (primary endpoint) and six months (follow-up). The intervention will provide access to a specifically developed mobile app, through which participants can set goals for active minutes, daily step counts, resistance training, sleep times and sleep hygiene practice. The app also allows participants to log their behaviours daily and view progress bars as well as instant feedback in relation to goals. The personalised support system will consist of weekly summary reports, educational and instructional materials, prompts on disengagement and weekly facts.

Ethics and dissemination

The Human Research Ethics Committee of The University of Newcastle, Australia granted full approval: H-2016–0181. This study will assess the efficacy of a combined behaviour intervention, mechanisms of behaviour change and gather high-quality process data, all of which will help refine future trials. Dissemination of findings will include publication in a peer-reviewed journal and presentation at national or international conferences. Participants will receive a plain English summary report of results.

Trial registration number

ACTRN12617000376347; Pre-results.

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Effect of long-term electroacupuncture stimulation on recovery of sensorimotor function after peripheral nerve anastomosis

Background

Recently, application of electroacupuncture (EA) to stimulate nerve regeneration has become a mainstream treatment in clinical rehabilitation and related basic research, but the efficacy of long-term stimulation has not been confirmed.

Objective

To evaluate the influence of long term EA on peripheral nerve injury (PNI) from multiple angles.

Method

Twenty-four rats were divided into three groups: control, PNI and PNI+EA. In the latter two groups, PNI was modelled by transection followed by re-anastomosis of thesciatic nerve. In the PNI+EA group only,EA was delivered using a discontinuous wave with frequency 5 Hz, pulse width 2 ms, and intensity approximately 2 mA, until the affected limb was observed to twitch slightly. The treatment was given for 15 min each time, six times a week (continuously for 6 days followed by a 1-day break) for a total of 8 weeks. The effects of EA on anastomotic sciatic nerve regeneration were evaluated using the sciatic function index (SFI), mechanical withdrawal thresholds, thermo-nociceptive thresholds, conduction velocity of the sciatic nerve and bilateral gastrocnemius wet weight.

Results

From weeks 2 to 4 after modelling, the SFI recovery rate in the PNI+EA group was faster than that in the PNI group. In week 4, the SFI of the PNI+EA group was significantly higher than that of the PNI group (p<0.05). However, a significant effect of EA was no longer evident from weeks 5 to 8. There was no effect of acupuncture on anti-amyotrophy and conduction velocity of the sciatic nerve at 8 weeks after modelling. EA did not shorten the paw withdrawal threshold time, but appeared to alleviate thermo-nociceptive sensitivity.

Conclusion

Long term repeated stimulation of the same site with EA does not appear to be conducive to the functional recovery of an injured sciatic nerve in rats.

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Acupuncture relieves motion sickness via the IR{beta}-ERK1/2-dependent insulin receptor signalling pathway

Objective

Acupuncture has been widely used for the treatment of motion sickness (MS), but the underlying mechanisms are unclear. The aim of this research was to study the mechanism of acupuncture in the treatment of MS.

Methods

To observe the effects of acupuncture in the treatment of MS, 80 rats were randomised into five groups that were subjected to acceleration and either remained untreated (CTRL), or received restraint (REST), scopolamine (SCOP) or acupuncture at SP4 (sham) or PC6+ST36 (verum) acupuncture points. To study the mechanism underlying the effects of acupuncture in the treatment of MS, 48 rats were randomised into three groups: acupuncture+extracellular regulated protein kinases (ERK) 1/2 inhibitor (ERKinh), acupuncture+insulin receptor (IR) antagonist (IRant), and acupuncture+vehicle (VEH). After acceleration, the MS index (MSI) and spontaneous activity (SA) of the rats were recorded. Serum stress hormones, Fos-positive cells, c-fos mRNA in the vestibular nucleus, and IRβ-, p-IRβ-, ERK1/2- and p-ERK1/2-positive cells in the dorsal motor nucleus of the vagus nerve (DMV) were detected.

Results

After acceleration, MS symptoms in the PC6+ST36 and SCOP groups were reduced compared with the CTRL, REST, and SP4 groups. The number of p-IRβ- and p-ERK1/2-positive cells and insulin levels were higher in the PC6+ST36 group than in the CTRL, REST, and SP4 groups. After ERK1/2 inhibitor and IR antagonist treatment, MS symptoms in the VEH group were lower than in the ERKinh and IRant groups.

Conclusions

Our study demonstrates that acupuncture significantly alleviates MS through the IRβ-ERK1/2-dependent insulin receptor signalling pathway in the DMV

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Using photography to enhance GP trainees reflective practice and professional development

The capacity and the commitment to reflect are integral to the practice of medicine and are core components of most general practitioners (GP) training programmes. Teaching through the humanities is a growing area within medical education, but one which is often considered a voluntary ‘add-on’ for the interested doctor. This article describes an evaluation of a highly innovative pedagogical project which used photography as a means to enhance GP trainees’ reflective capacity, self-awareness and professional development. Photography was used as a tool to develop GP trainees’ skills in recognising and articulating the attitudes, feelings and values that might impact on their clinical work and to enhance their confidence in their ability to deal with these concerns/issues. We submit that photography is uniquely well suited for facilitating insight and self-reflection because it provides the ability to record ‘at the touch of a button’ those scenes and images to which our attention is intuitively drawn without the need for—or the interference of—conscious decisions. This allows us the opportunity to reflect later on the reasons for our intuitive attraction to these scenes. These photography workshops were a compulsory part of the GP training programme and, despite the participants’ traditional scientific backgrounds, the results clearly demonstrate the willingness of participants to accept—even embrace—the use of art as a tool for learning. The GP trainees who took part in this project acknowledged it to be beneficial for both their personal and professional development.

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At the intersection of self and not-self: finding the locus of 'self in autoimmunity

Individuals with chronic autoimmune disease experience a sense of vulnerability. In part, this relates to the struggle for finding the meaning of the illness. The consequent existential distress may manifest in an unseated sense of personhood. Insight into the mechanism of this state of powerlessness and of perceived loss of agency is central to establishing a supportive clinician–patient relationship. This present exposition underscores the concept of autoimmunity as one that represents a demarcation in the psyche: one that is not just a threat to our sense of self-hood but also to our humanity. Autoimmunity exposes the challenge imposed on the relating of the self to one’s own self and hence is an ontological challenge. The breach of the boundary between self and not-self that is caused by the autoimmune process culminates in feelings of alienation.

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Paradigm shift? Purity, progress and the origins of first-episode psychosis

First-episode psychosis has garnered significant attention and resources within mental health services in North America, Europe and Australia/New Zealand since the 1990s. Despite this widespread embrace, little scholarship exists that examines underlying concepts, ideologies and imagery embedded within the early intervention paradigm. In this paper, I offer a sociohistorical analysis of the emergence of first-episode psychosis and early intervention as entities in psychiatry, drawing on contemporary philosophical thought to explore various concepts embedded in them. Although scattered references to ‘prodrome’ and ‘incipient cases’ exist in the historic psychiatric literature, the notion of first-episode psychosis as a distinct chronological stage emerged in the late 1980s. This occurred in response to a desire for a homogeneous, medication-naive population within schizophrenia research. Thematically, concerns regarding ‘purity’ as well as notions of ‘progress’ can be read off of the body of work surrounding the creation of the term and its development into a clinical organising concept. Furthermore, examining the sociohistorical context of the term demonstrates its entanglement with the course of atypical antipsychotic drug development, the expansion of clinical rating scales and wider neoliberal biopolitics within healthcare. Within psychiatry, the early intervention model has been termed a ‘paradigm shift,’ with the promise that earlier interventions will translate into shorter durations of untreated illness, improved utilisation of services and better prognoses for recovery. While these are laudable goals, they are tied to assumptions about biomedical progress and idealisations of clinical populations that feminist and disability critiques problematise.

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Feedback: Botoxed camels disqualified from Saudi beauty contest

Plus: why a robot named Fabio was fired from its job, why old £1 coins are worth more than new ones, a new unit of time, drugs in videogames, and more

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Primitive human eggs matured in the lab for the first time

Human eggs have been removed in their most primitive state and brought to maturity in the lab for the first time, potentially boosting fertility treatments.

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Incidence and disease burden of chemotherapy-induced peripheral neuropathy in a population-based cohort

Objective

To assess disease burden of chemotherapy-induced peripheral neuropathy (CIPN), which is a common dose-limiting side effect of neurotoxic chemotherapy. Late effects of CIPN may increase with improved cancer survival.

Methods

Olmsted County, Minnesota residents receiving neurotoxic chemotherapy were identified and CIPN was ascertained via text searches of polyneuropathy symptoms in the medical record. Clinical records were queried to collect data on baseline characteristics, risk factors, signs and symptoms of CIPN, medications, impairments and International Classification of Diseases, Ninth Revision (ICD-9) diagnostic codes for all subjects.

Results

A total of 509 individuals with incident exposure to an inclusive list of neurotoxic chemotherapy agents between 2006 and 2008 were identified. 268 (52.7%) of these individuals were determined to have CIPN. The median time from incident exposure to first documented symptoms was 71 days. Patients with CIPN received a neuropathy ICD-9 diagnosis in only 37 instances (13.8%). Pain symptoms and use of pain medications were observed more often in patients with CIPN. Five-year survival was greater in those with CIPN (55.2%) versus those without (36.1%). Those with CIPN surviving greater than 5 years (n=145) continued to have substantial impairments and were more likely to be prescribed opioids than those without CIPN (OR 2.0, 1.06–3.69).

Conclusions

Results from our population-based study are consistent with previous reports of high incidence of CIPN in the first 2 years following incident exposure to neurotoxic chemotherapeutic agents, and its association with significant pain symptomatology and accompanied long-term opioid use. Increased survival following exposure to neurotoxic chemotherapy and its long-term disease burden necessitates further study among survivors.

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Meaning of psychiatric symptoms in frontotemporal dementia

The meaning of psychiatric symptoms prior to a diagnosis of genetic frontotemporal dementia is discussed as either being part of a prodrome or being a sign of congenital neuronal vulnerability.

Cheran et al1 in this journal investigated the nature of lifetime psychiatric symptoms in preclinical MAPT mutation carriers. Compared with their non-carrier relatives as well as the population, they more often had signs of atypical depression, not fulfilling the criteria of major depressive disorder, and they did not have the anxiety and mood disorders that characterised their non-carrier controls. Since atypical depression was a current condition, and no other psychiatric disturbances were reported from their earlier lifespan, some form of emotional blunting and a relative absence of fear might be among the prodromes or early beginning of behavioural variant frontotemporal dementia (bvFTD).

Defining the onset of bvFTD in persons belonging to a family with autosomal dominant bvFTD is important, both from...

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Co-occurrence of depressive symptoms and executive dysfunction after stroke: associations with brain pathology and prognosis

Objective

To examine, first, whether the co-occurrence of executive dysfunction (ED) and poststroke depression (PSD) shows different associations with neuroimaging markers and the course of depression and executive function, and second, whether it is associated with a different course on other cognitive domains and quality of life.

Methods

The present study included 245 stroke patients (35.9% female, mean age 67.5 years (SD=11.9). All patients completed neuropsychological and neuropsychiatric assessment 3 months poststroke, which were repeated at 6-month and 12-month follow-up. A subset (n=186) received 3-Tesla brain MRI at baseline to evaluate lesion-related imaging markers, white matter hyperintensity volume, global brain atrophy and total cerebral small vessel disease burden.

Results

Patients with ‘depression–executive dysfunction syndrome’ (DES) showed higher white matter hyperintensity volumes compared with all other groups and more frequently showed left-sided lesions compared with ED only and PSD only. They also had more frequently old infarcts and higher total cerebral small vessel disease burden compared with PSD only and patients with neither ED nor PSD, and more global brain atrophy compared with PSD only. Longitudinal analyses showed that patients with DES had a more chronic course of depressive symptoms relative to PSD only, and a stable pattern of worse cognitive performance similar to patients with ED only.

Conclusions

The co-occurrence of ED and PSD is associated with a worse prognosis of depression, persistent cognitive impairment and a higher amount of vascular and degenerative brain pathology. Future studies are needed to examine whether these patients represent a more severe subtype within the PSD spectrum.

Clinical trial registration

NCT02585349;Results.

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health technology; +250 new citations

250 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

health technology

These pubmed results were generated on 2018/02/09

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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American doctors expect to save money under new US tax law [News]

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The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants [Research]

BACKGROUND:

The Personal Genome Project Canada is a comprehensive public data resource that integrates whole genome sequencing data and health information. We describe genomic variation identified in the initial recruitment cohort of 56 volunteers.

METHODS:

Volunteers were screened for eligibility and provided informed consent for open data sharing. Using blood DNA, we performed whole genome sequencing and identified all possible classes of DNA variants. A genetic counsellor explained the implication of the results to each participant.

RESULTS:

Whole genome sequencing of the first 56 participants identified 207 662 805 sequence variants and 27 494 copy number variations. We analyzed a prioritized disease-associated data set (n = 1606 variants) according to standardized guidelines, and interpreted 19 variants in 14 participants (25%) as having obvious health implications. Six of these variants (e.g., in BRCA1 or mosaic loss of an X chromosome) were pathogenic or likely pathogenic. Seven were risk factors for cancer, cardiovascular or neurobehavioural conditions. Four other variants — associated with cancer, cardiac or neurodegenerative phenotypes — remained of uncertain significance because of discrepancies among databases. We also identified a large structural chromosome aberration and a likely pathogenic mitochondrial variant. There were 172 recessive disease alleles (e.g., 5 individuals carried mutations for cystic fibrosis). Pharmacogenomics analyses revealed another 3.9 potentially relevant genotypes per individual.

INTERPRETATION:

Our analyses identified a spectrum of genetic variants with potential health impact in 25% of participants. When also considering recessive alleles and variants with potential pharmacologic relevance, all 56 participants had medically relevant findings. Although access is mostly limited to research, whole genome sequencing can provide specific and novel information with the potential of major impact for health care.

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Whole genome sequencing in the clinic: empowerment or too much information? [Commentary]

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Reply to Safra et al.: Lack of theoretical rationale and selective analysis does not imply no strong evidence [Social Sciences]

Safra et al. (1) contend that lack of control is not the mechanism for our findings (2); instead, distrust is a better candidate because of its greater explanatory power. There are several issues with their conjecture. First, study 1 was aimed at demonstrating the main effect of economic uncertainty on...

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No strong evidence that authoritarian attitudes are driven by a lack of control [Social Sciences]

Kakkar and Sivanathan (1) provide new evidence of the link between economic crises and the preference for dominant leaders and strengthen previous evidence of the influence of economic crises on authoritarianism (2–5). However, the authors’ interpretation of why economic uncertainty favors dominant leaders entails two further predictions that are not...

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Modular origins of biological electron transfer chains [Biophysics and Computational Biology]

Oxidoreductases catalyze electron transfer reactions that ultimately provide the energy for life. A limited set of ancestral protein-metal modules are presumably the building blocks that evolved into this diverse protein family. However, the identity of these modules and their path to modern oxidoreductases is unknown. Using a comparative structural analysis...

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Full molecular trajectories of RNA polymerase at single base-pair resolution [Biophysics and Computational Biology]

In recent years, highly stable optical tweezers systems have enabled the characterization of the dynamics of molecular motors at very high resolution. However, the motion of many motors with angstrom-scale dynamics cannot be consistently resolved due to poor signal-to-noise ratio. Using an acousto-optic deflector to generate a “time-shared” dual-optical trap,...

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High-resolution cryo-EM structures of actin-bound myosin states reveal the mechanism of myosin force sensing [Biophysics and Computational Biology]

Myosins adjust their power outputs in response to mechanical loads in an isoform-dependent manner, resulting in their ability to dynamically adapt to a range of motile challenges. Here, we reveal the structural basis for force-sensing based on near-atomic resolution structures of one rigor and two ADP-bound states of myosin-IB (myo1b)...

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Correction for Noh et al., ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons [Correction]

COLLOQUIUM Correction for “ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons,” by Kyung-Min Noh, Ian Maze, Dan Zhao, Bin Xiang, Wendy Wenderski, Peter W. Lewis, Li Shen, Haitao Li, and C. David Allis, which was first published December 23, 2014; 10.1073/pnas.1411258112 (Proc Natl Acad...

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Confirmation of intersubunit connectivity and topology of designed protein complexes by native MS [Biophysics and Computational Biology]

Computational protein design provides the tools to expand the diversity of protein complexes beyond those found in nature. Understanding the rules that drive proteins to interact with each other enables the design of protein–protein interactions to generate specific protein assemblies. In this work, we designed protein–protein interfaces between dimers and...

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Global models underestimate large decadal declining and rising water storage trends relative to GRACE satellite data [Environmental Sciences]

Assessing reliability of global models is critical because of increasing reliance on these models to address past and projected future climate and human stresses on global water resources. Here, we evaluate model reliability based on a comprehensive comparison of decadal trends (2002–2014) in land water storage from seven global models...

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Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer’s disease [Neuroscience]

Mixed pathology, with both Alzheimer’s disease and vascular abnormalities, is the most common cause of clinical dementia in the elderly. While usually thought to be concurrent diseases, the fact that changes in cerebral blood flow are a prominent early and persistent alteration in Alzheimer’s disease raises the possibility that vascular...

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Shape-directed dynamics of active colloids powered by induced-charge electrophoresis [Physics]

The symmetry and shape of colloidal particles can direct complex particle motions through fluid environments powered by simple energy inputs. The ability to rationally design or “program” the dynamics of such active colloids is an important step toward the realization of colloidal machines, in which components assemble spontaneously in space...

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Increased thermogenesis by a noncanonical pathway in ANGPTL3/8-deficient mice [Medical Sciences]

Dietary triglyceride (TG) is the most efficient energy substrate. It is processed and stored at substantially lower metabolic cost than is protein or carbohydrate. In fed animals, circulating TGs are preferentially routed for storage to white adipose tissue (WAT) by angiopoietin-like proteins 3 (A3) and 8 (A8). Here, we show...

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Surface structure evolution in a homologous series of ionic liquids [Physics]

Interfaces of room temperature ionic liquids (RTILs) are important for both applications and basic science and are therefore intensely studied. However, the evolution of their interface structure with the cation’s alkyl chain length n from Coulomb to van der Waals interaction domination has not yet been studied for even a...

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Early hominids may have been weed species [Anthropology]

Panid, gorillid, and hominid social structures appear to have diverged as dramatically as did their locomotor patterns as they emerged from a late Miocene last common ancestor (LCA). Despite their elimination of the sectorial canine complex and adoption of bipedality with its attendant removal of their ready access to the...

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A neurochemical hypothesis for the origin of hominids [Anthropology]

It has always been difficult to account for the evolution of certain human characters such as language, empathy, and altruism via individual reproductive success. However, the striatum, a subcortical region originally thought to be exclusively motor, is now known to contribute to social behaviors and “personality styles” that may link...

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MYCN-amplified neuroblastoma maintains an aggressive and undifferentiated phenotype by deregulation of estrogen and NGF signaling [Medical Sciences]

Neuroblastoma (NB) is a remarkably heterogenic childhood tumor of the sympathetic nervous system with clinical behavior ranging from spontaneous regression to poorly differentiated tumors and metastasis. MYCN is amplified in 20% of cases and correlates with an undifferentiated, aggressive phenotype and poor prognosis. Estrogen receptor alpha (ERα) and the nerve...

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Hsp90 chaperones hemoglobin maturation in erythroid and nonerythroid cells [Cell Biology]

Maturation of adult (α2β2) and fetal hemoglobin (α2γ2) tetramers requires that heme be incorporated into each globin. While hemoglobin alpha (Hb-α) relies on a specific erythroid chaperone (alpha Hb-stabilizing protein, AHSP), the other chaperones that may help mature the partner globins (Hb-γ or Hb-β) in erythroid cells, or may enable...

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Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells [Microbiology]

Viruses causing chronic infection artfully manipulate infected cells to enable viral persistence in vivo under the pressure of immunity. Human T-cell leukemia virus type 1 (HTLV-1) establishes persistent infection mainly in CD4+ T cells in vivo and induces leukemia in this subset. HTLV-1–encoded Tax is a critical transactivator of viral...

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Extracellular vesicle budding is inhibited by redundant regulators of TAT-5 flippase localization and phospholipid asymmetry [Cell Biology]

Cells release extracellular vesicles (EVs) that mediate intercellular communication and repair damaged membranes. Despite the pleiotropic functions of EVs in vitro, their in vivo function is debated, largely because it is unclear how to induce or inhibit their formation. In particular, the mechanisms of EV release by plasma membrane budding...

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The eardrums move when the eyes move: A multisensory effect on the mechanics of hearing [Neuroscience]

Interactions between sensory pathways such as the visual and auditory systems are known to occur in the brain, but where they first occur is uncertain. Here, we show a multimodal interaction evident at the eardrum. Ear canal microphone measurements in humans (n = 19 ears in 16 subjects) and monkeys...

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Cytocapsular tubes conduct cell translocation [Cell Biology]

Cell locomotion is essential for multicellular organism embryo development, organ homeostasis, tissue regeneration, immune responses, and tumor metastasis. Here we report that single mammalian cells can generate two extracellular membranous compartments: cytocapsulae and cytocapsular tubes. Cells migrate in cytocapsulae and engender cytocapsular tubes, which exhibit pleiotropic biological functions and provide...

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High PRF ultrafast sliding compound doppler imaging: fully qualitative and quantitative analysis of blood flow

Ultrafast compound Doppler imaging based on plane-wave excitation (UCDI) can be used to evaluate cardiovascular diseases using high frame rates. In particular, it provides a fully quantifiable flow analysis over a large region of interest with high spatio-temporal resolution. However, the pulse-repetition frequency (PRF) in the UCDI method is limited for high-velocity flow imaging since it has a tradeoff between the number of plane-wave angles ( N ) and acquisition time. In this paper, we present high PRF ultrafast sliding compound Doppler imaging method (HUSDI) to improve quantitative flow analysis. With the HUSDI method, full scanline images (i.e. each tilted plane wave data) in a Doppler frame buffer are consecutively summed using a sliding window to create high-quality ensemble data so that there is no reduction in frame rate and flow sensitivity. In addition, by updating a new compounding set with a certain time difference (i.e. sliding window step size or L ), t...

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First heating measurements of endovascular stents in magnetic particle imaging

Description unavailable

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Comparison of Monte Carlo and analytical dose computations for intensity modulated proton therapy

To evaluate the effect of approximations in clinical analytical calculations performed by a treatment planning system (TPS) on dosimetric indices in intensity modulated proton therapy. TPS calculated dose distributions were compared with dose distributions as estimated by Monte Carlo (MC) simulations, calculated with the fast dose calculator (FDC) a system previously benchmarked to full MC. This study analyzed a total of 525 patients for four treatment sites (brain, head-and-neck, thorax and prostate). Dosimetric indices (D02, D05, D20, D50, D95, D98, EUD and Mean Dose) and a gamma-index analysis were utilized to evaluate the differences. The gamma-index passing rates for a 3%/3 mm criterion for voxels with a dose larger than 10% of the maximum dose had a median larger than 98% for all sites. The median difference for all dosimetric indices for target volumes was less than 2% for all cases. However, differences for target volumes as large as 10% were found for 2% of the thoracic...

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IJMS, Vol. 19, Pages 526: Correction: Wen-I Liao, et al. Ac2-26, an Annexin A1 Peptide, Attenuates Ischemia-Reperfusion-Induced Acute Lung Injury. Int. J. Mol. Sci. 2017, 18, 1771

IJMS, Vol. 19, Pages 526: Correction: Wen-I Liao, et al. Ac2-26, an Annexin A1 Peptide, Attenuates Ischemia-Reperfusion-Induced Acute Lung Injury. Int. J. Mol. Sci. 2017, 18, 1771

International Journal of Molecular Sciences doi: 10.3390/ijms19020526

Authors: Wen-I Liao Shu-Yu Wu Geng-Chin Wu Hsin-Ping Pao Shih-En Tang Kun-Lun Huang Shi-Jye Chu

The authors would like to make a correction to their published paper [1][...]

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IJERPH, Vol. 15, Pages 298: Suicidal Ideation among Youth Living in the Slums of Kampala, Uganda

IJERPH, Vol. 15, Pages 298: Suicidal Ideation among Youth Living in the Slums of Kampala, Uganda

International Journal of Environmental Research and Public Health doi: 10.3390/ijerph15020298

Authors: Rachel Culbreth Monica Swahn David Ndetei Lynnette Ametewee Rogers Kasirye

The purpose of this study is to examine the factors associated with suicidal ideation among youth living in the slums of Kampala, Uganda. Analyses are based on cross-sectional survey data, collected in 2014, of a convenience sample (n = 1134) of urban service-seeking youth participating in a Uganda Youth Development Link drop-in center. Logistic regression analyses were computed to determine the psychosocial factors associated with suicidal ideation. Among youth participants, 23.54% (n = 266) reported suicidal ideation in the past year. In the multivariable analysis, suicidal ideation was associated with being female (OR: 1.61; 95% CI: 1.15, 2.25), reporting one (OR: 1.51; 95% CI: 1.05, 2.18) or two deceased parents (OR: 1.55; 95% CI: 1.03, 2.35), ever living on the streets (OR: 2.65; 95% CI: 1.86, 3.79), problem drinking (OR: 1.83; 95% CI: 1.19, 2.80), sexually transmitted infection (OR: 1.59; 95% CI: 1.14, 2.21), ever being raped (OR: 1.49; 95% CI: 1.01, 2.20), and experiencing physical child abuse (OR: 2.40; 95% CI: 1.75, 3.27). Our findings underscore many unmet needs in this vulnerable population. However, strategies that specifically seek to address problem drinking—a modifiable risk factor for suicidal ideation—may be particularly warranted in this low-resource setting.

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IJERPH, Vol. 15, Pages 299: Urinary Arsenic in Human Samples from Areas Characterized by Natural or Anthropogenic Pollution in Italy

IJERPH, Vol. 15, Pages 299: Urinary Arsenic in Human Samples from Areas Characterized by Natural or Anthropogenic Pollution in Italy

International Journal of Environmental Research and Public Health doi: 10.3390/ijerph15020299

Authors: Fabrizio Minichilli Fabrizio Bianchi Anna Ronchi Francesca Gorini Elisa Bustaffa

Arsenic is ubiquitous and has a potentially adverse impact on human health. We compared the distribution of concentrations of urinary inorganic arsenic plus methylated forms (uc(iAs+MMA+DMA)) in four Italian areas with other international studies, and we assessed the relationship between uc(iAs+MMA+DMA) and various exposure factors. We conducted a human biomonitoring study on 271 subjects (132 men) aged 20–44, randomly sampled and stratified by area, gender, and age. Data on environmental and occupational exposure and dietary habits were collected through a questionnaire. Arsenic was speciated using chromatographic separation and inductively coupled mass spectrometry. Associations between uc(iAs+MMA+DMA) and exposure factors were evaluated using the geometric mean ratio (GMR) with a 90% confidence interval by stepwise multiple regression analysis. The 95th percentile value of uc(iAs+MMA+DMA) for the whole sample (86.28 µg/L) was higher than other national studies worldwide. A statistical significant correlation was found between uc(iAs+MMA+DMA) and occupational exposure (GMR: 2.68 [1.79–4.00]), GSTT gene (GMR: 0.68 [0.52–0.80]), consumption of tap water (GMR: 1.35 [1.02–1.77]), seafood (GMR: 1.44 [1.11–1.88]), whole milk (GMR: 1.34 [1.04–1.73]), and fruit/vegetables (GMR: 1.37 [1.03–1.82]). This study demonstrated the utility of uc(iAs+MMA+DMA) as a biomarker to assess environmental exposure. In a public health context, this information could be used to support remedial action, to prevent individuals from being further exposed to environmental arsenic sources.

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Transcriptionally inducible Pleckstrin homology-like domain, family A, member 1, attenuates ErbB receptor activity by inhibiting receptor oligomerization [Computational Biology]

Feedback control is a key mechanism in signal transduction, intimately involved in regulating the outcome of the cellular response. Here, we report a novel mechanism by which PHLDA1, Pleckstrin homology-like domain, family A, member 1, negatively regulates ErbB receptor signaling by inhibition of receptor oligomerization. We have found that the ErbB3 ligand, heregulin, induces PHILDA1 expression in MCF-7 cells. Transcriptionally-induced PHLDA1 protein directly binds to ErbB3, whereas knockdown of PHLDA1 increases complex formation between ErbB3 and ErbB2. To provide insight into the mechanism for our time-course and single-cell experimental observations, we performed a systematic computational search of network topologies of the mathematical models based on receptor dimer-tetramer formation in the ErbB activation processes. Our results indicate that only a model in which PHLDA1 inhibits formation of both dimers and tetramer can explain the experimental data. Predictions made from this model were further validated by single-molecule imaging experiments. Our studies suggest a unique regulatory feature of PHLDA1 to inhibit the ErbB receptor oligomerization process and thereby control the activity of receptor signaling network.

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Identification of essential amino acids for glucose transporter 5 (GLUT5)-mediated fructose transport [Protein Structure and Folding]

Intestinal fructose uptake is mainly mediated by glucose transporter 5 (GLUT5/SLC2A5). Its closest relative, GLUT7, is also expressed in the intestine but does not transport fructose. For rat Glut5, a change of glutamine to glutamic acid at codon 166 (p.Q166E) has been reported to alter the substrate-binding specificity by shifting Glut5-mediated transport from fructose to glucose. Using chimeric proteins of GLUT5 and GLUT7, here we identified amino acid residues of GLUT5 that define its substrate specificity. The proteins were expressed in NIH-3T3 fibroblasts, and their activities were determined by fructose radiotracer flux. We divided the human GLUT5 sequence into 26 fragments and then replaced each fragment with the corresponding region in GLUT7. All fragments that yielded reduced fructose uptake were analyzed further by assessing the role of individual amino acid residues. Various positions in the first extracellular loop, in the fifth, seventh, eighth, ninth, and tenth transmembrane domains (TMDs), and in the regions between the ninth and tenth TMDs and tenth and 11th TMDs were identified as being important for proper fructose uptake. Although the p.Q167E change did not render the human protein into a glucose transporter, molecular dynamics simulations revealed a drastic change in the dynamics and a movement of the intracellular loop connecting the sixth and seventh TMDs, which covers the exit of the ligand. Finally, we generated a GLUT7–GLUT5 chimera consisting of the N-terminal part of GLUT7 and the C-terminal part of GLUT5. Although this chimera was inactive, we demonstrate fructose transport after introduction of four amino acids derived from GLUT5.

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Stepwise processing analyses of the single-turnover PCSK9 protease reveal its substrate sequence specificity and link clinical genotype to lipid phenotype [Lipids]

Proprotein convertase subtilisin/kexin type 9 (PCSK9) down-regulates the low-density lipoprotein (LDL) receptor, elevating LDL cholesterol and accelerating atherosclerotic heart disease, making it a promising cardiovascular drug target. To achieve its maximal effect on the LDL receptor, PCSK9 requires autoproteolysis. After cleavage, PCSK9 retains its prodomain in the active site as a self-inhibitor. Unlike other proprotein convertases, however, this retention is permanent, inhibiting any further protease activity for the remainder of its life cycle. Such inhibition has proven a major challenge toward a complete biochemical characterization of PCSK9's proteolytic function, which could inform therapeutic approaches against its hypercholesterolemic effects. To address this challenge, we employed a cell-based, high-throughput method using a luciferase readout to evaluate the single-turnover PCSK9 proteolytic event. We combined this method with saturation mutagenesis libraries to interrogate the sequence specificities of PCSK9 cleavage and proteolysis-independent secretion. Our results highlight several key differences in sequence identity between these two steps, complement known structural data, and suggest that PCSK9 self-proteolysis is the rate-limiting step of secretion. Additionally, we found that for missense SNPs within PCSK9, alterations in both proteolysis and secretion are common. Last, we show that some SNPs allosterically modulate PCSK9's substrate sequence specificity. Our findings indicate that PCSK9 proteolysis acts as a commonly perturbed but critical switch in controlling lipid homeostasis and provide a new hope for the development of small-molecule PCSK9 inhibitors.

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Crystal structure of the FliF-FliG complex from Helicobacter pylori yields insight into the assembly of the motor MS-C ring in the bacterial flagellum [Microbiology]

The bacterial flagellar motor is a self-assembling supramolecular nanodevice. Its spontaneous biosynthesis is initiated by the insertion of the MS ring protein FliF into the inner membrane, followed by attachment of the switch protein FliG. Assembly of this multiprotein complex is tightly regulated to avoid nonspecific aggregation, but the molecular mechanisms governing flagellar assembly are unclear. Here, we present the crystal structure of the cytoplasmic domain of FliF complexed with the N-terminal domain of FliG (FliFC–FliGN) from the bacterium Helicobacter pylori. Within this complex, FliFC interacted with FliGN through extensive hydrophobic contacts similar to those observed in the FliFC–FliGN structure from the thermophile Thermotoga maritima, indicating conservation of the FliFC–FliGN interaction across bacterial species. Analysis of the crystal lattice revealed that the heterodimeric complex packs as a linear superhelix via stacking of the armadillo repeat–like motifs (ARM) of FliGN. Notably, this linear helix was similar to that observed for the assembly of the FliG middle domain. We validated the in vivo relevance of the FliGN stacking by complementation studies in Escherichia coli. Furthermore, structural comparison with apo FliG from the thermophile Aquifex aeolicus indicated that FliF regulates the conformational transition of FliG and exposes the complementary ARM-like motifs of FliGN, containing conserved hydrophobic residues. FliF apparently both provides a template for FliG polymerization and spatiotemporally controls subunit interactions within FliG. Our findings reveal that a small protein fold can serve as a versatile building block to assemble into a multiprotein machinery of distinct shapes for specific functions.

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The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis [Membrane Biology]

Copper is required for the activity of cytochrome c oxidase (COX), the terminal electron-accepting complex of the mitochondrial respiratory chain. The likely source of copper used for COX biogenesis is a labile pool found in the mitochondrial matrix. In mammals, the proteins that transport copper across the inner mitochondrial membrane remain unknown. We previously reported that the mitochondrial carrier family protein Pic2 in budding yeast is a copper importer. The closest Pic2 ortholog in mammalian cells is the mitochondrial phosphate carrier SLC25A3. Here, to investigate whether SLC25A3 also transports copper, we manipulated its expression in several murine and human cell lines. SLC25A3 knockdown or deletion consistently resulted in an isolated COX deficiency in these cells, and copper addition to the culture medium suppressed these biochemical defects. Consistent with a conserved role for SLC25A3 in copper transport, its heterologous expression in yeast complemented copper-specific defects observed upon deletion of PIC2. Additionally, assays in Lactococcus lactis and in reconstituted liposomes directly demonstrated that SLC25A3 functions as a copper transporter. Taken together, these data indicate that SLC25A3 can transport copper both in vitro and in vivo.

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Arabidopsis thaliana rapid alkalinization factor 1-mediated root growth inhibition is dependent on calmodulin-like protein 38 [Plant Biology]

Arabidopsis thaliana rapid alkalinization factor 1 (AtRALF1) is a small secreted peptide hormone that inhibits root growth by repressing cell expansion. Although it is known that AtRALF1 binds the plasma membrane receptor FERONIA and conveys its signals via phosphorylation, the AtRALF1 signaling pathway is largely unknown. Here, using a yeast two-hybrid system to search for AtRALF1-interacting proteins in Arabidopsis, we identified calmodulin-like protein 38 (CML38) as an AtRALF1-interacting partner. We also found that CML38 and AtRALF1 are both secreted proteins that physically interact in a Ca2+- and pH-dependent manner. CML38-knockout mutants generated via T-DNA insertion were insensitive to AtRALF1, and simultaneous treatment with both AtRALF1 and CML38 proteins restored sensitivity in these mutants. Hybrid plants lacking CML38 and having high accumulation of the AtRALF1 peptide did not exhibit the characteristic short-root phenotype caused by AtRALF1 overexpression. Although CML38 was essential for AtRALF1-mediated root inhibition, it appeared not to have an effect on the AtRALF1-induced alkalinization response. Moreover, acridinium-labeling of AtRALF1 indicated that the binding of AtRALF1 to intact roots is CML38-dependent. In summary, we describe a new component of the AtRALF1 response pathway. The new component is a calmodulin-like protein that binds AtRALF1, is essential for root growth inhibition, and has no role in AtRALF1 alkalinization.

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Filling the mitochondrial copper pool [Bioenergetics]

A host of critical metalloproteins reside in mitochondria, where metallation occurs within the organelle after protein import. Although the pathways by which proteins are imported into the mitochondria are well known, the mechanisms by which their metal partners are imported are more obscure. A new study by Boulet et al. demonstrates that the mammalian SLC25A3 inner membrane transporter, previously known as a phosphate carrier, is also a functional Cu(I) importer, clarifying the source of mitochondrial copper and raising new questions about cellular copper homeostasis.

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Cantu syndrome-associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms [Molecular Bases of Disease]

The complex disorder Cantu syndrome (CS) arises from gain-of-function mutations in either KCNJ8 or ABCC9, the genes encoding the Kir6.1 and SUR2 subunits of ATP-sensitive potassium (KATP) channels, respectively. Recent reports indicate that such mutations can increase channel activity by multiple molecular mechanisms. In this study, we determined the mechanism by which KATP function is altered by several substitutions in distinct structural domains of SUR2: D207E in the intracellular L0-linker and Y985S, G989E, M1060I, and R1154Q/R1154W in TMD2. We engineered substitutions at their equivalent positions in rat SUR2A (D207E, Y981S, G985E, M1056I, and R1150Q/R1150W) and investigated functional consequences using macroscopic rubidium (86Rb+) efflux assays and patch-clamp electrophysiology. Our results indicate that D207E increases KATP channel activity by increasing intrinsic stability of the open state, whereas the cluster of Y981S/G985E/M1056I substitutions, as well as R1150Q/R1150W, augmented Mg-nucleotide activation. We also tested the responses of these channel variants to inhibition by the sulfonylurea drug glibenclamide, a potential pharmacotherapy for CS. None of the D207E, Y981S, G985E, or M1056I substitutions had a significant effect on glibenclamide sensitivity. However, Gln and Trp substitution at Arg-1150 significantly decreased glibenclamide potency. In summary, these results provide additional confirmation that mutations in CS–associated SUR2 mutations result in KATP gain-of-function. They help link CS genotypes to phenotypes and shed light on the underlying molecular mechanisms, including consequences for inhibitory drug sensitivity, insights that may inform the development of therapeutic approaches to manage CS.

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Positive charge in the n-region of the signal peptide contributes to efficient post-translational translocation of small secretory preproteins [Protein Synthesis and Degradation]

Increasing evidence indicates that many small secretory preproteins can undergo post-translational translocation across the membrane of the endoplasmic reticulum. Although the cellular machinery involved in post-translational translocation of small secretory preproteins has begun to be elucidated, the intrinsic signals contained within these small secretory preproteins that contribute to their efficient post-translational translocation remain unknown. Here, we analyzed the eukaryotic secretory proteome and discovered the small secretory preproteins tend to have a higher probability to harbor the positive charge in the n-region of the signal peptide (SP). Eliminating the positive charge of the n-region blocked post-translational translocation of newly synthesized preproteins and selectively impaired translocation efficiency of small secretory preproteins. The pathophysiological significance of the positive charge in the n-region of SP was underscored by recently identified preproinsulin SP mutations that impair translocation of preproinsulin and cause maturity onset diabetes of youth (MODY). Remarkably, we have found that slowing the polypeptide elongation rate of small secretory preproteins could alleviate the translocation defect caused by loss of the n-region positive charge of the signal peptide. Together, these data reveal not only a previously unrecognized role of the n-region's positive charge in ensuring efficient post-translational translocation of small secretory preproteins, but they also highlight the molecular contribution of defects in this process to the pathogenesis of genetic disorders such as MODY.

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