Elongin C (ELOC/TCEB1)-associated von Hippel-Lindau disease.

Around 95% of patients with clinical features that meet the diagnostic criteria for von Hippel-Lindau disease (VHL) have a detectable inactivating germline variant in VHL. The VHL protein (pVHL) functions as part of the E3 ubiquitin ligase complex comprising pVHL, elongin C, elongin B, cullin 2 and ring box 1 (VCB-CR complex), which plays a key role in oxygen sensing and degradation of hypoxia-inducible factors. To date, only variants in VHL have been shown to cause VHL disease. We undertook trio analysis by whole-exome sequencing in a proband with VHL disease but without a detectable VHL mutation. Molecular studies were also performed on paired DNA extracted from the proband's kidney tumour and blood and bioinformatics analysis of sporadic renal cell carcinoma (RCC) dataset was undertaken. A de novo pathogenic variant in ELOC NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) gene was identified in the proband. ELOC encodes elongin C, a key component [C] of the VCB-CR complex. The p.Tyr79Cys substitution is a mutational hotspot in sporadic VHL-competent RCC and has previously been shown to mimic the effects of pVHL deficiency on hypoxic signalling. Analysis of an RCC from the proband showed similar findings to that in somatically ELOC-mutated RCC (expression of hypoxia-responsive proteins, no somatic VHL variants and chromosome 8 loss). These findings are consistent with pathogenic ELOC variants being a novel cause for VHL disease and suggest that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease with no detectable VHL variant.

Observation versus screening spinal MRI and pre-emptive treatment for spinal cord compression in patients with castration-resistant prostate cancer and spinal metastases in the UK (PROMPTS): an open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Early diagnosis of malignant spinal cord compression (SCC) is crucial because pretreatment neurological status is the major determinant of outcome. In metastatic castration-resistant prostate cancer, SCC is a clinically significant cause of disease-related morbidity and mortality. We investigated whether screening for SCC with spinal MRI, and pre-emptive treatment if radiological SCC (rSCC) was detected, reduced the incidence of clinical SCC (cSCC) in asymptomatic patients with metastatic castration-resistant prostate cancer and spinal metastasis. METHODS: We did a parallel-group, open-label, randomised, controlled, phase 3, superiority trial. Patients with metastatic castration-resistant prostate cancer were recruited from 45 National Health Service hospitals in the UK. Eligible patients were aged at least 18 years, with an Eastern Co-operative Oncology Group performance status of 0-2, asymptomatic spinal metastasis, no previous SCC, and no spinal MRI in the past 12 months. Participants were randomly assigned (1:1), using a minimisation algorithm with a random element (balancing factors were treatment centre, alkaline phosphatase [normal vs raised, with the upper limit of normal being defined at each participating laboratory], number of previous systemic treatments [first-line vs second-line or later], previous spinal treatment, and imaging of thorax and abdomen), to no MRI (control group) or screening spinal MRI (intervention group). Serious adverse events were monitored in the 24 h after screening MRI in the intervention group. Participants with screen-detected rSCC were offered pre-emptive treatment (radiotherapy or surgical decompression was recommended per treating physician's recommendation) and 6-monthly spinal MRI. All patients were followed up every 3 months, and then at month 30 and 36. The primary endpoint was time to and incidence of confirmed cSCC in the intention-to-treat population (defined as all patients randomly assigned), with the primary timepoint of interest being 1 year after randomisation. The study is registered with ISRCTN, ISRCTN74112318, and is now complete. FINDINGS: Between Feb 26, 2013, and April 25, 2017, 420 patients were randomly assigned to the control (n=210) or screening MRI (n=210) groups. Median age was 74 years (IQR 68 to 79), 222 (53%) of 420 patients had normal alkaline phosphatase, and median prostate-specific antigen concentration was 48 ng/mL (IQR 17 to 162). Screening MRI detected rSCC in 61 (31%) of 200 patients with assessable scans in the intervention group. As of data cutoff (April 23, 2020), at a median follow-up of 22 months (IQR 13 to 31), time to cSCC was not significantly improved with screening (hazard ratio 0·64 [95% CI 0·37 to 1·11]; Gray's test p=0·12). 1-year cSCC rates were 6·7% (95% CI 3·8-10·6; 14 of 210 patients) for the control group and 4·3% (2·1-7·7; nine of 210 patients) for the intervention group (difference -2·4% [95% CI -4·2 to 0·1]). Median time to cSCC was not reached in either group. No serious adverse events were reported within 24 h of screening. INTERPRETATION: Despite the substantial incidence of rSCC detected in the intervention group, the rate of cSCC in both groups was low at a median of 22 months of follow-up. Routine use of screening MRI and pre-emptive treatment to prevent cSCC is not warranted in patients with asymptomatic castration-resistant prostate cancer with spinal metastasis. FUNDING: Cancer Research UK.

High-Fidelity Ion State Detection Using Trap-Integrated Avalanche Photodiodes.

Integrated technologies greatly enhance the prospects for practical quantum information processing and sensing devices based on trapped ions. High-speed and high-fidelity ion state readout is critical for any such application. Integrated detectors offer significant advantages for system portability and can also greatly facilitate parallel operations if a separate detector can be incorporated at each ion-trapping location. Here, we demonstrate ion quantum state detection at room temperature utilizing single-photon avalanche diodes (SPADs) integrated directly into the substrate of silicon ion trapping chips. We detect the state of a trapped Sr^{+} ion via fluorescence collection with the SPAD, achieving 99.92(1)% average fidelity in 450 µs, opening the door to the application of integrated state detection to quantum computing and sensing utilizing arrays of trapped ions.

Quasi-diffusion magnetic resonance imaging (QDI): A fast, high b-value diffusion imaging technique.

To enable application of non-Gaussian diffusion magnetic resonance imaging (dMRI) techniques in large-scale clinical trials and facilitate translation to clinical practice there is a requirement for fast, high contrast, techniques that are sensitive to changes in tissue structure which provide diagnostic signatures at the early stages of disease. Here we describe a new way to compress the acquisition of multi-shell b-value diffusion data, Quasi-Diffusion MRI (QDI), which provides a probe of subvoxel tissue complexity using short acquisition times (1-4 â€‹min). We also describe a coherent framework for multi-directional diffusion gradient acquisition and data processing that allows computation of rotationally invariant quasi-diffusion tensor imaging (QDTI) maps. QDI is a quantitative technique that is based on a special case of the Continuous Time Random Walk model of diffusion dynamics and assumes the presence of non-Gaussian diffusion properties within tissue microstructure. QDI parameterises the diffusion signal attenuation according to the rate of decay (i.e. diffusion coefficient, D in mm2 s-1) and the shape of the power law tail (i.e. the fractional exponent, α). QDI provides analogous tissue contrast to Diffusional Kurtosis Imaging (DKI) by calculation of normalised entropy of the parameterised diffusion signal decay curve, Hn, but does so without the limitations of a maximum b-value. We show that QDI generates images with superior tissue contrast to conventional diffusion imaging within clinically acceptable acquisition times of between 84 and 228 â€‹s. We show that QDI provides clinically meaningful images in cerebral small vessel disease and brain tumour case studies. Our initial findings suggest that QDI may be added to routine conventional dMRI acquisitions allowing simple application in clinical trials and translation to the clinical arena.

Measurements of cesium mixing and quenching cross sections in methane gas: understanding sources of heating in cesium vapor lasers.

Accurate modeling of the operation of diode-pumped alkali lasers is a critical step toward the design of high-powered devices. We present precision measurements for the Cs-CH4 62P3/2 → 62P1/2 mixing cross section and the 62P3/2,1/2 → 62S1/2 quenching cross section, which are important parameters in understanding the operation and, in particular, the heat generated in a cesium vapor laser. Measurements are carried out using ultrafast laser pulse excitation and observation of fluorescence due to collisional excitation transfer in time is done using the technique of time-correlated single-photon counting. Mixing rate measurements are acquired over methane pressures of 10 - 40 Torr, resulting in a Cs-CH4 62P3/2 → 62P1/2 mixing cross section of (1.40 ± 0.08) × 10-15 cm2, while quenching rate measurements are carried out over methane pressures of 500 - 4000 Torr, resulting in a 62P3/2,1/2 → 62S1/2 quenching cross section of (1.57 ± 0.03) × 10-18 cm2. These results suggest only a slight contribution to the heating of a cesium vapor laser is due to Cs 62P quenching, contrary to previous studies. We also discuss additional possible sources of energy transfer from upper excited states of Cs.

PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment.

PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation.

Contrast Clearance Analysis (CCA) to Assess Viable Tumour following Stereotactic Radiosurgery (SRS) to Brain Metastasis in Non-Small Cell Lung Cancer (NSCLC).

BACKGROUND AND OBJECTIVE: Brain metastases are common in lung cancer and increasingly treated using targeted radiotherapy techniques such as stereotactic radiosurgery (SRS). Using MRI, post-SRS changes may be difficult to distinguish from progressive brain metastasis. Contrast clearance analysis (CCA) uses T1-weighted MRI images to assess the clearance of gadolinium and can be thus used to assess vascularity and active tumours. DESIGN AND METHODS: We retrospectively assessed CCAs in 62 patients with non-small cell lung cancer (NSCLC) undergoing 104 CCA scans in a single centre. RESULTS: The initial CCA suggested the aetiology of equivocal changes on standard MRI in 80.6% of patients. In all patients whose initial CCA showed post-SRS changes and who underwent serial CCAs, the initial diagnosis was upheld with the serial imaging. In only two cases of a presumed progressive tumour on the initial CCA, subsequent treatment for radionecrosis was instigated; a retrospective review and re-evaluation of the CCAs show that progression was reported where a thin rim of rapid contrast clearance was seen, and this finding has been subsequently recognised as a feature of post-treatment change on CCAs. The lack of concordance with CCA findings in those who underwent surgical resection was also found to be due to the over-reporting of the thin blue rim as disease in the early cases of CCA use and, in three cases, potentially related to timelines longer than 7 days prior to surgery, both factors being unknown during the early implementation phase of CCA at our centre but subsequently learned. CONCLUSIONS: Our single-centre experience shows CCA to be feasible and useful in patients with NSCLC in cases of diagnostic uncertainty in MRI. It has helped guide treatment in the majority of patients, with subsequent outcomes following the implementation of the treatment based on the results, suggesting correct classification. Recommendations from our experience of the implementation include the careful consideration of the thin rim of the rapid contrast clearance and the timing of the CCA prior to surgery for suspected brain metastasis progression.

Cerebral microbleeds and cognition in patients with symptomatic small vessel disease.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) are common in cerebral small vessel disease. They may cause cognitive impairment, possibly via white matter tract disruption but previous studies have produced inconsistent results. We determined whether CMB number and location are associated with impaired cognition in symptomatic small vessel disease and whether any association was independent of other magnetic resonance imaging markers of small vessel disease. METHODS: One hundred sixteen patients with lacunar stroke and radiological leukoaraiosis were studied. Neuropsychological assessment was performed. CMBs on gradient echo images were assessed using the Brain Observer Microbleed Rating Scale criteria. Magnetic resonance imaging measures, including diffusion tensor imaging, were also analyzed. Associations between cognitive function and the presence, number, and location of CMBs were determined. RESULTS: CMBs were present in 46 (39.7%) patients. CMB number correlated weakly with executive function (r=0.22; P=0.022) but not with other cognitive indices. CMBs count in the top decile (≥ 9 CMB, N=12) was more strongly associated with poor executive function; this association remained significant after controlling for T2-lesion load, brain volume, lacune count, and mean diffusivity (b=-0.51; P=0.043). CONCLUSIONS: In symptomatic small vessel disease, CMB number was weakly associated with executive dysfunction. There seemed to be a threshold effect with the association being largely accounted for by an association of impaired executive function with high CMB count. No association of CMBs with other cognitive domains, including processing speed, was found.

Recurrent acute necrotizing encephalopathy following influenza A in a genetically predisposed family.

Acute necrotizing encephalopathy (ANE) typically affects young, healthy children who develop rapid-onset severe encephalopathy triggered by viral infections. This disease is more commonly reported in Japan but occurs worldwide, although it remains under-recognized in Western countries. An autosomal dominant form, ANE1, was recently identified. We report the details of a 9-year-old Caucasian female who experienced recurrent ANE episodes at the ages of 9 months and 9 years. Brain magnetic resonance imaging findings were characteristic of ANE during both episodes, although more extensive in the recent episode, which resulted in severe neurological sequelae; influenza A was identified on bronchoalveolar lavage during this episode. Interestingly, there was evidence of peripheral polyneuropathy during the recent episode, which has not previously been described in sporadic ANE. Both the patient and her mother, who had also had postviral polyneuritis in the past, harbour a mutation in Ran-binding protein 2 (RANBP2); this occurred de novo in the mother and confers genetic susceptibility to ANE. Our case suggests that recurrent disease and/or an expanded clinical phenotype raises the possibility of ANE1; positive family history, although supportive, is not necessary as the mutation can occur de novo. Increased awareness may lead to earlier recognition and better treatment options.

The clinical value of early postoperative MRI after lumbar spine surgery.

INTRODUCTION: MRI scanning has historically been considered difficult to interpret in the early period following lumbar spine surgery, and hence of limited value. We investigate the hypothesis that MRI scanning within 6 weeks of lumbar spine surgery cannot accurately diagnose neural compression in symptomatic patients, and define the utility of postoperative MRI in this context. METHODS: A series of 32 consecutive patients had early postoperative MRI following lumbar discectomy or laminectomy for continued, worsening or new symptoms of neural compression. The neuroradiologists' reports were evaluated for the reported presence of neural compression and confidence level (low, medium, high). These MRI findings were then compared to the patients' subsequent course and findings of any surgery performed. RESULTS: Twenty of 29 scans (69%) were confidently predictive of the correct treatment pathway (reoperation with positive finding or conservative treatment with a good outcome) whereas 3/3 (100%) patients who had conservative management despite the MRI confidently suggesting compression had poor outcome. The MRI is highly likely to influence management: 11/14 (79%) patients with scans suggesting neural compression had revision surgery and 18/18 (100%) patients with no neural compression on MRI were managed conservatively. CONCLUSIONS: Our data suggest that early MRI scanning after lumbar laminectomy or discectomy accurately detects neural compression at the surgery site in patients with continued or worsening symptoms.

The imploding antrum syndrome: an unusual cause of double vision.

A 42-year-old man presented with a 3 day history of drooping of the right eyelid and intermittent double vision. He was found to have mechanical restriction of the left eye in elevation and MRI demonstrated an abnormality in the left maxillary sinus with descent of the left inferior rectus muscle. CT confirmed the diagnosis of 'imploding antrum' or 'silent sinus' syndrome. It was treated surgically with complete resolution of symptoms and signs.

Images of the month: Cavernous sinus venous thrombosis secondary to Streptococcus milleri maxillary sinusitis: An unusual cause of diplopia and headache.

Cavernous sinus venous thrombosis is an uncommon condition associated with high mortality rates if not recognised early. Symptoms include headache, visual loss, ophthalmoplegia, altered consciousness, proptosis and periorbital oedema. High-quality imaging is critical in early diagnosis and successful management. Primary infection (such as sinusitis) and possible complications (including meningitis) should be considered as potential aetiologies of cavernous sinus venous thrombosis, especially in those with a preceding history of localised infection. We present a case of a 50-year-old man with a bilateral cavernous sinus venous thrombosis with associated meningitis caused by Streptococcus milleri, secondary to maxillary sinusitis and otomastoiditis. He was successfully treated with antimicrobial treatment, surgical drainage and anticoagulation.

Noninvasive detection of vertebral artery stenosis: a comparison of contrast-enhanced MR angiography, CT angiography, and ultrasound.

BACKGROUND AND PURPOSE: Vertebral stenosis is associated with a high risk of recurrent stroke, but noninvasive imaging techniques to identify it have lacked sensitivity. Contrast-enhanced MR angiography and CT angiography have been recently developed and appear to have better sensitivity. However, no prospective studies have compared both of these techniques with ultrasound against the gold standard of intra-arterial angiography in the same group of patients. METHODS: Forty-six patients were prospectively recruited in whom intra-arterial angiography was being performed. Contrast-enhanced MR angiography, CT angiography, and duplex ultrasound were also performed. Angiographic images were analyzed blinded to patient identity by 2 experienced neuroradiologists. RESULTS: Contrast-enhanced MR angiography had the highest sensitivity and specificity (Radiologist 1, 0.83 and 0.91, respectively; Radiologist 2, 0.89 and 0.87) for detecting >or=50% stenosis. CT angiography had good sensitivity (Radiologist 1, 0.68; Radiologist 2, 0.58) and excellent specificity (Radiologist 1, 0.92; Radiologist 2, 0.93), whereas duplex had low sensitivity (0.44) but excellent specificity (0.95). For vertebral origin stenosis >or=50%, sensitivities were similar for contrast-enhanced MR angiography (Radiologist 1, 0.91; Radiologist 2, 0.82) but relatively higher for CT angiography (Radiologist 1, 0.82; Radiologist 2, 0.82) and duplex (0.67). CONCLUSIONS: Contrast-enhanced MR angiography is the most sensitive noninvasive technique to detect vertebral artery stenosis and also has high specificity. CT angiography has good sensitivity and high specificity. In contrast, ultrasound has low sensitivity and will miss many vertebral stenoses.

Calcifying Pseudoneoplasm of the Neuraxis: A Case Illustrating Natural History over 17 Years of Radiologic Surveillance.

BACKGROUND: Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare central nervous system lesion that can occur in both the brain and the spine. Although this entity is poorly understood, radiologic and histological features have been identified. CASE DESCRIPTION: We report a unique case of a 31-year-old patient who was managed with antiepileptic medication for 17 years before requiring neurosurgical intervention for tumor progression. T2-weighted magnetic resonance imaging revealed hyperintensity within the tumor with extensive associated vasogenic edema, which is not normally associated with CAPNON. Resection was successful with no complications. CONCLUSIONS: The present case illustrates the long-term natural history of CAPNON before resection and highlights the variations in radiologic appearance that may be associated with this poorly understood entity.

The spatial distribution of MR imaging abnormalities in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and their relationship to age and clinical features.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a condition causing recurrent subcortical strokes. MR imaging, which shows focal lacunar infarcts and leukoaraiosis, plays a central role in the diagnosis and evaluation. We studied MR imaging abnormalities in a large prospectively recruited cohort of CADASIL patients to describe the spatial distribution of abnormalities, determine how this distribution alters with age, and identify any correlations with the clinical features of the disease. METHODS: In this study, 112 CADASIL subjects from 64 families were prospectively recruited. MR imaging scans were graded by a single neuroradiologist, by using the modified Scheltens scale, to quantify the severity of high-signal-intensity changes in different brain regions. RESULTS: Lesion load increased progressively with age. Scores were maximal in the frontal, parietal, and anterior temporal cortex, and the external capsule; intermediate in the pons; and relatively low in the corpus callosum, caudate, globus pallidus, cerebellum, midbrain, and medulla. Anterior temporal pole involvement was common at all ages and, when present, usually confluent, but this was absent in 33% of patients 20-29 years of age. A history of stroke correlated with total Scheltens score and internal capsule and pontine scores. Dementia correlated with total Scheltens score and subcortical white matter score, whereas depression correlated with subcortical white matter score but not total Scheltens score. CONCLUSIONS: There is a characteristic pattern of MR imaging abnormalities in CADASIL that aids in differential diagnosis; however, some characteristic features, such as anterior temporal pole involvement, can be absent. MR imaging lesion load correlated with some clinical features including stroke and dementia, whereas depression is more common in individuals with deep white matter changes.

The influence of genetic and cardiovascular risk factors on the CADASIL phenotype.

The clinical phenotype in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), an autosomal dominant cerebral arteriopathy, is variable, but the reasons for this remain uncertain. Possible factors include the mutation site and the influence of additional modulating factors, which could include both epistatic interactions and interactions with cardiovascular risk factors known to cause sporadic small vessel disease. In a large prospectively recruited cohort of CADASIL subjects we determined relationships between phenotype and mutation site, the apoE genotype and cardiovascular risk factors. In addition to clinical features, disease severity was assessed by MRI lesion volume, measured both semiquantitatively (Scheltens scale) and quantitatively. One hundred and twenty-seven CADASIL cases from 65 families with 17 different mutations were studied. Site of mutation was not associated with the presence or age of onset of stroke, migraine, dementia, dependency or MRI lesion load. There was no evidence of intrafamilial clustering of particular phenotypes. Amongst subjects with stroke/transient ischaemic attack, smoking at the time of the event was independently associated with earlier age of onset (P = 0.01). There were no associations between age of onset or presence of stroke and other cardiovascular risk factors, including homocysteine. Homocysteine levels were higher in migraineurs [mean (SD) 12.8 (5.6) versus 9.8 (3.4) micromol/l, P = 0.02)] and elevated homocysteine was independently associated with an earlier age of onset of migraine (P = 0.01). No relationship was found between MRI lesion volume and risk factors, or between apoE genotype and phenotype. Our results show no notch 3 genotype-phenotype correlations. This implies that modulating factors influence phenotype. Smoking appears to increase the risk of stroke, while high homocysteine levels are associated with an increased risk of migraine.

Prenatal Diagnosis of WAGR Syndrome.

Wilm's tumour, aniridia, genitourinary abnormalities, and mental retardation (WAGR) syndrome is a rare genetic disorder with an estimated prevalence of 1 in 500,000 to 1 million. It is a contiguous gene syndrome due to deletion at chromosome 11p13 in a region containing WT1 and PAX6 genes. Children with WAGR syndrome mostly present in the newborn/infancy period with sporadic aniridia. The genotypic defects in WAGR syndrome have been well established. However, antenatal ultrasonographic presentation of this syndrome has never been reported. Prenatal diagnosis of this condition is possible in some cases with careful ultrasound examination of classical and nonclassical manifestations of this syndrome. The key point for this rare diagnosis was the decision to perform chromosomal microarray analysis after antenatal diagnosis of absent corpus callosum and absent cavum septum pellucidum, as this finding mandates search for potentially associated genetic disorders. We report a case of WAGR syndrome diagnosed prenatally at 29-week gestation. The diagnosis of the anomaly was based on two- and three-dimensional ultrasound as well as fetal MRI scan and microarray analysis. The ultrasonographic findings included borderline ventriculomegaly, absent corpus callosum, and absent cavum septum pellucidum. Cytogenetic results from the amniotic fluid confirmed WAGR syndrome. Parental karyotype was normal, with no evidence of copy number change, deletion, or rearrangement of this region of chromosome 11.