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Mucopolysaccharidosis type IIIA (MPS IIIA) is characterised by a progressive neurological decline leading to early death. It is caused by bi-allelic loss-of-function mutations in SGSH encoding sulphamidase, a lysosomal enzyme required for heparan sulphate glycosaminoglycan (HS GAG) degradation, that results in the progressive build-up of HS GAGs in multiple tissues most notably the central nervous system (CNS). Skin fibroblasts from two MPS IIIA patients who presented with an intermediate and a severe clinical phenotype, respectively, were reprogrammed into induced pluripotent stem cells (iPSCs). The intermediate MPS IIIA iPSCs were then differentiated into neural progenitor cells (NPCs) and subsequently neurons. The patient derived fibroblasts, iPSCs, NPCs and neurons all displayed hallmark biochemical characteristics of MPS IIIA including reduced sulphamidase activity and increased accumulation of an MPS IIIA HS GAG biomarker. Proliferation of MPS IIIA iPSC-derived NPCs was reduced compared to control, but could be partially rescued by reintroducing functional sulphamidase enzyme, or by doubling the concentration of the mitogen fibroblast growth factor 2 (FGF2). Whilst both control heparin, and MPS IIIA HS GAGs had a similar binding affinity for FGF2, only the latter inhibited FGF signalling, suggesting accumulated MPS IIIA HS GAGs disrupt the FGF2:FGF2 receptor:HS signalling complex. Neuronal differentiation of MPS IIIA iPSC-derived NPCs was associated with a reduction in the expression of neuronal cell marker genes βIII-TUBULIN, NF-H and NSE, revealing reduced neurogenesis compared to control. A similar result was achieved by adding MPS IIIA HS GAGs to the culture medium during neuronal differentiation of control iPSC-derived NPCs. This study demonstrates the generation of MPS IIIA iPSCs, and NPCs, the latter of which display reduced proliferation and neurogenic capacity. Reduced NPC proliferation can be explained by a model in which soluble MPS IIIA HS GAGs compete with cell surface HS for FGF2 binding. The mechanism driving reduced neurogenesis remains to be determined but appears downstream of MPS IIIA HS GAG accumulation., (© 2021 The Authors.)

Gangliosides are the most complex oligosaccharide-containing glycosphingolipids defined by the presence of sialic acid and although present in all tissues, predominate in the brain. Considering their importance in neural development, it is unsurprising that ganglioside metabolism is altered in neurodegenerative diseases. The severe form of mucopolysaccharidosis type I, Hurler syndrome (HS), is characterised by progressive loss of neuronal function through largely undefined mechanisms. Here, we sought to interrogate brain gangliosides in a murine model of HS and further, assessed whether dietary modulation of lipid metabolism effected correction of the metabolic abnormalities. The simple gangliosides, G M 2 , G M 3 , G D 2 and G D 3 were elevated in the five subregions examined - brain stem, cerebellum, cortex, hippocampus, subcortex - in HS mice as early as 2 months of age compared with their wild type counterparts. Their elevation persisted at 6 months of age, imparting protracted neurological development as these simple gangliosides have usually subsided by this stage of brain development. Their immediate synthetic precursor, lactosylceramide, was also elevated, suggesting that their increase arises at this metabolic intermediary, as dihydroceramide, ceramide and monohexosylceramide were unaffected. Dietary linoleic acid supplementation significantly reduced G M 2 and G M 3 , and furthermore, improved exploratory behaviour as assessed by the open field test, highlighting the possibility of further exploring dietary intervention as a therapeutic consideration., (© 2017 International Society for Neurochemistry.)

The aim of the current study was to enhance the assessment and predictive accuracy of risk assessments for sexual offenders by utilizing detailed crime scene analysis (CSA). CSA was conducted on a sample of 247 male acquaintance rapists from Berlin (Germany) using a nonmetric, multidimensional scaling (MDS) Behavioral Thematic Analysis (BTA) approach. The age of the offenders at the time of the index offense ranged from 14 to 64 years (M = 32.3; SD = 11.4). The BTA procedure revealed three behavioral themes of hostility, criminality, and pseudo-intimacy, consistent with previous CSA research on stranger rape. The construct validity of the three themes was demonstrated through correlational analyses with known sexual offending measures and criminal histories. The themes of hostility and pseudo-intimacy were significant predictors of sexual recidivism. In addition, the pseudo-intimacy theme led to a significant increase in the incremental validity of the Static-99 actuarial risk assessment instrument for the prediction of sexual recidivism. The results indicate the potential utility and validity of crime scene behaviors in the applied risk assessment of sexual offenders., (© The Author(s) 2015.)

Bis(monoacylglycero)phosphate (BMP) is a glycerophospholipid highly enriched in the lysosomal network and elevated in lysosomal diseases. To correct this elevation, BMP synthesis was manipulated by dietary fatty acid supplementation and the impact on subregional brain BMP and pathology assessed in the mouse model of mucopolysaccharidosis 1 (Hurler syndrome (HS)). There was widespread elevation of BMP in HS mice across all six sub-regions - brain stem, cortex, cerebellum, hippocampus, olfactory bulb and the sub-cortex - with 22:6/22:6 the most abundant species. Linoleic acid normalised total BMP in all regions except the cortex and cerebellum, although there were differences in fatty acid species; the major finding a decrease in 22:6- and a concomitant increase in 22:5-containing species. A battery of behaviour assessments showed that in the water cross maze both HS and wild type mice performed less well on the linoleic acid diet, and that both HS and wild type mice on the linoleic acid diet performed similarly and better in the exploratory open field test. This may be a consequence of differential subregional BMP composition in the brain. The effects of high fat and docosahexaenoic/eicosapentaenoic acid enriched diets were generally unremarkable. Although major pathologies were not completely abrogated, much of the neurobehavioural testing was confounded by skeletal pathology that did not resolve. This is the first detailed characterisation of subregional brain BMP species informing on the ability to manipulate this phospholipid in the brain, and as such, may hold promise as an adjunct therapy not only for HS but also for other lysosomal diseases., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The inclusion of crime scene behavior in actuarial risk assessment so far is insufficient, unsystematic, and neglecting factors theoretically relevant to sexual recidivism. Therefore, the goal of the current study was to develop a brief actuarial risk scale based on crime scene characteristics. The development sample consisted of data (police databases, paper records, and the National Conviction Registry) from 955 male sexual offenders (77% German citizens, 20% foreign nationals, mean age = 35 years, convicted for sexual abuse and/or sexual violence). Further, the independent cross-validation-sample consisted of data from 77 sexual offenders. The 7 items that are comprised by the Crime Scene Behavior Risk (CBR) measure showed high predictive accuracy for sexual recidivism with little variation between the development (c index = .72) and the replication sample (c index = .74). Further, the CBR was found to provide significant incremental validity and improve the predictive accuracy of the Static-99R risk assessment tool. Given the predictive and incremental validity of the CBR it is suggested that sexual offender risk assessment can be improved by utilizing crime scene behavior. The CBR is currently being used in addition to the Static-99R by the State Office of Criminal Investigations in Berlin to prioritize released sexual offenders for police supervision., (PsycINFO Database Record (c) 2014 APA, all rights reserved.)

This study tested 3 decision rules for combining actuarial risk instruments for sex offenders into an overall evaluation of risk. Based on a 9-year follow-up of 940 adult male sex offenders, we found that Rapid Risk Assessment for Sex Offender Recidivism (RRASOR), Static-99R, and Static-2002R predicted sexual, violent, and general recidivism and provided incremental information for the prediction of all 3 outcomes. Consistent with previous findings, the incremental effect of RRASOR was positive for sexual recidivism but negative for violent and general recidivism. Averaging risk ratios was a promising approach to combining these risk scales, showing good calibration between predicted (E) and observed (O) recidivism rates (E/O index = 0.93, 95% CI [0.79, 1.09]) and good discrimination (area under the curve = 0.73, 95% CI [0.69, 0.77]) for sexual recidivism. As expected, choosing the lowest (least risky) risk tool resulted in underestimated sexual recidivism rates (E/O = 0.67, 95% CI [0.57, 0.79]) and choosing the highest (riskiest) resulted in overestimated risk (E/O = 1.37, 95% CI [1.17, 1.60]). For the prediction of violent and general recidivism, the combination rules provided similar or lower discrimination compared with relying solely on the Static-99R or Static-2002R. The current results support an averaging approach and underscore the importance of understanding the constructs assessed by violence risk measures.

The current study sought to improve the predictive accuracy of sexual recidivism using the Static-99 risk assessment tool by the addition of detailed crime scene analysis (CSA). CSA was carried out using a Behavioral Thematic Analysis (BTA) approach, the gold-standard in CSA. BTA was conducted on a sample of 167 stranger rape cases using nonmetric multidimensional scaling (MDS). The BTA procedure revealed three behavioral themes of hostility, criminality, and sexual exploitation, consistent with previous research in sexual offending CSA. Logistic regression analysis indicated that the criminality theme was significantly predictive of sexual recidivism and also significantly correlated with previous sexual offense history. Further, the criminality theme led to a significant increase in the incremental validity of the Static-99 actuarial risk assessment instrument for the prediction of sexual recidivism.