Erasmus clinical model of the onset and development of stuttering 2.0.

A clinical, evidence-based model to inform clients and their parents about the nature of stuttering is indispensable for the field. In this paper, we propose the Erasmus Clinical Model of Stuttering 2.0 for children who stutter and their parents, and adult clients. It provides an up-to-date, clinical model summary of current insights into the genetic, neurological, motoric, linguistic, sensory, temperamental, psychological and social factors (be it causal, eliciting, or maintaining) related to stuttering. First a review is presented of current insights in these factors, and of six scientific theories or models that have inspired the development of our current clinical model. Following this, we will propose the model, which has proven to be useful in clinical practice. The proposed Erasmus Clinical Model of Stuttering visualizes the onset and course of stuttering, and includes scales for stuttering severity and impact, to be completed by the (parent of) the person who stutters. The pathway of the model towards stuttering onset is based on predisposing and mediating factors. In most children with an onset of stuttering, stuttering is transient, but if stuttering continues, its severity and impact vary widely. The model includes the circle of Engel (1977), which visualizes unique interactions of relevant biological, psychological, and social factors that determine the speaker's experience of stuttering severity and its impact. Discussing these factors and their interaction with an individual client can feed into therapeutic targets. The model is supplemented by a lifeline casus.

Drug-Induced Stuttering: Occurrence and Possible Pathways.

Background: Stuttering is a well-known condition that affects mainly children. Often, they recover as they get older. However, a drug-induced form of stuttering may occur at any age. The aim of the present study was to detect drugs that have been associated with stuttering and discuss the mechanisms involved. Method: A descriptive study based on reports submitted to the global pharmacovigilance database VigiBase of the WHO was conducted. Results: A total of 3,385 reports of dysphemia were retrieved from VigiBase. These reports were contributed by 51 countries. Antiepileptics, antidepressants, immunosuppressants, antipsychotics, and centrally acting sympathomimetics were among the most frequently implicated drugs. Conclusion: A wide variety of drugs has been linked to the occurrence or recurrence of stuttering. Several mechanisms, such as increased dopamine levels, reduction of GABA, anticholinergic properties of drugs, or changes in serotonin levels, have been associated with the development of drug-induced stuttering. Paradoxically, agents known to reduce stuttering in some people may induce it in others.

Identification of primary MAFB target genes in multiple myeloma.

OBJECTIVE: In multiple myeloma (MM), seven primary recurrent translocations involving the immunoglobulin heavy chain locus have been identified. One of the partner loci maps to 20q12 and involves the MAFB gene resulting in its ectopic expression. We attempt here to identify MAFB target genes in MM. MATERIALS AND METHODS: We used an inducible system to upregulate MAFB in MM cell lines not carrying the t(14;20). Microarray expression analysis was used to detect gene expression changes upon MAFB expression. These genes were further evaluated comparatively with gene expression profiles obtained from MM or plasma cell leukemia tumors carrying an activated MAFB gene. Functional implications of these upregulated genes were studied by testing their promoter activity in reporter assays. C-MAF was included comparatively as well. RESULTS: The inducible cell lines identified a total of 284 modulated transcripts. After further evaluation using ex vivo data 14 common upregulated genes were found, common to the C-MAF pathway as well. The promoter activity of some of these secondary genes proved a functional relationship with MAFB. In connection with one of these secondary genes (NOTCH2), even tertiary upregulated genes were found. Functional studies indicated that inducible MAFB expression conferred antiapoptotic effects. CONCLUSION: We identified 14 upregulated genes, and their downstream consequences in the combined MAFB/C-MAF pathway. Eleven of these genes are novel in the C-MAF pathway as well. These direct target genes may be responsible for the oncogenic transformation of MAF expressing myeloma cells.

The recurrent translocation t(14;20)(q32;q12) in multiple myeloma results in aberrant expression of MAFB: a molecular and genetic analysis of the chromosomal breakpoint.

Chromosomal translocations of the immunoglobulin heavy chain (IgH) gene region at 14q32 are regularly involved in B lymphoid malignancies; they may initiate transformation either by deregulation of existing (proto) oncogenes or creation of new hybrid genes with transforming properties. Previously, we reported a reciprocal novel translocation, t(14;20)(q32;q12), found in the myeloma cell line UM3. In this cell line, the t(14;20) is the only translocation involving the IgH locus. Using double colour immunofluorescence in situ hybridization, the t(14;20) was also found in the diagnostic bone marrow sample, excluding a possible in vitro artefact. We also have found this recurrent t(14;20) in four other cell lines and in additional patient material. We cloned the regions containing the breakpoints in the der(14) and der(20) chromosomes from UM3, and analysed ectopic mRNA expression of genes in the breakpoint regions of both derivative chromosomes. Ectopic gene expression was observed for the transcription factor MAFB in der(14). The breakpoint scatter in the five cell lines with a t(14;20)--all expressing MAFB--is comprised within a region of 0.8 Mb. Provisional data indicate that this t(14;20) is associated with an adverse prognosis. Aberrant expression of MAFB may be involved in the oncogenic transformation of myeloma cells that harbour the t(14;20).

IgE to Bet v 1 and profilin: cross-reactivity patterns and clinical relevance.

BACKGROUND: Individuals with pollen allergy often have IgE against plant-derived foods. This can be due to cross-reactive IgE against Bet v 1 and homologues, profilins, and/or cross-reactive carbohydrate determinants. OBJECTIVE: The aim of this study was to correlate sensitization to Bet v 1 and profilin with individual recognition patterns to plant foods and clinical relevance. METHODS: Fifty-two patients with pollen allergy and IgE against at least one plant-derived food were included in the study. Adverse reactions to plant-derived foods were documented by using standardized interviews. Skin prick tests were performed for pollen (grass, birch, and mugwort) and 14 plant-derived foods. In addition, recombinant (r) Bet v 1 and rBet v 2 (profilin) were tested intracutaneously. Specific IgE against the abovementioned allergens were determined by means of RAST. Cross-reactivity was studied by means of RAST inhibition. RESULTS: Eighty-five percent of patients were sensitized to Bet v 1, and 71% were sensitized to profilin. Profilin was associated with a higher number of positive RAST results to plant-derived foods than Bet v 1. In contrast, Bet v 1 was associated with more positive skin prick test responses and more food-related symptoms. Sensitization to Bet v 1 was associated with IgE against apple, hazelnut, and peach, whereas sensitization to profilin was associated with positive RAST results to all investigated plant-derived foods except apple, peach, and melon. CONCLUSIONS: IgE antibodies against Bet v 1 have a more limited spectrum of cross-reactivity than those against profilin, but they frequently give rise to clinically relevant cross-reactivities to food. In analogy to anticarbohydrate IgE, cross-reactive IgE against food profilins have no or very limited clinical relevance.

Production of bispecific antibodies.

Bispecific antibodies (bsAbs) contain two different binding specificities within a single molecule and can specifically bind two different molecules together. BsAbs can be produced by chemically cross-linking purified antibodies or Fab fragments with reducible disulfide bonds or nonreducible thioether bonds, both of which are described in this unit. Protocols are also presented for producing BsAbs by fusing two antibody-producing hybridomas that can be selected for based on drug resistance, or by double labeling with fluorochromes and FACS. Support protocols describe screening and purification of bsAbs.