Specific proteome changes in platelets from individuals with GATA1-, GFI1B-, and RUNX1-linked bleeding disorders.

Mutations in the transcription factors GATA binding factor 1 (GATA1), growth factor independence 1B (GFI1B), and Runt-related transcription factor 1 (RUNX1) cause familial platelet and bleeding disorders. Mutant platelets exhibit common abnormalities including an α-granule reduction resulting in a grayish appearance in blood smears. This suggests that similar pathways are deregulated by different transcription factor mutations. To identify common factors, full platelet proteomes from 11 individuals with mutant GATA1R216Q, GFI1BQ287*, RUNX1Q154Rfs, or RUNX1TD2-6 and 28 healthy controls were examined by label-free quantitative mass spectrometry. In total, 2875 platelet proteins were reliably quantified. Clustering analysis of more than 300 differentially expressed proteins revealed profound differences between cases and controls. Among cases, 44 of 143 significantly downregulated proteins were assigned to platelet function, hemostasis, and granule biology, in line with platelet dysfunction and bleedings. Remarkably, none of these proteins were significantly diminished in all affected cases. Similarly, no proteins were commonly overrepresented in all affected cases compared with controls. These data indicate that the studied transcription factor mutations alter platelet proteomes in distinct largely nonoverlapping manners. This work provides the quantitative landscape of proteins that affect platelet function when deregulated by mutated transcription factors in inherited bleeding disorders.

Assessment of cardiac load-responsiveness in veno-arterial extracorporeal life support: A case series.

INTRODUCTION: Well-timed explant of veno-arterial extracorporeal life support (V-A ECLS) depends on adequate assessment of cardiac recovery. Often, evaluation of cardiac recovery consists of reducing support flow while visualizing cardiac response using transoesophageal echocardiography (TEE). This method, however, is time consuming and based on subjective findings. The dynamic filling index (DFI) may aid in the quantitative assessment of cardiac load-responsiveness. The dynamic filling index is based on the relationship of support flow and pump speed, which varies with varying hemodynamic conditions. This case series intends to investigate whether the DFI may support TEE in facilitating the assessment of cardiac load-responsiveness. METHODS: Measurements for DFI-determination were performed in seven patients while simultaneously assessing ventricular function by measuring the aortic velocity time integral (VTI) using TEE. Measurements consisted of multiple consecutive transient speed manipulations (∼100 r/min) during weaning trials, both at full support and during cardiac reloading at reduced support. RESULTS: The VTI increased between full and reduced support in six weaning trials. In five of these trials DFI decreased or remained equal, and in one case DFI increased. Of the three trials in which VTI decreased between full and reduced support, DFI increased in two cases and decreased in one case. Changes in DFI, however, are mostly smaller than the detection threshold of 0.4 mL/rotation. CONCLUSION: Even though current level of accuracy of the parameter requires further investigation to increase reliability and possibly predictability, DFI seems likely to be a potential parameter in supporting TEE for the assessment of cardiac load-responsiveness.

[Multi-family therapy for adolescents with anorexia nervosa]. / Multi-familietherapie voor jongeren met anorexia nervosa.

Background Anorexia nervosa (AN) is a severe psychiatric disorder. Family based therapy is the most appropriate treatment. In recent decades, a particular form multi-family therapy (MFT) has been used. Aim To provide an overview of the scientific evidence regarding MFT in adolescents with AN. Method Literature search using PubMed, PsycInfo and Web of Knowledge. Literature was searched about the treatment of AN in adolescents through multi-family therapy in day therapy setting. Seven studies were included: one RCT with a strong methodology, two smaller controlled studies and four case series. Results After completing MFT, clear significant improvement is reported in terms of weight or BMI and eating disorder symptoms. Two studies suggest MFT is more effective in accelerating weight gain and achieving weight recovery. Depressive features, individual and family factors also improve. The low drop-out rate is remarkable. Conclusion MFT as an additional treatment for adolescents with AN is promising. Based on the available evidence, a good and at least equivalent outcome in comparison with family therapy is expected. In addition, it offers several unique benefits.

Experimental Evidence for Transverse Wobbling in

New rotational bands built on the ν(h_{11/2}) configuration have been identified in ^{105}Pd. Two bands built on this configuration show the characteristics of transverse wobbling: the ΔI=1 transitions between them have a predominant E2 component and the wobbling energy decreases with increasing spin. The properties of the observed wobbling bands are in good agreement with theoretical results obtained using constrained triaxial covariant density functional theory and quantum particle rotor model calculations. This provides the first experimental evidence for transverse wobbling bands based on a one-neutron configuration, and also represents the first observation of wobbling motion in the A∼100 mass region.

Can psychiatric childhood disorders be due to inborn errors of metabolism?

Many patients who visit a centre for hereditary metabolic diseases remarkably also suffer from a child psychiatric disorder. Those child psychiatric disorders may be the first sign or manifestation of an underlying metabolic disorder. Lack of knowledge of metabolic disorders in child psychiatry may lead to diagnoses being missed. Patients therefore are also at risk for not accessing efficacious treatment and proper counselling. To search the literature for the co-occurrence of child psychiatric disorders, such as ADHD, autism, psychosis, learning disorders and eating disorders and metabolic disorders. A search of the literature was conducted by performing a broad search on PubMed, using the terms "ADHD and metabolic disorders", "autism and metabolic disorders", "psychosis and metabolic disorders", "learning disorders and metabolic disorders", and "eating disorders and metabolic disorders". Based on inclusion criteria (concerning a clear psychiatric disorder and concerning a metabolic disorder) 4441 titles and 249 abstracts were screened and resulted in 71 relevant articles. This thorough literature search provides child and adolescent psychiatrists with an overview of metabolic disorders associated with child psychiatric symptoms, their main characteristics and recommendations for further investigations.

Blood warming, pump heating and haemolysis in low-flow extracorporeal life support; an in vitro study using freshly donated human blood.

Low-flow extracorporeal life support can be used for cardiopulmonary support of paediatric and neonatal patients and is also emerging as a therapy for patients suffering from exacerbation of chronic obstructive pulmonary disease. However, pump heating and haemolysis have proven to negatively affect the system and outcome. This in vitro study aimed at gaining insight into blood warming, pump heating and haemolysis related to the performance of a new low-flow centrifugal pump. Pump performance in the 400-1,500 ml/min flow range was modulated using small-sized dual-lumen catheters and freshly donated human blood. Measurements included plasma free haemoglobin, blood temperature, pump speed, pump pressure, blood flow and thermographic imaging. Blood warming (ΔTmax=0.5°C) had no relationship with pump performance or haemolysis (R2max=0.05). Pump performance-related parameters revealed no relevant relationships with haemolysis (R2max=0.36). Thermography showed no relevant heat zones in the pump (Tmax=36°C). Concerning blood warming, pump heating and haemolysis, we deem the centrifugal pump applicable for low-flow extracorporeal circulation.

Diets and trophic guilds of small fishes from coastal marine habitats in western Taiwan.

The diets and trophic guilds of small fishes were examined along marine sandy beaches and in estuaries at depths <1·5 m in western Taiwan, Republic of China. Copepods were the most frequently identified item in fish guts, indicating they are key prey for the fish assemblages studied. Piscivore, crustacivore, detritivore, omnivore, zooplanktivore and terrestrial invertivore trophic guilds were identified. The zooplanktivore guild contained the most fish species. Maximum prey size consumption was positively correlated with standard length (LS ) in seven species and at the assemblage level and negatively correlated with LS in a single detritivorous species. The diet data and trophic guild scheme produced by this study contribute to an understanding of coastal marine food webs and can inform ecosystem-based fisheries management.

The Healthy Primary School of the Future: study protocol of a quasi-experimental study.

BACKGROUND: Unhealthy lifestyles in early childhood are a major global health challenge. These lifestyles often persist from generation to generation and contribute to a vicious cycle of health-related and social problems. This design article presents a study evaluating the effects of two novel healthy school interventions. The main outcome measure will be changes in children's body mass index (BMI). In addition, lifestyle behaviours, academic achievement, child well-being, socio-economic differences, and societal costs will be examined. METHODS: In close collaboration with various stakeholders, a quasi-experimental study was developed, for which children of four intervention schools (n = 1200) in the southern part of the Netherlands are compared with children of four control schools (n = 1200) in the same region. The interventions started in November 2015. In two of the four intervention schools, a whole-school approach named 'The Healthy Primary School of the Future', is implemented with the aim of improving physical activity and dietary behaviour. For this intervention, pupils are offered an extended curriculum, including a healthy lunch, more physical exercises, and social and educational activities, next to the regular school curriculum. In the two other intervention schools, a physical-activity school approach called 'The Physical Activity School', is implemented, which is essentially similar to the other intervention, except that no lunch is provided. The interventions proceed during a period of 4 years. Apart from the effectiveness of both interventions, the process, the cost-effectiveness, and the expected legal implications are studied. Data collection is conducted within the school system. The baseline measurements started in September 2015 and yearly follow-up measurements are taking place until 2019. DISCUSSION: A whole-school approach is a new concept in the Netherlands. Due to its innovative, multifaceted nature and sound scientific foundation, these integrated programmes have the potential to form a template for primary schools worldwide. The effects of this approach may extend further than the outcomes associated with well-being and academic achievement, potentially impacting legal and cultural aspects in our society. TRIAL REGISTRATION: The study protocol was registered in the database ClinicalTrials.gov on 14-06-2016 with the reference number NCT02800616 .

Intrauterine insemination or intracervical insemination with cryopreserved donor sperm in the natural cycle: a cohort study.

STUDY QUESTION: Does intrauterine insemination in the natural cycle lead to better pregnancy rates than intracervical insemination (ICI) in the natural cycle in women undergoing artificial insemination with cryopreserved donor sperm. SUMMARY ANSWER: In a large cohort of women undergoing artificial insemination with cryopreserved donor sperm, there was no substantial beneficial effect of IUI in the natural cycle over ICI in the natural cycle. WHAT IS KNOWN ALREADY: At present, there are no studies comparing IUI in the natural cycle versus ICI in the natural cycle in women undergoing artificial insemination with cryopreserved donor sperm. STUDY DESIGN, SIZE, DURATION: We performed a retrospective cohort study among all eight sperm banks in the Netherlands. We included all women who underwent artificial insemination with cryopreserved donor sperm in the natural cycle between January 2009 and December 2010. We compared time to ongoing pregnancy in the first six cycles of IUI and ICI, after which controlled ovarian stimulation was commenced. Ongoing pregnancy rates (OPRs) over time were compared using life tables. A Cox proportional hazard model was used to compare the chances of reaching an ongoing pregnancy after IUI or ICI adjusted for female age and indication. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included 1843 women; 1163 women underwent 4269 cycles of IUI and 680 women underwent 2345 cycles of ICI with cryopreserved donor sperm. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics were equally distributed (mean age 34.0 years for the IUI group versus 33.8 years for the ICI group), while in the IUI group, there were more lesbian women than in the ICI group (40.6% for IUI compared with 31.8% for ICI). Cumulative OPRs up to six treatment cycles were 40.5% for IUI and 37.9% for ICI. This corresponds with a hazard rate ratio of 1.02 [95% confidence interval (CI) 0.84-1.23] after controlling for female age and indication. Increasing female age was associated with a lower OPR, in both the IUI and ICI groups with a hazard ratio for ongoing pregnancy of 0.94 per year (95% CI 0.93-0.97). LIMITATIONS, REASONS FOR CAUTION: This study is prone to selection bias due to its retrospective nature. As potential confounders such as parity and duration of subfertility were not registered, the effect of these potential confounders could not be evaluated. WIDER IMPLICATIONS OF THE FINDINGS: In women inseminated with cryopreserved donor sperm in the natural cycle, we found no substantial benefit of IUI over ICI. A randomized controlled trial with economic analysis alongside, it is needed to allow a more definitive conclusion on the cost-effectiveness of insemination with cryopreserved donor sperm. STUDY FUNDING/COMPETING INTERESTS: No funding was used and no conflicts of interest are declared.

Microsatellite evidence for obligate autogamy, but abundant genetic variation in the herbaceous monocarp Lobelia inflata (Campanulaceae).

Although high levels of self-fertilization (>85%) are not uncommon in nature, organisms reproducing entirely through selfing are extremely rare. Predominant selfers are expected to have low genetic diversity because genetic variation is distributed among rather than within lineages and is readily lost through genetic drift. We examined genetic diversity at 22 microsatellite loci in 105 individuals from a population of the semelparous herb Lobelia inflata L. and found (i) no evidence of heterozygosity through outcrossing, yet (ii) high rates of genetic polymorphism (2-4 alleles per locus). Furthermore, this genetic variation among lineages was associated with phenotypic traits (e.g. flower colour, size at first flower). Coupled with previous work characterizing the fitness consequences of reproductive timing, our results suggest that temporal genotype-by-environment interaction may maintain genetic variation and, because genetic variation occurs only among lineages, this simple system offers a unique opportunity for future tests of this mechanism.

Clinical phenotype in genetically confirmed von Willebrand disease type 2N patients reflects a haemophilia A phenotype.

INTRODUCTION: Von Willebrand disease (VWD) type 2N is characterized by a defective binding of factor VIII (FVIII) to von Willebrand factor (VWF) resulting in diminished plasma FVIII levels and a clinical phenotype mimicking mild haemophilia A. Several mutations in the FVIII binding site of VWF have been reported. AIM: This study aims to examine the effect of genotype on clinical phenotype in a cohort of VWD 2N patients. METHODS: Patients with at least one genetically confirmed 2N mutation were selected retrospectively from a cohort of patients with suspected VWD. Clinical and laboratory phenotypes including bleeding scores (BS) were obtained and analysed. RESULTS: Forty-two VWD 2N patients with a mean age of 44 years were included. Eleven patients were homozygous or compound heterozygous (genetically confirmed group) and 31 patients were heterozygously affected (carriers group). Statistically significant differences between genetically confirmed VWD 2N patients and carriers were found in FVIII activity, VWF antigen levels, VWF-FVIII binding capacity, FVIII/VWF antigen ratio (all P<0.001), VWF-ristocetin activity (p=0.001) and VWF collagen binding (P = 0.002). Median BS was 6 in genetically confirmed VWD 2N patients compared with 3 in carriers (P = 0.047). Haemarthrosis, muscle haematomas and postpartum haemorrhage were only reported in genetically confirmed 2N patients. CONCLUSION: Phenotypic analysis showed that all laboratory parameters are lower in genetically confirmed VWD 2N patients compared with heterozygous 2N carriers. The clinical phenotype in genetically confirmed VWD 2N patients is comparable to mild haemophilia A patients and more severe than heterozygous 2N carriers.

Centrifugal pump performance during low-flow extracorporeal CO2 removal; safety considerations.

AIM: The aim of this study was to examine the hydrodynamic performance and gaseous microemboli (GME) activity of two centrifugal pumps for possible use in low-flow extracorporeal CO2 removal. MATERIALS & METHODS: The performance of a Rotassist 2.8 and a Rotaflow 32 centrifugal pump (Maquet Cardiopulmonary AG, Hirrlingen, Germany) was evaluated in a water-glycerine mixture-filled in vitro circuit that enabled measurement of pressures and GME at the pump inlet and pump outlet. Pressure-flow curves were acquired in a 1,000 to 5,000 rpm range while increasing drainage resistance in one series and outlet resistance in another. RESULTS: Respective minimum pump inlet and maximum pump outlet pressures were -539 mmHg and 754 mmHg for the Rotassist 2.8 and -606 mmHg and 806 mmHg for the Rotaflow 32. Maximum standard deviations on pump pressures and flow amounted to 3.0 mmHg and 0.03 L/min, respectively, regardless of pump type and drainage or outlet resistance. The GME at the pump outlet were detectable at pump inlet pressures below -156 mmHg at 0.2 L/min and 2,500 rpm for the Rotassist 2.8 and below -224 mmHg at 0.9 L/min and 3,000 rpm for the Rotaflow 32. CONCLUSION: Both the Rotassist 2.8 and Rotaflow 32 centrifugal pumps show a comparably high hydrodynamic stability, but potential GME formation with decreasing pump inlet pressures should be taken into account to ensure safe centrifugal pump-based low-flow extracorporeal CO2 removal.

[Early-onset eating disorders: a review of the literature]. / Vroeg ontstane eetstoornissen: literatuuroverzicht.

BACKGROUND: The incidence of anorexia nervosa (AN) in adolescents has increased significantly in recent years. In several studies and in the media it has been suggested that AN has recently become more prevalent in the pre-adolescence. In view of the impact that an eating disorder can have on a child, it is important to diagnose and start treating the illness as early as possible. AIM: To review the literature on the characteristics and susceptibilities of patients with eating disorders because this information can be important for early diagnosis, prevention and identification of susceptibilities to early-onset eating disorders. METHOD: We searched the literature for articles relating to early-onset eating disorders. We based our search on PubMed and on related relevant articles listed in the references. We selected 34 relevant articles published between 1987 and 2014. RESULTS: The literature lists characteristics and susceptibilities at various levels. Many types of factors are involved; examples of 'biological' factors are prior streptococcal infection, previous consultations with GP and a patients medical history; psychological factors include comorbidity, temperament, a particular personality profile, maturation-anxiety; environmental factors such as family history, family functioning and/or stressful events can play a role in the development of eating disorders. CONCLUSION The literature indicates that the early development of AN in children is related to a complex combination of etiological factors. However, there is a need for more research into this group of patients.

Playing smart vs. playing safe: the joint expression of phenotypic plasticity and potential bet hedging across and within thermal environments.

Adaptive phenotypic plasticity evolves when cues reliably predict fitness consequences of life-history decisions, whereas bet hedging evolves when environments are unpredictable. These modes of response should be jointly expressed, because environmental variance is composed of both predictable and unpredictable components. However, little attention has been paid to the joint expression of plasticity and bet hedging. Here, I examine the simultaneous expression of plasticity in germination rate and two potential bet-hedging traits - germination fraction and within-season diversification in timing of germination - in seeds from multiple seed families of five geographically distant populations of Lobelia inflata (L.) subjected to a thermal gradient. Populations differ in germination plasticity to temperature, in total germination fraction and in the expression of potential diversification in the timing of germination. The observation of a negative partial correlation between the expression of plasticity and germination variance (potential diversification), and a positive correlation between plasticity and germination fraction is suggestive of a trade-off between modes of response to environmental variance. If the observed correlations are indicative of those between adaptive plasticity and bet hedging, we expect an optimal balance to exist and differ among populations. I discuss the challenges involved in testing whether the balance between plasticity and bet hedging depends on the relative predictability of environmental variance.

Efficacy and safety of strategies to preserve stable extracorporeal life support flow during simulated hypovolemia.

AIM: Without volume-buffering capacity in extracorporeal life support (ELS) systems, hypovolemia can acutely reduce support flow. This study aims at evaluating efficacy and safety of strategies for preserving stable ELS during hypovolemia. MATERIAL & METHODS: Flow and/or pressure-guided servo pump control, a reserve-driven control strategy and a volume buffer capacity (VBC) device were evaluated with respect to pump flow, venous line pressure and arterial gaseous microemboli (GME) during simulated normovolemia and hypovolemia. RESULTS: Normovolemia resulted in a GME-free pump flow of 3.1 ± 0.0 L/min and a venous line pressure of -10 ± 1 mmHg. Hypovolemia without servo pump control resulted in a GME-loaded flow of 2.3 ± 0.4 L/min with a venous line pressure of -114 ± 52 mmHg. Servo control resulted in an unstable and GME-loaded flow of 1.5 ± 1.2 L/min. With and without servo pump control, the VBC device stabilised flow (SD = 0.2 and 0.0 L/min, respectively) and venous line pressure (SD=51 and 4 mmHg, respectively) with near-absent GME activity. Reserve-driven pump control combined with a VBC device restored a near GME-free flow of 2.7 ± 0.0 L/min with a venous line pressure of -9 ± 0 mmHg. CONCLUSION: In contrast to a reserve-driven pump control strategy combined with a VBC device, flow and pressure servo control for ELS show evident deficits in preserving stable and safe ELS flow during hypovolemia.

[Paroxysmal events after anxiety treatment with fluoxetine in a child with autism spectrum disorder]. / Paroxismale verschijnselen bij fluoxe-tinebehandeling van angsten bij een kind met een autismespectrumstoornis.

Anxiety is common in children and adolescents with autism spectrum disorders and can cause severe dysfunction and suffering. An 11-year-old boy with an autism spectrum disorder and suffering from anxiety and mood problems responded positively to treatment with fluoxetine. After four weeks he developed clinically observable paroxysmal events accompanied by absence and confusion.

Cytogenetic Nomenclature: Changes in the ISCN 2013 Compared to the 2009 Edition.

The latest edition of the International System for Human Cytogenetic Nomenclature, ISCN 2013, has recently been published following a thorough revision of the 2009 issue and the incorporation of suggestions from the community by the current standing committee. This review will highlight the multiple nomenclature changes in the respective chapters of the 2013 version compared to the previous version of the ISCN published in 2009. These highlights are meant as a guide for the cytogeneticist to assist in the transition in the use of this updated nomenclature for describing cytogenetic and molecular cytogenetic findings in both clinical and research reports.

Effectiveness of indometacin to prevent ovulation in modified natural-cycle IVF: a randomized controlled trial.

Modified natural-cycle IVF has a lower pregnancy rate per started cycle as compared with IVF with ovarian stimulation due to, for example, premature ovulation. Indometacin administered before ovulation prevents follicle rupture. Therefore, addition of indometacin may improve the effectiveness of modified natural-cycle IVF. This double-blind, randomized, placebo-controlled trial with indometacin or placebo in 120 women aged 27-36 years compared the number of patients without premature ovulation as compared with the number of patients with one or more ovulations in a maximum of six cycles. Indometacin had no significant influence on the probability of a premature ovulation in patients during the six cycles (OR 2.38, 95% CI 0.94-6.04). A subgroup analysis showed a significant influence of indometacin in decreasing the probability of a premature ovulation in cycles without LH surge at the day of human chorionic gonadotrophin administration (OR 8.29, 95% CI 1.63-42.3, P=0.009). Although this study could not detect a significantly lower ovulation rate in the indometacin group versus the placebo group, the data suggest that a subgroup of patients without LH surge prior to oocyte retrieval might benefit from indometacin in modified natural-cycle IVF.

Can minimized cardiopulmonary bypass systems be safer?

Although a growing body of evidence indicates superiority of minimized cardiopulmonary bypass (mCPB) systems over conventional CPB systems, limited venous return can result in severe fluctuations of venous line pressure which can result in gaseous emboli. In this study, we investigated the influence of sub-atmospheric pressures and volume buffer capacity added to the venous line on the generation of gaseous emboli in the mCPB circuit. Two different mCPB systems (MEC - Maquet, n=7 and ECC.O - Sorin, n=8) and a conventional closed cardiopulmonary bypass (cCPB) system (n=12) were clinically evaluated. In the search for a way to increase volume buffer capacity of mCPB systems, we additionally evaluated the 'Better Bladder' (BB) in a mock circulation by simulating, repeatedly, decreased venous return while measuring pressure and gaseous embolic activity. Arterial gaseous emboli activity during clinical perfusion with a cCPB system was the lowest in comparison to the mCPB systems (312±465 versus 311±421 with MEC and 1,966±1,782 with ECC.O, counts per 10 minute time interval, respectively; p=0.03). The average volume per bubble in the arterial line was the highest in cases with cCPB (12.5±8.3 nL versus 8.0±4.2 nL with MEC and 4.6±4.8 nL with ECC.O; p=0.04 for both). Significant cross-correlation was obtained at various time offsets from 0 to +35 s between sub-atmospheric pressure in the venous line and gaseous emboli activity in both the venous and arterial lines. The in vitro data showed that incorporation of the BB dampens fluctuations of venous line pressure by approximately 30% and decreases gaseous emboli by up to 85%. In conclusion, fluctuations of sub-atmospheric venous line pressure during kinetic-assisted drainage are related to gaseous emboli. Volume buffer capacity added to the venous line can effectively dampen pressure fluctuations resulting from abrupt changes in venous return and, therefore, can help to increase the safety of minimized cardiopulmonary bypass by reducing gaseous microemboli formation resulting from degassing.