RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells.

In acute promyelocytic leukemia, granulocytic differentiation is arrested at the promyelocyte stage. The variant t(11;17) translocation produces two fusion proteins, promyelocytic leukemia zinc finger-retinoic acid receptor α (PLZF-RARα) and RARα-PLZF, both of which participate in leukemia development. Here we provide evidence that the activity of CCAAT/enhancer binding protein α (C/EBPα), a master regulator of granulocytic differentiation, is severely impaired in leukemic promyelocytes with the t(11;17) translocation compared with those associated with the t(15;17) translocation. We show that RARα-PLZF inhibits myeloid cell differentiation through interactions with C/EBPα tethered to DNA, using ChIP and DNA capture assays. Furthermore, RARα-PLZF recruits HDAC1 and causes histone H3 deacetylation at C/EBPα target loci, thereby decreasing the expression of C/EBPα target genes. In line with these results, HDAC inhibitors restore in part C/EBPα target gene expression. These findings provide molecular evidence for a mechanism through which RARα-PLZF acts as a modifier oncogene that subverts differentiation in the granulocytic lineage by associating with C/EBPα and inhibiting its activity.

[Are mental health disorders' characteristics such as presence and severity related to the nature of a crisis, its dangerousness and the types of services offered?]. / La présence et la gravité des troubles de santé mentale sont-elles liées à la nature de la crise, à la dangerosité et aux services de crise offerts ?

UNLABELLED: The mandate of crisis centres varies substantially from one country to the next according to the government policies in effect. In the United States, crisis centres were developed based on Caplan's theory, which defines crisis as a psychosocial disorganization following a life event that is resolved with a return to balance. This approach aims at preventing the onset of mental health disorders through short-term intervention. It is different in Quebec, where crisis centres were developed in a deinstitutionalization context and ought to constitute an alternative to hospitalisation. Such mandate of Quebec crisis centres is not necessarily of the preventive nature associated with Caplan's theory and it has led to services having to be adapted to a heterogeneous clientele that may or may not suffer from mental health problems. It has implications related to the crisis characteristics such as its nature, intensity, and dangerosity, as well as implications regarding the organization of crisis centre services, which have been the object of few studies so far. OBJECTIVE: The present study aims at distinguishing clinical profiles of crisis centre callers according to the presence or absence of a mental health disorder and its nature, that is severe and persistent (psychotic or bipolar disorder) or not (mood, anxiety or personality disorder). In order to do so, participants are compared on the characteristics of the crisis and the services they received. METHOD: In this descriptive study, the files of 1170 new assistance applicants are retrospectively analyzed based on a predetermined grid that was used to collect data according to the main clinical characteristics of persons in distress, as recognized in the literature. The subgroup of persons presenting a psychotic or bipolar disorder was examined separately from the one comprising persons with an anxiety, mood or personality disorder because of its clinical complexity, which generally requires intensive, multidisciplinary follow-up. RESULTS: Among the new applicants, 48% had a mental health disorder and, of these, 9% reported a serious mental health disorder, that is, a psychotic or bipolar disorder. The results indicate that having an anxiety-, mood- or personality-type disorder is associated with a higher probability of reporting stressful interpersonal-type events, a more intense crisis, as well as a greater risk of auto-aggressive behaviours. Meanwhile, persons with a psychotic or bipolar disorder are more frequently provided with accommodations and more likely to receive intensive and support services, such as emergency interventions or the use of the Act respecting the protection of persons whose mental state presents a danger to themselves or others (P-38). CONCLUSIONS: This descriptive portrait of the crisis centre clientele contributes to the reflection on differential intervention with persons in a crisis situation. It appears important to take an interest in the presence and type of mental health disorders of crisis centre callers, since these characteristics help to better foresee not only the nature and intensity of the crisis but also the type of services required. However, Quebec crisis centres have to respond to the needs of a heterogeneous clientele without having access to a typology and a theoretical model that consider this clinical diversity. Other studies should be conducted to validate, on the one hand, a crisis typology that would make it easier for caseworkers to collect data for evaluation purposes and, on the other hand, a differential intervention model.

Mutations in the nervous system--specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II.

Hereditary sensory and autonomic neuropathy type II (HSANII) is an early-onset autosomal recessive disorder characterized by loss of perception to pain, touch, and heat due to a loss of peripheral sensory nerves. Mutations in hereditary sensory neuropathy type II (HSN2), a single-exon ORF originally identified in affected families in Quebec and Newfoundland, Canada, were found to cause HSANII. We report here that HSN2 is a nervous system-specific exon of the with-no-lysine(K)-1 (WNK1) gene. WNK1 mutations have previously been reported to cause pseudohypoaldosteronism type II but have not been studied in the nervous system. Given the high degree of conservation of WNK1 between mice and humans, we characterized the structure and expression patterns of this isoform in mice. Immunodetections indicated that this Wnk1/Hsn2 isoform was expressed in sensory components of the peripheral nervous system and CNS associated with relaying sensory and nociceptive signals, including satellite cells, Schwann cells, and sensory neurons. We also demonstrate that the novel protein product of Wnk1/Hsn2 was more abundant in sensory neurons than motor neurons. The characteristics of WNK1/HSN2 point to a possible role for this gene in the peripheral sensory perception deficits characterizing HSANII.

Characterization of a growth hormone-releasing hormone binding site in the rat renal medulla.

Receptor binding analysis was performed in the renal medulla from 2-month-old rats, an extrapituitary tissue containing the highest level of GHRH receptor mRNA. At 4 degrees C, in the presence of a cocktail of protease inhibitors, binding of [125I-Tyr(10)]hGHRH (1-44)NH(2) to medullary homogenates was specific, time-dependent, reversible and saturable (K(d): 28 nM; B(max): 30 fmol/mgprot.). In these experimental conditions, no change of binding parameters could be detected in the course of aging. The structure-affinity profile was different in the two tissues and chemical cross-linking revealed the presence of 65-, 55- and 38-kDa 125I-GHRH-labeled complexes in the renal medulla compared to 65-, 47- and 28-kDa radioactive complexes in the anterior pituitary. It is suggested that GHRH binding sites, and possibly the receptor, may be different in the two tissues.

Characterization of a growth hormone-releasing hormone binding site in the rat renal medulla.

Receptor binding analysis was performed in the renal medulla from 2-month-old rats, an extrapituitary tissue containing the highest level of GHRH receptor mRNA. At 4 degrees C, in the presence of a cocktail of protease inhibitors, binding of [125I-Tyr(10)]hGHRH NH(2) to medullary homogenates was specific, time-dependent, reversible and saturable (K(d): 28 nM; B(max): 30 fmol/mg prot.). In these experimental conditions, no change of binding parameters could be detected in the course of aging. The structure-affinity profile was different in the two tissues and chemical cross-linking revealed the presence of 65-, 55- and 38-kDa 125I-GHRH-labeled complexes in the renal medulla compared to 65-, 47- and 28-kDa radioactive complexes in the anterior pituitary. It is suggested that GHRH binding sites, and possibly the receptor, may be different in the two tissues.