Proposed research criteria for prodromal behavioural variant frontotemporal dementia

At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed \u27mild behavioural and/or cognitive impairment in bvFTD\u27 (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal bvFTD group was divided into a Development Group (n = 22) and a Validation Group (n = 50). The Development Group was selected to be the subset of the prodromal bvFTD group for whom we had the strongest longitudinal evidence of conversion to bvFTD, and was used to develop the MBCI-FTD criteria. The Validation Group was the remainder of the prodromal bvFTD group and was used as a separate sample on which to validate the criteria. Familial non-carriers were included as healthy controls (n = 165). The frequencies of behavioural and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in the prodromal bvFTD Development Group and healthy controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate-severe dysphoria, behavioural disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviours (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioural changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of possible MBCI-FTD; probable MBCI-FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI-FTD criteria correctly classified 95% of the prodromal bvFTD Development Group, and 74% of the prodromal bvFTD Validation Group, with a false positive rate of \u3c10% in healthy controls. Finally, the MBCI-FTD criteria were tested on a cohort of individuals with prodromal Alzheimer\u27s disease, and the false positive rate of diagnosis was 11-16%. Future research will need to refine the sensitivity and specificity of these criteria, and incorporate emerging biomarker evidence

Evolving a lipase for hydrolysis of natural triglycerides along with enhanced tolerance towards a protease and surfactants

In the accompanying paper, we described evolving a lipase to the point where variants were soluble, stable and capable of degrading C8 TAG and C8 esters. These variants were tested for their ability to survive in an environment that might be encountered in a washing machine. Unfortunately, they were inactivated both by treatment with a protease used in laundry detergents and by very low concentrations of sodium dodecyl sulfate (SDS). In addition, all the variants had very low levels of activity with triglycerides with long aliphatic chains and with naturally occurring oils, like olive oil. Directed evolution was used to select variants with enhanced properties. In the first 10 rounds of evolution, the primary screen was selected for variants capable of hydrolyzing olive oil whereas the secondary screen was selected for enhanced tolerance towards a protease and SDS. In the final six rounds of evolution, the primary and secondary screens identified variants that retained activity after treatment with SDS. Sixteen cycles of evolution gave variants with greatly enhanced lipolytic activity on substrates that had both long (C16 and C18) as well as short (C3 and C8) chains. We found variants that were stable for more than 3 hours in protease concentrations that rapidly degrade the wild-type enzyme. Enhanced tolerance towards SDS was found in variants that could break down naturally occurring lipid and resist protease attack. The amino acid changes that gave enhanced properties were concentrated in the cap domain responsible for substrate binding

Improving on nature's shortcomings: evolving a lipase for increased lipolytic activity, expression and thermostability.

An enzyme must be soluble, stable, active and easy to produce to be useful in industrial applications. Not all enzymes possess these attributes. We set out to determine how many changes are required to convert an enzyme with poor properties into one that has useful properties. Lipase Lip3 from Drosophila melanogaster had been previously optimised for expression in Escherichia coli. The expression levels were good, but Lip3 was mainly insoluble with poor activity. Directed evolution was used to identify variants with enhanced activity along with improved solubility. Five variants and the wild-type (wt) enzyme were purified and characterised. The yield of the wt enzyme was just 2.2 mg/L of culture, while a variant, produced under the same conditions, gave 351 mg. The improvement of activity of the best variant was 200 times higher than that of the wt when the crude lysates were analysed using pNP-C8, but with purified protein, the improvement observed was 1.5 times higher. This means that most of the increase of activity is due to increase in solubility and stability. All the purified variants showed increased thermal stability compared with the wt enzyme that had a T1/2 of 37°C, while the mutant with P291L of 42.2°C and the mutant R7_47D with five mutations had a value of 52.9°C, corresponding to an improvement of 16°C. The improved variants had between five and nine changes compared with the wt enzyme. There were four changes that were found in all 30 final round variants for which sequences were obtained; three of these changes were found in the substrate-binding domain

The Surface of a Bose-Einstein Condensed Atomic Cloud

We investigate the structure and collective modes of a planar surface of a trapped Bose-Einstein condensed gas at zero temperature. In the long-wavelength limit we find a mode similar to the gravity wave on the surface of a fluid with the frequency $\omega$ and the wavenumber $q$ related by $\omega^2=Fq/m$. Here $F$ is the force due to the confining potential at the surface and $m$ is the particle mass. At shorter wavelengths we use a variational approach and find corrections to $\omega^2$ of order $q^4 \ln{q}$. We demonstrate the usefulness of the concept of an effective surface tension for describing both static and dynamic properties of condensed atomic clouds.Comment: 8 pages, REVTEX, submitted to Phys. Rev.

An exploration of the potential utility of fetal cardiovascular MRI as an adjunct to fetal echocardiography

Objectives: Fetal cardiovascular magnetic resonance imaging (MRI) offers a potential alternative to echocardiography, although in practice, its use has been limited. We sought to explore the need for additional imaging in a tertiary fetal cardiology unit and the usefulness of standard MRI sequences. Methods: Cases where the diagnosis was not fully resolved using echocardiography were referred for MRI. Following a three‐plane localiser, fetal movement was assessed with a balanced steady‐state free precession (bSSFP) cine. Single‐shot fast spin echo and bSSFP sequences were used for diagnostic imaging. Results: Twenty‐two fetal cardiac MRIs were performed over 12 months, at mean gestation of 32 weeks (26–38 weeks). The majority of referrals were for suspected vascular abnormalities (17/22), particularly involving the aortic arch (n = 10) and pulmonary vessels (n = 4). Single‐shot fast spin echo sequences produced ‘black‐blood’ images, useful for examining the extracardiac vasculature in these cases. BSSFP sequences were more useful for intracardiac structures. Real‐time SSFP allowed for dynamic assessment of structures such as cardiac masses, with enhancement patterns also allowing for tissue characterisation in these cases. Conclusions: Fetal vascular abnormalities such as coarctation can be difficult to diagnose by using ultrasound. Fetal MRI may have an adjunctive role in the evaluation of the extracardiac vascular anatomy and tissue characterisation. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd

The Bivariate Rogers-Szeg\"{o} Polynomials

We present an operator approach to deriving Mehler's formula and the Rogers formula for the bivariate Rogers-Szeg\"{o} polynomials $h_n(x,y|q)$. The proof of Mehler's formula can be considered as a new approach to the nonsymmetric Poisson kernel formula for the continuous big $q$-Hermite polynomials $H_n(x;a|q)$ due to Askey, Rahman and Suslov. Mehler's formula for $h_n(x,y|q)$ involves a ${}_3\phi_2$ sum and the Rogers formula involves a ${}_2\phi_1$ sum. The proofs of these results are based on parameter augmentation with respect to the $q$-exponential operator and the homogeneous $q$-shift operator in two variables. By extending recent results on the Rogers-Szeg\"{o} polynomials $h_n(x|q)$ due to Hou, Lascoux and Mu, we obtain another Rogers-type formula for $h_n(x,y|q)$. Finally, we give a change of base formula for $H_n(x;a|q)$ which can be used to evaluate some integrals by using the Askey-Wilson integral.Comment: 16 pages, revised version, to appear in J. Phys. A: Math. Theo

Segond's fracture: a biomechanical cadaveric study using navigation

Background Segond’s fracture is a well-recognised radiological sign of an anterior cruciate ligament (ACL) tear. While previous studies evaluated the role of the anterolateral ligament (ALL) and complex injuries on rotational stability of the knee, there are no studies on the biomechanical effect of Segond’s fracture in an ACL deficient knee. The aim of this study was to evaluate the effect of a Segond’s fracture on knee rotation stability as evaluated by a navigation system in an ACL deficient knee. Materials and methods Three different conditions were tested on seven knee specimens: intact knee, ACL deficient knee and ACL deficient knee with Segond’s fracture. Static and dynamic measurements of anterior tibial translation (ATT) and axial tibial rotation (ATR) were recorded by the navigation system (2.2 OrthoPilot ACL navigation system B. Braun Aesculap, Tuttlingen, Germany). Results Static measurements at 30 showed that the mean ATT at 30 of knee flexion was 5.1 ± 2.7 mm in the ACL intact condition, 14.3 ± 3.1 mm after ACL cut (P = 0.005), and 15.2 ± 3.6 mm after Segond’s fracture (P = 0.08). The mean ATR at 30 of knee flexion was 20.7 ± 4.8 in the ACL intact condition, 26.9 ± 4.1 in the ACL deficient knee (P[0.05) and 30.9 ± 3.8 after Segond’s fracture (P = 0.005). Dynamic measurements during the pivot-shift showed that the mean ATT was 7.2 ± 2.7 mm in the intact knee, 9.1 ± 3.3 mm in the ACL deficient knee(P = 0.04) and 9.7 ± 4.3 mm in the ACL deficient knee with Segond’s fracture (P = 0.07). The mean ATR was 9.6 ± 1.8 in the intact knee, 12.3 ± 2.3 in the ACL deficient knee (P[0.05) and 19.1 ± 3.1 in the ACL deficient knee with Segond’s lesion (P = 0.016). Conclusion An isolated lesion of the ACL only affects ATT during static and dynamic measurements, while the addition of Segond’s fracture has a significant effect on ATR in both static and dynamic execution of the pivot-shift test, as evaluated with the aid of navigation

Fake news or weak science? Visibility and characterization of anti-vaccine webpages returned by Google in different languages and countries

The 1998 Lancet paper by Wakefield et al , despite subsequent retraction and evidence indicating no causal link between vaccinations and autism, triggered significant parental concern. The aim of this study was to analyse the online information available on this topic. Using localized versions of Google, we searched “autism vaccine” in English, French, Italian, Portuguese, Mandarin and Arabic and analyzed 200 websites for each search engine result page (SERP). A common feature was the newsworthiness of the topic, with news outlets representing 25-50% of the SERP, followed by unaffiliated websites (blogs, social media) that represented 27-41% and included most of the vaccine-negative websites. Between 12% and 24% of websites had a negative stance on vaccines, while most websites were pro-vaccine (43-70%). However, their ranking by Google varied. While in Google.com the first vaccine-negative website was the 43rd in the SERP, there was one vaccine-negative webpage in the top 10 websites in both the British and Australian localized versions and in French and two in Italian, Portuguese and Mandarin, suggesting that the information quality algorithm used by Google may work better in English. Many webpages mentioned celebrities in the context of the link between vaccines and autism, with Donald Trump most frequently. Few websites (1-5%) promoted complementary and alternative medicine (CAM) but 50-100% of these were also vaccine-negative suggesting that CAM users are more exposed to vaccine-negative information. This analysis highlights the need for monitoring the web for information impacting on vaccine uptake

Taenia multiceps coenurosis in Tanzania: a major and under-recognised livestock disease problem in pastoral communities

A neurological syndrome of small ruminants, known locally as ‘ormilo’, has been reported among pastoralist livestock keepers in Tanzania. This study was carried out in four affected pastoral communities to determine the prevalence and associated risk factors, characterise the clinical signs and investigate the aetiology of the syndrome. Questionnaires were administered at all households (n=480) within four study villages. Overall, 94 per cent of households reported at least one case in the previous 12 months. By village, the individual-level 12-month period prevalence ranged from 11 per cent to 34 per cent, equivalent to about 10,000 small ruminants across the four villages. Thirty-eight households were randomly selected for further investigation. Proprioceptive deficits and weakness were the most commonly observed clinical signs in affected animals. Brain and spinal cord cysts consistent with Taenia multiceps infection were detected in 32 (82 per cent) of 39 affected animals selected for postmortem examination. Feeding small ruminant brains to dogs was identified as an important risk factor for the syndrome, even in households that did not own dogs. This study confirms cerebral coenurosis as a major cause of small ruminant neurological disease in northern Tanzania and highlights the urgent need for further investigation to quantify the disease burden and to identify and implement control measures