Oestrogen and progesterone do not regulate the expression of retinoic acid receptors and retinoid 'X' receptors in human endometrial stromal cells in vitro

Elucidation of the gene structure for retinoic acid receptor-(RAR-) has suggested a potential role for oestrogen in regulatingthe expression of RAR-. We have previously shown that all threeRAR types are expressed in human endometrial stromal cells invitro and that RAR- expression is induced in response to retinoicacid. The aim of this study was to ask whether oestradiol andprogesterone could play a part in regulating the expressionof RARs in human endometrial stromal cells and to establishthe patterns of expression of a related group of nuclear retinoidreceptors, retinoid ‘X’ receptors (RXRs) and theirpotential for regulation by steroid hormones. The RAR expressionpatterns of endometrial stromal cells, grown in steroid-freemedium, did not change in response to the presence of steroidhormones. Furthermore, the retinoic acid-mediated inductionof RAR- was not affected by oestradiol or progesterone, andwas dependent on the continued presence of retinoic acid. Ofthe three RXR types, only RXR- was detectably expressed in stromalcells in vitro and the expression of RXR- did not change inresponse to steroid hormones or retinoic acid. These data indicatethat oestradiol and progesterone are not important in the regulationof RAR and RXR expression in human endometrial stromal cells.     

A 24-hour rhythm in passive-avoidance behaviour in rats

The 24 h variation in the passive avoidance response of rats was measured. Different groups of 18 animals were tested at 4 hourly intervals throughout 24 h. In all cases, retention was measured 48 h after the first trial. All animals were housed under controlled conditions for 14 days before testing. A significant 24-h rhythm in passive avoidance response was found, the maximum and minimum effects being in the middle of the light and dark phases respectively.     

Changes in gait when anticipating slippery floors

Falls precipitated by slipping are listed among the leading causes of injuries. The biomechanical analysis of such events is a necessary component of the slips/falls prevention research. One of the challenges of biomechanical studies is reproducing the unexpected nature of real-life slipping accidents. Thus, the goal of this study was to quantify changes in gait biomechanics when subjects anticipate slippery environments. Foot ground reaction forces and body dynamics of 16 subjects were recorded during level walking and descending ramps of varying frictional properties and inclination. Gait biomechanics were compared among three types of dry trials: (1) baseline (subjects knew the floor was dry); (2) anticipation (subjects were uncertain of the contaminant condition, dry, water, soap or oil); and (3) recovery trials recorded after a contaminated trial (subjects again knew the floor was dry). Subjects were asked to walk as naturally as possible throughout testing. Anticipation trials produced peak required coefficient of friction (RCOF(peak)) values that were on average 16-33% significantly lower than those collected during baseline trials, thus reducing slip potential. During recovery trials, RCOF(peak) values did not return to baseline characteristics (5-12% lower). Postural and temporal gait adaptations, which affected ground reaction forces, were used to achieve RCOF(peak) reductions. Statistically significant gait adaptations included reductions in stance duration (SD) and loading speed on the supporting foot, shorter normalized stride length (NSL), reduced foot-ramp angle and slower angular foot velocity at heel contact. As a result of these adaptations, anticipation of slippery surfaces led to significant changes in lower extremity joint moments, a reflection of overall muscle reactions. Thus, this study suggests that significant gait changes are made when there is a potential risk of slipping even though subjects were asked to walk as naturally as possible. Insights are also gained into the adaptations that are used to reduce the potential of slips/falls.     

Increased DNA-incorporated thiopurine metabolite as a possible mechanism for leukocytopenia through cell apoptosis in inflammatory bowel disease patients with NUDT15 mutation

Journal of Gastroenterology - Polymorphisms in the nucleotide diphosphate-linked moiety X-type motif 15 (NUDT15) gene are associated with thiopurine-induced leukopenia in patients with inflammatory...     

Methods of collecting and evaluating non-clinical cardiac electrophysiology data in the pharmaceutical industry: results of an international survey

OBJECTIVE: To assess current practice in the pharmaceutical industry for assessing the potential for QT interval prolongation by non-cardiovascular medicinal products. METHODS: The survey was based on responses from the Toxicology and (Safety) Pharmacology laboratories (a total of 74 laboratories) of 54 companies based in Europe, Japan/Asia and the USA, received between January and March 1999. RESULTS: All 54 companies conducted preclinical in vivo electrocardiography (EGG) evaluation of new active substances (NASs). Thirty of these companies also conducted in vitro cardiac electrophysiology studies on their compounds. The majority of in vivo work was done in conscious beagle dogs. There was no consistency within the industry in defining the magnitude of change in QT interval that is considered biologically important. Most companies considered a change greater than 10% to be important, although the design of the studies suggested that group sizes used may not give sufficient statistical power to detect this size of change. Bazett's formula was used by 41% of laboratories to correct QT for changes in heart rate, despite the fact that this formula is generally deemed to be unsuitable for use in dogs. For studies in anaesthetised dogs, the majority of laboratories used barbiturate anaesthesia, but researchers should be aware of the effects of this and some other anaesthetic agents on QT interval. As for in vitro cardiac electrophysiology, there was wide diversity in the testing methodologies, particularly with regard to the test species and tissue type. As with QT prolongation, there was no consensus on the degree of action potential prolongation to cause concern. For both in vitro and in vivo testing, the majority of companies tested a minimum of three dose (or concentration) levels in order to ascertain any dose-response relationship. CONCLUSIONS: The survey provides a snapshot of the practice in the industry prior to any internationally-agreed consensus on the most effective and efficient approaches to minimising the risk of QT prolongation by new drugs in man. It must be stated that for any given methodology, the 'majority view' in the industry is not necessarily best practice.     

Evaluation of nebulised hypertonic saline (7%) as an adjunct to physiotherapy in patients with stable bronchiectasis

Sputum clearance is of prime importance in the management of patients with bronchiectasis. While nebulised normal isotonic saline (0.9%) (IS) has been anecdotally used to treat patients with tenacious sputum, the use of hypertonic saline (7%) (HS) could have potential muco-protective and clearance properties. 24 patients with bronchiectasis were randomised to receive four single treatment schedules in random order: (1) active cycle breathing technique (ACBT) alone, (2) nebulised terbutaline then ACBT, (3) nebulised terbutaline, nebulised IS then ACBT and (4) nebulised terbutaline, nebulised HS then ACBT. Sputum weights were significantly higher after HS than IS (P = 0.002). Ease of expectoration also differed overall (P < 0.0001) and was significantly lower with HS than with IS (P = 0.0005). Sputum viscosity differed between treatment phases, with a significant linear trend to reduced sputum viscosity with HS (P = 0.0002). These changes were associated with small but statistically significant differences in FEV1 (P = 0.043) and FVC (P = 0.011) between treatment phases. Nebulised hypertonic saline can be used safely and effectively as an adjunct to physiotherapy in selected patients. A long-term prospective trial is now indicated to determine its effectiveness on long-term infection rate, quality of life and lung function.     

COX2 expression in neuroblastoma increases tumorigenicity but does not affect cell death in response to the COX2 inhibitor celecoxib

COX2 is an inducible cyclooxygenase implicated in the metastasis and migration of tumour cells. In neuroblastoma, COX2 expression has been detected in both cell lines and tumours. The treatment of neuroblastoma cells in vitro with celecoxib, a COX2 inhibitor, induces apoptosis. The aim of this study was to investigate the role of COX2 in neuroblastoma tumour biology by creating a cell line in which COX2 could be conditionally expressed. Xenograft studies showed that the conditional expression of COX2 enhanced tumour growth and malignancy. Elevated COX2 expression enhanced the proliferation and migration of neuroblastoma cells in vitro. However, elevated COX2 expression or variation between cell lines did not affect sensitivity to the COX2 inhibitor celecoxib, indicating that celecoxib does not promote cell death through COX2 inhibition. These data show that increased COX2 expression alone can enhance the tumorigenic properties of neuroblastoma cells; however, high levels of COX2 may not be a valid biomarker of sensitivity to non-steroidal anti-inflammatory drugs such as celecoxib.