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Despite increasing knowledge of disease‐causing genes in human genetics, approximately half of the individuals affected by neurodevelopmental disorders remain genetically undiagnosed. Part of this missing heritability might be caused by genetic variants outside of protein‐coding genes, which are not routinely diagnostically investigated. A recent preprint identified de novo variants in the non‐coding spliceosomal snRNA gene RNU4‐2 as a cause of a frequent novel syndromic neurodevelopmental disorder. Here we mined 164 whole genome sequencing (WGS) trios from individuals with neurodevelopmental or multiple congenital anomaly disorders that received diagnostic genomic investigations at our clinic. We identify a recurrent de novo RNU4‐2 variant (NR_003137.2(RNU4‐2):n.64_65insT) in a 5‐year‐old girl with severe global developmental delay, hypotonia, microcephaly, and seizures that likely explains her phenotype, given that extensive previous genetic investigations failed to identify an alternative cause. We present detailed phenotyping of the individual obtained during a 5‐year follow‐up. This includes photographs showing recognizable facial features for this novel disorder, which might allow prioritizing other currently unexplained affected individuals sharing similar facial features for targeted investigations of RNU4‐2. This case illustrates the power of re‐analysis to solve previously unexplained cases even when a diagnostic genome remains negative. [ABSTRACT FROM AUTHOR]

Introduction: Preterm prelabor rupture of membranes (PPROM) remains a major complication of fetal laser surgery in the treatment of twin‐to‐twin transfusion syndrome (TTTS). The aim of the study was to determine the impact of cannula size on pregnancy outcomes, with a particular focus on PPROM. Material and methods: The protocol was developed and registered in the PROSPERO database under registration number CRD42022333630. The PubMed, Web of Science, and EMBASE databases were searched electronically on May 18, 2022, and updated on March 2, 2023, utilizing a combination of the relevant MeSH terms, keywords, and word variants for "TTTS" and "laser". Randomized controlled trials, prospective and retrospective cohorts, case–control studies, and case reports/series with more than five participants were considered eligible for inclusion. Studies reporting the cannula diameter and PPROM rate after laser surgery in the treatment of monochorionic pregnancies affected by TTTS between 16‐ and 26 weeks' gestation were included. Data was extracted independently, and when appropriate, a random‐effects meta‐analysis was undertaken to calculate pooled estimates and their confidence intervals. Heterogeneity in the effect estimates of the individual studies was calculated using the I2 statistic. The primary outcome was PPROM rate. Secondary outcomes were survival rate, preterm birth, and incomplete surgery. The quality of the included studies was assessed using a modified quality in prognosis study tool. Results: We included a total of 22 studies, consisting of 3426 patients. Only one study was scored as low quality, seven as moderate quality, and the remaining 14 as high quality. The mean PPROM rate after laser surgery treating TTTS was 22.9%, ranging from 11.6% for 9 French (Fr) to 54.0% for 12 Fr. Subsequent meta‐regression for the clinically relevant PPROM rate before 34 weeks of gestation, showed increased PPROM rates for increased cannula size (p‐value 0.01). Conclusions: This systematic review confirmed PPROM as a frequent complication of fetal laser surgery, with a mean PPROM rate of 22.9%. A larger cannula diameter relates to a significant higher PPROM risk for PPROM before 34 weeks gestation. Hence, the ideal balance between optimal visualization requiring larger port diameters and shorter operation time and more complete procedures that benefit from larger diameters is crucial to reduce iatrogenic PPROM rates. [ABSTRACT FROM AUTHOR]

Translational medicine (TM) is an interdisciplinary branch of biomedicine that bridges the gap from bench‐to‐bedside to improve global health. Fundamental TM skills include interdisciplinary collaboration, communication, critical thinking, and creative problem‐solving (4Cs). TM is currently limited in undergraduate biomedical education programs, with little patient contact and opportunities for collaboration between different disciplines. In this study, we developed and evaluated a novel interdisciplinary challenge‐based educational concept, grounded in the theoretical framework of experimental research‐based education, to implement TM in undergraduate biomedicine and medicine programs. Students were introduced to an authentic clinical problem through an interdisciplinary session with patients, medical doctors, and scientists. Next, students collaborated in groups to design unique laboratory‐based research proposals addressing this problem. Stakeholders subsequently rewarded the best proposal with funding to be executed in a consecutive interdisciplinary laboratory course, in which mixed teams of biomedicine and medicine students performed the research in a fully equipped wet laboratory. Written questionnaires and focus groups revealed that students developed 4C skills and acquired a 4C mindset. Working on an authentic patient case and the interdisciplinary setting positively contributed to communication, collaboration, critical thinking, and creative problem‐solving skills. Furthermore, students were intrinsically motivated by (i) the relevance of their work that made them feel taken seriously and competent, (ii) the patient involvement that highlighted the societal relevance of their work, and (iii) the acquisition of a realistic view of what doing science in a biomedical research laboratory is. In conclusion, we showcase a widely applicable interdisciplinary challenge‐based undergraduate concept fostering TM. [ABSTRACT FROM AUTHOR]

Embedded 3D bioprinting has great value for the freeform fabrication of living matter. However, embedded 3D bioprinting is currently limited to highly viscous liquid baths or liquid-like solid baths. In contrast, prior to crosslinking, most hydrogels are formulated as low-viscosity solutions and are therefore not directly compatible with bioprinting due to low shape fidelity and poor print stability. The authors here present a method to enable low-viscosity ink 3D (LoV3D) bioprinting, based on aqueous two-phase stabilization of the ink-bath interface. LoV3D allows for the printing of living constructs at high extrusion speeds (up to 1.8 m s-1) with high viability due to its exceedingly low-viscosity. Moreover, LoV3D liquid/liquid interfaces offer unique advantages for fusing printed structures, creating intricate vasculature, and modifying surfaces at higher efficiencies than traditional systems. Furthermore, the low interfacial tension of LoV3D bioprinting offers unprecedented nozzle-independent control over filament diameter via large-dimension strand-thinning, which allows for the printing of an exceptionally wide range of diameters down to the width of a single cell. Overall, LoV3D bioprinting is a unique all-aqueous approach with broad material compatibility without the need for rheological ink adaption, which opens new avenues of application in cell patterning, drug screening, engineered meat, and organ fabrication. [ABSTRACT FROM AUTHOR]

Fetal laser surgery has emerged as the preferred treatment of twin-to-twin transfusion syndrome (TTTS). However, the limited field of view of the fetoscope and the complexity of the procedure make the treatment challenging. Therefore, preoperative planning and intraoperative guidance solutions have been proposed to cope with these challenges. This review uncovers the literature on computer-assisted software solutions focused on TTTS. These solutions are classified by the pre- or intraoperative phase of the procedure and further categorized by discussed hardware and software approaches. In addition, it evaluates the current maturity of technologies by the technology readiness level and enumerates the necessary aspects to bring these new technologies to clinical practice. [ABSTRACT FROM AUTHOR]

ABSTRACT Moyamoya angiopathy is a cerebral vasculopathy causing progressive stenosis of the internal carotid arteries and the compensatory development of collateral blood vessels, leading to brain ischemia and an increased risk of cerebral haemorrhage. Although multiple non‐genetic causes have been associated with moyamoya syndrome, it can also be associated with rare genetic syndromes. Moyamoya Disease 4, characterised by a short stature, hypergonadotropic hypogonadism and facial dysmorphism (MYMY4, OMIM #300845), also referred to as BRCC3‐associated moyamoya syndrome, has so far been described in 11 individuals. Here, we describe a 23‐year‐old male presenting with moyamoya syndrome, global developmental delay and intellectual disability, epilepsy, short stature and dysmorphic features, who after > 17 years of uninformative diagnostics was diagnosed with BRCC3‐associated moyamoya syndrome after clinical RNA‐seq. Transcriptome analysis showed reduced expression of the likely disease‐causing gene BRCC3 in patient‐derived fibroblasts, which was subsequently found to be caused by a ~ 26 kb Xq28 deletion. We furthermore review all reported cases of BRCC3‐associated moyamoya syndrome, further delineating this clinical entity. [ABSTRACT FROM AUTHOR]

Optimal integration of education and ongoing faculty research in many undergraduate science programs is limited to the capstone project. Here, we aimed to develop a novel course‐based undergraduate research experience (CURE) in synergy with ongoing faculty research. This 10‐week course called Biomedical Research Lab is embedded in the curriculum of the undergraduate program Biomedical Sciences and grounded in the theoretical framework of research‐based learning. Four groups of four students work together in a dedicated laboratory on an actual ongoing research problem of faculty. All groups work on the same research problem, albeit from different (methodological) perspectives, thereby stimulating interdependence between all participants. Students propose new research, execute the experiments, and collectively report in a single research article. According to students, the course enhanced scientific, laboratory, and academic skills. Students appreciated ownership and responsibilities of the research, laboratory teachers as role models, and they were inspired and motivated by doing authentic actual research. The course resulted in a better understanding of what doing research entails. Faculty valued the didactical experience, research output and scouting opportunities. Since topics can change per course edition, we have showcased a widely applicable pedagogy creating synergy between ongoing research and undergraduate education. [ABSTRACT FROM AUTHOR]

The Ganges‐Brahmaputra‐Meghna (GBM) delta plain within Bangladesh is one of the most vulnerable to relative sea level rise (RSLR) in the world especially under current anthropogenically modified (i.e., embanked) conditions. Tidal river management (TRM) as practiced in coastal regions of Bangladesh may provide an opportunity to combat RSLR by raising the land level through controlled sedimentation inside beels (depression within embanked polders) with re‐opening of polders. To date, TRM has been applied to tide‐dominated coastal regions, but the potential applicability of TRM for the beels within the polders of river‐dominated and mixed flow (MF) regimes remains to be assessed. We apply a calibrated 2D numerical hydromorphodynamic model to quantify sediment deposition in a beel flooded through breaching of the polder dike under conditions of river‐dominated, tide‐dominated and MF regimes for different seasons and applying different regulation schemes for the flow into the beel. Simulation results show considerable seasonality in sediment deposition with largest deposition during the monsoon season. The potential of controlled flooding is highest in the tide‐dominated region, where sediment accumulation can be up to 28 times higher than in the river‐dominated region. Regulating flow into a beel increases trapping efficiency, but results in slightly lower total deposition than without regulation. We conclude that re‐establishing flooding of the beel within the polder without regulating the flow into the beel through breaching of the polder dike is a promising strategy for the mixed and tide‐dominated flow regions in the delta as the sediment accumulation can raise the land surface at a higher rate than RSLR and effective SLR (ESLR). In the more upstream river‐dominated section of the delta, accumulation rates would be much lower, but the pressure of sea level rise on these areas is lower as well. Owing to the abundant availability of sediment, application of controlled flooding like TRM therefore provides an opportunity to counteract the impact of RSLR and ESLR by means of land raising, particularly along the tidal river reaches in the GBM delta. [ABSTRACT FROM AUTHOR]

Goldberg–Shprintzen syndrome (GOSHS) is caused by loss of function variants in the kinesin binding protein gene (KIFBP). However, the phenotypic range of this syndrome is wide, indicating that other factors may play a role. To date, 37 patients with GOSHS have been reported. Here, we document nine new patients with variants in KIFBP: seven with nonsense variants and two with missense variants. To our knowledge, this is the first time that missense variants have been reported in GOSHS. We functionally investigated the effect of the variants identified, in an attempt to find a genotype–phenotype correlation. We also determined whether common Hirschsprung disease (HSCR)‐associated single nucleotide polymorphisms (SNPs), could explain the presence of HSCR in GOSHS. Our results showed that the missense variants led to reduced expression of KIFBP, while the truncating variants resulted in lack of protein. However, no correlation was found between the severity of GOSHS and the location of the variants. We were also unable to find a correlation between common HSCR‐associated SNPs, and HSCR development in GOSHS. In conclusion, we show that reduced, as well as lack of KIFBP expression can lead to GOSHS, and our results suggest that a threshold expression of KIFBP may modulate phenotypic variability of the disease. [ABSTRACT FROM AUTHOR]

We describe the clinical presentation and 17 years follow up of a boy, born to consanguineous parents and presenting with intellectual disability (ID), autism, 'marfanoid' dysmorphic features, and moderate abnormalities of sulfite metabolism compatible with molybdenum cofactor deficiency, but normal sulfite oxidase activity in cultured skin fibroblasts. Genomic exome analysis revealed a homozygous MOCS3 missense mutation, leading to a p.Ala257Thr substitution in the highly conserved ubiquitin-like-domain of the protein. MOCS3 is the third protein, besides MOCS1 and MOCS2, involved in the biosynthesis of the molybdenum cofactor and has a dual ubiquitin-like function in tRNA thiolation. It is plausible that the phenotype results from deficiency of this dual function, not only from defective synthesis of molybdenum cofactor, which would explain similarities and differences from the MOCS1 and MOCS2-related disorders. This observation should encourage testing of additional ID patients with mild abnormalities of sulfite metabolism for MOCS3 mutations. [ABSTRACT FROM AUTHOR]

Landscape-scale ecohydrological mapping is commonly restrained to one-dimensional ecohydrological transect studies or two-dimensional vegetation distributions lacking adequate spatial coverage of explanatory hydrological data. The objective of this paper is to construct a two-dimensional (semi-3D) landscape-scale ecohydrological map based on vegetation distribution maps and detailed spatial, multi-year, floodplain inundation water quality data. The dataset comes from the near-natural Biebrza floodplain mire in Poland encompassing 658 inundation water quality analyses over the period 2002-2012, covering 17 different vegetation communities of freshwater marshes and rich fens. The data represent the main hydrological gradients from valley edge to river encompassing groundwater seepage, local stagnant precipitation influences and river flooding and drainage. We used chi-squared Haberman residuals analysis to correlate communities to inundation water quality types, resembling river water and three different types of groundwater. Out of 17 communities, six showed a preference for river water, three showed a preference for clean groundwater, four for diluted groundwater and one for polluted groundwater. For three communities, no significant preference was found. Spatial patterns in vegetation and attributed water quality preference can be linked to three dominant hydrological processes at the landscape scale, i.e. discharge of clean and polluted groundwater near the valley edges, dilution of exfiltrated groundwater with local snowmelt and precipitation water and flooding with river water along the river. The ecohydrological relations are depicted in two-dimensional maps and a semi-3D diagram with typical cross sections. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Hippocampal volume deficits have been linked to life stress. However, the degree to which genes and environment influence the association between hippocampal volume and life events is largely unknown. In total, 123 healthy twins from monozygotic and dizygotic twin pairs underwent magnetic resonance imaging (MRI), and 57 healthy twins were interviewed with the Life Events and Difficulties Schedule (LEDS), with an overlap of 54 twins undergoing both MRI and the life events interview. Hippocampal volumes were segmented with Freesurfer software. Data were analyzed with OpenMx software. Smaller hippocampal volume was associated with higher severe life event load ( rph= −0.39), where shared environmental factors influencing both measures fully explained the association. Hippocampal volume was not associated with total or mild life event load. Hippocampal volume showed high heritability (range, h2: 57%-81%) whereas life event measures were influenced by shared ( c2) and unique ( e2) environmental factors only (range, c2:40%-64%, e2: 36%-60%). The results suggested that shared environmental factors influenced the relationship between smaller hippocampal volume and severe (but not mild) stress. This indicated that particularly severe life events that were shared between twins were associated with smaller hippocampal volume. Furthermore, it is suggested to distinguish between mild and severe life events in life event research. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Mutations in WDR62 are associated with primary microcephaly; however, they have been reported with wide phenotypic variability. We report on six individuals with novel WDR62 mutations who illustrate this variability and describe three in greater detail. Of the three, one lacks neuromotor development and has severe pachygyria on MRI, another has only delayed speech and motor development and moderate polymicrogyria, and the third has an intermediate phenotype. We observed a rare copy number change of unknown significance, a 17q25qter duplication, in the first severely affected individual. The 17q25 duplication included an interesting candidate gene, tubulin cofactor D ( TBCD), crucial in microtubule assembly and disassembly. Sequencing of the non-duplicated allele showed a TBCD missense mutation, predicted to cause a deleterious p.Phe1121Val substitution. Sequencing of a cohort of five patients with WDR62 mutations, including one with an identical mutation and different phenotype, plus 12 individuals with diagnosis of microlissencephaly and another individual with mild intellectual disability (ID) and a 17q25 duplication, did not reveal TBCD mutations. However, immunostaining with tubulin antibodies of cells from patients with both WDR62 and TBCD mutation showed abnormal tubulin network when compared to controls and cells with only the WDR62 mutation. Therefore, we propose that genetic factors contribute to modify the severity of the WDR62 phenotype and, although based on suggestive evidence, TBCD could function as one of such factors. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT Sustainable development issues are characterised by their multidisciplinary character, and the fact they are not merely an academic exercise but pertain to real-world problems. Academic sustainable development curricula should therefore not only focus on developing the analytical and research skills and theoretical and professional knowledge of their students; they should also include real-world learning opportunities in the curriculum. This paper evaluates the added value and constraints associated with a specific type of real-world learning called transdisciplinary learning, based on the experiences with three courses from the undergraduate and graduate Environmental Sciences curriculum of Utrecht University, the Netherlands. In these courses, students carry out a small multidisciplinary research project or a consultancy project for a real-life client. It is concluded that transdisciplinary courses have clear added value for students, involved stakeholders, and the university alike, making them an essential part of the sustainable development curricula. The main constraint is the balance between academic quality (grading) vs stakeholder satisfaction. Although time investments for adequate problem definition with clients may constitute a constraint for university supervisors, it has the potential added value of sparking research cooperation with societal stakeholders, and internships and employment opportunities for graduates. Copyright © 2013 John Wiley & Sons, Ltd and ERP Environment. [ABSTRACT FROM AUTHOR]

Background Regulatory B cells have been identified that strongly reduce allergic and auto-immune inflammation in experimental models by producing IL-10. Recently, several human regulatory B-cell subsets with an impaired function in auto-immunity have been described, but there is no information on regulatory B cells in allergic asthma. Objective In this study, the frequency and function of IL-10 producing B-cell subsets in allergic asthma were investigated. Methods Isolated peripheral blood B cells from 13 patients with allergic asthma and matched healthy controls were analyzed for the expression of different regulatory B-cell markers. Next, the B cells were activated by lipopolysaccharide ( LPS), CpG or through the B-cell receptor, followed by co-culture with endogenous memory CD4+ T cells and house dust mite allergen DerP1. Results Lower number of IL-10 producing B cells were found in patients in response to LPS, however, this was not the case when B cells were activated through the B-cell receptor or by CpG. Further dissection showed that only the CD24hi CD27+ B-cell subset was reduced in number and IL-10 production to LPS. In response to DerP1, CD4+ T cells from patients co-cultured with LPS-primed total B cells produced less IL-10 compared to similar cultures from controls. These results are in line with the finding that sorted CD24hi CD27+ B cells are responsible for the induction of IL-10+ CD4+ T cells. Conclusions Taken together, these data indicate that CD24hi CD27+ B cells from allergic asthma patients produce less IL-10 in response to LPS leading to a weaker IL-10 induction in T cells in response to DerP1, which may play a role in allergic asthma. [ABSTRACT FROM AUTHOR]

ABSTRACT Mutations in FLNA (Filamin A, OMIM 300017) cause X-linked periventricular nodular heterotopia (XL-PNH). XL-PNH-associated mutations are considered lethal in hemizygous males. However, a few males with unusual mutations (including distal truncating and hypomorphic missense mutations), and somatic mosaicism have been reported to survive past infancy. Two brothers had an atypical presentation with failure to thrive and distinct facial appearance including hypertelorism. Evaluations of these brothers and their affected cousin showed systemic involvement including severe intestinal malfunction, malrotation, congenital short bowel, PNH, pyloric stenosis, wandering spleen, patent ductus arteriosus, atrial septal defect, inguinal hernia, and vesicoureteral reflux. The unanticipated finding of PNH led to FLNA testing and subsequent identification of a novel no-stop FLNA mutation (c.7941_7942delCT, p.(*2648Serext*100)). Western blotting and qRT-PCR of patients' fibroblasts showed diminished levels of protein and mRNA. This FLNA mutation, the most distal reported so far, causes in females classical XL-PNH, but in males an unusual, multi-organ phenotype, providing a unique insight into the FLNA-associated phenotypes. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

To evaluate a nonanthracycline-containing regimen consisting of 24 weekly administrations of paclitaxel, carboplatin, and trastuzumab as neo-adjuvant therapy for human epidermal growth factor receptor 2 ( HER2)-positive breast cancer. Patients with stage II or III breast cancer, including inflammatory disease, with HER2 overexpression (immunohistochemistry and/or fluorescent in situ hybridization) were treated with 24 weekly administrations of paclitaxel 70 mg/m2, carboplatin AUC = 3 mg/mL/minute, and trastuzumab 2 mg/kg (loading dose 4 mg/kg). In cycles 7, 8, 15, 16, 23, and 24, only trastuzumab was given. The primary end point was pathologic complete response ( pCR) in both breast and axilla. Of 61 evaluable patients, 61% had stage II disease and 75% were node-positive. The median NRI (Neoadjuvant Response Index, a measure of the degree of downstaging by chemotherapy) of all patients was 0.86. Twenty-seven (44%) had a NRI of 1.0, which corresponds to pCR in breast and lymph nodes. The most commonly reported grade 3/4 toxicities were neutropenia (72%) and thrombocytopenia (36%). Dose reduction was necessary in 51% of the patients. A weekly carboplatin-paclitaxel-trastuzumab neo-adjuvant regimen is highly active in HER2-positive breast cancer with an acceptable toxicity profile. A multicenter phase 2 trial has recently reached its accrual target and will serve as a basis for a subsequent randomized phase 3 study comparing this regimen to a similar regimen preceded by anthracyclines. [ABSTRACT FROM AUTHOR]

Mutations in the ARX gene, at Xp22.3, cause several disorders, including infantile spasms, X-linked lissencephaly with abnormal genitalia (XLAG), callosal agenesis and isolated intellectual disability. Genotype/phenotype studies suggested that polyalanine tract expansion is associated with non-malformative phenotypes, while missense and nonsense mutations cause cerebral malformations, however, patients with structural normal brain and missense mutations have been reported. We report on a male patient born with cleft lip and palate who presented with infantile spasms and hemiplegia. MRI showed agenesis of corpus callosum (ACC), an interhemispheric cyst, periventricular nodular heterotopia (PVNH), and extensive left frontal polymicrogyria (PMG). Sequencing of the ARX gene in the patient identified a six basepair insertion (c.335ins6, exon 2). The insertion leads to a two-residue expansion of the first polyalanine tract and was described previously in a family with non-syndromic X-linked mental retardation. To our knowledge, ARX mutation causing PMG and PVNH is unique, but the spasms and ACC are common in ARX mutations. Clinicians should be aware of the broad clinical range of ARX mutations, and further studies are necessary to investigate the association with PMG and PVNH and to identify possible modifying factors. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Otic suspensions have a positive effect on the duration of otorrhea in children with a tympanostomy tube. It is still questionable how eardrops reach the middle ear. We hypothesized that otic suspensions do not pass the tympanostomy tube if the middle ear is dry but pass by diffusion when wet. The median concentration of Evans blue (colorant) in the middle ear was <15.6 mg/mL (lower limit of quantification) when diffusion was impossible but 45.3 µg/mL when diffusion was possible (P = .01). When the outward flow was increased to 0.1 mL/h, the concentration of Evans blue in the middle ear increased significantly (P = .03). With further-increasing outward flows, the concentration of Evans blue decreased linearly (β = -144, P < .001, R (2) = 0.44). We conclude that diffusion is the mechanism by which otic suspensions enter the middle ear in children with tympanostomy tubes and otorrhea. [ABSTRACT FROM AUTHOR]

Background: von Hippel–Lindau (VHL) inactivation is common in sporadic clear cell renal cell carcinomas (ccRCC). pVHL is part of the ubiquitin ligase complex that targets the alpha subunits of hypoxia-inducible transcription factor (HIF) for degradation under well-oxygenated conditions. In the absence of wild-type pVHL, as observed in VHL patients and most sporadic ccRCCs, constitutive upregulation of HIF results in transcriptional activation of angiogenesis-related genes, such as VEGF. Differences in angiogenic activity within the group of ccRCCs were reported and strong genotype-phenotype correlations were found in patients with VHL disease, raising a question about the importance of VHL inactivation status in angiogenic behaviour and tumour progression. Methods: To address this question, we investigated the influence of VHL mutation (direct sequencing)/hypermethylation (methylation-specific PCR) on angiogenesis/tumour parameters (immunohistochemistry) in 150 patients with sporadic ccRCC. Results: We found no significant association between VHL mutation or methylation and angiogenesis/tumour parameters. Conclusion: These data indicate that tumour progression and angiogenesis are not directly influenced by VHL alterations and that additional genetic/epigenetic events should be considered to explain the diverse angiogenic and proliferative behaviour during tumour progression. [ABSTRACT FROM AUTHOR]

Some 25 years after the introduction of the first geo-information technologies in public organizations, strategies to manage their diffusion are still inadequate. This is problematic in light of the new generation of geo-information technologies that has become available and aims to invest in these new information technologies in order to advance e-government. This study questions how strategies for diffusion of geo-information technologies in public planning organizations can be improved. It shows that classic top-down management often enhances informal diffusion activities that deviate from the formal diffusion strategy. A knowledge management approach, in which geo-information specialists and planners participate in the formation of diffusion policies, can enhance the quality of the formal strategy, thereby preventing deviation and informal diffusion activities. The authors recommend that public planning organizations use this knowledge to improve their diffusion strategies for geo-information technologies. [ABSTRACT FROM AUTHOR]

Aim: The present study is the first to compare the physiological impact of either forced treadmill or voluntary wheel running exercise on hindlimb muscle in mice. Methods: Male C57BL/6 mice were subjected to either 6 weeks of forced treadmill or voluntary wheel running exercise. Mice in the treadmill running exercise group (TRE; n = 8) ran 1.9 km day−1 at a speed of 16 m min−1 against an uphill incline of 11 °. In the running wheel exercise group (RWE; n = 8) animals ran 8.8 ± 0.2 km per day (average speed 42 ± 2 m min−1). After the experimental period, animals were killed and mechanical performance and oxygen consumption of isolated extensor digitorum longus (EDL) muscle were determined during serial electrical stimulation at 0.5, 1 and 2 Hz. Results: Steady-state half-width time (HWT) of twitch contraction at 0.5 Hz was significantly shorter in TRE and RWE than controls (CON) (41.3 ± 0.2, 41.3 ± 0.1 and 44.3 ± 0.1 s respectively; P < 0.05). The rate of fatigue development and HWT lengthening at 2 Hz was the same in RWE and CON but lower in TRE (1.2-fold and twofold respectively; P < 0.05). EDL oxygen consumption, mitochondrial content and myosin heavy chain (MyHC) composition were not different between the groups. Conclusion: These results indicate that both exercise modalities have an effect on a hindlimb fast-twitch muscle in mice, with the greatest impact seen with forced treadmill running. [ABSTRACT FROM AUTHOR]

Questions: Were continued groundwater discharge and mowing regimes sufficient for vegetation preservation from 1944 to 1993? Which has a stronger effect on vegetation development; groundwater discharge or mowing? What is the role of surface water eutrophication as driver of vegetation change? Location: Het Hol, The Netherlands (ca. 92 ha, 52°13′ N, 5°05′ E). Methods: Hydrology was simulated for the late 1940s, early 1960s and 1987. Vegetation maps (1944, 1960, 1975 and 1993) were compared for biotope cover. Vegetation recordings in 1944 and 1987 were compared. Surface water quality was compared between 1950 and 1987. Which sites were mown was reconstructed from an interview. Effects of periodic mowing and groundwater discharge on vegetation development were tested for correlation. Results: Biotope diversity reduced significantly through decrease of semi-aquatic and tall-herb biotopes, and expansion of forest. The quagfen terrestrialization sere nearly disappeared from 1987 recordings, while the reed sere did well concerning abundance and species richness. Several typical (rich) fen species disappeared from recordings, while new species were mostly field margin species. Periodic mowing and discharge combined are correlated with increasing species numbers. The P-concentration in surface water increased while N-concentration decreased. Conclusions: Preservation of the reed sere was successful, whereas preservation of the quagfen sere was not. Periodic mowing and discharge stimulate species richness, discharge more so than periodic mowing. But slight eutrophication likely induced a shift from P-limitation to N-limitation, which stimulated the reed sere at the expense of the quagfen sere. [ABSTRACT FROM AUTHOR]

Wetlands show a large decline in biodiversity. To protect and restore this biodiversity, many restoration projects are carried out. Hydrology in wetlands controls the chemical and biological processes and may be the most important factor regulating wetland function and development. Hydrological models may be used to simulate these processes and to evaluate management scenarios for restoration. HYDRUS2D, a combined saturated–unsaturated groundwater flow and transport model, is presented. This simulates near‐surface hydrological processes in an acidified floating fen, with the aim to evaluate the effect of hydrological restoration in terms of conditions for biodiversity. In the acidified floating fen in the nature reserve Ilperveld (The Netherlands), a trench system was dug for the purpose of creating a runoff channel for acid rainwater in wet periods and to enable circum‐neutral surface water to enter the fen in dry periods. The model is calibrated against measured conductivity values for a 5 year period. From the model simulations, it was found that lateral flow in the floating raft is limited. Furthermore, the model shows that the best management option is a combination of trenches and inundation, which gave the best soil water quality in the root zone. It is concluded that hydrological models can be used for the calculation of management scenarios in restoration projects. The combined saturated–unsaturated model concept used in this paper is able to incorporate the governing hydrological processes in the wetland root zones. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Exercise-induced loss of skeletal muscle K+ can seriously impede muscle performance through membrane depolarization. Thus far, it has been assumed that the negative equilibrium potential and large membrane conductance of Cl− attenuate the loss of force during hyperkalaemia. We questioned this idea because there is some evidence that Cl− itself can exert a depolarizing influence on membrane potential (Vm). With this study we tried to identify the possible roles played by Cl− during hyperkalaemia. Isolated rat soleus muscles were kept at 25°C and twitch contractions were evoked by current pulses. Reducing[Cl−]o to 5 mm, prior to introducing 12.5 mmKo, prevented the otherwise occurring loss of force. Reversing the order of introducing these two solutions revealed an additional effect, i.e. the ongoing hyperkalaemia-related loss of force was sped up tenfold after reducing[Cl−]o. However, hereafter twitch force recovered completely. The recovery of force was absent at[K+]o exceeding 14 mm. In addition, reducing[Cl−]o increased membrane excitability by 24%, as shown by a shift in the relationship between force and current level. Measurements ofVm indicated that the antagonistic effect of reducing[Cl−]o on hyperkalaemia-induced loss of force was due to low-Cl−-induced membrane hyperpolarization. The involvement of specific Cl− conductance was established with 9-anthracene carboxylic acid (9-AC). At 100μm, 9-AC reduced the loss of force due to hyperkalaemia, while at 200μm, 9-AC completely prevented loss of force. To study the role of the Na+−K+−2Cl− cotransporter (NKCC1) in this matter, we added 400μmof the NKCC inhibitor bumetanide to the incubation medium. This did not affect the hyperkalaemia-induced loss of force. We conclude that Cl− exerts a permanent depolarizing influence onVm. This influence of Cl− onVm, in combination with a large membrane conductance, can apparently have two different effects on hyperkalaemia-induced loss of force. It might exert a stabilizing influence on force production during short periods of hyperkalaemia, but it can add to the loss of force during prolonged periods of hyperkalaemia. [ABSTRACT FROM AUTHOR]

18F-fluoro-deoxyglucose (FDG) positron emission tomography (PET) might be a better tool than computerized tomography (CT) in predicting long-term treatment outcome in patients with relapsed chemosensitive lymphoma who are candidates for autologous stem cell transplantation (ASCT). We studied patients with recurrent or persistent aggressive non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD), who were treated with three courses of second-line induction chemotherapy [DHAP–VIM (dexamethasone, cytarabine, cisplatin followed by etoposide, iphosphamide and methotrexate)-DHAP], followed by myeloablative therapy and ASCT if chemosensitive. FDG-PET was performed in parallel to conventional diagnostic methods before starting, and after two courses of, second-line therapy. Of 68 relapsed lymphoma patients, 46 chemosensitive patients (33 NHL and 13 HD) were included, of whom 39 were transplanted. After DHAP-VIM, the second PET scan was normalized in 15/46 patients; progression-free survival at 2 years was 62% for PET-negative patients versus 32% for PET-positive patients ( P = 0·048). The relative risk for progressive disease in patients with < 90% intensity reduction was 2·85 (95% confidence interval 1·15–7·05, P = 0·018). Early FDG-PET may help to predict the long-term treatment outcome of ASCT in chemosensitive patients with relapsed lymphoma and identify those patients who need extra or alternative treatment. Disappearance or > 90% reduction of intensity of abnormal FDG uptake after two courses of reinduction therapy was correlated with a favourable outcome. [ABSTRACT FROM AUTHOR]

Finding a strategy that allows economically efficient drinking water production at minimal environmental cost is often a complex task. A systematic trade-off among the costs and benefits of possible strategies is required for determining the optimal production configuration. Such a trade-off involves the handling of interdependent and nonlinear relations for drawdown-related objective categories like damage to wetland vegetation, agricultural yield depression, reduction of river base flow rates, and soil subsidence. We developed a method for multiple-objective optimization of drinking water production by combining Busacker and Gowen's [1961] 'minimum cost flow' procedure for optimal use of the transport network with a genetic algorithm (GA) for optimization of other impacts. The performance of the GA was compared with analytically determined solutions of a series of hypothetical case studies. Pareto-optimality and uniqueness of solutions proved to be effective fitness criteria for identifying trade-off curves with the GA. [ABSTRACT FROM AUTHOR]

In the present study, the consequences of individual rearing during the play period on adult responses to aggression were investigated in a complex social setting. In a group of either socially or individually reared rats, an aggressor was repeatedly introduced. Separate control groups of individually and socially reared rats were not exposed to an aggressor. To allow an interpretation of the altered reactivity to aggression in terms of (in)efficient or (in)adequate behavior, not only the responses in the presence of the aggressor but also the consequences of the altered reactivity on subsequent behavior in the absence of the aggressor were observed. We demonstrated that a higher number of injuries, more agitation of the aggressor, and more ultrasonic distress vocalizations accompanied the altered responses of individually reared rats in the presence of the aggressor. In the absence of the aggressor, individually reared rats displayed less social stress-reducing behaviors (play and social grooming) than socially reared rats. It was concluded that individually reared rats display a less adequate response to aggression in this social context. © 2002 Wiley Periodicals, Inc. Dev Psychobiol 41: 58–69, 2002. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/dev.10057 [ABSTRACT FROM AUTHOR]

After a conceptual and methodological critique of Social Identity Theory (SIT), it is argued, in sharp contrast to SIT but consistent with a behavioural Interaction Model (BIM), that the allocations in the standard Minimal Group Paradigm (MGP) - which provide the main evidence for SIT- can be best reinterpreted as instrumental rational behaviour aimed at maximizing he economic self-interests of the subjects rather than efforts on their part to strive for a positive social identity as SIT has claimed. Explicit social categorization appears to be only one of the many unit-forming factors which may affect allocations within and between group boundaries in the MGP. Group polarization effects indicate that groups, guided by their perceived inter- dependence on the recipients of their allocations seem more rational and effective than their individual members prior to the group discussion in maximizing their economic outcomes. Finally, it is concluded that BIM provides probably a more parsimonious explanation of all the usual findings obtained by the standard MGP than SIT. [ABSTRACT FROM AUTHOR]

In 1995 the coordinators of the Netherlands Advisory Council for Research on Nature and Environment (RMNO) and the Greening of Industry Network initiated a process of developing an international research agenda on sustainable development and the role of industry. The purposeof this initiative was two-fold: -- To develop a research agenda on the process of greening of industry in the context of sustainable development which defines main research priorities for the coming decade; -- To provide a clearer perspective on how research priorities are currently developed and how to improve this process. After a two yearprocess of discussions via workshops and interviews including various stakeholders, four main research themes were selected: -- Transformation towards sustainable development -- Changing consumption patterns -- Finance, capital and performance indicators -- Technological breakthroughs. We hope to solicit a discussion on the future of the greening of industry research agenda. This article is based on a report 'The Greening of Industry for a Sustainable Future: Building an International Research Agenda (1997)'. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "TAMIS of a rectal haemangioma - a video vignette" in previous issue.

Vonk R, van der Schot AC, Kahn RS, Nolen WA. Comorbidity in the Dutch twin study on bipolar disorder: challenge or methodological problem? Bipolar Disord 2002: 4(Suppl. 1): 33–34. ©Blackwell Munksgaard, 2002. [ABSTRACT FROM AUTHOR]