Efficacy of rational-emotive therapy: A quantitative analysis.

Meta-analysis of 28 controlled studies on the efficacy of rational-emotive therapy (RET) showed RET to be superior to placebo and no treatment but equally effective in comparison with other types of treatment such as combination therapies and systematic desensitization. No support was found for the view that RET with a main or balanced emphasis on behavioral techniques is more efficacious than RET with a primarily or exclusively cognitive approach. However, given the heterogeneity of the set of studies and its relatively small sample size, interpretations of results have to be made with caution, particularly because evidence was found for a relationship between study characteristics and magnitude of effect size. For the sake of meta-analysis, outcome studies should be required to report at least the means and standard deviations for all experimental groups. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Constructivism and rational-emotive therapy: A critique.

Comments on the work of M. J. Mahoney and T. J. Gabriel (see record 1989-12682-001) by (1) addressing the claim that rational-emotive therapy (RET) is rationalistic, (2) examining the technical language of A. Ellis's (published 1962–1989) RET and A. T. Beck's (1976) cognitive therapy as a source of confusion about their epistemology, and (3) proposing a view of the constructivistic vs rationalistic dichotomy as an attempt to discriminate a humanistic orientation in counseling and psychotherapy from one that seems more scientific in its aims and methods. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Signal transduction pathways activated by RET oncoproteins in PC12 pheochromocytoma cells

Gene alterations in the ret proto-oncogene, which encodes a receptor tyrosine kinase, have been found to associate with several human diseases. In this study, we showed that induction of the vgf promoter activity is a good molecular indicator for RET activation in PC12 cells, a rat pheochromocytoma cell line. We demonstrated that all forms of RET oncoprotein, including RET chimeric oncoproteins found in human papillary thyroid carcinomas (RET/PTC) as well as RET oncoproteins found in patients with multiple endocrine neoplasia type 2A and 2B (2A/RET and 2B/RET) can induce vgf promoter activity in PC12 cells. In contrast, a RET mutant found in a patient with Hirschsprung's disease, as well as a RET/PTC1 mutant with deletion of the dimerization domain, failed to induce vgf promoter activity in PC12 cells. We further determined that the signaling events mediated by phosphorylated Tyr294 and phosphorylated Tyr451 binding sites are essential for RET/PTC1 to induce vgf promoter activity in PC12 cells. We also showed that RET/PTC1, 2A/RET, and 2B/RET induce ELK-, cAMP-responsive element binding protein (CREB), or JUN-mediated gene expression in PC12 cells, and these three signaling events are mediated by phosphorylated Tyr294 and phosphorylated Tyr451 binding sites in RET/PTC1.     

Mutation of the RET proto-oncogene is correlated with RET immunostaining in subpopulations of cells in sporadic medullary thyroid carcinoma

Mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, are associated with the pathogenesis of medullary thyroid carcinoma (MTC). Somatic mutations in RET, predominantly at codon 918, and very rarely at codon 883, have been found in a proportion of sporadic MTC. We have previously shown that approximately 80% of sporadic MTCs had at least one subpopulation with a somatic RET mutation. Uneven distribution of somatic mutation within a single tumor or among metastases from a single individual was notable. In the present study, we sought to correlate RET expression, as demonstrated by RET immunohistochemistry, with mutation status in sporadic MTC for each tumor. Seventy evaluable subpopulations, belonging to 28 unrelated sporadic cases, comprising primary MTC and metastases, were immunostained with two different polyclonal antibodies raised against the C-terminus of RET. The regional presence of codon 918 or 883 seemed to coincide with increased RET immunopositivity in at least 62 of 70 (89%, P < 0.000001) tumor subpopulations. The reasons for this concordance are not entirely clear but could be related to either RNA or protein stability. Preliminary studies have suggested that the presence of somatic codon 918 mutation in MTC has a prognostic significance. If these preliminary results prove true, then given our data, we can further explore the feasibility of RET immunocytochemistry as a rapid assessment for the presence of somatic codon 918 for molecular diagnostic and prognostic purposes.     

Distinct multiple RET/PTC gene rearrangements in multifocal papillary thyroid neoplasia

Rearrangements involving the RET protooncogene have been implicated in the development of papillary thyroid carcinoma (PC). Transgenic mice, expressing thyroid-targeted RET/PTC-1, develop PC; but the clinical significance of this oncogene remains uncertain. We examined the expression of RET/PTC-1, -2, and -3 in human thyroid microcarcinomas and clinically evident PC to determine its role in early stage vs. developed PC and to examine the diversity of RET/PTC in multifocal disease. RNA was extracted from paraffin-embedded microcarcinomas and clinically evident PCs; the results obtained from paraffin-embedded tissue were confirmed on RNA from corresponding snap-frozen tissue of clinically evident PCs. RT and PCR was performed using primers for RET/PTC-1, -2, and -3; PGK-1 (the housekeeping gene) analysis was used to ensure integrity of the RNA and efficiency of the RT reaction. PCR products were resolved by gel electrophoresis, and Southern hybridization was performed with RET/PTC-1, -2, and -3 probes. A polyclonal antibody to the carboxyterminus of RET was used for immunohistochemistry on paraffin sections. Thirty-nine occult papillary thyroid microcarcinomas from 21 patients were analyzed. Of the 30 tumors (77%) positive for RET/PTC rearrangements, 12 were positive for RET/PTC-1, 3 for RET/ PTC-2, 6 for RET/PTC-3, and 9 for multiple RET/PTC oncogenes. In clinically evident tumors, 47% had RET/PTC rearrangements. Immunohistochemistry demonstrated close correlation with RT-PCR-derived findings. RET/PTC expression is highly prevalent in microcarcinoma and occurs more frequently than in clinically evident PC (P < 0.005). Multifocal disease, identified in 17 of the 21 patients, exhibited identical RET/PTC rearrangements within multiple tumors in only 2 patients; the other 15 patients had diverse rearrangements in individual tumors. Our results indicate that RET/PTC oncogene rearrangements may play a role in early-stage papillary thyroid carcinogenesis, but they seem to be less important in determining progression to clinically-evident disease. In multifocal disease, the diversity of RET/PTC profiles, in the majority of cases, suggests that individual tumors arise independently in a background of genetic or environmental susceptibility.     

A guide to interpreting discordant systematic reviews

Systematic reviews are becoming prominent tools to guide health care decisions. As the number of published systematic reviews increases, it is common to find more than 1 systematic review addressing the same or a very similar therapeutic question. Despite the promise for systematic reviews to resolve conflicting results of primary studies, conflicts among reviews are now emerging. Such conflicts produce difficulties for decision-makers (including clinicians, policy-makers, researchers and patients) who rely on these reviews to help them make choices among alternative interventions when experts and the results of trials disagree. The authors provide an adjunct decision tool--a decision algorithm--to help decision-makers select from among discordant reviews.     

The relevance of Freud's psychoanalysis in the 21st century: Its science and its research.

The relevance of psychoanalysis and its place within its intellectual and cultural surround has been a major issue over the whole of its now more than a century-long history. A very significant aspect of that concern has been the status of psychoanalysis as a theory of the mind, and as a basis for the application of that theory in the conduct of a therapy for the disorders of the mind. This article reviews in depth the long-standing debate about psychoanalysis as a scientific theory, the kind of science that psychoanalysis is--or can be--and the place of research, empirical as well as conceptual (with particular focus upon research into the nature of the therapeutic change process and its desired outcomes), in the incremental growth of that theory and its therapeutic applications in an ever expanding and increasingly secure knowledge base. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Various mechanisms cause RET-mediated signaling defects in Hirschsprung's disease

Hirschsprung's disease (HSCR) is a common congenital malformation characterized by the absence of intramural ganglion cells of the hindgut. Recently, mutations of the RET tyrosine kinase receptor have been identified in 50 and 15-20% of familial and sporadic HSCR, respectively. These mutations include deletion, insertion, frameshift, nonsense, and missense mutations dispersed throughout the RET coding sequence. To investigate their effects on RET function, seven HSCR missense mutations were introduced into either a 1114-amino acid wild-type RET isoform (RET51) or a constitutively activated form of RET51 (RET-MEN 2A). Here, we report that one mutation affecting the extracytoplasmic cadherin domain (R231H) and two mutations located in the tyrosine kinase domain (K907E, E921K) impaired the biological activity of RET-MEN 2A when tested in Rat1 fibroblasts and pheochromocytoma PC12 cells. However, the mechanisms resulting in RET inactivation differed since the receptor bearing R231H extracellular mutation resulted in an absent RET protein at the cell surface while the E921K mutation located within the catalytic domain abolished its enzymatic activity. In contrast, three mutations mapping into the intracytoplasmic domain neither modified the transforming capacity of RET-MEN 2A nor stimulated the catalytic activity of RET in our ligand-independent system (S767R, P1039L, M1064T). Finally, the C609W HSCR mutation exerts a dual effect on RET since it leads to a decrease of the receptor at the cell surface and converted RET51 into a constitutively activated kinase due to the formation of disulfide-linked homodimers. Taken together, our data show that allelic heterogeneity at the RET locus in HSCR is associated with various molecular mechanisms responsible for RET dysfunction.     

Rational-emotive therapy, placebo, and no-treatment effects on public-speaking anxiety.

In a partial replication and refinement of an earlier study by the authors, 33 undergraduates reporting high levels of public-speaking anxiety received rational-emotive therapy (RET), attention placebo (AP), or no treatment (NT). Primary analyses of pre- to posttherapy changes as assessed with a variety of self-report and observational measures tended to support the conclusion that RET is more effective than either NT or the AP treatment used (relaxation training). Secondary analyses which included AP and NT Ss, who received RET immediately after serving in the AP and NT conditions, further support RET treatment effects. (32 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The RET gene in thyroid pathology]

The RET proto-oncogene encodes a receptor tyrosine kinase which plays a crucial role during the embryonic development of the enteric nervous system and of the kidney. Cytogenetic analyses of papillary thyroid carcinoma (PTC), a neoplasm which originates from thyrocytes, have revealed that somatic rearrangements of the RET gene are involved in the etiology of a significant proportion of this tumour. Medullary thyroid carcinoma (MTC) which arises from neural-crest derived C-cells is the cardinal disease feature of multiple endocrine neoplasia type 2 (MEN 2), a dominantly inherited cancer syndrome. Recent studies have provided evidence that germline mutations of the RET gene are the underlying genetic events responsible for MEN 2. This review focuses on the role of RET mutations in the pathogenesis of PTC and MTC and summarizes our present knowledge on the consequences of these alterations on the RET tyrosine kinase function. We further describe a transgenic mouse model for hereditary MTC. Mice carrying a MEN 2A allele of RET under the control of the CGRP/calcitonin promoter develop bilateral and multifocal MTC, morphologically and biologically similar to human MTC.     

RET/PTC and RET tyrosine kinase expression in adult papillary thyroid carcinomas

The prevalence of RET/PTC rearrangements in papillary thyroid carcinomas (PTCs) varies widely in different studies, and an association of RET/PTC presence with tumor behavior remains to be clarified. A prospective study of 50 adult PTCs examined, using RT-PCR, the prevalence of the 3 main RET rearrangements and also of RET tyrosine kinase (TK) domain sequence expression. The genetic findings were correlated with the MACIS clinical prognostic score and with individual clinical parameters. Three of the patients had been exposed to radiation in childhood or adolescence. Four of the PTCs contained RET/PTC1, confirmed by sequencing, and none contained RET/PTC2 or RET/PTC3. The prevalence of RET rearrangements overall was 8%, but in the subgroup of 3 radiation-exposed patients it was 66.6%. Interestingly, RET tyrosine kinase domain messenger ribonucleic acid was detectable in 70% of PTCs using RET exon 12/13 primers and was detectable in 24% of PTCs using RET exon 15/17 primers. RT-PCR for calcitonin and RET extracellular domain, however, was negative. There was no association between the presence or absence of RET/PTC in the patient's tumor and clinical parameters. We conclude that RET/PTC1 is the predominant rearrangement in PTCs from adults with a history of external irradiation in childhood. RET TK messenger ribonucleic acid expression is common in PTCs, using RT-PCR, and cannot be used to infer the presence of specific RET rearrangements or of RET activation.     

No mutations found by RET mutation scanning in sporadic and hereditary neuroblastoma

Neuroblastoma occasionally occurs in diseases associated with abnormal neurocrest differentiation, e.g. Hirschsprung disease. Expression studies in developing mice suggest that the proto-oncogene RET plays a role in neurocrest differentiation. In humans expression of RET is limited to certain tumor types, including neuroblastoma, that derive from migrating neural crest cells. Mutations of RET are found associated with Hirschsprung disease. These data prompted us to investigate expression of RET and to search for gene mutations in neuroblastoma. Out of 16 neuroblastoma cell lines analyzed, 9 show clear expression of RET in a Northern blot analysis. In a single strandt conformation polymorphism (SSCP) analysis of all exons, no mutations were detected other than neutral polymorphisms. In a patient with neuroblastoma, from a family in which different neurocrestopathies, including neuroblastoma and Hirschsprung disease, had occurred, we also failed to detect RET mutations. Possibly, expression of RET in neuroblastoma merely reflects the differentiation status of the tumor cells. The absence of mutations suggests that RET does not play a crucial role in the tumorigenesis of neuroblastoma.     

Presence of physiologically stimulated RET in adult rat brain: induction of RET expression during nerve regeneration

The product of the RET proto-oncogene is a protein belonging to the receptor-like tyrosine kinase superfamily. RET is expressed in several neural crest-derived cell lineages and has been implicated in the correct development of the peripheral nervous system. To gain further insight into RET function, we investigated the presence of active RET in adult rat tissues. We show, by immunoblotting, that the products of the RET proto-oncogene (p155ret) are present in specific regions of adult rat brain, including the cerebellum, striatum, brainstem, hypothalamus, hippocampus, and olfactory bulb. Moreover, in the cerebellum, p155ret is phosphorylated in tyrosine residues, thus indicating that this brain structure contains p155ret in an activated state. Finally, the presence of RET in motoneurons prompted us to analyze the effects of hypoglossal nerve section on its expression. We observed a dramatic increase in p155ret in the motoneuron nuclei, thus suggesting that RET tyrosine kinase plays a role in the neuronal response to axotomy and/or during nerve regeneration.     

Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKS): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

The RET proto-oncogene encodes a functional receptor tyrosine kinase (Ret) for the Glial cell line Derived Neurotrophic Factor (GDNF). RET is involved in several neoplastic and non-neoplastic human diseases. Oncogenic activation of RET is detected in human papillary thyroid tumours and in multiple endocrine neoplasia type 2 syndromes. Inactivating mutations of RET have been associated to the congenital megacolon, i.e. Hirschprung's disease. In order to identify pathways that are relevant for Ret signalling to the nucleus, we have investigated its ability to induce the c-Jun NH2-terminal protein kinases (JNK). Here we show that triggering the endogenous Ret, expressed in PC12 cells, induces JNK activity; moreover, Ret is able to activate JNK either when transiently transfected in COS-1 cells or when stably expressed in NIH3T3 fibroblasts or in PC Cl 3 epithelial thyroid cells. JNK activation is dependent on the Ret kinase function, as a kinase-deficient RET mutant, associated with Hirschsprung's disease, fails to activate JNK. The pathway leading to the activation of JNK by RET is clearly divergent from that leading to the activation of ERK: substitution of the tyrosine 1062 of Ret, the Shc binding site, for phenylalanine abrogates ERK but not JNK activation. Experiments conducted with dominant negative mutants or with negative regulators demonstrate that JNK activation by Ret is mediated by Rho/Rac related small GTPases and, particularly, by Cdc42.     

Characterization of ret oncogenic activation in MEN2 inherited cancer syndromes

Germline mutations of c-ret, encoding a receptor-type tyrosine kinase, were found to be associated with variants of multiple endocrine neoplasia type 2 (MEN2A, MEN2B), and familial medullary thyroid carcinoma. NIH/3T3 stable transfectants expressing RET with a mutation of MEN2A (MEN2A/RET) or MEN2B (MEN2B/RET) gained a transformed morphology, formed colonies in soft agar, and formed tumors in nude mice. These results confirmed that both MEN2A/RET and MEN2B/RET exert dominant transforming activities in NIH/3T3 cells. However, in contrast to their clinical manifestation, transfectants expressing MEN2A/RET exhibited a higher tumorigenicity in nude mice than transfectants expressing MEN2B/RET may depend on the presence of its ligand and/or substrates that are absent in NIH/3T3 cells. No change in the cellular localization of the mutated RET proteins was observed compared to c-RET. Interestingly, ret activation in NIT/3T3 cells appeared to be associated with up-regulation of homologous gap-junctional intercellular communication and increased expression of a gap-junctional protein, connexin43.     

Papillary thyroid carcinoma oncogene (RET/PTC) alters the nuclear envelope and chromatin structure

Current evidence suggests the papillary thyroid carcinoma oncogene (RET/PTC) generates papillary thyroid carcinomas in one genetic step. We tested a resulting prediction that RET/PTC expression in thyroid epithelium should be sufficient to cause the changes in nuclear morphology diagnostic of this tumor. Primary cultures of human thyroid epithelial cells were infected with a RET/PTC retroviral construct. Morphological scoring by two independent cytopathologists shows RET/PTC expression by immunohistochemistry to be highly associated (p < 0.0001) with an irregular nuclear contour and a euchromatic appearance compared with non-expressing cells in the same cultures. The altered nuclear morphology is not due to gene transfer or transformation per se as primary thyroid cell cultures infected with a retroviral H-RAS construct differ from RET/PTC-infected cells by showing round nuclear envelopes and coarser chromatin, as determined by the independent scoring of two cytopathologists (p < 0.0001). In addition, RET/ PTC-transfected cells appear to disperse, whereas RAS-transfected cells grow as discrete colonies. The results provide additional support for the hypothesis that RET/PTC is sufficient to cause papillary thyroid carcinomas. A signaling pathway downstream of RET/ PTC leads to restructuring of the nuclear envelope and chromatin, and the signal does not depend entirely, if at all, on a RAS pathway.     

Electroconvulsive therapy: indications and improvement

Electroconvulsive therapy (ECT) is considered today as an affective and safe treatment, although some indications for its use are based more in the professional consensus than in the clinical research. As with any treatment, both therapeutic outcome and adverse effects can be expected to vary considerably across patients. It is incumbent upon the practitioner to be aware of factors that serve to influence the benefits and risks associated with this treatment modality. The author reviews current indications, and those factors that may be useful in response prediction, as well as, technical modifications of the ECT procedure itself.     

A comprehensive treatment model for anger disorders.

Notes that because anger can be a frequent and debilitating client problem, it is important for practitioners to have a clear conceptualization of available and effective treatment strategies. This article presents a comprehensive treatment model based on reviews of empirical outcome studies of anger interventions. However, because this outcome literature is relatively small and restricted to a few therapeutic approaches, additional suggestions for therapeutic interventions are presented based on what is known about the emotion of anger. It is concluded that although knowledge of anger treatment is still developing, the scientific literature can provide much-needed guidance for working with angry clients. (PsycINFO Database Record (c) 2010 APA, all rights reserved)