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We highlight a specific and hitherto poorly characterised phenotype of functional gait impairments: functional freezing of gait. Unique to the presented case is the use of compensation strategies, many of which at first sight might appear to hint towards the presence of freezing of gait typical of Parkinson's disease or another form of Parkinsonism. Importantly, however, this patient's compensation strategies involved various inconsistent and incongruent elements, supporting the diagnosis of a functional neurological disorder. Recognising the features of functional freezing also helps to appreciate better the classical manifestations of freezing of gait in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Background: Counseling for whole‐exome sequencing (WES) could benefit from aligning parents' pre‐ and post‐disclosure attitudes. A few studies have qualitatively compared parents' pre‐ and post‐disclosure attitudes toward receiving WES results for their child in a diagnostic setting. This study explored these attitudes in the context of children with a developmental delay. Methods: Semi‐structured interviews were conducted with parents (n = 27) of 16 children undergoing diagnostic WES in trio‐analysis, both before and after receiving results. Results: Three key insights emerged. First, the distinction between hoping and expecting was relevant for shaping parents' experiences with receiving results related to the primary indication. Second, parents of young children whose development of autonomous capacities was uncertain sometimes found themselves in a situation resembling a Catch‐22 when confronted with decisions about unsolicited findings (UFs): an important reason for consenting to WES was to gain a better picture of how the child might develop, but in order to make responsible choices about UFs, some ideas of their child's development is needed. Third, default opt‐ins and opt‐outs helped parents fathom new kinds of considerations for accepting or declining UFs in different categories, thereby aiding decision‐making. Conclusion: Results from this study are relevant for counseling and policy development. [ABSTRACT FROM AUTHOR]

Background: Patients with Functional Neurological Disorder (FND) experience complex patterns of motor and/or sensory symptoms. Treatment studies of psychological interventions are promising but limited. Objectives: The aim of the current pilot study is to investigate the effect of treatment consisting of a combination of hypnosis and catalepsy induction on FND symptom severity. Methods: A within‐subject waiting list‐control design was used with 46 patients diagnosed with FND. The treatment consisted of 10 sessions. The primary outcome measure was FND symptom severity (The Psychogenic Movement Disorder Rating Scale; PMDRS). The secondary outcome measures were psychological distress and quality of life. Results: The repeated measures (RM) ANOVA for the PMDRS as outcome measure revealed a significant effect for time with a large effect size (η2 = 0.679). Pairwise comparisons indicated that the effect of time in the treatment period was significant for the measure of FND symptom severity, whereas the waiting list period was not. The effect remained stable even at 8 weeks post treatment. As for the additional measurement, general psychological distress and quality of life, no statistically significant differences between individual time points were found. Conclusions: This pilot study showed that eight sessions of treatment consisting of a combination of hypnosis and catalepsy induction was effective in reducing FND symptom severity. Some explanations and limitations are provided in the paper as well as several avenues of future research. [ABSTRACT FROM AUTHOR]

Research into strong light–matter interactions continues to fascinate, being spurred on by unforeseen and often spectacular experimental observations. Properties that were considered to depend exclusively on material composition have been found to be drastically altered when a material is placed inside a resonant optical cavity. This is nowhere more the case than in the field of intermolecular energy transfer, where polaritonic states formed as a result of strong light–matter interactions have been shown to promote energy transfer over distances vastly exceeding conventional limits. In this review, we provide the reader with a succinct account of the fundamental concepts of intermolecular energy transfer, and how they are modified by strong light–matter interactions. We also summarize recent experimental advances in the area, including in optoelectronic device contexts, and highlight both the potential and challenges that remain in this exciting field of research going forward. [ABSTRACT FROM AUTHOR]

[Display omitted] • DNA methylation has unique functional relevance in different genomic contexts. • DNA methyltransferases are allosterically regulated by histone lysine methylation. • DNA methylation and histone lysine methylation crosstalk regulates transcription and genome integrity. • Imbalances in DNA methylation and histone lysine methylation are associated with human neurodevelopmental disorders and cancers. DNA methylation is a well-studied epigenetic modification that has key roles in regulating gene expression, maintaining genome integrity, and determining cell fate. Precisely how DNA methylation patterns are established and maintained in specific cell types at key developmental stages is still being elucidated. However, research over the last two decades has contributed to our understanding of DNA methylation regulation by other epigenetic processes. Specifically, lysine methylation on key residues of histone proteins has been shown to contribute to the allosteric regulation of DNA methyltransferase (DNMT) activities. In this review, we discuss the dynamic interplay between DNA methylation and histone lysine methylation as epigenetic regulators of genome function by synthesizing key recent studies in the field. With a focus on DNMT3 enzymes, we discuss mechanisms of DNA methylation and histone lysine methylation crosstalk in the regulation of gene expression and the maintenance of genome integrity. Further, we discuss how alterations to the balance of various sites of histone lysine methylation and DNA methylation contribute to human developmental disorders and cancers. Finally, we provide perspectives on the current direction of the field and highlight areas for continued research and development. [ABSTRACT FROM AUTHOR]

• First reported quantitative assay for the determination of galunisertib in human plasma. • Fast and elegant HPLC-MS/MS method for quantification of galunisertib in human plasma. • Application of a simple chromatographic method for quantification of galunisertib in small volumes of mouse plasma. Galunisertib is an anti-cancer drug currently evaluated in phase I and II clinical trials. This study describes the development and validation of a bioanalytical assay to quantify galunisertib in human plasma using HPLC-MS/MS. Stable isotope labelled galunisertib was added as internal standard and the analyte and internal standard were extracted from the matrix by protein precipitation using acetonitrile-methanol (50:50, v/v). Final extracts were injected onto a C18 column, gradient elution was applied for chromatographic separation and detection was performed using a triple quadrupole mass spectrometer operating in the positive ion mode. The assay was linear over the range 0.05–10 ng/mL, with acceptable accuracy (bias ranging from −6.1 to 3.1%) and precision (below 5.7% C.V.) values. The applicability of the assay was demonstrated in a pharmacokinetic experiment in mice. [ABSTRACT FROM AUTHOR]

Amongst the main reasons people at risk for Huntington's disease (HD) have for undergoing predictive genetic testing are planning a family and prevention of passing on an expanded CAG-repeat to future offspring. After having received an unfavourable test result, a couple may consider prenatal testing in the foetus or preimplantation genetic diagnostic testing (PGD) in embryos. Testing of the foetus or embryos is possible by means of direct testing of the expanded repeat. Optimal reliability in testing the foetus or embryos requires the establishment of the origin of the repeats of both parents in the foetus. For PGD the analysis is combined with or sometimes solely based on identification of the at-risk haplotype in the embryo. This policy implies that in the context of direct testing, the healthy partner's CAG repeat lengths in the HD gene are also tested, but with the expectation that the repeat lengths of the partner are within the normal range, with the proviso that the partner's pedigree is free of clinically confirmed HD. However, recent studies have shown that the expanded repeat has been observed more often in the general population than previously estimated. Moreover, we have unexpectedly observed an expanded repeat in the non-HD partner in four cases which had far-reaching consequences. Hence, we propose that in the context of reproductive genetic counselling, prior to a planned pregnancy, and irrespective of the outcome of the predictive test in the HD-partner, the non-HD partner should also be given the option of being tested on the expanded allele. International recommendations for predictive testing for HD should be adjusted. [ABSTRACT FROM AUTHOR]

Purpose: Plitidepsin absorption, distribution, metabolism and excretion characteristics were investigated in a mass balance study, in which six patients received a 3-h intravenous infusion containing 7 mg 14C-plitidepsin with a maximum radioactivity of 100 µCi.Methods: Blood samples were drawn and excreta were collected until less than 1% of the administered radioactivity was excreted per matrix for two consecutive days. Samples were pooled within-patients and between-patients and samples were screened for metabolites. Afterwards, metabolites were identified and quantified. Analysis was done using Liquid Chromatography linked to an Ion Trap Mass Spectrometer and offline Liquid Scintillation Counting (LC-Ion Trap MS-LSC).Results: On average 4.5 and 62.4% of the administered dose was excreted via urine over the first 24 h and in faeces over 240 h, respectively. Most metabolites were found in faeces.Conclusion: Plitidepsin is extensively metabolised and it undergoes dealkylation (demethylation), oxidation, carbonyl reduction, and (internal) hydrolysis. The chemical formula of several metabolites was confirmed using high resolution mass data. [ABSTRACT FROM AUTHOR]

Information and communication technologies (ICTs) have been associated with development programmes for many decades. A theme of Lamberton’s commentary on such initiatives focuses on the lack of attention given to information as a key factor in the development process. His writing reiterated a number of arguments that he saw as being fundamental to the application of an information perspective to development issues. With a focus on agricultural development policy in the Pacific region, the paper uses a number of propositions that are suggested by Lamberton to analyse contemporary development initiatives in Pacific Island agriculture. These propositions focus attention on information costs that can influence the transfer of information and development of knowledge. Document analysis of selected published sources from a Pacific Island development programme are reviewed to illustrate the significance of information costs for development processes. The paper addresses the contention between traditional authority and knowledge and its significance for development. [ABSTRACT FROM PUBLISHER]

The popularity of case study methods in information and communications technology for development research presents challenges in comparing findings across studies for the purpose of theory building. The object of this paper is to describe a qualitative study in which theory triangulation was used to systematically compare multiple cases to develop theory. The concept of development provided the theoretical context for the study. The work of Hall and Midgley was used to provide three rival philosophical positions that give rise to differing approaches to social development. These are: populist, enterprise and statist. The application of these three contrasting perspectives using theory triangulation is demonstrated in the analysis of multiple case studies taken from a community technology center program in Australia. The relative strengths and weaknesses of each approach are identified and used as the rationale for theory development. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the presence of thoughts or wishes for the end of life in patients with Huntington's disease (HD) or identified gene carriers (further mentioned together as patients). A custom-made questionnaire, based on previous qualitative research, was sent out to 242 patients with HD and identified gene carriers. Presence of wishes was investigated and correlated to demographic and clinical characteristics. A total of 134 patients (55 %) returned the questionnaire. 101 respondents (75 %) reported to have some kind of thoughts or wishes for the end of life. For 15 respondents (11 %) these thoughts concerned care; 86 respondents (64 %) reported to have also thoughts about euthanasia or physician-assisted suicide (PAS). The presence of any thoughts about the end of life was significantly related to being familiar with HD in the family, but not related to any other demographic or clinical variable. Participants with thoughts specifically about euthanasia or PAS were of higher education and in earlier stages of the disease than participants without such thoughts. Thoughts or wishes for the end of life are present amongst patients with HD. These thoughts include euthanasia or PAS in a majority of the respondents. It is suggested that prudential addressing of these issues may enhance the doctor-patient relationship. [ABSTRACT FROM AUTHOR]

The author reflects regarding physician assisted suicide (PAS) an euthanasia for Huntington's disease (HD) patients in Europe. It discusses the views and perception of physicians on the legality of SAS and euthanasia. Moreover. it mentioned the consideration of neurodegenerative disease patients as identified gene carriers which drives decision to end life.

The article presents guidelines for predictive genetic testing of Huntington's disease (HD). It notes that the guidelines were published after the gene mutation for HD was identified by the World Federation of Neurology (WFN) and the International Huntington Association (IHA). It mentions that the guidelines have contributed to the standards setting of predictive testing for HD and for other neurodegenerative diseases such as spinocerebellar ataxias (SCA's) and familial frontotemporal dementia.

Abstract: A sensitive liquid chromatography tandem mass spectrometry (LC–MS/MS) assay is described for the quantification of the anti-cancer agent bendamustine and its phase I metabolites γ-hydroxy-bendamustine (M3) and N-des-methylbendamustine (M4) and for its product of two-fold hydrolysis, dihydroxy-bendamustine (HP2), in human plasma and urine. Like most alkylating nitrogen mustards, bendamustine is prone to chemical hydrolysis in aqueous solution. To minimize degradation of bendamustine, urine samples were stabilized by a 100-fold dilution with human plasma and then processed identically to plasma samples. Sample aliquots of 200μL were mixed with an internal standard solution and acidified before separation of the analytes from the biomatrix with solid phase extraction. Dried and reconstituted extracts were injected on a Synergi Hydro RP column for the analysis of bendamustine, M3 and M4 or a Synergi Polar RP column for the analysis of HP2. Gradient elution was applied using 5mM ammonium formate with 0.1% formic acid in water and methanol as mobile phases. Analytes were ionized using an electrospray ionisation source in positive mode and detected with a triple quadrupole mass spectrometer. The quantifiable range for bendamustine, M3 and M4 was 0.5–500ng/mL in plasma and 0.5–50μg/mL in urine, and that for HP2 was 1–500ng/mL in plasma and 0.1–50μg/mL in urine. The assays were accurate and precise, with inter-assay and intra-assay accuracies within ±20% of nominal and CV values below 20% at the lower limit of quantification and within ±15% of nominal and below 15% at the other concentration levels tested. These methods were successfully applied to evaluate the pharmacokinetic profile of bendamustine and its metabolites in cancer patients treated with bendamustine. [Copyright &y& Elsevier]

Abstract: Huntington''s disease is characterised by a complex set of motor, neuropsychologic and psychiatric symptoms which start slowly and progress over many years to a state of complete dependency. The symptomatic treatment during the ambulatory years is divers. In the northern part of the Netherlands coordinated multidisciplinary care is offered to patients diagnosed with Huntington''s disease. A team of a neurologist, psychologist, occupational therapist, speech and language therapist, social worker and nursing home doctor monitors the patient and companion on a half-year basis and provide them with a plan of care. A case manager coordinates the plan of care in the dwelling place of the patient. In this article this type of care is outlined and illustrated with case histories. [Copyright &y& Elsevier]

We present a highly sensitive method for the determination of platinum (Pt) in DNA extracts of peripheral blood mononuclear cells (PBMCs) and tissue samples from patients treated with cisplatin. The method is based on the measurement of Pt by inductively coupled plasma mass spectrometry (ICP-MS) and allows quantification of Pt-DNA adducts in PBMCs isolated from 10 mL blood and 1 mg tissue. The lower limit of quantification is 0.75 pg Pt or 7.5 fg Pt μg−1 DNA when using 100 μg DNA. The method proved to be accurate and precise. The results obtained using the ICP-MS method were in good agreement with results from the alternative 32P-postlabelling assay. The ICP-MS method was, however, more sensitive and proved to be less laborious. The advantages of the presented ICP-MS technique were demonstrated by the analysis of PBMCs, normal gastric tissue, and gastric tumour tissue of patients treated with cisplatin. [ABSTRACT FROM AUTHOR]

Abstract: Worldwide, predictive testing for Huntington''s disease has become an accepted clinical application that has allowed many individuals from HD-families to proceed with their life without the uncertainty of being at risk. International guidelines have extensively contributed to establishing counselling programmes of high quality, and have served as a model for other genetic disorders. Psychological follow-up studies have increased the insight into the far-reaching impact of test results for all individuals involved. Although the guidelines have served as a useful frame of reference, clinical experience has shown the importance of a case-by-case approach to do justice to the specific needs of the individual test candidate. Issues such as ambiguous test results, lack of awareness in a test candidate of early signs of the disease, non-compliance to the test protocol, or the test candidate''s need for information on the relationship between age at onset and CAG-repeat require careful consideration. Receiving a test result is only one of the transition points in the life of an individual at risk; such result needs to be valued from a life-cycle perspective. [Copyright &y& Elsevier]

A method for sensitive determination of the anti-cancer agent oxaliplatin in human plasma and human plasma ultrafiltrate (pUF) is presented. The method is based on the quantification of platinum by graphite-furnace atomic-absorption spectrometry, with Zeeman correction and an atomisation temperature of 2,700°C. Sample pretreatment involves dilution of the samples with a solution containing 0.15 mol L−1 NaCl and 0.20 mol L−1 HCl in water. Validation was performed in accordance with the most recent FDA guidelines for bioanalytical method validation. All results were within requirements. The validated ranges of quantification were 0.10–400 μmol L−1 for human pUF and 0.50–400 μmol L−1 for plasma. The assay is now successfully used to support pharmacokinetic studies of cancer patients treated with oxaliplatin. [ABSTRACT FROM AUTHOR]

An investigation on the presence of larval cestodes in musk rats (Ondatra zibethicus) was carried out in two regions of the Netherlands (east Groningen and south Limburg) where in a earlier study foxes with Echinococcus multilocularis were found. A total of 1726 musk rats were dissected (1200 in Groningen, 526 in Limburg). Larval stages of Taenia taeniaeformis were most frequently found (total 44.8%: Groningen 42%, Limburg 51.3%), followed by T. martis (total 6.1%: Groningen 0.7%, Limburg 18.6%). Infections with T. crassiceps (total 0.3%: Groningen 0%, Limburg 1.0%), T. polyacantha (total 0.2%; Groningen 0.3%, Limburg 0%) and E. multilocularis (0.1%: Groningen 0.1%, Limburg 0%) were rare. Infections with T. taeniaeformis were more frequent in adults (71.8%) than in juveniles (34.2%). The same was found for T. martis: adults 15.3%, juveniles 2.5%. This difference was also reflected in the relation between weight of the animals and presence of infection. Heavier animals (>1000 g) were more often infected with T. taeniaeformis (74.1%) than animals less than 1000 g (34.8%). In musk rats weighing less than 500 g (n=155) only 5.2% were infected, but above 1200 g, 82.6%. The highest number of T. taeniaeformis was 28, of T. martis 13, of T. crassiceps >1000 and of T. polyacantha 24. The E. multilocularis was in a very young stage, a few white spots in the liver. Although E. multilocularis infections were exceptional, it is expected that with a rise in the number of infected foxes in the Netherlands the number of infected musk rats will increase. [Copyright &y& Elsevier]

A reversed-phase high performance liquid chromatographic (HPLC) method for the determination of the activated cyclophosphamide (CP) metabolite 4-hydroxycyclophosphamide (4-OHCP) in human plasma and red blood cells is described. 4-OHCP is very unstable in biological matrices. Therefore, it was treated, immediately after sampling, with semicarbazide to form a stable semicarbazone derivative, which was identified with electron spray mass spectrometry. The derivative was analysed with HPLC with ultraviolet (UV) detection at 230 nm. Sample pre-treatment consisted of a liquid-liquid extraction with ethyl acetate, the chromatography system was a 25 cm C8 column (particle size 5 μm) with a mobile phase of acetonitrile-0.025 M potassium phosphate buffer (15:85 v/v) pH 6.0. After assay optimisation, the method was validated and stability studies were carried out. The method proved linear in clinically relevant concentrations (50-5000 ng/mL). The lower limit of quantitation was 50 ng/mL. Accuracy and precision were below 7% over the full concentration range. A calibration curve in plasma can also be used for the quantification of 4-OHCP in red blood cells. The derivative was found to be stable for at least 11 months when stored at -70 °C. A pharmacokinetic pilot study in a patient treated with 1000 mg/m2 CP in combination with thioTEPA and carboplatin demonstrated the applicability of the assay for the determination of 4-OHCP in plasma and red blood cells. [ABSTRACT FROM AUTHOR]

• Simultaneous quantification of abemaciclib and its active metabolites by UHPLC–MS/MS. • This method is selective, linear, accurate and precise. • This method is suitable for the analysis of mouse and human plasma samples. • Isomers of M20 and M18 were detected in mouse plasma. • M20 isomers were confirmed by HR-MS measurements. Abemaciclib is the third cyclin-dependent kinase 4 and 6 inhibitor approved for the treatment of advanced or metastatic breast cancer. In humans, abemaciclib is extensively metabolized by CYP3A4 with the formation of three active metabolites: N -desethylabemaciclib (M2), hydroxyabemaciclib (M20) and hydroxy- N -desethylabemaciclib (M18). These metabolites showed similar potency compared to the parent drug and were significantly abundant in plasma circulation. Thus, M2, M20, and M18 may contribute to the clinical activity of abemaciclib. For this reason, an UHPLC–MS/MS method for the simultaneous quantification of abemaciclib and its active metabolites in human and mouse plasma was developed and validated to support further clinical or preclinical investigations on this drug. Samples were processed by protein precipitation with acetonitrile, followed by supernatant dilution and filtration. Chromatographic separation was performed on a Kinetex C 18 column (150 × 2.1 mm ID, 2.6 μm) using gradient elution with 10 mM ammonium bicarbonate in water (eluent A) and in methanol-water (9:1, v/v, eluent B). This method was selective, linear, accurate and precise within the range of 1−600 ng/mL for abemaciclib, 0.5−300 ng/mL for M2 and M20, and 0.2−120 ng/mL for M18. Furthermore, stability of the analytes in human and mouse plasma samples in several conditions was demonstrated. Finally, this assay was successfully used in a preclinical pharmacokinetic study, where abemaciclib and its active metabolites were identified and quantified. Inter-species differences between human and mouse samples were encountered, especially in the formation of M20, where isomers of this compound were detected in mouse plasma, but not in human plasma. This was confirmed by high resolution-mass spectrometry (HR-MS) measurements. [ABSTRACT FROM AUTHOR]

Background and Objectives: We described a new treatment model for Posttraumatic Stress Disorder (PTSD) and Dissociative Identity Disorder (DID), based on cognitive-behavioural principles. In this model, dissociation is seen as a maladaptive avoidant coping strategy. In addition, we stress that patients have dysfunctional beliefs about dissociation. Both elements, avoidance behaviour and dysfunctional beliefs, are challenged during the brief, intensive trauma-focused treatment. When the PTSD-symptoms decrease, the patient is offered a fare-well ritual to say goodbye to their identities in one or more additional sessions.Methods: We illustrate this treatment approach with a case report of a woman with PTSD as a result of sexual abuse in her childhood, and DID with four identities. Treatment outcome was measured at intake, at pre-treatment, at post-treatment and at 3 and 6 months follow-up.Results: After the short treatment of only 2 weeks, she no longer fulfilled the DSM-5 diagnostic criteria for PTSD nor DID. These results were maintained at the follow-ups.Limitations: Although we included a baseline-controlled time phase, it was not a controlled study, and only one patient was treated.Conclusions: This new treatment model for DID-patients is promising but results should be interpreted cautiously since we described only one patient. [ABSTRACT FROM AUTHOR]

Deals with the significance of information networks to the development of technological knowledge among engineers in the Islands of the Pacific. Relevance of innovation studies in industrialized countries on the technological capability development of developing countries; Contribution of communication linkages to the development of technical knowledge; Factors that influence information access.

Memory deficits are considered the most prominent characteristics of mental deterioration in the early stages of Huntington's disease (HD) but empirical studies report contradictory results. The aim of this study was to assess memory and learning in 9 individuals with an increased risk (≥ 96%) of HD but without clinical symptoms and signs. Seventeen individuals with a decreased risk (≤ 5 %) formed a group of controls. Verbal and visual memory, various aspects of learning, word fluency and procedural learning were assessed. Conventional group comparisons showed no significant differences in the performances of the high risk and the low risk groups. [ABSTRACT FROM AUTHOR]

Abstract. In this study the potential of intraperitoneal (J.p.) and intravenous (i.v.) administration of chimeric iodine-131-labelled MOv18 IgG for radioimmunotherapy was determined. The dosimetry associated with both routes of administration of cMOv18 IgG was studied in patients. Eight patients suspected of having ovarian carcinoma received 150 MBq [sup 13]I-cMOv18 IgG i.p. Blood and urine were collected and serial gamma camera images were acquired. Another group of four patients received 7.5 MBq [sup 13]I-cMOv18 IgG i.v. For all patients, tissue biopsies were obtained at surgery. Activity in the blood after i.p. administration was described by a bi-exponential curve with a mean uptake and elimination half-life of 6.9+/-3.2 h and 160+/-45 h, respectively. For i.v. infusion the mean half-life for the elimination phase was 103+/-12 h. Cumulative excretion in the urine was 17%+/-3% ID and 21%+/-7% ID in 96 h for i.p. and i.v. administration, respectively. Scintigraphic images after i.p. administration showed accumulation in ovarian cancer lesions, while all other tissues showed decreasing activity with time. Tumour uptake determined in the ovarian cancer tissue specimens ranged from 3.4% to 12.3% ID/kg for i.p. administration and from 3.6% to 5.4% ID/kg for i.v. administration. Dosimetric analysis of the data indicated that 1.7-4.3 mGy/MBq and 1.7-2.2... [ABSTRACT FROM AUTHOR]

In recent literature the psychological impact of predictive DNA-testing for Heraditary Breast and Ovarian Cancer (HBOC) for male individuals at-risk has not been considered. We have observed chat confrontation with the hereditary nature of breast/ovarian cancer does have a psychological impact on males at-risk. From the first Dutch family for whom predictive DNA-testing for HBOC became an option. four males started the testing protocol with the inclusion of pre-test genetic and psychological counselling and psychological follow-up. They all postponed appointments and only one took the test. During counselling of the men, the main focus of attention was on the impact of the past and future (possible) deaths and serious illnesses of female relatives. They tended to deny or minimise the emotional impact of the occurrence of HBOC in their personal life and their future. They avoided discussion about their emotions and focused upon the medical implications of the disorder for their female relatives. It is important to understand the underlying conflicts which lead to warding off the test in males at risk, in order to offer adequate genetic counselling and to enable the males to better cope with the hereditary disorder in the family. [ABSTRACT FROM AUTHOR]

Highlights from the article: Letter in response to Tibben et al Risk assessment for Huntington's Disease for (future) offspring requires offering preconceptual CAG analysis to both partners. Risk Assessment for Huntington's Disease for (Future) Offspring Requires Offering Preconceptional CAG Analysis to Both Partners.

• A sensitive assay for the simultaneous quantification of aprepitant and dexamethasone was developed and validated. • This assay only requires small sample volumes. • The LC-MS/MS method is selective, linear, accurate and precise. • The assay is suitable for pharmacokinetic studies in pediatric patients. A pharmacokinetic study was set up to investigate the pharmacokinetics of the anti-emetic agents aprepitant and dexamethasone and the drug-drug interaction between these drugs in children. In order to quantify aprepitant and dexamethasone, a liquid chromatography-tandem mass spectrometry assay was developed and validated for the simultaneous analysis of aprepitant and dexamethasone. Protein precipitation with acetonitrile-methanol (1:1, v/v) was used to extract the analytes from plasma. The assay was based on reversed-phase chromatography coupled with tandem mass spectrometry detection operating in the positive ion mode. The assay was validated based on the guidelines on bioanalytical methods by the US Food and Drug Administration and European Medicines Agency. The calibration model was linear and a weighting factor of 1/concentration2 was used over the range of 0.1–50 ng/mL for aprepitant and 1–500 ng/mL for dexamethasone. Intra-assay and inter-assay bias were within ±20% for all analytes at the lower limit of quantification and within ±15% at remaining concentrations. Dilution integrity tests showed that samples exceeding the upper limit of quantification can be diluted 100 times in control matrix. Stability experiments showed that the compounds are stable in the biomatrix for 25 h at room temperatures and 89 days at −20 °C. This assay is considered suitable for pharmacokinetic studies and will be used to study the drug-drug interaction between aprepitant and dexamethasone in pediatric patients. [ABSTRACT FROM AUTHOR]

• The first described bioanalytical assay for milciclib. • This method is suitable for the quantification of milciclib in several biomatrices. • A full validation in human plasma is described. • An application of a pharmacokinetic study of milciclib in mice is included. Milciclib is a promising cyclin-dependent kinase inhibitor currently in phase II clinical trials to treat several types of cancer. The first bioanalytical method for the quantitative analysis of milciclib in several biomatrices using liquid chromatography-tandem mass spectrometry is described here. This method was fully validated in human plasma according to FDA and EMA guidelines, and partially validated in mouse plasma, homogenates of mouse brain, kidney, liver, small intestine, spleen, and tissue culture medium. Palbociclib, an analog compound, was used as internal standard. A simple and fast sample pre-treatment by protein precipitation with acetonitrile was used, leading to efficient extraction of the analyte with recoveries between 95–100%. Chromatographic separation was achieved with a C 18 analytical column and a gradient elution using 10 mM ammonium bicarbonate in water and 10 mM ammonium bicarbonate in water-methanol (1:9, v/v). This assay was selective, accurate, precise and linear in the concentration range of 1−1000 ng/mL. Moreover, samples above the upper limit of quantification can be integrally diluted up to 10-fold prior to analysis. The use of human plasma as a surrogate matrix to quantify milciclib in tissue culture medium and mouse matrices resulted in acceptable accuracy and precision, however tissue culture medium samples required a dilution with human plasma prior the pre-treatment. All performance parameters of the method complied with the acceptance criteria recommended by the guidelines, except for the carry-over, which was slightly above (22.9% of the lower limit of quantification) the recommended percentage (20%). Therefore, additional measures were taken to assure data integrity. Stability of milciclib in all matrices was evaluated, and in some matrices the analyte was unstable under the tested conditions. It is therefore recommended to keep these samples as briefly as possible at room temperature during the pre-treatment, and to store them at –70 °C to avoid analyte degradation. This method was successfully applied to support preclinical pharmacokinetic studies of milciclib. [ABSTRACT FROM AUTHOR]

We demonstrate, in a specific scenario, the effect of negative test results from relatives in families at risk for an autosomal dominant hereditary late-onset disorder. A hypothetical pedigree, of a family at risk of Huntington's disease, was used to demonstrate the consequences for the risk status of various family members in the case where relatives have been tested, and found to be mutation negative. We argue that accurate assessment of conditional probabilities in clinical genetics is important for individuals at risk for hereditary disorders with Mendelian transmission patterns; our formulae offer the opportunity – when simplifying assumptions are met – to determine the changed risk status of individuals in such cases.Heredity (2006) 96, 259–261. doi:10.1038/sj.hdy.6800790; published online 4 January 2006 [ABSTRACT FROM AUTHOR]

Patients with prostate cancer (PCa) have a lower docetaxel exposure for both intravenous (1.8‐fold) and oral administration (2.4‐fold) than patients with other solid cancers, which could influence efficacy and toxicity. An altered metabolism by cytochrome P450 3A (CYP3A) due to castration status might explain the observed difference in docetaxel pharmacokinetics. In this in vivo phenotyping, pharmacokinetic study, CYP3A activity defined by midazolam clearance (CL) was compared between patients with PCa and male patients with other solid tumors. All patients with solid tumors who did not use CYP3A‐modulating drugs were eligible for participation. Patients received 2 mg midazolam orally and 1 mg midazolam intravenously on 2 consecutive days. Plasma concentrations were measured with a validated liquid chromatography–tandem mass spectrometry method. Genotyping was performed for CYP3A4 and CYP3A5. Nine patients were included in each group. Oral midazolam CL was 1.26‐fold higher in patients with PCa compared to patients with other solid tumors (geometric mean [coefficient of variation], 94.1 [33.5%] L/h vs 74.4 [39.1%] L/h, respectively; P =.08). Intravenous midazolam CL did not significantly differ between the 2 groups (P =.93). Moreover, the metabolic ratio of midazolam to 1′‐hydroxy midazolam did not differ between the 2 groups for both oral administration (P =.67) and intravenous administration (P =.26). CYP3A4 and CYP3A5 genotypes did not influence midazolam pharmacokinetics. The observed difference in docetaxel pharmacokinetics between both patient groups therefore appears to be explained neither by a difference in midazolam CL nor by a difference in metabolic conversion rate of midazolam. [ABSTRACT FROM AUTHOR]

The author reflects on the findings of a study which investigated the nature and prevalence of genetic discrimination in asymptomatic genetically tested and untested people who are at risk for Huntington's disease in Canada. He described the varying views on genetic discrimination among countries, including the self-reports of genetic discrimination. The author described the influence of family and social discrimination on the fear and anger that people project on to others.

Increased community knowledge of and access to clinical trials for Duchenne and Becker muscular dystrophy (DBMD) may amplify adaptive optimism, but also inappropriately high expectations. This study explored parental and clinician motivations and expectations for DBMD clinical trials. We interviewed 15 parents of children with DBMD and 11 clinicians participating in 10 clinical trials for DBMD. Interviews were transcribed and coded for thematic analysis. All parents hoped for, and most expected, direct benefit to their child; this was their primary motivator. Other motivators were a desire to affect the disease course; that “doing something is better than nothing;” and altruism. Most parents actively sought out a trial and described making their decision before the informed consent process (IC). The majority hoped for a cure but recognized this as unrealistic. Parents’ reported expectations were inconsistent in different contexts during the interviews. Some had difficulty differentiating between expectations and optimistic hopes. Some reported efforts to temper their expectations, or outside factors tempering expectations such as being in a placebo-controlled trial. Many parents described changes to expectations and hopes over time. Clinicians reported that families were motivated by desperation and hope for benefit. Altruism was a less important motivator. Clinicians’ motivations included optimism, enthusiasm for having more to offer, and personal commitment. Clinicians’ expectations ranged from modest gains in knowledge to clinical improvement. This study suggests the importance of interventions that help parents clarify expectations and identify inappropriately high expectations, and anticipatory guidance regarding challenges to optimistic hopes. As parents reported decision making before IC, interventions prior to IC may be most effective. Further studies are needed to identify predictors of inappropriately high expectations in DBMD clinical trials. [Copyright &y& Elsevier]

Introduction: Aprepitant is used for the treatment of chemotherapy induced nausea and vomiting. A liquid formulation is needed for treatment of young children. However, the commercial (powder for) suspension was not available worldwide for a prolonged period of time and, therefore, a 10 mg/mL aprepitant oral suspension was extemporarily prepared to prevent suboptimal antiemetic treatment. The current pharmacokinetic study was developed to investigate whether this extemporaneous oral suspension offers an appropriate treatment option. Methods: From 49 pediatric patients (0.7–17.9 years) 235 plasma concentrations were collected. Patients were either treated with our extemporaneous oral suspension (n = 26; 53%), commercially available capsules (n = 18; 37%), or the intravenous prodrug formulation of aprepitant (fosaprepitant, n = 5; 10%). Pharmacokinetic analyses were performed using nonlinear mixed effects modelling. Results: A one-compartment model adequately described the pharmacokinetics of aprepitant in children. The bioavailability of the extemporaneous oral suspension was not significantly different to that of the capsules (P = 0.26). The observed bioavailability throughout the total population was 83% (95% CI 69%-97%). The absorption of the extemporaneous oral suspension was 39.4% (95%CI 19.5–57.4%) faster than that of capsules (mean absorption time of 1.78 h (95%CI 1.32–2.35), but was comparable to that of the commercial oral suspension. The median area under the curve after (fos)aprepitant was 22.2 mg/L*h (range 8.9–50.3 mg/L*h) on day 1. Conclusion: Our extemporaneous oral suspension is an adequate alternative for the commercially (un)available oral suspension in young children. An adequate exposure to aprepitant in children was yielded and the bioavailability of the extemporaneous suspension was comparable to capsules. [ABSTRACT FROM AUTHOR]

Background Guidelines for the molecular genetic predictive testing in Huntington's disease (HD) were issued in 1994, soon after the discovery of the gene. Since then, the research on HD has made remarkable advancements and a considerable amount of experience was acquired by centres offering the presymptomatic and prenatal HD tests. After 16 years the EHDN WG on Genetic Testing and Counselling thought that some recommendations should be updated and some added, on the basis of scientific evidence and documents collected so far. Methods WG participants, including members of the lay association, psychologists, neurologists, geneticists, genetic counsellors and ethicists from all over Europe were divided into subgroups, each devoted to a particular topic. Each subgroup had to collect the relevant scientific literature and documents, discuss the possible changes and propose an update. The updates proposed by each subgroup were discussed in plenary meetings. The proposed updates were posted on the EHDN website to be electronically discussed by EHDN members. A revised version will be submitted to IHA and WFNHDRG members for further discussion. The final approval is foreseen at the World Congress on Huntington's Disease in Melbourne, September 2011. Results The following topics were selected for review: testing of minors (Rec 2.), lab standard of accuracy (Rec 2.8), limitation of the test information about age of onset and intermediate/low penetrance alleles (5.2.3, 5.2.4) and discrimination (4.2, 5.3) In addition, new guidelines were proposed, dealing with PGD and information about clinical trials. The proposed updates will be reported at the meeting in Prague as well as the evidence and documents on which they are based. Conclusions The results indicate the need to fill the gap between the present guidelines and the state of the art in research and ethical elaboration. Comments, reactions and suggestions from the EHDN Congress participants are essential for the update validation. [ABSTRACT FROM PUBLISHER]

Purpose: To examine the pharmacokinetic (PK) profile of several candidate extended-release (ER) formulations of capecitabine in patients. Methods: In a phase 0 clinical study, PK profiles of several oral candidate ER formulations of capecitabine were compared to the PK profile of capecitabine after administration of the commercially available immediate-release (IR) tablet. A single dose of 1000 mg IR formulation (two 500 mg tablets) was administered on day 1, and a single dose of a 1000 mg candidate ER formulation of capecitabine (two 500 mg tablets) was administered on day 2. Candidate ER formulations of capecitabine differed with regard to the amount of the ER excipient (Kollidon(®) SR) in tablet matrix (0-5 % w/w) and coating (0-12 mg/cm(2)). Results: PK profiles of nine different candidate ER formulations were examined. The tablet coating seemed the main determinant for ER of capecitabine and tablet integrity. Average (±standard deviation) AUC0-2h, relative to AUC0-2h after oral administration of the IR tablet, were 43.3 % (±34.9 %) and 1.2 % (±1.2 %) for candidate ER formulations coated with 3 and 6 mg/cm(2), respectively. Corresponding AUC0-last were 93.6 % (±40.2 %) and 44.0 % (±5.4 %). Conclusion: Modulation of capecitabine release in patients can be accomplished by varying tablet coating content. Proof of principle was demonstrated for candidate ER formulations with coating content of 3 mg/cm(2). [ABSTRACT FROM AUTHOR]

Purpose: Chemotherapy-induced nausea and vomiting (CINV) are common side effects in pediatric oncology treatment. Besides 5-HT3-antagonists, both dexamethasone and aprepitant are cornerstone drugs in controlling these side effects. Based on results of adult studies, the dexamethasone dose is reduced by 50% when combined with aprepitant, because of a drug-drug interaction, even though data on the interaction in children is lacking. The current study was developed to investigate the effect of aprepitant on dexamethasone clearance (CL) in children, in order to assess if dexamethasone dose reduction for concomitant use of aprepitant is appropriate in the current antiemetic regimen. Methods: In total, 65 children (0.6–17.9 years), receiving intravenous or oral antiemetic therapy (dexamethasone ± aprepitant) as standard of care, were included. 305 dexamethasone plasma concentrations were determined using LC–MS/MS. An integrated dexamethasone and aprepitant pharmacokinetic model was developed using non-linear mixed effects modelling in order to investigate the effect of aprepitant administration on dexamethasone CL. Results: In this population, dexamethasone CL in patients with concomitant administration of aprepitant was reduced by approximately 30% of the uninhibited CL (23.3 L/h (95% confidence interval 20.4–26.0)). This result is not consistent with the results of adult studies (50% reduction). This difference was not age dependent, but might be related to the route of administration of dexamethasone. Future studies are needed to assess the difference in oral/intravenous dexamethasone. Conclusion: When dexamethasone is given intravenously as a component of triple therapy to prevent CINV in children, we advise to reduce the dexamethasone dose by 30% instead of 50%. [ABSTRACT FROM AUTHOR]

Objective This interview study explored clinicians' perspectives and parents' decision making about children's participation in Duchenne muscular dystrophy (DMD) clinical trials. Methods Data from semi-structured interviews conducted with clinicians and parents in U.S. or Canada were assessed using thematic analysis. Results Eleven clinicians involved in ten trials and fifteen parents involved in six trials were interviewed. Parents described benefit–risk assessments using information from advocacy, peers, professionals, and sponsors. Strong influence was attributed to the progressive nature of DMD. Most expected direct benefit. Few considered the possibility of trial failure. Most made decisions to participate before the informed consent (IC) process, but none-the-less perceived informed choice with little to lose for potential gain. Clinicians described more influence on parental decisions than attributed by parents. Clinicians felt responsible to facilitate IC while maintaining hope. Both clinicians and parents reported criticisms about the IC process and regulatory barriers. Conclusions The majority of parents described undertaking benefit–risk assessments that led to informed choices that offered psychological and potential disease benefits. Parents' high expectations influenced their decisions while also reflecting optimism. Clinicians felt challenged in balancing parents' expectations and likely outcomes. Prognosis-related pressures coupled with decision making prior to IC suggest an obligation to ensure educational materials are understandable and accurate, and to consider an expanded notion of IC timeframes. Anticipatory guidance about potential trial failure might facilitate parents' deliberations while aiding clinicians in moderating overly-optimistic motivations. Regulators and industry should appreciate special challenges in progressive disorders, where doing nothing was equated with doing harm. [ABSTRACT FROM AUTHOR]

STUDY QUESTION How do couples with a BRCA1/2 mutation decide on preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND) for hereditary breast and ovarian cancer syndrome (HBOC)? SUMMARY ANSWER BRCA couples primarily classify PGD and/or PND as reproductive options based on the perceived severity of HBOC and moral considerations, and consequently weigh the few important advantages of PGD against numerous smaller disadvantages. WHAT IS KNOWN ALREADY Awareness of PGD is generally low among persons at high risk for hereditary cancers. Most persons with HBOC are in favour of offering PGD for BRCA1/2 mutations, although only a minority would consider this option for themselves. Studies exploring the motivations for using or refraining from PGD among well-informed BRCA carriers of reproductive age are lacking. We studied the reproductive decision-making process by interviewing a group of well-informed, reproductive aged couples carrying a BRCA1/2 mutation, regarding their decisional motives and considerations. STUDY DESIGN, SIZE, DURATION This exploratory, qualitative study investigated the motives and considerations taken into account by couples with a BRCA1/2 mutation and who have received extensive counselling on PGD and PND and have made a well-informed decision regarding this option. Eighteen couples took part in focus group and dyadic interviews between January and September 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS Semi-structured focus groups were conducted containing two to four couples, assembled based on the reproductive method the couple had chosen: PGD (n = 6 couples) or conception without testing (n = 8 couples). Couples who had chosen PND for BRCA (n = 4) were interviewed dyadically. Two of the women, of whom one had chosen PND and the other had chosen no testing, had a history of breast cancer. MAIN RESULTS AND THE ROLE OF CHANCE None of the couples who opted for PGD or conception without testing found the use of PND, with possible pregnancy termination, acceptable. PND users chose this method because of decisive, mainly practical reasons (natural conception, high chance of favourable outcome). Motives and considerations regarding PGD largely overlapped between PGD users, PND users and non-users, all mentioning some significant advantages (e.g. protecting the child and family from the mutation) and many smaller disadvantages (e.g. the necessity of in vitro fertilization (IVF), low chance of pregnancy by IVF/PGD). For female carriers, the safety of hormonal stimulation and the time required for PGD before undergoing preventive surgeries were important factors in the decision. Non-users expressed doubts about the moral justness of their decision afterwards and emphasized the impact the decision still had on their lives. LIMITATIONS, REASON FOR CAUTION The interviewed couples were at different stages in their chosen trajectory, up to 3 years after completion. This may have led to recall bias of original motives and considerations. Couples who did not actively seek information about PGD were excluded. Therefore the results may not be readily generalizable to all BRCA couples. WIDER IMPLICATIONS OF THE FINDINGS The perceived severity of HBOC and, for female carriers, the safety of hormonal stimulation and the time frames for PGD planning before preventive surgeries are essential items BRCA couples consider in reproductive decision-making. The emotional impact of this decision should not be underestimated; especially non-users may experience feelings of doubt or guilt up to several years afterwards. PGD counselling with tailored information addressing these items and decisional support in order to guarantee well-informed decision-making is needed. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by ... [ABSTRACT FROM AUTHOR]