Positive behavior support (PBS) with children with fetal alcohol spectrum disorders: Characterizing caregivers' use of PBS using follow-up clinical trial data.

BACKGROUND: Fetal alcohol spectrum disorders (FASD) are associated with neurodevelopmental challenges leading to difficulties with everyday life tasks. The Families Moving Forward (FMF) Program teaches caregivers to use positive behavior support (PBS), integrated with other techniques. However, it is unknown how caregivers retain and use these PBS strategies after the intervention. METHODS: About 4.5 months after completing the FMF Program, twenty-three caregivers of children with FASD aged 4-12 were interviewed about problem behaviors targeted during the FMF Program and their continued use of PBS strategies. Interviews were recorded and coded thematically by a five-coder team. Higher-level pattern codes were developed to facilitate themes across descriptive codes. RESULTS: Caregivers commonly targeted task incompletion and rule breaking, and problem behaviors were often complex or combined. Caregivers identified environmental and interpersonal triggers for problem behavior. They used many accommodations to prevent problem behaviors, most often related to task or environment simplification. Caregivers also used consequence-based strategies. CONCLUSIONS: This study is the first to characterize caregivers' use of PBS strategies for children with FASD using mixed methods. Problem behaviors such as rule breaking were more difficult to target. Caregivers found most success when using a combination of multiple different accommodations per problem behavior. WHAT THIS PAPER ADDS: This is the first study to use mixed methods to characterize how caregivers of children with fetal alcohol spectrum disorders (FASD) use positive behavior support (PBS) strategies to target problem behavior after completion of the empirically validated Families Moving Forward (FMF) Program. Among other techniques involved in the FMF Program, PBS strategies are taught to caregivers and are used to target two distinct, caregiver-identified problem behaviors. This data provides essential information about behaviors responsive to PBS supports, for children with FASD, to inform clinical intervention and research. Notably, multiple problem behaviors often occurred together, emphasizing complexity of behavior challenges in this population and the resulting need for individualized supports. This study is the first to describe commonly observed triggers (antecedents) and commonly used supports (accommodations) from the perspective of caregivers of children with FASD. Importantly, results indicate that use of a wide variety of accommodations, or antecedent-based strategies, are effective in supporting behavior in children with FASD. However, success was most common when caregivers used multiple accommodations for any given concerning behavior. Findings represent 'real-world' strategies caregivers use to support adaptive behavior in their children several months after completion of the FMF Program, suggesting these strategies are applicable to clinical practice.

One for all or all for one? An integrative review of research on frequent callers.

Objective: Telephone health services is an increasing and integral part of health care in several countries. Callers who call repeatedly, in the current study "frequent callers" are present in all kinds of healthcare services, often constitute a considerable proportion of the total amount of calls and are complicated to help. The aim was to provide a comprehensive overview of research on frequent callers at a variety of telephone health services. Methods: An integrative literature review. Literature was searched for the period 2011-2020 in CINAHL Plus, MEDLINE, APA PsycArticles, APA PsycInfo, and PubMed, and resulted in the inclusion of 20 articles. Results: Studies on frequent callers (FCs) were found in the context of emergency medical services, telephone helplines, primary healthcare, and specialist medicine clinics. Frequent calling was associated with psychiatric comorbidity, and the reasons for calling were often multifaceted. Conclusion: The strategies suggested for handling calls involved an individual approach, which could be enabled through multidisciplinary work. Innovation: The main findings indicate a need for a systematic approach and guidelines to enable optimal help for FCs. Cooperation among healthcare instances seems to contribute to a more individual care for FCs.

Bi-allelic variants in DNA mismatch repair proteins MutS Homolog MSH4 and MSH5 cause infertility in both sexes.

STUDY QUESTION: Do bi-allelic variants in the genes encoding the MSH4/MSH5 heterodimer cause male infertility? SUMMARY ANSWER: We detected biallelic, (likely) pathogenic variants in MSH5 (4 men) and MSH4 (3 men) in six azoospermic men, demonstrating that genetic variants in these genes are a relevant cause of male infertility. WHAT IS KNOWN ALREADY: MSH4 and MSH5 form a heterodimer, which is required for prophase of meiosis I. One variant in MSH5 and two variants in MSH4 have been described as causal for premature ovarian insufficiency (POI) in a total of five women, resulting in infertility. Recently, pathogenic variants in MSH4 have been reported in infertile men. So far, no pathogenic variants in MSH5 had been described in males. STUDY DESIGN, SIZE, DURATION: We utilized exome data from 1305 men included in the Male Reproductive Genomics (MERGE) study, including 90 males with meiotic arrest (MeiA). Independently, exome sequencing was performed in a man with MeiA from a large consanguineous family. PARTICIPANTS/MATERIALS, SETTING, METHODS: Assuming an autosomal-recessive mode of inheritance, we screened the exome data for rare, biallelic coding variants in MSH4 and MSH5. If possible, segregation analysis in the patients' families was performed. The functional consequences of identified loss-of-function (LoF) variants in MSH5 were studied using heterologous expression of the MSH5 protein in HEK293T cells. The point of arrest during meiosis was determined by γH2AX staining. MAIN RESULTS AND THE ROLE OF CHANCE: We report for the first time (likely) pathogenic, homozygous variants in MSH5 causing infertility in 2 out of 90 men with MeiA and overall in 4 out of 902 azoospermic men. Additionally, we detected biallelic variants in MSH4 in two men with MeiA and in the sister of one proband with POI. γH2AX staining revealed an arrest in early prophase of meiosis I in individuals with pathogenic MSH4 or MSH5 variants. Heterologous in vitro expression of the detected LoF variants in MSH5 showed that the variant p.(Ala620GlnTer9) resulted in MSH5 protein truncation and the variant p.(Ser26GlnfsTer42) resulted in a complete loss of MSH5. LARGE SCALE DATA: All variants have been submitted to ClinVar (SCV001468891-SCV001468896 and SCV001591030) and can also be accessed in the Male Fertility Gene Atlas (MFGA). LIMITATIONS, REASONS FOR CAUTION: By selecting for variants in MSH4 and MSH5, we were able to determine the cause of infertility in six men and one woman, leaving most of the examined individuals without a causal diagnosis. WIDER IMPLICATIONS OF THE FINDINGS: Our findings have diagnostic value by increasing the number of genes associated with non-obstructive azoospermia with high clinical validity. The analysis of such genes has prognostic consequences for assessing whether men with azoospermia would benefit from a testicular biopsy. We also provide further evidence that MeiA in men and POI in women share the same genetic causes. STUDY FUNDING/COMPETING INTEREST(S): This study was carried out within the frame of the German Research Foundation sponsored Clinical Research Unit 'Male Germ Cells: from Genes to Function' (DFG, CRU326), and supported by institutional funding of the Research Institute Amsterdam Reproduction and Development and funds from the LucaBella Foundation. The authors declare no conflict of interest.

Towards an evidence-based process for the clinical interpretation of copy number variation.

The evidence-based review (EBR) process has been widely used to develop standards for medical decision-making and to explore complex clinical questions. This approach can be applied to genetic tests, such as chromosomal microarrays, in order to assist in the clinical interpretation of certain copy number variants (CNVs), particularly those that are rare, and guide array design for optimal clinical utility. To address these issues, the International Standards for Cytogenomic Arrays Consortium has established an EBR Work Group charged with building a framework to systematically assess the potential clinical relevance of CNVs throughout the genome. This group has developed a rating system enumerating the evidence supporting or refuting dosage sensitivity for individual genes and regions that considers the following criteria: number of causative mutations reported; patterns of inheritance; consistency of phenotype; evidence from large-scale case-control studies; mutational mechanisms; data from public genome variation databases; and expert consensus opinion. The system is designed to be dynamic in nature, with regions being reevaluated periodically to incorporate emerging evidence. The evidence collected will be displayed within a publically available database, and can be used in part to inform clinical laboratory CNV interpretations as well as to guide array design.

Novel PHEX nonsense mutation in a patient with X-linked hypophosphatemic rickets and review of current therapeutic regimens.

INTRODUCTION: The most common form of familial hypophosphatemic rickets is X-linked. PHEX has been identified as the gene defective in this phosphate wasting disorder leading to decreased renal phosphate reabsorption, hypophosphatemia and inappropriate concentrations of 1,25-dihydroxyvitamin D in regard to hypophosphatemia. Clinical manifestation are skeletal deformities, short stature, osteomalacia, dental abscesses, bone pain, and loss of hearing. SUBJECTS AND METHODS: We report 3 cases of hypophosphatemic rickets with genetic mutational analysis of the PHEX gene. In 1 male patient an unknown nonsense mutation was found in exon 7, codon 245 (c.735T>G, Tyr245Term, Y245X). In both female patients known mutations were found: c.682delTC (exon 6, codon 228) and c.1952G>C (exon 19, codon 651, R651P). Age at diagnosis ranged from early childhood to the age of 35 years. Clinical complications were hip replacement in 1 patient, mild nephrocalcinosis in 2 patients and loss of hearing in 1 patient. All 3 patients have been treated with phosphate supplements and receive 1,25-dihydroxyvitamin D. Under this regimen all patients show stable biochemical markers with slight hyperparathyreoidism. In all patients at least one family member is affected by rickets, as well. CONCLUSIONS: We report a novel nonsense mutation of PHEX that has not been identified so far. The recent discovery of FGF23 and MEPE has changed our understanding of the kidney-bone metabolism, but also raises concerns about the efficacy of current therapeutic regimens that are reviewed in this context.

A new mutation in the menin gene causes the multiple endocrine neoplasia type 1 syndrome with adrenocortical carcinoma.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor syndrome that may be caused by mutations in the MEN1 gene on 11q13. Loss of function of the tumor suppressor gene MEN1 leads to synchronous or metachronous appearance of neuroendocrine tumors arising from neuroendocrine cells of the parathyroid and pituitary glands, the duodenum and pancreatic islets, and other endocrine organs such as the adrenal cortex. We here present a patient with MEN1 who developed hyperparathyroidism, multiple well differentiated functionally inactive neuroendocrine tumors of the pancreas and an adrenal carcinoma. We describe a new mutation at codon 443 in the coding region of exon 9 in the MEN1 gene, where a cytosine residue was exchanged for adenosine (TCC > TAC) and, consequently, serine for tyrosine (p.Ser443Tyr; c.1328C > A). [corrected] Also, we provide clinical data that may add to the genotype-phenotype discussion. We conclude that the novel mutation in the MEN1 gene described herein was clinically relevant.

U-type exchange is the most frequent mechanism for inverted duplication with terminal deletion rearrangements.

BACKGROUND: Chromosomal rearrangements resulting in an interstitial inverted duplication with concomitant terminal deletion were first described for the short arm of chromosome 8 in 1976. Since then, this type of alteration has been identified and characterised for most chromosome arms. Three mechanisms are commonly proposed to explain the origin of this type of rearrangement. All three mechanisms involve formation of a dicentric chromosome that then breaks in a subsequent meiotic division to produce a monocentric duplicated and deleted chromosome. However, the events leading to the formation of the dicentric chromosome differ between the mechanisms. In one mechanism, either parent carries a paracentric inversion. This results in formation of a loop during meiotic pairing with a recombination event occurring in the loop. In the second mechanism, inverted low copy repeats in the same chromosome arm allow partial folding of one homologue onto itself with a recombination event between the inverted repeats. The third mechanism involves a pre-meiotic double-strand break with subsequent fusion, or U-type exchange, between the sister chromatids. The first two mechanisms require a single copy region to exist between the duplicated and deleted regions on the derivative chromosome, and therefore high resolution analysis of the rearrangement can be used to distinguish between these mechanisms. METHODS AND RESULTS: Using G-banded chromosome analysis, fluorescence in situ hybridisation (FISH) and array comparative genomic hybridisation (CGH), we describe 17 new cases of inverted duplication with terminal deletion of 2q, 4p, 5p, 6q, 8p, 9p, 10q, 13q, 15q, 18p, 18q, and 22q. CONCLUSIONS: These new cases, combined with previously described cases, demonstrate that U-type exchange is the most frequent mechanism for this rearrangement and can be observed on most, or perhaps all, chromosome arms.

[Multiple endocrine neoplasia 2a: late manifestation of a newly-discovered mutation]. / Multiple Endokrine Neoplasie 2a: Spätmanifestation bei neuer Mutation.

HISTORY: A 55-year-old patient presented with a painless right-sided cervical swelling, which had been present for four months and seemed to get larger. The patient denied dyspnea, dysphagia, "a lump in the throat" or thyroid disease. Two of his paternal aunts had thyroid carcinoma and an adrenal tumor. INVESTIGATIONS: Ultrasonography revealed an enlarged lymphoid nodule and a large lesion in the right thyroid lobe, the latter with deficient technetium uptake on scintigraphy. THERAPY AND COURSE: A total thyroidectomy with bilateral centrocervical and lateral neck dissection was performed. Histology revealed a bilateral medullary thyroid carcinoma [MTC: pT3, pN1b (9/34), pM0 (UICC 2002)] and the genetic screening showed a double mutation in codon 611 (TGC>TAT; p.Cys611Tyr; C611Y), and exon 10 of the RET proto-oncogene, which has not been described before. Pheochromocytoma and hyperparathyroidism were excluded. Genetic screening of all close family members was initiated and showed that four of them were gene carriers. Three of them have been operated and a MTC found. CONCLUSION: The described newly discovered mutation is associated with MTC and pheochromocytoma. This case underlines the need of genetic screening in all patients who present with a MTC only, no matter what the person's age of manifestation, even in the absence of any other MEN-related disease.

Induction of mRNA for tumor necrosis factor-alpha and interleukin-1 beta in mice brain, spleen and liver in an animal model of Shigella-related seizures.

BACKGROUND: The pathogenesis of neurological symptoms, the most common extraintestinal complication of childhood shigellosis, is unclear. To elucidate the mechanisms involved, we developed an animal model and demonstrated that TNF alpha and IL-1 beta play a role. OBJECTIVES: To determine whether TNF alpha and IL-1 beta genes are expressed in the brain following peripheral administration of Shigella dysenteriae 60R. METHODS: Expression of mRNA for TNF alpha and IL-1 beta was examined in the brain structures (hypothalamus and hippocampus) and peripheral organs by reverse transcriptase polymerase chain reaction, at different time points after intraperitoneal injection of S. dysenteriae sonicate. RESULTS: In our animal model of Shigella-related seizures, TNF alpha and IL-1 beta mRNA were induced in the brain, spleen and liver already 1 hour after injection of S. dysenteriae sonicate. The expression of TNF alpha and IL-1 beta mRNA in spleen, hippocampus and hypothalamus decreased after 6 h and increased again at 18 h post-injection. CONCLUSIONS: Local production of TNF alpha and IL-1 beta in the brain may be involved in the enhanced seizure response of mice after administration of S. dysenteriae. It is possible that intracerebral production of TNF alpha and IL-1 beta plays a role in neurological disturbances of human shigellosis.

Role of nitric oxide in the enhancement of pentylenetetrazole-induced seizures caused by Shigella dysenteriae.

Convulsions and encephalopathy are frequent complications of childhood shigellosis. We studied the role of nitric oxide (NO) in Shigella-related seizures in an animal model. Pretreatment of mice with Shigella dysenteriae 60R sonicate elevated serum NO levels and enhanced the convulsive response to pentylenetetrazole (PTZ), as indicated by a higher mean convulsion score and a higher number of mice responding with seizures. Treatment of the mice with S-methylisothiourea sulfate (SMT), a potent inhibitor of inducible NO synthase (NOS), prevented the elevation of serum NO levels and concomitantly reduced the enhanced response to PTZ. The mean convulsion scores were 0.7, 0.7, 1.3, and 0.8 for mice treated with saline, saline and SMT, S. dysenteriae 60R sonicate, and S. dysenteriae 60R sonicate with SMT, respectively (P = 0.001 for 60R sonicate versus saline and P = 0.013 for 60R sonicate versus 60R sonicate with SMT). The corresponding seizure rates were 40, 44, 75, and 47% for saline, saline with SMT, S. dysenteriae 60R sonicate, and S. dysenteriae 60R sonicate with SMT, respectively (P = 0.0004 for 60R sonicate versus saline and P = 0.005 for 60R sonicate versus 60R sonicate with SMT). In contrast, injection of N-nitro-L-arginine, a selective inhibitor of constitutive NOS, neither abolished the elevation of serum NO nor attenuated the enhancement of seizures. These findings indicate that NO, induced by S. dysenteriae 60R sonicate, is involved in enhancing the susceptibility to seizures caused by S. dysenteriae.

Involvement of tumor necrosis factor alpha and interleukin-1beta in enhancement of pentylenetetrazole-induced seizures caused by Shigella dysenteriae.

Neurologic manifestations, mainly convulsions, are the most frequent extraintestinal complications of shigellosis. We used an animal model to study the roles of tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) in Shigella-related seizures. Administration of Shigella dysenteriae 60R sonicate enhanced the sensitivity of mice to the proconvulsant pentylenetetrazole (PTZ) within 7 h. This was indicated by a significantly higher mean convulsion score and an increased number of mice responding with clonic-tonic seizures in the Shigella-pretreated group. Preinjection of mice with anti-murine TNF-alpha (anti-mTNF-alpha) or anti-murine IL-1beta (anti-mIL-1beta) 30 min prior to administration of Shigella sonicate abolished their enhanced response to PTZ at 7 h. Mean convulsion scores were reduced by anti-mTNF-alpha from 1.2 to 0.8 (P = 0.017) and by anti-mIL-1beta from 1.3 to 0.7 (P = 0.008). Preinjection of anti-mTNF-alpha also reduced the percentage of mice responding with clonic-tonic seizures, from 48 to 29% (P = 0.002), and preinjection of anti-mIL-1beta reduced it from 53 to 21% (P = 0. 012). Neutralization of TNF-alpha or IL-1beta did not protect the mice from death due to S. dysenteriae 60R. These findings indicate that TNF-alpha and IL-1beta play a role in the very early sensitization of the central nervous system to convulsive activity after S. dysenteriae administration. Similar mechanisms may trigger neurologic disturbances in other infectious diseases.

Induction of tumor necrosis factor and nitric oxide by Shigella strains isolated from patients with or without neurologic manifestations.

The pathogenesis of the Shigella-associated neurological symptoms is unclear. We examined the potential role of host factors. Sonicates of Shigella strains isolated from children with and without neurologic disturbances were compared regarding their ability to induce tumor necrosis factor (TNF) and nitric oxide (NO) in vitro, in mouse macrophage J744 cell line. The mean concentrations of TNF (14.6 vs. 4.4 ng/ml) and NO (7.4 vs. 3.7 microM) induced were higher in response to strains isolated from children with neurologic complications; the differences were not statistically significant. TNF was also measured in plasma of children with shigellosis, and was found to be elevated in all patients. The mean concentration of TNF in plasma of children with neurologic manifestations was higher than that of children with no neurologic symptoms (450 vs. 138 pg/ml, P <0.05). It is concluded that TNF and NO may play a role in the development of neurologic manifestations of shigellosis.

Induction of nitric oxide production in mouse macrophages by Shiga toxin.

Host mediators play an important role in the pathogenesis of shigellosis and Shiga toxin toxicity. Nitric oxide (NO) production in mouse peritoneal macrophages and in the macrophage J744 cell line in response to purified Shiga toxin and lipopolysaccharide (LPS) from Shigella flexneri were studied. Shiga toxin induced NO production in a dose-dependent manner up to 800 ng/ml. Detectable levels of NO were present as early as 4 h after induction and continued to increase during 72 h; Shiga toxin induced greater NO production with time than did LPS. Pre-treatment of Shiga toxin (400 ng/ml) or LPS (10 ng/ml) with polymyxin B, which inactivates LPS, reduced their ability to induce NO by 28% and 96%, respectively. Induction in the presence of anti-TNF alpha antibodies did not reduce the amount of NO in the supernate. These studies showed that Shiga toxin induces NO production in murine macrophages.

The immunosuppressive human placental ferritin subunit p43 is produced by activated CD4+ lymphocytes.

Human placental ferritin is an immunosuppressive protein composed of a 43-kDa subunit (p43) and ferritin light chains. Its physiological action seems to be downregulation of the immune response of the mother against her embryo. Elevated levels of p43 in serum are associated with pregnancy, lymphomas, breast cancer, and AIDS. Although it is known that p43 is produced by activated T lymphocytes, the specific T-lymphocyte subset involved is unknown. p43 is measured by enzyme-linked immunosorbent assays with CM-H-9 monoclonal antibody specific for p43. We studied the de novo biosynthesis of p43 by isolated activated CD4+ and CD8+ T lymphocytes in a normal donor and in a patient with elevated levels of p43 in serum. The results indicated that p43 was synthesized by activated CD4+ lymphocytes from the normal donor (0.45% of the total de novo proteins) but that its biosynthesis by CD8+ lymphocytes was below the level of detection. The activated CD4+ lymphocytes from the patient with elevated levels of p43 in serum overproduced p43 (3.8% of the nascent proteins). Since it was shown that a subset of CD8+ lymphocytes has receptors for p43, the latter may be considered an immunoregulatory cytokine produced mainly by activated CD4+ lymphocytes.

The effect of shiga toxin and sonicates of Shigella isolates from children with neurologic manifestation on neuroblastoma cell lines.

Although neurologic manifestations are frequent during childhood shigellosis, their pathogenesis is unclear and controversial. Shiga toxin and other cytotoxins are often implicated, but their effect on neuronal cells has not been determined. We examined the effect of purified Shiga toxin and sonicates of Shigella isolates from children with neurologic symptoms on well-characterized human neuroblastoma cells in vitro. Quantitative determinations showed high cytotoxicity of Shiga toxin on HeLa cells (1.2 x 10(6) CD50/mg purified toxin), but no effect on LA-N-1, LA-N-5 and IMR neuroblastoma cell lines. Pretreatment with tumor necrosis factor, which increases expression of the Shiga toxin receptor, globotriosyl ceramide, in endothelial cells and enhanced Shiga toxin cytotoxicity, did not affect the susceptibility of neuroblastoma cells to the toxin. Low dilutions (up to 1:16-1:64) of sonicates of Shigella isolates from children with neurologic symptoms caused agglutination of neuroblastoma cells, but no cell killing was observed morphologically. This study shows that Shiga toxin does not exhibit cytotoxic activity on the human neuroblastoma cell lines examined, neither do sonicates of relevant Shigella strains. The mechanism and significance of the agglutination activity on neuroblastoma cells should be further studied.

Mosaicism in 45,X Turner syndrome: does survival in early pregnancy depend on the presence of two sex chromosomes?

Cytogenetic and molecular genetic findings in 91 patients with Turner syndrome are reported. In 87 patients, chromosome studies were carried out both in lymphocyte and fibroblast cultures. Mosaicism was demonstrated in 58 of these patients (66.7%), whereas only 18 (20.7%) were apparent non-mosaic 45,X, and 11 patients (12.6%) showed non-mosaic structural aberrations of the X chromosome. Among the mosaic cases 16 (18.4% of all patients) displayed a second cell line containing small marker chromosomes. The association of Y-specific chromosomal material with the presence of marker chromosomes was demonstrated in 6 out of 7 mixoploid fibroblast cell lines by polymerase chain reaction amplification and by Southern-blot analysis. The observation of ring formation and morphological variability in vivo and in vitro, and the continuous reduction in the percentage of cells containing marker chromosomes in longterm cultivation experiments indicated an increased instability of marker chromosomes. The findings suggest that in vivo selection of structurally altered sex chromosomes exists. Thus, the observation of apparent non-mosaic 45,X chromosomal complements in liveborn individuals with Turner syndrome does not contradict the hypothesis that some degree of mosaicism is necessary for survival in early pregnancy.