[Self-harming behavior of patients on a closed psychiatric ward]. / Zelfbeschadigend gedrag bij patiënten op een gesloten psychiatrische afdeling.

BACKGROUND: Self-harming behavior is a frequent problem seen in patients admitted to a closed ward in a psychiatric hospital. Little is known about prevalence and characteristics of this behavior as well as the preceding triggering factors. AIM: To gain insights in the self-harming behavior of patients admitted to a closed ward in a psychiatric hospital. METHOD: From September 2019 till January 2021 was gathered information on self-harming incidents and aggressive behavior towards others or objects, of 27 patients admitted to the closed department of the Centre Intensive Treatment (Centrum Intensieve Behandeling). RESULTS: 20 of 27 patients examined (74%) showed 470 incidents of self-harming behavior. Head banging (40.9%) and self-harming using straps/ropes (29.7%) occured most. Tension/stress as triggering factor was mentioned most (19.1%). Self-harming behavior occured more during evenings. Besides self-harm, a high degree of aggressive behavior towards others or objects was registered. CONCLUSION: This study delivers insights in self-harming behavior of patients admitted to closed psychiatric departments that can be used for prevention and treatment.

Consultations for refractory cases in mental health services: a descriptive study.

BACKGROUND: Yearly, almost six percent, which is more than 1,000.000 people, in the Netherlands receive mental health treatment, which usually improves their quality of life. Concurrently, mental healthcare professionals recognize clinically refractory cases in which improvement fails to occur, with severe ongoing burdens for patients. The Dutch Centre for Consultation and Expertise (CCE) is available to support such refractory cases. The Dutch government's (financial) facilitation of consultation through the CCE is unique in the world. CCE consultations provide therefore unique insight into and an overview of refractory cases in mental health services. The objective of this study was to gain insight into the commonalities underlying the reasons for CCE consultations and the solutions proposed that play roles in (the reduction of) refractory cases for which consultation has been requested. METHODS: This descriptive study was conducted with quantitative and qualitative data from 472 CCE consultations in the Netherlands. Using descriptive statistics and thematic content analysis, four exemplary situations were distilled from the qualitative data. RESULTS: Most (83%) cases in the sample could be explained with four exemplary situations involving self-harm (24.2%), aggression (21.8%), self-neglect (24.4%), and socially unacceptable behavior (12.5%), respectively. Each situation could be characterized by a specific interaction pattern that unintentionally maintained or aggravated the situation. At the time of closure of the consultation applicants' questions had been answered and their situations had improved in 60.4% of cases. CONCLUSIONS: This study offers an overview of approaches that provided new perspectives for patients and professionals in many refractory cases in the Dutch mental health services.

[Consultation in refractory cases in mental health care: a descriptive study]. / Consultaties bij vastgelopen behandel­situaties: een descriptieve studie.

BACKGROUND: Yearly, over 1.000.000 people receive mental health care treatment in the Netherlands. Treatment usually results in improvement in quality of life. Concurrently, each professional recognizes clinically refractory cases in which improvement fails to occur with severe ongoing burden for the client. In the Netherlands, for these clinically refractory cases the Centre of Consultation and Expertise (CCE) is available. The CCE is an independent nation-wide organisation offering free consultations to care providers. Therefore, CCE-consultations provide a unique insight in and overview of refractory cases. AIM: Providing overview of and insight into backgrounds and themes that play a role in (the reduction of) refractory cases. METHOD: Descriptive study of quantitative and qualitative data from 472 consultations in mental health care. RESULTS: 83% of cases could be explained with 4 exemplary vignettes of refractoriness: self-harm, aggression, self-neglect and socially unacceptable behaviour. CONCLUSION: Refractory cases result from an interaction pattern that unintentionally maintains or aggravates the situation. This study offers an overview of approaches that proved to be helpful in providing new perspective for clients and professionals in many therapy refractory cases in Dutch mental health care.

Extracellular Vesicles Released by Glioblastoma Cells Stimulate Normal Astrocytes to Acquire a Tumor-Supportive Phenotype Via p53 and MYC Signaling Pathways.

The role of astrocytes is becoming increasingly important to understanding how glioblastoma (GBM) tumor cells diffusely invade the brain. Yet, little is known of the contribution of extracellular vesicle (EV) signaling in GBM/astrocyte interactions. We modeled GBM-EV signaling to normal astrocytes in vitro to assess whether this mode of intercellular communication could support GBM progression. EVs were isolated and characterized from three patient-derived GBM stem cells (NES+/CD133+) and their differentiated (diff) progeny cells (NES-/CD133-). Uptake of GBM-EVs by normal primary astrocytes was confirmed by fluorescence microscopy, and changes in astrocyte podosome formation and gelatin degradation were measured. Quantitative mass spectrometry-based proteomics was performed on GBM-EV stimulated astrocytes. Interaction networks were generated from common, differentially abundant proteins using Ingenuity® (Qiagen Bioinformatics) and predicted upstream regulators were tested by qPCR assays. Podosome formation and Cy3-gelatin degradation were induced in astrocytes following 24-h exposure to GBM-stem and -diff EVs, with EVs released by GBM-stem cells eliciting a greater effect. More than 1700 proteins were quantified, and bioinformatics predicted activations of MYC, NFE2L2, FN1, and TGFß1 and inhibition of TP53 in GBM-EV stimulated astrocytes that were then confirmed by qPCR. Further qPCR studies identified significantly decreased Δ133p53 and increased p53ß in astrocytes exposed to GBM-EVs that might indicate the acquisition of a pro-inflammatory, tumor-promoting senescence-associated secretory phenotype (SASP). Inhibition of TP53 and activation of MYC signaling pathways in normal astrocytes exposed to GBM-EVs may be a mechanism by which GBM manipulates astrocytes to acquire a phenotype that promotes tumor progression.

Cyclin-dependent kinase 7 is a therapeutic target in high-grade glioma.

High-grade glioma (HGG) is an incurable brain cancer. The transcriptomes of cells within HGG tumors are highly heterogeneous. This renders the tumors unresponsive or able to adapt to therapeutics targeted at single pathways, thereby causing treatment failure. To overcome this, we focused on cyclin-dependent kinase 7 (CDK7), a ubiquitously expressed molecule involved in two major drivers of HGG pathogenesis: cell cycle progression and RNA polymerase-II-based transcription. We tested the activity of THZ1, an irreversible CDK7 inhibitor, on patient-derived primary HGG cell lines and ex vivo HGG patient tissue slices, using proliferation assays, microarray analysis, high-resolution respirometry, cell cycle analysis and in vivo tumor orthografts. The cellular processes affected by CDK7 inhibition were analyzed by reverse transcriptase-quantitative PCR, western blot, flow cytometry and immunofluorescence. THZ1 perturbed the transcriptome and disabled CDK activation, leading to cell cycle arrest at G2 and DNA damage. THZ1 halted transcription of the nuclear-encoded mitochondrial ribosomal genes, reducing mitochondrial translation and oxidative respiration. It also inhibited the expression of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor-α (PDGFR-α), reducing signaling flux through the AKT, extracellular-signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) downstream pathways. Finally, THZ1 disrupted nucleolar, Cajal body and nuclear speckle formation, resulting in reduced cytosolic translation and malfunction of the spliceosome and thus leading to aberrant mRNA processing. These findings indicate that CDK7 is crucial for gliomagenesis, validate CDK7 as a therapeutic target and provide new insight into the cellular processes that are affected by THZ1 and induce antitumor activity.

[Prescribing psychotropic medication by the nurse practitioner in mental health care: an explorative study]. / Voorschrijven van psychofarmaca door verpleegkundig specialist ggz: een exploratief onderzoek.

BACKGROUND: Since January 1, 2012, nurse practitioners (NP) working in mental health care are allowed to prescribe psychotropic medication. So far, there has been very little research on the results of this decision that now let NPS share with doctors prescribing psychotropic drugs. AIM: To provide insight into how patients and psychiatrists experience the prescribing behaviours of NPS and how NPS themselves regard their extended role. METHOD: We performed an explorative study in which we used the data given in prescriptions written by NPS, questionnaires exploring patients' experiences and semi-structured interviews with psychiatrists and NPS. RESULTS: Between May 2014 and May 2015, 13 NPS wrote 3542 prescriptions for 565 unique patients. On the whole, patients, psychiatrists and NPS expressed positive views on the prescribing of psychotropic medication by NPS. CONCLUSION: Our research project confirms that the various stakeholders are satisfied with the prescribing practices of NPS. A follow-up study is needed in order to ascertain whether there are qualitative differences between the prescriptions of NPS and those of doctors.

EphA3 as a target for antibody immunotherapy in acute lymphoblastic leukemia.

The human EphA3 gene was discovered in a pre-B acute lymphoblastic leukemia (pre-B-ALL) using the EphA3-specific monoclonal antibody (mAb), IIIA4, which binds and activates both human and mouse EphA3. We use two models of human pre-B-ALL to examine EphA3 function, demonstrating effects on pre-B-cell receptor signaling. In therapeutic targeting studies, we demonstrated antitumor effects of the IIIA4 mAb in EphA3-expressing leukemic xenografts and no antitumor effect in the xenografts with no EphA3 expression providing evidence that EphA3 is a functional therapeutic target in pre-B-ALL. Here we show that the therapeutic effect of the anti-EphA3 antibody was greatly enhanced by adding an α-particle-emitting 213Bismuth payload.

'They prefer hidden treatment': anti-tuberculosis drug-taking practices and drug regulation in Karakalpakstan.

SETTING: The joint Médecins Sans Frontières/Ministry of Health Multidrug-Resistant Tuberculosis (MDR-TB) Programme, Karakalpakstan, Uzbekistan. OBJECTIVE: Uzbekistan has high rates of MDR-TB. We aimed to understand patients' and prescribers' attitudes to anti-tuberculosis drug prescription, regulation and drug-taking behaviour. METHODS: Participants (12 patients, 12 practitioners) were recruited purposively. Data were gathered qualitatively using field notes and in-depth interviews and analysed thematically. FINDINGS: Our analysis highlighted two main themes. First, shame and stigma were reported to increase the likelihood of self-treatment and incorrect use of anti-tuberculosis drugs, most commonly at the initial stages of illness. A health system failure to promote health information was perceived, leading to wrong diagnoses and inappropriate therapies. Motivated by shame, patients hid their condition by resorting to drug treatment options outside the programme, compounding the risk of chaotic management and dissemination of erroneous information through lay networks. Second, positive influences on treatment were reported through patients, practitioners and peers working effectively together to deliver the correct information and support, which acted to normalise TB, reduce stigma and prevent misuse of anti-tuberculosis drugs. CONCLUSION: Effective case finding, patient support and community education strategies are essential. Patients, practitioners and peers working together can help reduce stigma and prevent misuse of anti-tuberculosis drugs.

Patient-derived glioblastoma cells show significant heterogeneity in treatment responses to the inhibitor-of-apoptosis-protein antagonist birinapant.

BACKGROUND: Resistance to temozolomide (TMZ) greatly limits chemotherapeutic effectiveness in glioblastoma (GBM). Here we analysed the ability of the Inhibitor-of-apoptosis-protein (IAP) antagonist birinapant to enhance treatment responses to TMZ in both commercially available and patient-derived GBM cells. METHODS: Responses to TMZ and birinapant were analysed in a panel of commercial and patient-derived GBM cell lines using colorimetric viability assays, flow cytometry, morphological analysis and protein expression profiling of pro- and antiapoptotic proteins. Responses in vivo were analysed in an orthotopic xenograft GBM model. RESULTS: Single-agent treatment experiments categorised GBM cells into TMZ-sensitive cells, birinapant-sensitive cells, and cells that were insensitive to either treatment. Combination treatment allowed sensitisation to therapy in only a subset of resistant GBM cells. Cell death analysis identified three principal response patterns: Type A cells that readily activated caspase-8 and cell death in response to TMZ while addition of birinapant further sensitised the cells to TMZ-induced cell death; Type B cells that readily activated caspase-8 and cell death in response to birinapant but did not show further sensitisation with TMZ; and Type C cells that showed no significant cell death or moderately enhanced cell death in the combined treatment paradigm. Furthermore, in vivo, a Type C patient-derived cell line that was TMZ-insensitive in vitro and showed a strong sensitivity to TMZ and TMZ plus birinapant treatments. CONCLUSIONS: Our results demonstrate remarkable differences in responses of patient-derived GBM cells to birinapant single and combination treatments, and suggest that therapeutic responses in vivo may be greatly affected by the tumour microenvironment.

Eph receptors as therapeutic targets in glioblastoma.

The dismal outlook for patients with the most aggressive and common form of adult brain cancer, glioblastoma (GBM), motivates a search for new therapeutic strategies and targets for this aggressive disease. Here we review the findings to date on the role of Eph family receptor tyrosine kinases and their ephrin ligands in brain cancer. Expression of the Eph family of cell surface proteins is generally downregulated to very low levels in normal adult tissues making them particularly attractive for directed therapeutic targeting. Recent Eph targeting studies in pre-clinical models of GBM have been very encouraging and may provide an avenue to treat these highly refractory aggressive tumours.

User involvement in mental health care: the role of nurses. A literature review.

This literature review was carried out to examine the effects of user involvement in shared decision-making processes and the methods/tools available to psychiatric nurses to measure and encourage user involvement. A systematic literature review was then used in this study. Many studies indicate that an increased involvement of service users leads to better care, better treatment compliance, improved health outcomes and higher levels of patient satisfaction. The tools and methods described are designed to measure the ability to participate, the process of implementation and the evaluation of healthcare services. An adequate instrument to measure user involvement will be necessary to underpin the positive effects. Although care providers have a statutory duty to help shape user involvement, and the tools required are available, care providers are still insufficiently inclined to take up this duty.

Effectiveness of the hands-free technique in reducing operating theatre injuries.

BACKGROUND: Operating theatre personnel are at increased risk for transmission of blood borne pathogens when passing sharp instruments. The hands-free technique, whereby a tray or other means are used to eliminate simultaneous handling of sharp instruments, has been recommended. AIMS: To prospectively evaluate the effectiveness of the hands-free technique in reducing the incidence of percutaneous injuries, contaminations, and glove tears arising from handling sharp instruments. METHODS: For each of 3765 operations carried out in main and surgical day care operating theatres in a large urban hospital, over six months, circulating nurses recorded the proportion of use of the hands-free technique during each operation, as well as other features of the operation. The hands-free technique, considered to be used when 75% or more of the passes in an operation were done in this way, was used in 42% of operations. The relative rate of incidents (percutaneous injuries, contaminations, and glove tears) in operations where the hands-free technique was used and not used, with adjustment via multiple logistic regression for the different risk profiles of the two sets of operations, was calculated. RESULTS: A total of 143 incidents (40 percutaneous injuries, 51 contaminations, and 52 glove tears) were reported. In operations with greater than 100 ml blood loss, the incident rate was 4% (18/486) when the hands-free technique was used and 10% (90/880) when it was not, approximately 60% less. When adjusted for differences in type and duration of surgery, emergency status, noisiness, time of day, and number present for 75% of the operation, the reduction in the rate was 59% (95% CI 23% to 72%). In operations with less than 100 ml blood loss, the corresponding rates were 1.4% (15/1051) when the hands-free technique was used and 1.5% (19/1259) when it was not used. Adjustment for differences in risk factors did not alter the difference. CONCLUSIONS: Although not effective in all operations, use of the hands-free technique was effective in operations with more substantial blood loss.

Quantifying and reducing the risk of bloodborne pathogen exposure.

The risk of becoming infected with bloodborne pathogens (e.g., hepatitis B, hepatitis C, HIV) during surgery is real. The degree of risk for perioperative personnel is related to factors that include participating in large numbers of surgical procedures each year; the nature of perioperative work (e.g., use of different types of sharp instruments): exposure to large amounts of blood and body fluids; the prevalence of bloodborne pathogens in the surgical population; the variation in different organisms' ability to be transmitted; the existence of vaccines and the level of vaccination; the availability of postexposure treatment; and the consequences of acquiring the disease. Controlling risks to perioperative personnel can be accomplished by using the Occupational Safety and Health Administration's three methods of control--redesigning surgical equipment and procedures, changing work practices, and enhancing the personal protection equipment of perioperative personnel.

Overexpression of the G-protein inwardly rectifying potassium channel 1 (GIRK1) in primary breast carcinomas correlates with axillary lymph node metastasis.

The acquisition of genetic alterations in tumor cells is a hallmark of cancer progression. Genetic alterations, including chromosomal sequence alterations and abnormal gene expression, increase the malignant potential of tumors by affecting pathways that regulate cell growth, cell death, tumor angiogenesis, and invasion/metastasis. We used an expression profiling technique, representational difference analysis, to identify genes the expressions of which are aberrantly increased in invasive breast carcinomas as compared with adjacent normal breast tissue from the same individual. Among the genes we identified was GIRK1, which encodes a 501 amino acid, G-protein inwardly rectifying potassium channel protein. We then measured GIRK1 mRNA expression in benign breast tissues, primary invasive breast carcinomas, and metastatic breast carcinomas from axillary lymph nodes using quantitative TaqMan reverse transcription-PCR and correlated the results with clinical parameters. We found that GIRK1 overexpression correlated with lymph node metastasis (P < 0.0029), and overexpression was greatest in tumors with more than one positive lymph node. These results indicate that GIRK1 may be useful as a biomarker for lymph node metastasis and possibly a pharmaceutical target.

Detection of a novel mutation in X-linked amelogenesis imperfecta.

Amelogenesis imperfecta (AI) is a heterogeneous group of inherited disorders of defective enamel formation. The major protein involved in enamel formation, amelogenin, is encoded by a gene located at Xp22.1-Xp22.3. This study investigated the molecular defect producing a combined phenotype of hypoplasia and hypomineralization in a family with the clinical features and inheritance pattern of X-linked amelogenesis imperfecta (XAI). Genomic DNA was prepared from buccal cells sampled from family members. The DNA was subjected to the polymerase chain-reaction (PCR) in the presence of a series of oligonucleotide primers designed to amplify all 7 exons of the amelogenin gene. Cloning and sequencing of the purified amplification products identified a cytosine deletion in exon VI at codon 119. The deletion resulted in a frameshift mutation, introducing a premature stop signal at codon 126, producing a truncated protein lacking the terminal 18 amino acids. Identifying mutations assists our understanding of the important functional domains within the gene, and finding another novel mutation emphasizes the need for family-specific diagnosis of amelogenesis imperfecta.

Alveolar cell stretching in the presence of fibrous particles induces interleukin-8 responses.

Inhalation of fibrous particulates is strongly associated with lung injury, but the molecular and cellular mechanisms that could explain the fiber-induced pathogenesis are not fully understood. We hypothesized that the physical stress exerted on the alveolar epithelium by the deposited fibers is greatly enhanced by the tidal cyclic motion of the epithelial cells that is associated with breathing, and that this initial mechanical interaction triggers a subsequent cell response. To test this hypothesis, we developed a dynamic model of fiber-induced cell injury using a cell-stretcher device. We exposed a cyclically stretched monolayer of the human alveolar epithelial cell line A549 to glass or crocidolite asbestos fibers for 8 h and then measured the production of the proinflammatory cytokine interleukin (IL)-8 as a readout of fiber-induced cell injury. Cyclic stretching significantly increased IL-8 production in the fiber-treated cultures, suggesting that the physical stress on the cells caused by the fibers was indeed enhanced by the motion. Coating of the asbestos fibers with fibronectin, a glycoprotein abundant in the alveolar lining fluid, further increased the fiber-induced cell response when the cells were cyclically stretched. This response was, however, significantly reduced by introducing into the culture medium, before fiber treatment, soluble RGD (Arg-Gly-Asp)-containing peptides, which specifically block binding to integrin receptors upon RGD attachment. These results suggested that adhesive interactions between protein-coated fibers and cell surface molecules are involved in the fiber-induced pathogenic process. Our novel findings indicate the importance of physical insults in fiber-induced cell stress, and bring to the forefront the need to study the mechanisms involved in this process.

Genetic regulatory elements introduced into neural stem and progenitor cell populations.

The genetic manipulation of neural cells has advantage in both basic biology and medicine. Its utility has provided a clearer understanding of how the survival, connectivity, and chemical phenotype of neurones is regulated during, and after, embryogenesis. Much of this achievement has come from the recent generation by genetic means of reproducible and representative supplies of precursor cells which can then be analyzed in a variety of paradigms. Furthermore, advances made in the clinical use of transplantation for neurodegenerative disease have created a demand for an abundant, efficacious and safe supply of neural cells for grafting. This review describes how genetic methods, in juxtaposition to epigenetic means, have been used advantageously to achieve this goal. In particular, we detail how gene transfer techniques have been developed to enable cell immortalization, manipulation of cell differentiation and commitment, and the controlled selection of cells for purification or safety purposes. In addition, it is now also possible to genetically modify antigen presentation on cell surfaces. Finally, there is detailed the transfer of therapeutic products to discrete parts of the central nervous system (CNS), using neural cells as elegant and sophisticated delivery vehicles. In conclusion, once the epigenetic and genetic controls over neural cell production, differentiation and death have been more fully determined, providing a mixture of hard-wired elements and more flexibly expressed characteristics becomes feasible. Optimization of the contributions and interactions of these two controlling systems should lead to improved cell supplies for neurotransplantation.

Ionic mechanisms underlying excitatory effects of serotonin on embryonic rat motoneurons in long-term culture.

The actions of serotonin were investigated on motoneurons isolated from embryonic day 14 rat spinal cord and enriched by metrizamide density gradient centrifugation. Trophic support was provided by a spinal cord glial monolayer, ciliary neurotrophic factor and heat-inactivated serum. Cultures were maintained for 17-83 days and investigated using whole-cell patch-clamp recording. Serotonin evoked slow depolarizations (6.2+/-0.7 or 9.3+/-1.3 mV in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione and strychnine, EC50 8.2 nM), which were reversibly blocked by 0.1 microM ketanserin. Serotonin generated synaptic potentials in motoneurons, lowered the threshold for repetitive firing and changed the slope of the current intensity-firing frequency relationship. The inward current evoked by serotonin (-147+/-15.2 pA) was ascribed to a complex ionic mechanism, which varied amongst neurons in the sampled population. It was due to closure of barium-sensitive potassium channels, effects on Ih and increase in a separate mixed cation current which comprised both transient voltage-sensitive and sustained components. We conclude that serotonergic responses develop in motoneurons cultured under these conditions in the absence of serotonergic input, sensory neurons or many interneurons.

DNase I hypersensitive sites in the 5' flanking region of the human plasminogen activator inhibitor type 2 (PAI-2) gene are associated with basal and tumor necrosis factor-alpha-induced transcription in monocytes.

The plasminogen activator inhibitor type 2 (PAI-2) gene encodes a serine proteinase inhibitor (serpin) which is rapidly induced in response to the inflammatory cytokine, tumour necrosis factor-alpha (TNFalpha) in monocytes and macrophages. As an initial step towards understanding the molecular mechanisms underlying PAI-2 gene regulation in monocytes, we report here the analysis of the chromatin structure of 9.6 kb of 5' flanking region of the human PAI-2 gene for potential cis-acting regulatory regions using DNase I hypersensitivity mapping. Sites sensitive to DNase I were mapped in two monocytic cell lines representative of early monocytic differentiation; U937 cells, which synthesise low constitutive levels of PAI-2 that were induced following treatment with TNFalpha, and a MonoMac6 cell line which did not synthesise PAI-2 even after treatment with TNFalpha. Six DNase I hypersensitive sites (DHS) were identified; three upstream of the transcription initiation site (DH1, DH2, DH3) and three downstream of the transcription initiation site which were contained within intron A (DH4, DH5) and the exon 2/intron B junction (DH6). Among these, one distally located DH site (DH2) disappeared in both cell lines following treatment with TNFalpha. Two DH sites (DH1, DH6) were absent in PAI-2-producing U937 cells, but were present in MonoMac6 cells, which did not produce PAI-2, indicating the possible involvement of negative regulatory elements in the suppression of PAI-2 gene expression. The results demonstrate the involvement of chromatin structure in transcriptional responsiveness of the PAI-2 gene promoter and identify several loci which may be key control regions for PAI-2 gene transcription.