MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation.

Restoration of p53 tumor suppressor function through inhibition of its interaction and/or enzymatic activity of its E3 ligase, MDM2, is a promising therapeutic approach to treat cancer. However, because the MDM2 targetome extends beyond p53, MDM2 inhibition may also cause unwanted activation of oncogenic pathways. Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1. Importantly, decreasing Mdm2 gene dosage in mouse mammary epithelial cells potentiates estrogen-dependent AKT activation owing to HPIP stabilization. In addition, we identified HPIP as a novel p53 transcriptional target, and pharmacological inhibition of MDM2 causes p53-dependent increase in HPIP transcription and also prevents HPIP degradation by turning off TBK1 activity. Our data indicate that p53 reactivation through MDM2 inhibition may result in ectopic AKT oncogenic activity by maintaining HPIP protein levels.

[How I explore: ventricular arrhythmias in athletes]. / Une arythmie ventriculaire chez le sportif.

Documented ventricular tachyarrhythmias or related symptoms need meticulous cardiac investigations. The mechanism of ventricular arrhythmia must be defined. The prognosis is related to underlying cardiac electrical or structural disorders. In the absence of cardiovascular abnormalities, the prognosis is good. No disqualification to competitive activity is required in most cases. Assessment of the risk of sudden death remains a continuing challenge in athletes. This article reviews the diagnostic and therapeutic approaches of ventricular arrhythmias encountered in trained athletes.

Recruitment and growth of two small-bodied resident fish species (Gobiidae and Atherinidae) in oligohaline, seasonally open lagoons.

Spatio-temporal recruitment patterns, growth and survival of the Swan River goby Pseudogobius olorum and western hardyhead Leptatherina wallacei are described from two small, coastal lagoons on the south coast of Western Australia. In these lagoons, estuarine salinity dynamics were relatively stable over much of the autumn-spring period when freshwater inputs from rivers were reduced and there was no oceanic connection. Preflexion and flexion stages of both fish species contributed strongly to population size structure in downstream reaches, whereas upstream reaches were dominated by postflexion larvae and juvenile stages. Spawning of both species was protracted and largely asynchronous, although the episodic presence of stronger preflexion and flexion cohorts suggested some synchronized spawning had occurred. Comparison with estuarine conditions over this period provided evidence that synchronized spawning may be related to temperature and salinity variations from a combination of freshwater inputs and periods of marine exchange. Uninterrupted growth and the progression of cohorts through to juvenile stages were consistent with the generally stable estuarine conditions. Larval and juvenile stages of both species were also tolerant of abrupt changes in salinity and temperature, which occurred due to a non-seasonal oceanic connection. These findings were consistent with the euryhaline nature of adults of both species.

Molecular effectors and modulators of hypericin-mediated cell death in bladder cancer cells.

Photodynamic therapy (PDT) is an anticancer approach utilizing a light-absorbing molecule and visible light irradiation to generate, in the presence of O(2), cytotoxic reactive oxygen species, which cause tumor ablation. Given that the photosensitizer hypericin is under consideration for PDT treatment of bladder cancer we used oligonucleotide microarrays in the T24 bladder cancer cell line to identify differentially expressed genes with therapeutic potential. This study reveals that the expression of several genes involved in various metabolic processes, stress-induced cell death, autophagy, proliferation, inflammation and carcinogenesis is strongly affected by PDT and pinpoints the coordinated induction of a cluster of genes involved in the unfolded protein response pathway after endoplasmic reticulum stress and in antioxidant response. Analysis of PDT-treated cells after p38(MAPK) inhibition or silencing unraveled that the induction of an important subset of differentially expressed genes regulating growth and invasion, as well as adaptive mechanisms against oxidative stress, is governed by this stress-activated kinase. Moreover, p38(MAPK) inhibition blocked autonomous regrowth and migration of cancer cells escaping PDT-induced cell death. This analysis identifies new molecular effectors of the cancer cell response to PDT opening attractive avenues to improve the therapeutic efficacy of hypericin-based PDT of bladder cancer.

[Molecular and cellular characterization ion of IKAP protein and the Elongator complex. Implications for familial dysautonomia]. / Caractérisation moléculaire et cellulaire des fonctions de la protéine IKAP et du complexe Elongator: implications pour la dysautonomie familiale.

Familial dysautonomia (FD), a severe neuro-developmental and neurodegenerative genetic disorder, is caused by mutations of IKBKAP encoding a subunit of Elongator. FD patients have decreased expression of IKAP in a tissue-specific manner and consequently impaired Elongator function. The biological roles of human IKAP/Elongator remained elusive for a while. However, recent data based on the generation of cellular loss of function models of IKAP through RNA interference strongly suggest a role for this protein in transcriptional elongation. Other data also provide evidence for a role of Elongator in tRNA modifications. Importantly, cells depleted for IKAP have defects in cell motility because of impaired transcriptional elongation of some genes coding for proteins involved in cell migration. Therefore, cell motility deficiency seen in IKAP depleted cells may underlie the neuropathology of FD patients.

[The "footscan" in sport medicine]. / Intérêt du footscan en pathologie sportive.

Clinical examination of the foot in a patient or sportsman requires a detailed analysis of walking (and running). Current technology allows to study temporal fluctuations of plantar pressures and to detect the anomalies responsible for sport specific pathologies or pathologies encountered in sick predisposed people.

[Physiopathology of respiratory muscles]. / Dysfonction des muscles respiratoires.

Different factors can have deleterious effect the inspiratory muscles: increased intrinsic mechanical loading of the inspiratory muscles, functional inspiratory muscle weakness, increased ventilatory demand related to capacity... These muscle changes influence exercise tolerance and contribute to dyspnea.

[Hemochromatosis: the most common of rare diseases]. / L'hémochromatose. La plus fréquente des maladies rares.

Familial (hereditary) haemochromatosis (HH) is an iron storage disorder characterized by an increased intestinal absorption of iron and its accumulation in numerous tissues. The disease generates an iron overload with tissue damages also seen in haematologic disturbances (with dyserythropoiesis and haemolysis) and hepatic disorders. Besides typical mutations linked to HH (C282 Y and H63D, HFE locus), three other mutations have been identified and more have to be defined. A complete genetic testing is important to assess the risk of morbidity. Indeed, the clinical picture of HH is dependent upon the specific mutations as well as the individual context (sex, environment, associated hepatic and/or haematologic disorders). Porphyria cutanea tarda (PCT) has for long been found significantly associated with HH. It is now considered that hepatic iron overload related to the combination of heterogeneous genetic traits and environmental factors, including alcoholism and viral hepatitis, precipitates the expression of PCT through the inhibition of uroporphyrinogen decarboxylase (Uro.D).

[How I investigate...respiratory muscle disorders]. / Comment j'explore...un dysfonctionnement des muscles respiratoires.

As for other skeletal muscles, ventilatory muscle performance can be described in terms of strength and endurance. Ventilatory muscle strength is measured, for example, as the maximum inspiratory and expiratory mouth pressures. It is now a routine procedure in many pulmonary function laboratories. Measurements of ventilatory muscle endurance are more difficult but two general types of tests are used: maximum voluntary ventilation and inspiratory threshold loading.

Epidermoid cyst in a solitary testis: a case for non-surgical management.

This is a case report of a 71-year-old man who presented with an incidental finding of a mass in a solitary right testis. A scrotal ultrasound scan showed the typical features of a testicular epidermoid cyst. Tumour markers were not elevated and the patient was managed non-operatively. On reviewing the literature, we found no previous report on the non-operative management of testicular epidermoid cysts

[Mucosal immunity in elite athletes]. / Influence de l'effort physique sur le système immunitaire muqueux.

It is now generally accepted that strenuous exhausting exercise can increase susceptibility to viral infection during the following days or weeks. This review addresses the role of mucosal immunity in respiratory illness and associations with the intensity, volume and duration of exercise. Indeed habitual exercise at an intense level can cause suppression of mucosal immune parameters.

[Exercise spirometry in medical practice]. / Ergospirométrie en pratique médicale.

Cardiopulmonary exercise testing is a unique tool to assess the limits and mechanisms of exercise tolerance. It is also useful for establishing the profiles and adequacy of the responses of the systems at submaximal and maximal exercises. The measure of VO2 max (maximal oxygen uptake) has become the "benchmark" to quantify cardiovascular functional capacity and aerobic fitness.

Improved prognosis of Epstein-Barr virus associated childhood Hodgkin's lymphoma: study of 47 South African cases.

AIM: To study the distribution of Hodgkin's lymphoma in South African children and report the incidence of Epstein-Barr virus (EBV) as regards age, race, sex, and histological subtype; to investigate whether EBV is relevant to survival. METHODS: Immunohistochemistry (IHC) and in situ hybridisation (ISH) to detect EBV were performed on 47 South African children with classical Hodgkin's lymphoma, ranging in age from 3 to 14 years and coming from different ethnic backgrounds. The correlation between the presence of the virus and clinical outcome was assessed. RESULTS: The nodular sclerosing subtype predominated, comprising 89% of cases; the remaining 11% were of the mixed cellularity subtype. EBV was present in 68%. Full clinical data were available for 36 cases; EBV positive patients presented with less aggressive symptoms at diagnosis and had a significantly longer median survival than EBV negative patients. CONCLUSIONS: The distribution of EBV in South African childhood Hodgkin's lymphoma follows a pattern intermediate to that of industrialised and non-industrialized countries. Furthermore, our data suggest that there is an association between poor prognosis and the non-detection of EBV products in South African childhood Hodgkin's lymphoma.

Detection of the T(14;18) translocation in follicle centre cell lymphomas in South African ethnic groups using PCR.

PCR was used to detect the t(14;18) translocation in 64 South African cases with follicle centre cell lymphoma. DNA was purified from paraffin-embedded tissue collected from different ethnic groups namely white, black and "mixed" race patients, and primers used to detect both mbr and mcr. The overall incidence of the translocation was 45%, which is similar to that of Caucasian and Chinese patients. The ratio of rearrangements occurring at the mbr and mcr was 7:1 which may be an overestimation. The ratio was three times higher for the "mixed" race group compared to whites, and this suggests that there may be ethnic variation in breakpoints in South African patients.

Objective benefit of laser palatoplasty for non-apnoeic snoring.

Laser palatoplasty (LPP) is widely used for the treatment of non-apnoeic snoring, despite the lack of objective data supporting its use. We report measurements of snoring in a prospective study of LPP, and we compare the results with a previous study of uvulopalatopharyngoplasty (UPPP). Twenty patients with an apnoea/hypopnoea index < 20 h-1 underwent LPP for habitual snoring. Overnight sound recordings were compared before and 6 months after operation using three objective indices; L, (the level exceeded by the loudest 1% of sound), L5 (the level exceeded by the loudest 5% of sound) and P50 (% total sleep time above 50 dBA). The subjective impression of snoring severity (Wilcoxon test, P < 0.001), and objective indices L1 and P50 (t-test, P < 0.001) showed significant reductions after LPP. The mean change in L1 was 4.2 dBA, comparable to that we previously reported for UPPP, while P50 was reduced to less than one-third its preoperative value. No other sleep variables changed significantly following LPP. We conclude that LPP results in reduced snoring volume comparable to that following UPPP.

Psychometric performance before and after laser palatoplasty for non-apnoeic snoring.

Psychometric tests are an objective way of examining cognitive functioning, and have shown impairment in patients with obstructive sleep apnoea. Non-apnoeic snoring may cause reduced concentration, but psychometric tests have been used rarely in this population. We investigate whether their use can demonstrate an improvement in cognitive performance in 20 non-apnoeic snorers following Laser Palatoplasty (LPP). The subjects completed psychometric tests, Beck Anxiety and Depression Inventories and an Epworth Sleepiness Scale on two occasions before LPP and once postoperatively. The only index to show any significant change with LPP was the Beck Depression Inventory (P < 0.005), which was reduced by a mean of 1.6 units following surgery. There was also a highly significant improvement in information processing between the preoperative tests, for which no explanation could be found. Our results suggest that commonly applied psychometric tests are unable to demonstrate significant improvements following surgery for non-apnoeic snoring. However, we have demonstrated for the first time a significant reduction in depression following surgery, which is evidence that snoring is more than a social nuisance.

Congenital gastrointestinal pacemaker cell tumor.

The interstitial cells of Cajal complex within the gut wall function as a pacemaker to direct peristalsis. Their neoplastic counterpart is the gastrointestinal pacemaker cell tumor, a spindle and/or epithelioid cell mesenchymal tumor previously known as gastrointestinal stromal tumor or incorrectly called leiomyosarcoma in some cases of older reports. Although numerous cases of gastrointestinal leiomyosarcomas have been documented in the English-language literature, no pediatric case of gastrointestinal stromal tumor or gastrointestinal pacemaker cell tumor has, to our knowledge, been recorded. Herein, we report a case of congenital gastrointestinal pacemaker cell tumor confirmed by immunohistochemistry and electron microscopy in a full-term male newborn.

Relationship of physical exercise and ageing to growth hormone production.

OBJECTIVE: The normal decline in physiological function with ageing is associated with a decrease in bioavailable growth hormone. Growth hormone has been shown to alter body composition and increase fat-free mass in older men. Increased physical fitness is accompanied by an increase in 24-h growth hormone release. The purpose of this study was to examine the effect of exercise on declining growth hormone concentrations with increasing age. DESIGN AND PATIENTS: The growth hormone production of 10 male subjects running over 40 miles per week was compared to 10 healthy age-matched sedentary males (controls 57.7 +/- 2.8 vs. runners 60.5 +/- 3.4 years). All subjects underwent a basal assessment including a two-hour serum growth hormone profile followed by estimation of maximal exercise capacity on a cycle ergometer with growth hormone estimations at peak exercise activity and every five minutes whilst cycling at 40% of maximal exercise capacity. RESULTS: Maximal exercise capacity confirmed the lifestyles of the two groups (VO2 max controls 22.36 +/-6.05 vs. runners 34.91 +/- 13.13 l/min/kg, P = 0.01). The runners had lower body-mass indices than controls (BMI 22. 3 +/- 1.5 vs. 25.5 +/- 2.0 kg/m2, P = 0.002). Peak growth hormone level during a two-hour resting profile was higher in the runners (median (range) controls 2.10 (0.20-12.20) vs. runners 5.25 (0.80-21. 00) mU/l, P = 0.03) as was the average growth hormone level during the two hour profile (mean growth hormone per 2 h median (range): controls 0.54 (0.03-4.88) vs. runners 2.17 (0.25-7.45) mU/l, P = 0. 04). Growth hormone production at maximal exercise capacity was similar. Sex hormone binding globulin and testosterone were significantly higher in the runners. CONCLUSIONS: The results suggest that regular intensive exercise in older male subjects is associated with higher growth hormone and testosterone levels and that exercise may have a role in counteracting the normal decline in growth hormone with ageing.

RAS mutations in pediatric leukemias with MLL gene rearrangements.

Translocations of the MLL gene at chromosome band 11q23 are the most common cytogenetic alterations in de novo leukemia in infants and in leukemia related to chemotherapy with DNA topoisomerase II inhibitors. Experiments on knock-in mice suggest that additional mutational events may by required for full leukemogenesis. Therefore, we used single-strand conformation polymorphism analysis and an allele-specific restriction enzyme assay to investigate the frequency of KRAS and NRAS mutations in 32 pediatric leukemias with translocation of the MLL gene. Of 25 de novo cases, 13 were acute lymphoblastic leukemia (ALL), 10 were acute myeloid leukemia (AML), and 2 were biphenotypic. Three secondary leukemias were AML, 1 was biphenotypic, 1 was ALL, and 2 were diagnosed as myelodysplasia. The frequency of RAS mutations was 2 of 10 in de novo AML. Both mutations occurred in infant monoblastic variants. RAS mutations were otherwise absent in this series. This is the first report of congenital leukemias where translocation of the MLL gene and RAS mutation coexist. The frequency of RAS mutations in de novo AMLs with MLL gene translocations is similar to that in other forms of AML, but RAS mutations play a limited role in lymphoid and treatment-related leukemias with similar translocations.