Phosphodiesterase 10A levels are related to striatal function in schizophrenia: a combined positron emission tomography and functional magnetic resonance imaging study.

Pharmacological inhibition of phosphodiesterase 10A (PDE10A) is being investigated as a treatment option in schizophrenia. PDE10A acts postsynaptically on striatal dopamine signaling by regulating neuronal excitability through its inhibition of cyclic adenosine monophosphate (cAMP), and we recently found it to be reduced in schizophrenia compared to controls. Here, this finding of reduced PDE10A in schizophrenia was followed up in the same sample to investigate the effect of reduced striatal PDE10A on the neural and behavioral function of striatal and downstream basal ganglia regions. A positron emission tomography (PET) scan with the PDE10A ligand [11C]Lu AE92686 was performed, followed by a 6 min resting-state magnetic resonance imaging (MRI) scan in ten patients with schizophrenia. To assess the relationship between striatal function and neurophysiological and behavioral functioning, salience processing was assessed using a mismatch negativity paradigm, an auditory event-related electroencephalographic measure, episodic memory was assessed using the Rey auditory verbal learning test (RAVLT) and executive functioning using trail-making test B. Reduced striatal PDE10A was associated with increased amplitude of low-frequency fluctuations (ALFF) within the putamen and substantia nigra, respectively. Higher ALFF in the substantia nigra, in turn, was associated with lower episodic memory performance. The findings are in line with a role for PDE10A in striatal functioning, and suggest that reduced striatal PDE10A may contribute to cognitive symptoms in schizophrenia.

The anti-ageing effects of a natural peptide discovered by artificial intelligence.

OBJECTIVE: As skin ages, impaired extracellular matrix (ECM) protein synthesis and increased action of degradative enzymes manifest as atrophy, wrinkling and laxity. There is mounting evidence for the functional role of exogenous peptides across many areas, including in offsetting the effects of cutaneous ageing. Here, using an artificial intelligence (AI) approach, we identified peptide RTE62G (pep_RTE62G), a naturally occurring, unmodified peptide with ECM stimulatory properties. The AI-predicted anti-ageing properties of pep_RTE62G were then validated through in vitro, ex vivo and proof of concept clinical testing. METHODS: A deep learning approach was applied to unlock pep_RTE62G from a plant source, Pisum sativum (pea). Cell culture assays of human dermal fibroblasts (HDFs) and keratinocytes (HaCaTs) were subsequently used to evaluate the in vitro effect of pep_RTE62G. Distinct activities such as cell proliferation and ECM protein production properties were determined by ELISA assays. Cell migration was assessed using a wound healing assay, while ECM protein synthesis and gene expression were analysed, respectively, by immunofluorescence microscopy and PCR. Immunohistochemistry of human skin explants was employed to further investigate the induction of ECM proteins by pep_RTE62G ex vivo. Finally, the clinical effect of pep_RTE626 was evaluated in a proof of concept 28-day pilot study. RESULTS: In vitro testing confirmed that pep_RTE62G is an effective multi-functional anti-ageing ingredient. In HaCaTs, pep_RTE62G treatment significantly increases both cellular proliferation and migration. Similarly, in HDFs, pep_RTE62G consistently induced the neosynthesis of ECM protein elastin and collagen, effects that are upheld in human skin explants. Lastly, in our proof of concept clinical study, application of pep_RTE626 over 28 days demonstrated anti-wrinkle and collagen stimulatory potential. CONCLUSION: pep_RTE62G represents a natural, unmodified peptide with AI-predicted and experimentally validated anti-ageing properties. Our results affirm the utility of AI in the discovery of novel, functional topical ingredients.

OBJECTIF: À mesure que la peau vieillit, une altération de la synthèse des protéines de la matrice extracellulaire (ECM) et une action accrue des enzymes dégradantes se manifestent par une atrophie, des rides et un laxisme. Il existe de plus en plus de preuves du rôle fonctionnel des peptides exogènes dans de nombreux domaines, y compris pour compenser les effets du vieillissement cutané. Ici, en utilisant une approche d'intelligence artificielle (AI), nous avons identifié le peptide RTE62G (pep_RTE62G), un peptide naturel non modifié avec des propriétés de stimulation ECM. Les propriétés anti-âge prédites par l'IA de pep_RTE62G ont ensuite été validées par des tests cliniques in vitro, ex vivo et de validation de principe. LES MÉTHODES: Une approche d'apprentissage en profondeur a été appliquée pour déverrouiller pep_RTE62G à partir d'une source végétale, Pisum sativum (pois). Des tests de culture cellulaire de fibroblastes dermiques humains (HDF) et de kératinocytes (HaCaTs) ont ensuite été utilisés pour évaluer l'effet in vitro de pep_RTE62G. Des activités distinctes telles que la prolifération cellulaire et les propriétés de production de protéines ECM ont été déterminées par des tests ELISA. La migration cellulaire a été évaluée à l'aide d'un test de cicatrisation des plaies, tandis que la synthèse des protéines ECM et l'expression des gènes ont été analysées, respectivement, par microscopie à immunofluorescence et PCR. L'immunohistochimie des explants de peau humaine a été utilisée pour approfondir l'induction des protéines ECM par pep_RTE62G ex vivo. Enfin, l'effet clinique de pep_RTE626 a été évalué dans une étude pilote de 28 jours de validation de principe. RÉSULTATS: Les tests in vitro ont confirmé que pep_RTE62G est un ingrédient anti-âge multifonctionnel efficace. Dans HaCaTs, le traitement pep_RTE62G augmente de manière significative à la fois la prolifération et la migration cellulaire. De même, dans les HDF, pep_RTE62G a induit de manière cohérente la néosynthèse de la protéine ECM élastine et collagène, effets qui sont maintenus dans les explants de peau humaine. Enfin, dans notre étude clinique de preuve de concept, l'application de pep_RTE626 sur 28 jours a démontré un potentiel stimulant anti-rides et collagène. CONCLUSION: pep_RTE62G représente un peptide naturel, non modifié avec des propriétés anti-âge prédites par l'IA et validées expérimentalement. Nos résultats confirment l'utilité de l'IA dans la découverte de nouveaux ingrédients topiques fonctionnels.

Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer's disease dementia.

The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer's disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. All patients underwent PET scans with [18F]THK5317 (tau deposition) and [18F]FDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with [11C]PIB (amyloid-ß deposition) at baseline only. At a group level, patients with AD (prodromal or dementia) showed unchanged [18F]THK5317 retention over time, in contrast to significant decreases in [18F]FDG uptake in temporoparietal areas. The pattern of changes in [18F]THK5317 retention was heterogeneous across all patients, with qualitative differences both between the two AD groups (prodromal and dementia) and among individual patients. High [18F]THK5317 retention was significantly associated over time with low episodic memory encoding scores, while low [18F]FDG uptake was significantly associated over time with both low global cognition and episodic memory encoding scores. Both patients with corticobasal syndrome had a negative [11C]PIB scan, high [18F]THK5317 retention with a different regional distribution from that in AD, and a homogeneous pattern of increased [18F]THK5317 retention in the basal ganglia over time. These findings highlight the heterogeneous propagation of tau pathology among patients with symptomatic AD, in contrast to the homogeneous changes seen in glucose metabolism, which better tracked clinical progression.

Is the global prevalence rate of adult mental illness increasing? Systematic review and meta-analysis.

OBJECTIVES: The question whether mental illness prevalence rates are increasing is a controversially debated topic. Epidemiological articles and review publications that look into this research issue are often compromised by methodological problems. The present study aimed at using a meta-analysis technique that is usually applied for the analysis of intervention studies to achieve more transparency and statistical precision. METHODS: We searched PubMed, PsycINFO, CINAHL, Google Scholar and reference lists for repeated cross-sectional population studies on prevalence rates of adult mental illness based on ICD- or DSM-based diagnoses, symptom scales and distress scales that used the same methodological approach at least twice in the same geographical region. The study is registered with PROSPERO (CRD42018090959). RESULTS: We included 44 samples from 42 publications, representing 1 035 697 primary observations for the first time point and 783 897 primary observations for the second and last time point. Studies were conducted between 1978 and 2015. Controlling for a hierarchical data structure, we found an overall global prevalence increase in odds ratio of 1.179 (95%-CI: 1.065-1.305). A multivariate meta-regression suggested relevant associations with methodological characteristics of included studies. CONCLUSIONS: We conclude that the prevalence increase in adult mental illness is small, and we assume that this increase is mainly related to demographic changes.

A Three-Part Bayesian Network for Modeling Dwelling Fires and Their Impact upon People and Property.

In the United Kingdom, dwelling fires are responsible for the majority of all fire-related fatalities. The development of these incidents involves the interaction of a multitude of variables that combine in many different ways. Consequently, assessment of dwelling fire risk can be complex, which often results in ambiguity during fire safety planning and decision making. In this article, a three-part Bayesian network model is proposed to study dwelling fires from ignition through to extinguishment in order to improve confidence in dwelling fire safety assessment. The model incorporates both hard and soft data, delivering posterior probabilities for selected outcomes. Case studies demonstrate how the model functions and provide evidence of its use for planning and accident investigation.

Intraoral features and considerations in face transplantation.

Face transplantation (FT) is a unique and novel addition to the field of reconstructive surgery, which offers new hope to facially disfigured individuals. This review provides an overview of FT, including clinical indications, immunological principles, and functional outcomes, as well as an in-depth characterization of the intraoral hard and soft tissue findings in the six patients transplanted to date at Brigham and Women's Hospital in Boston, MA, USA. Six FT recipients underwent comprehensive clinical and radiographic evaluation to assess their intraoral status, function, and overall health. The extra- and intraoral soft tissue was assessed via quantitative sensory testing. The vitality of the transplanted dental hard tissue was evaluated with clinically available testing methods. Native teeth and prostheses were also assessed. Sensation of transplanted oral mucosa varied based on time elapsed from FT, ranging from minimal at 3 months post-FT, to nearly complete recovery by approximately 24 months. There was mixed success with the integration of donor teeth (Patients 1, 4 and 6), including associated occlusal discrepancies. Mucosal complications included constriction at the donor/recipient interface (Patients 2 and 5) and solitary episodes of mucosal rejection presenting as lichenoid inflammation (Patients 2 and 4). Face transplantation represents a pivotal moment in the history of reconstructive surgery and transplant medicine, providing new optimism to patients with gross facial deformities. This report highlights the successes of FT, but also the challenges of transplanting hard and soft tissues to restore complex stomatognathic function. Further attention directed toward comprehensive oral rehabilitation in FT will contribute to improved outcomes, with the ultimate goal of restoring and optimizing patient quality of life.

Osteoarthritis patients' perceptions of "appropriateness" for total joint replacement surgery.

OBJECTIVE: To understand patients' perspectives on 'appropriateness' for hip and knee total joint arthroplasty (TJA). METHODS: Focus groups were conducted, stratified by history of a previous TJA, in English-speaking men and women aged 40+ years with moderate to severe hip and knee osteoarthritis. Participants discussed: their appropriateness for TJA; the ideal candidate; patients' role in TJA decision making; and the relationship between appropriateness and willingness to consider TJA. Participants self-completed a questionnaire assessing demographics, arthritis severity (Western Ontario McMaster University Osteoarthritis index - WOMAC), perceived TJA candidacy and willingness to consider TJA. Focus groups were audio-taped and transcribed verbatim. Content analysis was performed. RESULTS: Eleven focus groups were conducted with 58 participants in total: mean age 72 years; 79% female; 25 (43%) with prior TJA; mean WOMAC summary score 43.1. Half reported willingness to consider TJA and 43% felt they were appropriate for TJA. Appropriateness was equated with candidacy for the procedure. Pain intensity and the ability to cope with pain were identified as the most important factors determining surgical candidacy, but felt to be inadequately evaluated by physicians. TJA appropriateness and willingness were felt to be distinct, yet related, concepts; those unwilling had stricter criteria about candidacy than those who were willing. CONCLUSIONS: Participants equated appropriateness for TJA with surgical candidacy. Patients' pain experience (intensity, impact on quality of life, ability to cope) was seen as most important in determining appropriateness, but felt to be inadequately evaluated currently. Enhanced patient-physician communication, possibly through use of patient decision aids, has potential to improve patient selection for TJA.

Pittsburgh compound-B and Alzheimer's disease biomarkers in CSF, plasma and urine: An exploratory study.

BACKGROUND: The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PIB) is an in vivo ligand for measuring beta-amyloid (Abeta) load. Associations between PET PIB and cerebrospinal fluid (CSF) Abeta1-42 and apolipoprotein E epsilon4 (APOE epsilon4) have been observed in several studies, but the relations between PIB uptake and other biomarkers of Alzheimer's disease (AD) are less investigated. METHOD: PET PIB, PET 18Fluoro-2-deoxy-D-glucose and different AD biomarkers were measured twice in CSF, plasma and urine 12 months apart in 10 patients with a clinical diagnosis of mild to moderate AD. RESULTS: PIB retention was constant over 1 year, inversely related to low CSF Abeta1-42 (p = 0.01) and correlated positively to the numbers of the APOE epsilon4 allele (0, 1 or 2) (p = 0.02). There was a relation between mean PIB retention and CSF ApoE protein (r = -0.59, p = 0.07), and plasma cystatin C (r = -0.56, p = 0.09). CONCLUSION: PIB retention is strongly related to CSF Abeta1-42, and to the numbers of the APOE epsilon4 allele.

A questionnaire study on perception and clinical management of molar incisor hypomineralisation (MIH) by Irish dentists.

AIM: Molar incisor hypomineralisation (MIH) is a significant global health problem frequently encountered by dentists. The aim of this questionnaire-based study was to gain a better understanding of how dentists in the Republic of Ireland perceive and manage MIH. In addition, to compare these findings with results of existing international studies. METHODS: Following ethical approval, an online survey was created consisting of 16 questions based on previous surveys regarding perception and treatment of MIH. Photographs and information regarding three specific cases were also included. The questionnaire was distributed by email and the data were analysed using SPSS statistical software. RESULTS: The total number of respondents was 230, of which 204 were general dentists. The majority of dentists (58%) reported that they observe MIH on a weekly basis. Those dentists exclusively in private practice and respondents aged 36 and older were less likely to note frequent MIH (p = 0.042). The vast majority of respondents felt either confident or very confident in diagnosing MIH (91%). Overall, 71% reported to feel comfortable managing MIH; however, those in private practice only (p = 0.023) and those aged 36 and older (p = 0.011) were less likely to report being comfortable managing MIH. The most commonly cited barrier to care was the child's behaviour, followed by difficulty in achieving local anaesthesia. Composite resin was the most commonly selected material used to restore teeth affected by MIH (84%). In the scenario on cavity design, the results showed a similar number of dentists selected the most conservative and the most aggressive preparation indicating a disparity among choices. CONCLUSIONS: MIH is frequently encountered by Irish general dentists. The overall wide disparity of responses is in line with other studies, and further highlights the need for the development of strong treatment guidelines and continuing dental education to assist dentists in treatment planning for MIH.

Toward optimisation of water use efficiency in dryland pastures using carbon isotope discrimination as a tool to select plant species mixtures.

Pastoral agriculture is important for supplying global demand for animal products but pasture productivity is often water limited. Increased plant diversity has been shown to increase water use efficiency (ω) and productivity under water limitation but the optimal mix of species varies spatially, dependent on climate, soil type, and plant water requirements. Consequently, a cost-effective method to screen for high ω plant species and mixes in situ at farm scale is needed. Using carbon isotope discrimination (∆13C) to examine ω is attractive because the method integrates over useful time scales, does not modify the measurement environment, and is cost-effective. Field scale ω was measured using eddy covariance (EC) at two sites with contrasting plant diversity (2 species, 7 species) and compared to the seasonal progression of ω calculated from foliage ∆13C (ω∆). Soil water evaporation (ES) was removed from EC measured total ecosystem evaporation using a modelling approach and canopy ω (ωC) was calculated as gross primary production (GPP) divided by canopy evaporation. Mixed species foliage samples were harvested pre-grazing, dried, sub-sampled, ground, and the ratio of 13C to 12C was measured. A strong positive correlation was found between ω∆ and ωC at both study sites (r2 > 0.83, p < 0.01). In addition to bulk biomass samples, individual species were also harvested seasonally. Relative increases in both ω∆ and production for some species showed that manipulation of pasture species mixtures may lead to increased ω. Combined with production monitoring, ∆13C could be developed as a tool to optimise species selection for site specific climate and soil conditions to maximise ω and farm production and profit.

Cerebral venous thrombosis associated with ulcerative colitis.

Thromboembolic complications, such as deep venous thrombosis and pulmonary embolism, are well recognized in patients with inflammatory bowel disease (IBD). We describe three cases of cerebral venous thrombosis complicating ulcerative colitis. Cerebral venous thrombosis is a rare but potentially devastating complication of IBD, and the diagnosis needs to be considered in any patient with IBD presenting with neurological symptoms.

Stepwise effects of the BCR sequential chemical extraction procedure on dissolution and metal release from common ferromagnesian clay minerals: a combined solution chemistry and X-ray powder diffraction study.

Sequential extraction procedures (SEPs) are commonly used to determine speciation of trace metals in soils and sediments. However, the non-selectivity of reagents for targeted phases has remained a lingering concern. Furthermore, potentially reactive phases such as phyllosilicate clay minerals often contain trace metals in structural sites, and their reactivity has not been quantified. Accordingly, the objective of this study is to analyze the behavior of trace metal-bearing clay minerals exposed to the revised BCR 3-step plus aqua regia SEP. Mineral quantification based on stoichiometric analysis and quantitative powder X-ray diffraction (XRD) documents progressive dissolution of chlorite (CCa-2 ripidolite) and two varieties of smectite (SapCa-2 saponite and SWa-1 nontronite) during steps 1-3 of the BCR procedure. In total, 8 (+/-1) % of ripidolite, 19 (+/-1) % of saponite, and 19 (+/-3) % of nontronite (% mineral mass) dissolved during extractions assumed by many researchers to release trace metals from exchange sites, carbonates, hydroxides, sulfides and organic matter. For all three reference clays, release of Ni into solution is correlated with clay dissolution. Hydrolysis of relatively weak Mg-O bonds (362 kJ/mol) during all stages, reduction of Fe(III) during hydroxylamine hydrochloride extraction and oxidation of Fe(II) during hydrogen peroxide extraction are the main reasons for clay mineral dissolution. These findings underscore the need for precise mineral quantification when using SEPs to understand the origin/partitioning of trace metals with solid phases.

Marine and offshore safety assessment by incorporative risk modeling in a fuzzy-Bayesian network of an induced mass assignment paradigm.

The incorporation of the human element into a probabilistic risk-based model is one that requires a possibilistic integration of appropriate techniques and/or that of vital inputs of linguistic nature. While fuzzy logic is an excellent tool for such integration, it tends not to cross its boundaries of possibility theory, except via an evidential reasoning supposition. Therefore, a fuzzy-Bayesian network (FBN) is proposed to enable a bridge to be made into a probabilistic setting of the domain. This bridge is formalized by way of the mass assignment theory. A framework is also proposed for its use in maritime safety assessment. Its implementation has been demonstrated in a maritime human performance case study that utilizes performance-shaping factors as the input variables of this groundbreaking FBN risk model.

Understanding interactions of organic nitrates with the surface and bulk of organic films: implications for particle growth in the atmosphere.

Understanding impacts of secondary organic aerosol (SOA) in air requires a molecular-level understanding of particle growth via interactions between gases and particle surfaces. The interactions of three gaseous organic nitrates with selected organic substrates were measured at 296 K using attenuated total reflection Fourier transform infrared spectroscopy. The organic substrates included a long chain alkane (triacontane, TC), a keto-acid (pinonic acid, PA), an amorphous ester oligomer (poly(ethylene adipate) di-hydroxy terminated, PEA), and laboratory-generated SOA from α-pinene ozonolysis. There was no uptake of the organic nitrates on the non-polar TC substrate, but significant uptake occurred on PEA, PA, and α-pinene SOA. Net uptake coefficients (γ) at the shortest reaction times accessible in these experiments ranged from 3 × 10-4 to 9 × 10-6 and partition coefficients (K) from 1 × 107 to 9 × 104. Trends in γ did not quantitatively follow trends in K, suggesting that the intermolecular forces involved in gas-surface interactions are not the same as those in the bulk, which is supported by theoretical calculations. Kinetic modeling showed that nitrates diffused throughout the organic films over several minutes, and that the bulk diffusion coefficients evolved as uptake/desorption occurred. A plasticizing effect occurred upon incorporation of the organic nitrates, whereas desorption caused decreases in diffusion coefficients in the upper layers, suggesting a crusting effect. Accurate predictions of particle growth in the atmosphere will require knowledge of uptake coefficients, which are likely to be several orders of magnitude less than one, and of the intermolecular interactions of gases with particle surfaces as well as with the particle bulk.

Modeling the effect of dispersed doping agents in carbon nanotubes.

Theoretical studies of how the electronic properties of a nanotube are affected by one isolated doping agent is commonly done by ab-initio electronic structure calculations. Although these calculations are essential to understand how the system responds to doping, they are by no means sufficient, since, in reality, a large disordered array of doping agents must be considered. It is then necessary to combine ab-initio techniques with less-computationally-demanding methods if one wishes to describe the real effect of doping on the electronic properties of nanotubes. Here we propose a method that makes use of ab-initio results for single impurities as an input to generate the parameters of the less-demanding tight-binding technique. The method is based on suitable sum rules for the Green functions of the impurity-free nanotubes and does not rely on any fitting scheme. The resulting parametrization allows us to describe disordered systems without losing the important contributions due to charge transfer and screening. Transport properties are subsequentially investigated.

Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study.

The enzyme phosphodiesterase 10A (PDE10A) is abundant in striatal medium spiny neurons and has been implicated in the pathophysiology of schizophrenia in animal models and is investigated as a possible new pharmacological treatment target. A reduction of prefrontal cortical thickness is common in schizophrenia, but how this relates to PDE10A expression is unknown. Our study aim was to compare, we believe for the first time, the striatal non-displaceable binding potential (BPND) of the new validated PDE10A ligand [11C]Lu AE92686 between patients with schizophrenia and healthy controls. Furthermore, we aimed to assess the correlation of PDE10A BPND to cortical thickness. Sixteen healthy male controls and 10 male patients with schizophrenia treated with clozapine, olanzapine or quetiapine were investigated with positron emission tomography (PET) and magnetic resonance imaging (MRI). Striatal binding potential (BPND) of [11C]Lu AE92686 was acquired through dynamic PET scans and cortical thickness by structural MRI. Clinical assessments of symptoms and cognitive function were performed and the antipsychotic dosage was recorded. Patients with schizophrenia had a significantly lower BPND of [11C]Lu AE92686 in striatum (P=0.003) than healthy controls. The striatal BPND significantly correlated to cortical thickness in the medial prefrontal cortex and superior frontal gyrus across patients with schizophrenia and healthy controls. No significant correlation was observed between the BPND for [11C]Lu AE92686 in striatum and age, schizophrenia symptoms, antipsychotic dosage, coffee consumption, smoking, duration of illness or cognitive function in the patients. In conclusion, PDE10A may be important for functioning in the striato-cortical interaction and in the pathophysiology of schizophrenia.

Tyrosinase mutants are capable of prodrug activation in transfected nonmelanotic cells.

Tyrosinase has been suggested as a prodrug-converting enzyme for the treatment of melanoma. We hypothesized that tyrosinase expression in transfected nonmelanotic cells can be used in a gene therapy paradigm of prodrug activation. To verify our hypothesis, we used the following tyrosinase variants: (a) a full-length human tyrosinase clone (T); (b) a mutant lacking the COOH-terminal cytoplasmic domain (TdeltaC); (c) a mutant lacking the COOH-terminal transmembrane and cytoplasmic domains (TdeltaTC); and (d) a fusion with the eight COOH-terminal amino acids of lysosome-associated membrane protein-1 (TL). Expression of mutant and wild-type tyrosinases was induced by transfection in nontumorigenic human cells of epithelial origin (293HEK, MCF-10A adenoma, and NHDF-Ad human dermal fibroblasts) as well as in tumor cells (9L gliosarcoma, MCF7 adenocarcinoma, and HT-1080 fibrosarcoma). When compared with the wild-type tyrosinase transfectants, truncated mutant expression resulted in higher mRNA levels that paralleled higher enzyme activity of the truncated mutants. Two model tyrosinase prodrugs, hydroxyphenyl-propanol (HPP) and N-acetyl-4-S-cysteaminylphenol (NAcSCAP) inhibited proliferation and caused cell death of transfected cells in a dose-dependent manner. Effects of prodrug treatment were compared for tumorigenic cells and their nontumorigenic counterparts. Two truncated mutants (TdeltaC and TdeltaTC) showed low endogenous cytotoxicity and efficiently suppressed proliferation and induced cytotoxicity in transfected tumor cells in the presence of NAcSCAP. Overall, these results indicate that the developed tyrosinase mutants hold promise as prodrug activation systems for tumoral gene therapy.

The clinical safety, biodistribution and internal radiation dosimetry of [18F]AH113804 in healthy adult volunteers.

BACKGROUND: Quantitative biodistribution, venous blood and excretion data have been obtained following the intravenous bolus injection of AH113804 (18F) Injection in six healthy volunteers (HVs), four males and two females, up to approximately 5 h post-injection. For each subject, key organs and tissues were delineated and analytical fits were made to the image data as functions of time to yield the normalised cumulated activities. These were input to an internal radiation dosimetry calculation based upon the Medical Internal Radiation Dose (MIRD) schema for the Cristy-Eckerman adult male or female phantom. The absorbed doses per unit administered activity to the 24 MIRD-specified target organs were evaluated for an assumed 3.5-h urinary bladder voiding interval using the Organ Level INternal Dose Assessment/Exponential Modelling (OLINDA/EXM) code. The sex-specific absorbed doses were then averaged, and the effective dose per unit administered activity was calculated. RESULTS: Excluding the remaining tissue category, the three source regions with the highest mean initial 18F activity uptake were the liver (18.3%), lung (5.1%) and kidney (4.5%) and the highest mean normalised cumulated activities were the urinary bladder contents and voided urine (1.057 MBq h/MBq), liver (0.129 MBq h/MBq) and kidneys (0.065 MBq h/MBq). The three organs/tissues with the highest mean sex-averaged absorbed doses per unit administered activity were the urinary bladder wall (0.351 mGy/MBq), kidneys (0.052 mGy/MBq) and uterus (0.031 mGy/MBq). CONCLUSIONS: AH113804 (18F) Injection was safe and well tolerated. Although the effective dose, 0.0298 mSv/MBq, is slightly greater than for other common 18F PET imaging radiopharmaceuticals, the biodistribution and radiation dosimetry profile remain favourable for clinical PET imaging.