Reliability and validity of the dynamic risk outcome scales-short version for clients with mild intellectual disabilities or borderline intellectual functioning.

INTRODUCTION: This study investigated the reliability and validity of the dynamic risk outcome scales-short version (DROS-SV). This instrument is developed to monitor treatment progress using dynamic risk factors in clients with mild intellectual disabilities or borderline intellectual functioning and behavioural and/or mental health problems. METHOD: Data were collected from 264 clients who received Flexible Assertive Community Treatment (FACT), a form of intensive outpatient treatment. RESULTS: A principal component analysis showed that there were six components explaining 73.9% of the variance. Furthermore, the DROS-SV showed good internal consistency of its subscales and total score (α > 0.78). Correlating the DROS-SV with the Historical and Clinical subscales of the Historical, Clinical and Future-30 indicated convergent and divergent validity. DISCUSSION: The DROS-SV has good psychometric properties for measuring dynamic risk factors in clients with mild intellectual disabilities or borderline intellectual functioning in FACT teams.

Psychometric analysis of the Group Climate Inventory-Revised in adults with mild intellectual disability or borderline intellectual functioning in a secure residential facility.

BACKGROUND: In secure residential facilities, group climate perceptions of clients with mild intellectual disability or borderline intellectual functioning are systematically assessed for quality improvement. A valid and reliable measure may ensure that this process is consistent. The Group Climate Inventory-Revised (GCI-R) is a new measure to assess group climate perceptions. METHOD: Confirmatory factor analysis was conducted in 148 adult clients (79% male) with mild intellectual disability or borderline intellectual functioning in a secure facility to examine internal structure validity and internal consistency reliability of the GCI-R. RESULTS: The results indicate support for the five-factor structure of the GCI-R ('Support', 'Growth', 'Repression', 'Peer interactions', and 'Physical environment'). The internal consistency reliability of its scales ranged from acceptable to good (α: .72-.87; ω: .76-.86). CONCLUSION: The GCI-R demonstrates evidence of psychometric adequacy when applied to adult clients with mild intellectual disability or borderline intellectual functioning in secure residential facilities.

Relationships between dynamic risk factors for externalising problem behaviour and group climate in adults with mild intellectual disability in forensic treatment.

BACKGROUND: Relationships between dynamic risk factors for externalising problem behaviour and group climate were investigated in 151 adult in-patients with mild intellectual disability or borderline intellectual functioning in a Dutch secure residential facility. METHOD: Regression analysis was used to predict total group climate score and Support, Growth, Repression, and Atmosphere subscales of the 'Group Climate Inventory'. Predictor variables were Coping Skills, Attitude towards current treatment, Hostility, and Criminogenic attitudes subscales of the 'Dynamic Risk Outcome Scales'. RESULTS: Less hostility predicted a better overall group climate, better support and atmosphere, and less repression. A positive attitude towards current treatment predicted better growth. CONCLUSION: Results indicate relationships of hostility and attitude towards current treatment with group climate. A focus on both dynamic risk factors and group climate may provide a basis for improving treatment for this target group.

The predictive value of the dynamic risk outcome scales (DROS) for recidivism in (forensic) clients with mild intellectual disabilities or borderline intellectual functioning.

BACKGROUND: The dynamic risk outcome scales (DROS) was developed to assess treatment progress of clients with mild intellectual disability or borderline intellectual functioning using dynamic risk factors. We studied the predictive value of the DROS on various classifications and severity levels of recidivism. METHOD: Data of 250 forensic clients with intellectual disabilities were linked to recidivism data from the Judicial Information Service in the Netherlands. Receiver operating characteristics (ROC) analyses were used to determine the predictive values. RESULTS: The DROS total score could not significantly predict recidivism. A DROS recidivism subscale predicted general, violent and other recidivism. These predictive values were comparable to those of a Dutch tool validated for risk assessment in the general forensic population. CONCLUSIONS: The DROS recidivism subscale predicted various classifications of recidivism better than chance. At present, the DROS appears to have no added value beyond the HKT-30 for the purpose of risk assessment.

ABO-Rh Blood Types and Clinical Consequences of COVID-19 Infection.

Aim and Background: Because of there is no sufficient evidence showing a relationship between blood types and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, this study was planned to investigate the effects of ABO blood group on the clinical outcomes of SARS-CoV-2 infection. Patients and Methods: The data of the patients were examined retrospectively. The patients who were hospitalized in wards or intensive care unit, constituted the study group. The patients who presented to the hospital because of other causes and whose blood type examinations were performed, were included in the control group. Results: The study group consisted of 406 six patients were diagnosed with SARS-CoV-2 infection. Control group consisted of 38079 patients whose blood group was determined for any reason in the same period. The rate of Rh negativity was significantly higher in the patient group (p = 0,01). Hospitalization duration in intensive care was significantly longer in the blood type A and AB groups compared to the blood type O group (p = 0,03). Conclusion: Our results are in agreement with other studies suggesting that blood group O individuals are somewhat more resistant to clinically overt infection with SARS-CoV-2 than other blood groups. In addition, Rh negativity may also be an individual risk factor for SARS-CoV-2 infection.

[The predictive value of the Dynamic Risk Outcome Scales (DROS) for predicting recidivism in (forensic) patients with mild intellectual disabilities or borderline intellectual functioning]. / De voorspellende waarde van de Dynamic Risk Outcome Scales (DROS) voor recidive bij (forensische) patiënten met een lichte verstandelijke beperking.

BACKGROUND: The Dynamic Risk Outcome Scales (DROS) was developed to assess treatment progress of patients with mild intellectual disability (MID) or borderline intellectual functioning (BIF) and severe behavioral and/or psychiatric problems. Because of the focus on dynamic risk factors, practitioners also see this instrument as a tool for risk assessment.
AIM: To investigate the predictive value of the DROS on different classifications and severities of recidivism.
METHOD: DROS data from the routine outcome monitoring (ROM) of 250 forensic patients with MID-BIF who were discharged between 2007 and end of 2014 were linked to recidivism data from the Judicial Information Service.
RESULTS: The DROS total score predicted general, violence and sexual recidivism better than chance (AUCs > 0.58), although the effect was small. A DROS-recidivism subscale predicted general, violence and other recidivism with a medium to large effect (AUCs > 0.67). The predictive values of the DROS total score and DROS-recidivism subscale were comparable to those of the Historic, Clinical, Future (in Dutch: HKT)-30.
CONCLUSION: The DROS total score and DROS-recidivism subscale predict different classifications of recidivism better than chance. However, for risk assessment the DROS appears to have no added value to the HKT-30.

Cerebro-retinal microangiopathy with calcifications and cysts due to recessive mutations in the CTC1 gene.

Cerebro-retinal microangiopathy with calcifications and cysts (CRMCC) or Coats plus syndrome is a pleiotropic disorder affecting the eyes, brain, bone and gastrointestinal tract. Its primary pathogenesis involves small vessel obliterative microangiopathy. Recently, autosomal recessively inherited mutations in CTC1 have been reported in CRMCC patients. We herein report an adolescent referred to our hospital following new seizures in a context of an undefined multisystem disorder. Cerebral imaging disclosed asymmetrical leukopathy, intracranial calcifications and cysts. In addition, he presented other typical CRMCC features i.e. a history of intrauterine growth retardation, skeletal demineralization and osteopenia, bilateral exudative vitreo-retinopathy reminiscent of Coats disease, recurrent gastrointestinal hemorrhages secondary to watermelon stomach and variceal bleeding of the esophagus due to idiopathic portal hypertension and telangiectatic and angiodysplasic changes in the small intestine and colon, and anemia due to recurrent bleeding and bone marrow abnormalities. The patient was diagnosed with Coats plus syndrome. CTC1 gene screening confirmed the diagnosis with the identification of heterozygous deleterious mutations. CRMCC due to CTC1 mutations has a broad clinical expressivity. Our case report illustrates the main possible associated phenotypes and their complications, demonstrating the need for a careful etiological search in order to initiate appropriate therapeutic and preventive measures.

Metal endoclips for the closure of the appendiceal stump in laparoscopic appendectomy.

Closure of the appendiceal stump in laparoscopic appendectomy is the most crucial part of the procedure. In this retrospective clinical study, we describe a technique for laparoscopic appendectomy, in which the appendiceal stump is secured by metal endoclips. Medical data of the patients who underwent laparoscopic appendectomy for acute appendicitis between January 2005 and January 2011 at our institution were reviewed. The patients who had their appendiceal stump secured by metal endoclips were recruited for the study. The outcome measures were the rate of intraoperative and postoperative complications, operative time, and the length of hospital stay. A total of 233 patients were included to the study. The rate of intraoperative and postoperative complications, the mean operative time, and median length of hospital stay were 3 and 4%, 31.1 (15-75) min, and 18 (8-96) h, respectively. The closure of the appendiceal stump with metal endoclips in laparoscopic appendectomy is simple, quick, and safe with outcomes comparable to those of other methods.

In vitro and in vivo evaluation of the haematopoietic potential of skeletal muscle in a non-human primate model.

This study was aimed at evaluating the in vitro and in vivo haematopoietic potential in macaque skeletal muscle cells. Biopsy samples showed the presence of CD34(+) (7.6%), CD90(+) (8.4%), CD117(+), CD31(+), side population (SP) cells (7-10%) and a low number of CD45(+) cells. In clonogenic and long-term culture-initiating cell assays, no haematopoietic potential could be detected in either total mononuclear cells or SP cells. Regarding in vivo studies, two animals were transplanted with unfractionated fresh muscle cells after lethal irradiation. Both animals died early after transplant without any evidence of haematopoietic reconstitution. In two other monkeys, harvested muscle cells were frozen and secondarily marked using a green fluorescent protein (GFP)-lentiviral vector. After sublethal irradiation, both animals were transplanted with GFP-expressing muscle cells followed by a bone marrow rescue. Both animals had haematopoietic reconstitution at days 22 and 25, but no GFP-expressing haematopoietic cells could be detected by flow cytometry, either in the blood or in clonogenic cells from marrow aspirates. Using PCR assays, GFP(+) cells were detected in a single marrow sample of one animal at 41 days after transplantation. These results strongly suggest that as opposed to murine muscle, the non-human primate skeletal muscle does not harbour cells with a straightforward haematopoietic potential.

p210(BCR-ABL) reprograms transformed and normal human megakaryocytic progenitor cells into erythroid cells and suppresses FLI-1 transcription.

The BCR-ABL oncoprotein exhibits deregulated protein tyrosine kinase activity and is implicated in the pathogenesis of Philadelphia chromosome (Ph)-positive human leukemias. Here, we report that ectopic expression of p210(BCR-ABL) in the megakaryoblastic Mo7e cell line and in primary human CD34(+) progenitors trigger erythroid differentiation at the expense of megakaryocyte (MK) differentiation. Clonal culture of purified CD41(+)CD42(-) cells, a population highly enriched in MK progenitors, combined with the conditional expression of p210(BCR-ABL) tyrosine kinase activity by imatinib identified a true lineage reprogramming. In both Mo7e or CD41(+)CD42(-) cells transduced with p210(BCR-ABL), lineage switching was associated with a downregulation of the friend leukemia Integration 1 (FLI-1) transcription factor. Re-expression of FLI-1 in p210(BCR-ABL)-transduced Mo7e cells rescued the megakaryoblastic phenotype. Altogether, these results demonstrate that alteration of signal transduction via p210(BCR-ABL) reprograms MK cells into erythroid cells by a downregulation of FLI-1. In addition, our findings underscore the role of kinases in lineage choice and infidelity in pathology and suggest that downregulation of FLI-1 may have important implications in CML pathogenesis.

Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies.

The leukemic stem cells in patients with chronic myeloid leukemia (CML) are well known to be clinically resistant to conventional chemotherapy and may also be relatively resistant to BCR-ABL-targeted drugs. Here we show that the lesser effect of imatinib mesylate (IM) on the 3-week output of cells produced in vitro from lin(-)CD34(+)CD38(-) CML (stem) cells compared with cultures initiated with the CD38(+) subset of lin(-)CD34(+) cells is markedly enhanced (>10-fold) when conditions of reduced growth factor stimulation are used. Quantitative analysis of genes expressed in these different CML subsets revealed a differentiation-associated decrease in IL-3 and G-CSF transcripts, a much more profound decrease in expression of BCR-ABL than predicted by changes in BCR expression, decreasing expression of ABCB1/MDR and ABCG2 and increasing expression of OCT1. p210(BCR-ABL) and kinase activity were also higher in the lin(-)CD34(+)CD38(-) cells and formal evidence that increasing BCR-ABL expression decreases IM sensitivity was obtained from experiments with a cell line model. Nevertheless, within the entire CD34(+) subset of CML cells, BCR-ABL expression was not strongly affected by changes in cell cycle status. Taken together, these results provide the first evidence of multiple mechanisms of innate IM resistance in primitive and quiescent CML cells.

Transient suppression of clonal hemopoiesis associated with pregnancy in a patient with a myeloproliferative disorder.

We have used restriction fragment length polymorphism analysis to study the clonal involvement of the blood cells in a woman with myeloproliferative disease, whose initially high platelet count (940,000/microliter) spontaneously decreased during a normal pregnancy but then returned rapidly to the same high level after delivery of her child. Analysis of her erythroid progenitors showed the presence of erythropoietin-independent progenitors before, during, and after her pregnancy, consistent with a diagnosis of myeloproliferative disease, and persistence of the abnormal clone throughout the period of study. Analysis of DNA from her blood granulocytes showed these to be polyclonal at mid-pregnancy, when her platelet count had decreased to normal values, in comparison to the monoclonal pattern exhibited by her blood granulocytes 3 mo postpartum, when her platelet count was again elevated. These results demonstrate a partial conversion to normal, polyclonal hemopoiesis during her pregnancy and suggest a previously unanticipated differential sensitivity of normal and neoplastic hemopoietic cells to physiological changes associated with this state.

Familial bone marrow monosomy 7. Evidence that the predisposing locus is not on the long arm of chromosome 7.

Loss of expression of a tumor-suppressing gene is an attractive model to explain the cytogenetic and epidemiologic features of cases of myelodysplasia and acute myelogenous leukemia (AML) associated with bone marrow monosomy 7 or partial deletion of the long arm (7q-). We used probes from within the breakpoint region on 7q-chromosomes (7q22-34) that detect restriction fragment length polymorphisms (RFLPs) to investigate three families in which two siblings developed myelodysplasia with monosomy 7. In the first family, probes from the proximal part of this region identified DNA derived from the same maternal chromosome in both leukemias. The RFLPs in these siblings diverged at the more distal J3.11 marker due to a mitotic recombination in one patient, a result that suggested a critical region on 7q proximal to probe J3.11. Detailed RFLP mapping of the implicated region was then performed in two additional unrelated pairs of affected siblings. In these families, DNA derived from different parental chromosome 7s was retained in the leukemic bone marrows of the siblings. We conclude that the familial predisposition to myelodysplasia is not located within a consistently deleted segment on the long arm of chromosome 7. These data provide evidence implicating multiple genetic events in the pathogenesis of myelodysplasia seen in association with bone marrow monosomy 7 or 7q-.

Generation of an induced pluripotent stem cell line from a patient with hereditary multiple endocrine neoplasia 2B (MEN2B) syndrome with "highest risk" RET mutation.

Multiple Endocrine Neoplasia Type 2B (MEN2B) is a cancer-predisposing syndrome that affects patients with germline RET mutations. The clinical spectrum of the syndrome includes medullary thyroid carcinoma (MTC) and pheochromocytoma. Currently, there is no satisfactory model recapitulating all the features of the disease especially at the level of stem cells. We generated induced pluripotent stem cells (iPSCs) from a patient with RET mutation at codon 918 who developed pheochromocytoma and MTC. These iPSC had normal karyotype, harboured the RETM918T mutation and expressed pluripotency hallmarks. A comprehensive pathological assessment of teratoma was performed after injection in immunodeficient mice.

Generation of an induced pluripotent stem cell line from a patient with chronic myeloid leukemia (CML) resistant to targeted therapies.

Chronic myeloid leukemia (CML) is a clonal malignancy initiated by the occurrence of a t (9;22) translocation, generating Ph1 chromosome and BCR-ABL oncogene in a primitive hematopoietic stem cell (HSC). The resistance of HSC to targeted therapies using tyrosine kinase inhibitors remains a major obstacle towards the cure. We have generated an iPSC line from a patient with CML using leukemic CD34+ cells cryopreserved at diagnosis. Ph1+ CML cells were reprogrammed by non-integrative viral transduction. These iPSCs harboured Ph1 chromosome and expressed pluripotency hallmarks as well as BCR-ABL. Teratoma assays revealed normal differentiation after injection in immunodeficient mice.

Generation of an induced pluripotent stem cell line from a patient with hereditary multiple endocrine neoplasia 2A (MEN2A) syndrome with RET mutation.

Multiple Endocrine Neoplasia Type 2A (MEN2A) is a cancer-predisposing syndrome that affects patients with germline RET mutations. The clinical spectrum of the syndrome includes medullary thyroid carcinoma (MTC), pheochromocytoma, hyperparathyroidism and cutaneous lichen amyloidosis (CLA) and/or Hirschsprung disease in some variants. Currently, there is no satisfactory animal model recapitulating all the features of the disease especially at the level of stem cells. We generated induced pluripotent stem cells (iPSCs) from a patient with RET mutation at codon 634 who developed pheochromocytoma and MTC. RETC634Y-mutated cells were reprogrammed by non-integrative viral transduction. These iPSCs had normal karyotype, harboured the RETC634Y mutation and expressed pluripotency hallmarks as well as RET. A comprehensive pathological assessment of teratoma was performed after injection in immunodeficient mice.

The leukaemic oncoproteins Bcr-Abl and Tel-Abl (ETV6/Abl) have altered substrate preferences and activate similar intracellular signalling pathways.

Inappropriate activation of Abl family kinases plays a crucial role in different human leukaemias. In addition to the well known oncoproteins p190Bcr-Abl and p210Bcr-Abl, Tel-Abl, a novel fusion protein resulting from a different chromosomal translocation, has recently been described. In this study, the kinase specificities of the Bcr-Abl and Tel-Abl proteins were compared to the physiological Abl family kinases c-Abl and Arg (abl related gene). Using short peptides which correspond to the target epitopes in known substrate proteins of Abl family kinases, we found a higher catalytic promiscuity of Bcr-Abl and Tel-Abl. Similar to Bcr-Abl, Tel-Abl was found in complexes with the adapter protein CRKL. In addition, c-Crk II and CRKL are tyrosine phosphorylated and complexed with numerous other tyrosine phosphorylated proteins in Tel-Abl expressing Ba/F3 cells. GTPase analysis with a Ras-GTP-specific precipitation assay showed constitutive elevation of GTP-loaded Ras in cells expressing the leukaemic Abl proteins. The mitogenic MAPK/Erk kinases as well as Akt/PKB, a kinase implicated to negatively regulate apoptosis, were also constitutively activated by both Bcr-Abl and Tel-Abl. The results indicate that the leukaemic Abl-fusion proteins have catalytic specificities different from the normal kinases c-Abl and Arg and that Tel-Abl is capable to activate at least some pathways which are also upregulated by Bcr-Abl.

BCR-ABL and constitutively active erythropoietin receptor (cEpoR) activate distinct mechanisms for growth factor-independence and inhibition of apoptosis in Ba/F3 cell line.

The interleukin-3 dependent murine Ba/F3 cell line has been widely used as an experimental model of cell transformation by BCR-ABL oncogenes as assessed by induction of growth-factor-independence and inhibition of apoptosis in vitro. The signaling pathways used by BCR-ABL oncogenes to exert these effects are unknown. To gain insights into this phenomenon, we have introduced the p190- and p210-encoding BCR-ABL oncogenes as well as the constitutively activated oncogenic murine erythropoietin receptor (cEpoR) into Ba/F3 and compared the behavior of individual clones in response to apoptotic stimuli. Both p210 and p190 BCR-ABL vectors induced IL-3-independent growth and the same result was obtained with the cEpo-R vector. Individual clones of Ba/F3 cells expressing BCR-ABL exhibited significant resistance to apoptosis induced by either etoposide, serum deprivation or growth-factor withdrawal. In contrast, Ba/F3 cells expressing the constitutively active cEpoR behaved like parental Ba/F3 cells undergoing apoptosis when similarly treated with etoposide or upon serum deprivation. Bc12 and Bax levels were similar in all BCR-ABL and cEpoR-transfected clones. However, in band-shift assays, nuclear extracts from growth-factor-independent Ba/F3 clones expressing cEpoR had no detectable STAT activity as opposed to the constitutive STAT activation detected in all Ba/F3 clones expressing p210 or p190 BCR-ABL. Our results indicate that although both constitutively activated cEpoR and BCR-ABL oncogenes induce growth-factor independence in Ba/F3 cells, only BCR-ABL is able to protect cells from etoposide and serum-deprivation-induced apoptosis and induce a strong constitutive activation of STAT factors, suggesting a role for these molecules in the anti-apoptotic activity of BCR-ABL.

Mutator phenotype of BCR--ABL transfected Ba/F3 cell lines and its association with enhanced expression of DNA polymerase beta.

Chronic myelogenous leukemia (CML) is characterized by the Philadelphia chromosome resulting from the translocation t(9-22) producing the chimeric 190 and 210 kDa BCR-ABL fusion proteins. Evolution of the CML to the more agressive acute myelogenous leukemia (AML) is accompanied by increased cellular proliferation and genomic instability at the cytogenetic level. We hypothezised that genomic instability at the nucleotide level and spontaneous error in DNA replication may also contribute to the evolution of CML to AML. Murine Ba/F3 cell line was transfected with the p190 and p210-encoding BCR-ABL oncogenes, and spontaneous mutation frequency at the Na-K-ATPase and the hypoxanthine guanine phosphoribosyl transferase (HPRT) loci were measured. A significant 3-5-fold increase in mutation frequency for the transfected cells relative to the untransfected control cells was found. Furthermore, we observed that BCR-ABL transfection induced an overexpression of DNA polymerase beta, the most inaccurate of the mammalian DNA polymerases, as well as an increase in its activity, suggesting that inaccuracy of DNA replication may account for the observed mutator phenotype. These data suggest that the Philadelphia abnormality confers a mutator phenotype and may have implications for the potential role of DNA polymerase beta in this process.