Complex regulation of LCoR signaling in breast cancer cells.

Ligand-dependent corepressor (LCoR) is a transcriptional repressor of ligand-activated estrogen receptors (ERs) and other transcription factors that acts both by recruiting histone deacetylases and C-terminal binding proteins. Here, we first studied LCOR gene expression in breast cancer cell lines and tissues. We detected two mRNAs variants, LCoR and LCoR2 (which encodes a truncated LCoR protein). Their expression was highly correlated and localized in discrete nuclear foci. LCoR and LCoR2 strongly repressed transcription, inhibited estrogen-induced target gene expression and decreased breast cancer cell proliferation. By mutagenesis analysis, we showed that the helix-turn-helix domain of LCoR is required for these effects. Using in vitro interaction, coimmunoprecipitation, proximity ligation assay and confocal microscopy experiments, we found that receptor-interacting protein of 140 kDa (RIP140) is a LCoR and LCoR2 partner and that this interaction requires the HTH domain of LCoR and RIP140 N- and C-terminal regions. By increasing or silencing LCoR and RIP140 expression in human breast cancer cells, we then showed that RIP140 is necessary for LCoR inhibition of gene expression and cell proliferation. Moreover, LCoR and RIP140 mRNA levels were strongly correlated in breast cancer cell lines and biopsies. In addition, RIP140 positively regulated LCoR expression in human breast cancer cells and in transgenic mouse models. Finally, their expression correlated with overall survival of patients with breast cancer. Taken together, our results provide new insights into the mechanism of action of LCoR and RIP140 and highlight their strong interplay for the control of gene expression and cell proliferation in breast cancer cells.

Relationship between progression-free survival and overall survival in chronic lymphocytic leukemia: a literature-based analysis.

BACKGROUND: The endpoints of progression-free survival (pfs) and time-to-progression (ttp) are frequently used to evaluate the clinical benefit of anticancer drugs. However, the surrogacy of those endpoints for overall survival (os) is not validated in all cancer settings. In the present study, we used a trial-based approach to assess the relationship between median pfs or ttp and median os in chronic lymphocytic leukemia (cll). METHODS: The pico (population, interventions, comparators, outcomes) method was used to conduct a systematic review of the literature. The population consisted of patients with cll; the interventions and comparators were standard therapies for cll; and the outcomes were median pfs, ttp, and os. Two independent reviewers screened titles, abstracts, and full papers for eligibility and then extracted data from selected studies. Correlation coefficients were calculated to assess the relationship between median pfs or ttp and median os. Subgroup correlation analyses were also conducted according to the characteristics of the selected studies (such as line of treatment and type of treatment under investigation). RESULTS: Of the 1263 potentially relevant articles identified during the literature search, twenty-three were included. On average, median pfs or ttp was 16.0 months (standard deviation: 12.4 months) and median os was 43.5 months (standard deviation: 31.2 months). Results of the correlation analysis indicated that median pfs or ttp is highly correlated with median os (Spearman correlation coefficient: 0.813; p ≤ 0.001). A significant correlation between median pfs or ttp and median os was observed in second- and subsequent-line therapies, but not in the first-line setting. CONCLUSIONS: Our study demonstrates a strong correlation between median pfs or ttp and median os in previously treated cll, which reinforce the hypothesis that pfs and ttp could be adequate surrogate endpoints for os in this cancer setting.

Cognitive impairments in adult mice with constitutive inactivation of RIP140 gene expression.

Receptor-interacting protein 140 (RIP140) is a negative transcriptional coregulator of nuclear receptors such as estrogen, retinoic acid or glucocorticoid receptors. Recruitment of RIP140 results in an inhibition of target gene expression through different repressive domains interacting with histone deacetylases or C-terminal binding proteins. In this study, we analyzed the role of RIP140 activity in memory processes using RIP140-deficient transgenic mice. Although the RIP140 protein was clearly expressed in the brain (cortical and hippocampus areas), the morphological examination of RIP140(-/-) mouse brain failed to show grossly observable alterations. Using male 2-month-old RIP140(-/-) , RIP140(+/-) or RIP140(+/+) mice, we did not observe any significant differences in the open-field test, rotarod test and in terms of spontaneous alternation in the Y-maze. By contrast, RIP140(-/-) mice showed long-term memory deficits, with an absence of decrease in escape latencies when animals were tested using a fixed platform position procedure in the water maze and in the passive avoidance test. Noteworthy, RIP140(-/-) mice showed decreased swimming speed, suggesting swimming alterations that may in part account for the marked alterations measured in the water maze. Moreover, RIP140(+/-) and RIP140(-/-) mice showed a significant increase in immobility time in the forced swimming test as compared with wild-type animals. These observations showed that RIP140 gene depletion results in learning and memory deficits as well as stress response, bringing to light a major role for this transcriptional coregulator in the neurophysiological developmental mechanisms underlying cognitive functions.

Balanced complex chromosomal rearrangements (BCCR) with at least three chromosomes and three or more breakpoints: report of three new cases.

Balanced complex chromosomal rearrangements (BCCR) encompass a heterogeneous group of rare chromosomal aberrations. In this paper, we report three cases of BCCRs. In two the probands were referred for either genetic counseling or prenatal management. One case was ascertained after chromosome analysis performed because of psychiatric manifestations; this was an isolated finding. We also outline the molecular cytogenetic techniques, which were essential in confirming and precisely delineating the BCCRs identified in these patients. In addition the various aspects of genetic counseling for this type of chromosomal rearrangement, highlighting the details particular to each individual case are discussed. We discuss the classification for this type of chromosomal mutation.

The sternoclavicular joint: variants of the discus articularis.

OBJECTIVE: To study the anatomy of the sternoclavicular joint, its discus and its variations.Design. Anatomical study (macroscopic dissection). BACKGROUND: Textbooks on manual therapy give different descriptions of the movements of this joint. These apparent contradictions could be due to poor understanding of the anatomy of this joint resulting in ignoring specific movement patterns under particular conditions. METHODS: Macroscopic dissection of 22 embalmed sternoclavicular joints. RESULTS: The sternoclavicular and the costoclavicular parts of the discus always were quite distinct in orientation, thickness, surface and consistency. The sternoclavicular part was attached to the dorso-cranial part of the extremitas sternalis claviculae by a broad insertion in which several small blood vessels are visible. This part is grossly vertical, thicker than the lateral part and has a fibrous aspect. The costoclavicular part of the discus is always thinner than the sternoclavicular part. Sometimes it is reduced to a fine translucent pellet or is perforated. Subsynovial vascular arcades run along the insertion of the discus on the joint capsule, both on sternal and on clavicular sides. The costosternal articular surface can be divided into a sternal and a costal segment, separated by a vascular zone. CONCLUSIONS: Findings suggest different functions of the distinct parts of the joint. The smooth aspect of the lateral segment of the costosternal articular surface and of the costoclavicular part of the discus could be an argument to consider a functionally distinct costoclavicular compartment. The insertion of the discus on the clavicula strongly suggests that small movements take place between clavicula and discus and that the discus itself is moved only when the increasing amplitude stretches this insertion. We hypothesise that all midrange movements take place between the convex inferior edge of the clavicula and the costoclavicular part of he discus and that larger elevation depression and pro- and retraction movement take place, respectively, between clavicula and discus or discus and sternum. In three specimens we observed a previously not described arterial ramus articularis originating from the left thyrocervical trunk.RelevanceThese findings might explain differences of the arthrokinematic behaviour of this joint between midrange and full range motions.

The domain of hypertrophic chondrocytes in growth plates growing at different rates.

In this study, we tested the hypotheses that (a) both the domain volume (volume of the cell and the matrix it has formed) and matrix volume of juxtametaphyseal hypertrophic chondrocytes in the growth plate is tightly controlled, and that (b) the domain volume of juxtametaphyseal hypertrophic chondrocytes is a strong determinant of the rate of bone length growth. We analyzed the rate of bone length growth (oxytetracycline labeling techniques) and nine stereologic and kinetic parameters related to the juxtametaphyseal chondrocytic domain in the proximal and distal radial and tibial growth plates of 21- and 35-day-old rats. The domain volume increased with increasing growth rates, independent of the location of the growth plate and the age of the animal. Within age groups, the matrix volume per cell increased with increasing growth rates, but an identical growth plate had the same matrix volume per cell in 21- and 35-day-old rats. The most suitable regression model (R2 = 0.992) to describe the rate of bone length growth included the mean volume of juxtametaphyseal hypertrophic chondrocytes and the mean rate of cell loss/cell proliferation. This relationship was independent of the location of the growth plate and the age of the animal. The data suggest that the domain volume of juxtametaphyseal hypertrophic chondrocytes, as well as the matrix volume produced per cell, may be tightly regulated. In addition, the volume of juxtametaphyseal hypertrophic chondrocytes and the rate of cell loss/rate of cell proliferation may play the most important role in the determination of the rate of bone length growth.

Target detection deficits in frontal lobectomy.

We examined the hypothesis of dorsomedial frontal lobe involvement in target detection through the effects of distractor interference and multiple target interference on unilateral lobectomy patients. Seven patients who underwent a unilateral frontal lobectomy for epilepsy involving dorsomedial cortex and variable amounts of lateral cortex were compared to 10 patients with a unilateral temporal lobectomy and to 10 normal adults on a visual character cancellation task. The task involved detecting occurrences of target characters embedded in rows of characters under three conditions: detection of one target character in the absence of distractors, detection of one target character among distractors, and detection of three targets among distractors. Visual detection performance was compared to that in the Stroop reading interference task. Frontals were predictably slower than the other groups in the baseline conditions of the character cancellation task and the Stroop task. After partialing out baseline detection performance in the character cancellation task, frontals showed an almost normal detection in the presence of distractors but were distinctly slower and made more errors than the other groups in multiple target detection. Frontals were also slower on the Stroop even after partialing out baseline naming performance. Temporals were normal on all tasks. Results suggest that frontal damage can affect selectivity in target detection as well as the Stroop and that this deficit is independent of the general psychomotor slowing observed in these patients.

[Acute pancreatitis and valproic acid]. / Pancréatite aiguë et acide valproïque.

An 11 year-old epileptic boy, treated with valproic acid developed after 11 months on therapy a severe acute pancreatitis. Pancreatitis recurred 18 months after re-exposure to the same drug. Twenty-four cases of valproic-acid induced acute pancreatitis have been reported in the literature. However, it remains a major anticonvulsant drug whose tolerance is usually excellent. This complication, although exceptional needs to be known so that the treatment can be stopped in due-time if not tolerated or to avoid eventual recurrence.

[Determination of apolipoproteins B in children: use in the screening of atherogenic risk and influence of diet]. / Dosage des apoprotéines B chez l'enfant: utilisation pour le dépistage du risque athérogène et influence de la diététique.

The determination of plasma concentrations of apolipoproteins B (apo B) among 390 children (age 2-18 years) and the study of their antecedents showed that the prevalence of family histories of ischaemic cardiovascular diseases was higher among children whose apo B reached or exceeded 1.20 g/l. A low cholesterol diet was prescribed for children whose apo B levels were equal to or higher than 1.20 g/l. Two years later 45 of them were re-examined: they showed decreased apo B levels and a significant relationship between the magnitude of the decrease and the dietetic score related to the observance of the diet.

Hyperthyroidism due to selective pituitary resistance to thyroid hormones in a 15-month-old boy: efficacy of D-thyroxine therapy.

A 15-month-old boy had clinical features of hyperthyroidism. In spite of elevated serum thyroid hormone levels (mean serum T4, 230 nmol/L; T3, 4.2 nmol/L), serum TSH levels ranged between 3.3-5.6 mU/L and rose to 35.4 mU/L after TRH stimulation. There was no abnormal serum thyroid hormone binding or any evidence of a pituitary tumor. The boy was treated with carbimazole for 6 months and became euthyroid. However, his thyroid size enlarged, and serum TSH rose to 45 mU/L. In an attempt to suppress TSH secretion, 3,5,3'-triiodothyroacetic acid was added to carbimazole in daily doses from 0.7-1.4 mg. This combined therapy failed to suppress TSH secretion (serum TSH, 10.2 mU/L) and led to recurrence of symptoms of hyperthyroidism. A trial using highly purified dextrothyroxine (contamination by L-T4, 0.05%) as sole therapy then was carried out. Serum TSH levels promptly declined to normal, both basally and after TRH stimulation (basal, 2.4 mU/L; peak, 13.8 mU/L). During a 24-month follow-up period, the boy remained euthyroid. Serum TSH levels remained in the normal range, as did his serum L-T4 levels (93 nmol/L). Complete remission was achieved using a 5-mg daily dose of D-T4. Temporary discontinuation of D-T4 led to prompt relapse of hyperthyroidism. Our patient's TSH hypersecretion appears to be due to selective pituitary resistance to thyroid hormones. Purified D-T4 effectively inhibited TSH secretion in this patient, without inducing significant side-effects, even when the daily dose was high. The cause of partial pituitary unresponsiveness to thyroid hormones is not known. We suggest that transport of thyroid hormones into the thyrotroph cells could be deficient in our patient.

[Digitalis poisoning in children. Treatment with anti-digoxin Fab antibody fragments. Apropos of a case and a discussion of therapeutic indications]. / Intoxication digitalique chez l'enfant. Traitment par fragments Fab d'anticorps anti-digoxine. A propos d'un cas et discussion des indications thérapeutiques.

We report one case of Digoxin intoxication in a child treated with Fab Fragments of Digoxin-Specific antibodies (Fabad), although there was no evidence of early life threatening complications. The efficacy of this treatment, which prevents further complications as well as its safety, represent strong arguments to treat children at the early stage of the intoxication in order to avoid temporary cardiac pacing.

[A rare localization of osteomyelitis in a child]. / Une localisation rare d'ostéomyélite chez l'enfant.

The authors report a case of osteomyelitis of the anterio-inferior spina iliaca. This original observation actually illustrate the difficulty of the diagnosis of osteomyelitis. They stress the interest of plain radiographs which, if correctly read, would have enabled an early diagnosis, thus avoiding more complex examinations.

[Pyridoxine-dependent convulsions : familial case]. / Convulsions pyridoxino-dépendantes: observation familiale.

A 32 hours old boy was diagnosed as vitamin B6 dependent convulsions. This boy was the third from family, the first two died in status epilepticus at 34 hours and 15 months.

[Severe Legionella pneumopathy in an immunologically normal infant]. / Pneumopathie grave à légionelle chez un nourrisson immunologiquement normal.

A case of legionnaires' disease is described in a 9 months old boy. He had a rapidly extensive bilateral pneumoniae. There was no premorbidity. The diagnosis was made by demonstrating legionella pneumophila serogroup 1 in pulmonary biopsy and pleural liquid, by direct immunofluorescence assay and positive culture. There was no seroconversion. An adenovirus type 2 was also isolated in pulmonary biopsy, with an strong seroconversion. The course was favorable, with Doxycycline therapy.