Establishing a multidisciplinary specialist centre for fetal alcohol spectrum disorders-Lessons learned from a model project in Germany.

BACKGROUND: Inadequate coordination between relevant professionals hampers the provision of appropriate care for individuals with fetal alcohol spectrum disorder (FASD). Integrated, multidisciplinary care is thus urgently required. Hence, we aimed at establishing the first university-bound, interdisciplinary specialist centre for FASD in Germany, systematically collecting data on its utilisation and evaluation by attendees. METHODS: After our centre started to provide consultation and support services in July 2019 until May 2021, we collected 233 questionnaires on the centre's utilisation (including attendees' sociodemographic characteristics and the topics on which they requested consultation, e.g., general information about FASD, consultation on therapy options, and educational consultation). Ninety-four of 136 individuals who received consultation at our centre submitted an evaluation questionnaire that recorded attendees' satisfaction with the support they had received (e.g., the extent to which the consultation met their needs). RESULTS: Of 233 participants who completed the utilisation questionnaire, 81.8% were female, and 56.7% were aged 40 to 60 years. Moreover, 42% were foster parents, while 38% were professionals. Most attendees had questions on FASD in general as well as on a specific child or adolescent with FASD. Almost three quarters of the attendees requested consultation on adequate therapies for FASD patients, while 64% had questions on parenting issues. The overall quality of the consultation was rated very well. DISCUSSION: Our service was used by both caregivers and professionals who reported numerous and complex concerns and needs. Professionally sound and multidisciplinary services are viable instruments to meet those needs, bearing the potential for quick and notable relief among individuals affected. We propose further advancement of networking and coordination between care providers, the expansion of multidisciplinary services, and securing early diagnosis and consistency of care as relevant steps to even better support children and adolescents with FASD and their families in the future.

Inhibiting O-GlcNAcylation impacts p38 and Erk1/2 signaling and perturbs cardiomyocyte hypertrophy.

The dynamic cycling of O-linked GlcNAc (O-GlcNAc) on and off Ser/Thr residues of intracellular proteins, termed O-GlcNAcylation, is mediated by the conserved enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase. O-GlcNAc cycling is important in homeostatic and stress responses, and its perturbation sensitizes the heart to ischemic and other injuries. Despite considerable progress, many molecular pathways impacted by O-GlcNAcylation in the heart remain unclear. The mitogen-activated protein kinase (MAPK) pathway is a central signaling cascade that coordinates developmental, physiological, and pathological responses in the heart. The developmental or adaptive arm of MAPK signaling is primarily mediated by Erk kinases, while the pathophysiologic arm is mediated by p38 and Jnk kinases. Here, we examine whether O-GlcNAcylation affects MAPK signaling in cardiac myocytes, focusing on Erk1/2 and p38 in basal and hypertrophic conditions induced by phenylephrine. Using metabolic labeling of glycans coupled with alkyne-azide "click" chemistry, we found that Erk1/2 and p38 are O-GlcNAcylated. Supporting the regulation of p38 by O-GlcNAcylation, the OGT inhibitor, OSMI-1, triggers the phosphorylation of p38, an event that involves the NOX2-Ask1-MKK3/6 signaling axis and also the noncanonical activator Tab1. Additionally, OGT inhibition blocks the phenylephrine-induced phosphorylation of Erk1/2. Consistent with perturbed MAPK signaling, OSMI-1-treated cardiomyocytes have a blunted hypertrophic response to phenylephrine, decreased expression of cTnT (key component of the contractile apparatus), and increased expression of maladaptive natriuretic factors Anp and Bnp. Collectively, these studies highlight new roles for O-GlcNAcylation in maintaining a balanced activity of Erk1/2 and p38 MAPKs during hypertrophic growth responses in cardiomyocytes.

Effects of delay to stroke unit admission in patients with ischemic and hemorrhagic stroke.

OBJECTIVE: To determine the association between delay in transfer to a central stroke unit from peripheral institutions and outcomes. METHODS: We conducted a retrospective cohort study of all patients with acute stroke, admitted to a comprehensive stroke center (CSC) from three emergency departments (EDs), between 2016 and 2018. The primary outcomes were length of stay, functional status at 3 months, discharge destination, and time to stroke investigations. RESULTS: One thousand four hundred thirty-five patients were included, with a mean age of 72.9 years, and 92.4% ischemic stroke; 663 (46.2%) patients were female. Each additional day of delay was associated with 2.0 days of increase in length of stay (95% confidence interval [CI] 0.8-3.2, p = 0.001), 11.5 h of delay to vascular imaging (95% CI 9.6-13.4, p < 0.0001), 24.2 h of delay to Holter monitoring (95% CI 7.9-40.6, p = 0.004), and reduced odds of nondisabled functional status at 3 months (odds ratio 0.98, 95% CI 0.96-1.00, p = 0.01). Factors affecting delay included stroke onset within 6 h of ED arrival (605.9 min decrease in delay, 95% CI 407.9-803.9, p < 0.0001), delay to brain imaging (59.4 min increase in delay for each additional hour, 95% CI 48.0-71.4, p < 0.0001), admission from an alternative service (3918.7 min increase in delay, 95% CI 3621.2-4079.9, p < 0.0001), and transfer from a primary stroke center (PSC; 740.2 min increase in delay, 95% CI 456.2-1019.9, p < 0.0001). CONCLUSION: Delay to stroke unit admission in a system involving transfer from PSCs to a CSC was associated with longer hospital stay and poorer functional outcomes.

Like Visiting an Old Friend: Fischer Glycosylation in the Twenty-First Century: Modern Methods and Techniques.

Fischer glycosylation is typically the chemical reaction of a monosaccharide and an alcohol in presence of an acidic catalyst to afford glycosides in pyranosidic and furanosidic forms. This reaction is still applied today for the synthesis of specialized glycosides, and optimization and modification of the method have continued since its discovery by Emil Fischer in the 1890s. This review presents advancements in Fischer glycosylation described in literature of the past 15 years and its implementation in modern chemical methods.

Considerations in Methods and Timing for Delivery of Genetic Counseling Information to Pediatric Oncology Patients and Families.

Many pediatric oncology patients and their families may benefit from genetic counseling and testing; however, identifying the best timing and delivery method for these referrals is sometimes a challenge. The goal of this study was to understand how and when caregivers prefer to receive information about genetic counseling and testing. A total of 56 surveys completed by caregivers at The Johns Hopkins Hospital Pediatric Oncology unit in Baltimore, Maryland were analyzed. A sizeable subset of respondents was interested in receiving information about the availability of genetic counseling from an oncology doctor or nurse, but not a genetic counselor (n=13/55, 24%). Most respondents preferred to be informed about genetic services at diagnosis (n=28/54, 52%) or within 1 to 2 months of diagnosis (n=14/54, 26%). In conclusion, patients and their families may benefit from prompt and early recognition of the risk of cancer predisposition syndromes, preferably within the first 2 months following diagnosis. Oncology professionals are an important source of information, and can introduce the availability of genetic counseling services and motivate families to undergo genetic testing, though alternative communication methods such as brochures may also be useful.

Evidence-based interventions for children and adolescents with fetal alcohol spectrum disorders - A systematic review.

INTRODUCTION: Brain function deficits cause strong negative impacts for the everyday lives of children and adolescents with fetal alcohol spectrum disorders (FASD). Therefore, evidence-based intervention programs that are specifically designed for patients with FASD are needed but still scarce. The aim of the presented article is a systematic literature review of evidence-based intervention strategies for children and adolescents with FASD. MATERIALS AND METHODS: A comprehensive systematic literature search was conducted in several relevant databases to identify randomized-controlled intervention studies for children and adolescents with FASD. RESULTS: We identified 25 randomized-controlled studies regarding interventions in FASD. Overall, evidence indicating that some therapeutic interventions are effective in children and adolescents with FASD was found. Even though evidence-based interventions rarely lead to improvements of performance into a "normal range", those measures can alleviate negative consequences of prenatal alcohol exposure and relieve daily burdens. CONCLUSION: There are only a few randomized-controlled trials regarding therapy research for children and adolescents with FASD. Their results indicate that especially the combination of parent and child sessions present a promising approach for the treatment of FASD. Positive treatment effects of interventions seem to be domain specific, except for interventions regarding self-regulation or social interaction.

Assessing the needs of caregivers of children and adolescents with fetal alcohol spectrum disorders: Results from a survey among families and professionals in Germany.

INTRODUCTION: Caring for individuals with fetal alcohol spectrum disorders (FASD) puts a substantial and often life-long burden on affected families. Caregivers' specific needs and demands are, however, not well understood so far. We thus aimed at systematically collecting data on the needs of individuals caring for children and adolescents with FASD. MATERIALS AND METHODS: Between May 2019 and November 2020, a quantitative survey among caregivers and professionals from across Germany was performed. Participants completed a questionnaire collecting information on the perceived support caregivers receive from various sources as well as the current fulfilment of caregivers' needs. Specifically, the fulfilment of a variety of specific needs summarised in five categories was rated by the participants on a scale ranging from 1 (very good) to 6 (insufficient). RESULTS: Both caregivers and professionals rated the overall fulfilment of needs rather poorly (mean: 3.94 and 4.27, respectively). Caregivers indicated needs concerning coordination of support (4.74) and relief services (4.44) to be fulfilled the least while needs in the relief services category also received the lowest average grade among professionals (4.57). The needs that the caregivers regarded as most sufficiently fulfilled were their own knowledge about FASD (mean: 1.95) and their knowledge about the causes of their child's problems (mean: 1.87). CONCLUSIONS: The results of the present study indicate that FASD caregivers are supported insufficiently, while most of their needs remain unmet. Health care planners and providers thus urgently need to identify and implement measures to better address FASD caregivers' needs and demands.

[Fetal alcohol spectrum disorders-diagnosis, prognosis, and prevention]. / Fetale Alkoholspektrumstörungen ­ Diagnose, Prognose und Prävention.

Fetal alcohol spectrum disorder is one of the most common chronic diseases at birth. It is very often not or falsely diagnosed. This leads to inadequate, ineffective care and treatment of the affected children as well as to insufficient support of their families. The result is not only a high rate of secondary disorders, but it also leads to fewer opportunities for secondary and tertiary prevention for each child and family. With the right diagnosis these opportunities are guaranteed. The primary prevention in the field of alcohol consumption during pregnancy and fetal alcohol spectrum disorder should be planned and performed by the medical and political partners in a structured interdisciplinary and scientifically based way. Besides health promotion and education of the general population, the knowledge transfer to doctors and other medical, psychological, and pedagogical professionals is of particular relevance.

Inhibition of c-Yes induces differentiation of HT-29 human colon cancer stem cells through midbody elongation.

Recent research suggests that a small group of cells, named cancer stem cells (CSCs), is responsible for initiating tumor formation, recurrence, and metastasis. c-Yes, a proto-oncogene that is a subfamily of Src family kinase, is often activated in human colon cancer; this implicates c-Yes in the onset and progression of the disease. The objective of this study was to investigate the correlation between c-Yes and CSCs. We performed a sphere formation assay and reverse transcription-polymerase chain reaction for studying the differentiation of HT-29 human colon CSCs. To demonstrate the specific role of c-Yes in CSCs, we performed live cell microscopy and a cell cycle assay. These study shows, for the first time, that c-Yes is enriched in CD133+ CSCs, compared to their CD133- counterparts, and that c-Yes depletion in CD133+ cells induces cell differentiation. Moreover, c-Yes depletion was found to elongate the midbody and increase the proliferation doubling time. This also suggested that the misregulation of microtubules during chromosomal separation causes aneuploidy. Our results suggest that c-Yes may play a crucial role in initiating, maintaining, and driving the tumorigenic property of colon cancer.

Modulation of biomechanical properties of hyaluronic acid hydrogels by crosslinking agents.

Modulation of both mechanical properties and biocompatibilities of hyaluronic acid (HA) hydrogels is very importance for their applications in biomaterials. Pure HA solution was converted into a hydrogel by using butanediol diglycidyl ether (BDDE) as a crosslinking agent. Mechanical properties of the HA hydrogels have been evaluated by adding up different amount of BDDEs. While the mechanical properties of the obtained HA hydrogels were evaluated by measuring their crosslinking degrees, elastic modulus and viscosity, their in vitro biocompatibilities were done by measuring the degrees of anti-inflammatory reactions, cell viabilities and cytotoxicity. The degrees of anti-inflammatory reactions were determined by measuring the amount of nitric oxides (NOs) released from lipopolysaccharide(LPS)(+)-induced macrophages; cell viability was evaluated by observing differences in the behaviors of fibroblasts covered with the HA hydrogels, compared with those covered with the films of Teflon and Latex. Cytotoxicity of the HA hydrogels was also evaluated by measuring the degrees of viability of the cells exposed on the extracts of the HA hydrogels over those of Teflon, Latex and pure HA solutions by the assays of thiazoly blue tetrazolium bromide (MTT), neutral reds, and bromodeoxyuridine (BrdU). The results showed that employment of BDDEs beyond critical amounts showed lower biocompatibility of the crosslinked HA hydrogels but higher crosslinking degrees and mechanical properties, indicating the importance of controlling the HA concentrations, BDDE amounts and their reaction times for the synthesis of the crosslinked HA hydrogels for their clinical applications as biomaterials.

Extremely low-frequency electromagnetic fields induce neural differentiation in bone marrow derived mesenchymal stem cells.

Extremely low-frequency electromagnetic fields (ELF-EMF) affect numerous biological functions such as gene expression, cell fate determination and even cell differentiation. To investigate the correlation between ELF-EMF exposure and differentiation, bone marrow derived mesenchymal stem cells (BM-MSCs) were subjected to a 50-Hz electromagnetic field during in vitro expansion. The influence of ELF-EMF on BM-MSCs was analysed by a range of different analytical methods to understand its role in the enhancement of neural differentiation. ELF-EMF exposure significantly decreased the rate of proliferation, which in turn caused an increase in neuronal differentiation. The ELF-EMF-treated cells showed increased levels of neuronal differentiation marker (MAP2), while early neuronal marker (Nestin) was down-regulated. In addition, eight differentially expressed proteins were detected in two-dimensional electrophoresis maps, and were identified using ESI-Q-TOF LC/MS/MS. Among them, ferritin light chain, thioredoxin-dependent peroxide reductase, and tubulin ß-6 chain were up-regulated in the ELF-EMF-stimulated group. Ferritin and thioredoxin-dependent peroxide reductase are involved in a wide variety of functions, including Ca(2+) regulation, which is a critical component of neurodegeneration. We also observed that the intracellular Ca(2+) content was significantly elevated after ELF-EMF exposure, which strengthens the modulatory role of ferritin and thioredoxin-dependent peroxide reductase, during differentiation. Notably, western blot analysis indicated significantly increased expression of the ferritin light chain in the ELF-EMF-stimulated group (0.60 vs. 1.08; P < 0.01). These proteins may help understand the effect of ELF-EMF stimulation on BM-MSCs during neural differentiation and its potential use as a clinically therapeutic option for treating neurodegenerative diseases.

Resting state EEG oscillatory power differences in ADHD college students and their peers.

BACKGROUND: Among the most robust neural abnormalities differentiating individuals with Attention-Deficit/Hyperactivity Disorder (ADHD) from typically developing controls are elevated levels of slow oscillatory activity (e.g., theta) and reduced fast oscillatory activity (e.g., alpha and beta) during resting-state electroencephalography (EEG). However, studies of resting state EEG in adults with ADHD are scarce and yield inconsistent findings. METHODS: EEG profiles, recorded during a resting-state with eyes-open and eyes-closed conditions, were compared for college students with ADHD (n = 18) and a nonclinical comparison group (n = 17). RESULTS: The ADHD group showed decreased power for fast frequencies, especially alpha. This group also showed increased power in the slow frequency bands, however, these effects were strongest using relative power computations. Furthermore, the theta/beta ratio measure was reliably higher for the ADHD group. All effects were more pronounced for the eyes-closed compared to the eyes-open condition. Measures of intra-individual variability suggested that brains of the ADHD group were less variable than those of controls. CONCLUSIONS: The findings of this pilot study reveal that college students with ADHD show a distinct neural pattern during resting state, suggesting that oscillatory power, especially alpha, is a useful index for reflecting differences in neural communication of ADHD in early adulthood.

High-content flow cytometry and temporal data analysis for defining a cellular signature of graft-versus-host disease.

Acute graft-versus-host disease (GVHD) is diagnosed by clinical and histologic criteria that are often nonspecific and typically apparent only after the disease is well established. Because GvHD is mediated by donor T cells and other immune effector cells, we sought to determine whether changes within a wide array of peripheral blood lymphocyte populations could predict the development of GvHD. Peripheral blood samples from 31 patients undergoing allogeneic blood and marrow transplant were analyzed for the proportion of 121 different subpopulations defined by 4-color combinations of lymphocyte phenotypic and activation markers at progressive time points posttransplant. Samples were processed using a newly developed high content flow cytometry technique and subjected to a spline- and functional linear discriminant analysis (FLDA)-based temporal analysis technique. This strategy identified a consistent posttransplant increase in the proportion and extent of fluctuation of CD3+CD4+CD8beta+ cells in patients who developed GVHD compared to those that did not. Although larger prospective clinical studies will be necessary to validate these results, this study demonstrates that high-content flow cytometry coupled with temporal analysis is a powerful approach for developing new diagnostic tools, and may be useful for developing a sensitive and specific predictive test for GVHD.