The effects of a novel metabotropic glutamate receptor 5 antagonist (AZD2066) on transient lower oesophageal sphincter relaxations and reflux episodes in healthy volunteers.

BACKGROUND: Selective metabotropic glutamate receptor 5 (mGluR5) antagonists inhibit transient lower oesophageal sphincter relaxations (TLESRs) in animals and acid reflux in humans. AIM: To assess the effect of single doses of the mGluR5 antagonist AZD2066 on TLESRs and reflux in humans. METHODS: Healthy male volunteers received AZD2066 13 mg and placebo (part A), or AZD2066 2 mg and AZD2066 6 mg and placebo (part B), in a randomised crossover study. Postprandial manometry/pH-impedance measurements were taken after each dose. RESULTS: A total of 13 individuals completed part A of the study and 19 individuals completed part B. There was a significant reduction in the geometric mean number of TLESRs (27%; P = 0.02) and the geometric mean number of reflux episodes (51%; P = 0.01) in subjects receiving AZD2066 13 mg compared with placebo. Adverse events in participants receiving AZD2066 13 mg were mostly related to the nervous system [dizziness (3/13); disturbance in attention (3/13)]. Adverse events were reversible and of mild intensity. There were no serious adverse events. The effects of AZD2066 appeared dose-dependent, with smaller reductions in TLESRs and reflux episodes (relative to placebo) and fewer adverse events observed for AZD2066 2 mg and AZD2066 6 mg compared with AZD2066 13 mg. CONCLUSION: The mGluR5-mediated inhibition of TLESRs may be a useful approach for inhibiting gastro-oesophageal reflux.

Randomised clinical trial: the efficacy of a transient receptor potential vanilloid 1 antagonist AZD1386 in human oesophageal pain.

BACKGROUND: Many patients with gastro-oesophageal reflux disease (GERD) are hypersensitive to heat and acid and may respond insufficiently to standard treatment. Antagonists of the heat and acid receptor 'transient receptor potential vanilloid 1'(TRPV1) are a potential drug class for GERD treatment. AIM: To investigate the effect of a TRPV1 antagonist (AZD1386) on experimentally induced oesophageal pain. METHODS: Twenty-two healthy men (20-31 years) participated in this randomised, placebo-controlled, double-blinded, crossover study examining the effects of a single-dose oral AZD1386 (30 and 95 mg). Subjects were block-randomised. On treatment days, participants were stimulated with painful heat, distension, electrical current and acid in the oesophagus. Heat and pressure pain on the forearm were somatic control stimuli. DATA ANALYSIS: intention-to-treat. RESULTS: A total of 21 participants completed the protocol and 1 voluntarily discontinued. In the oesophagus, both 30 and 95 mg of AZD1386 increased pain thresholds to heat stimuli 23% [95% confidence interval (CI): 10-38%] and 28%, respectively (CI: 14-43%). The skin heat tolerance was increased 2.1 °C (CI: 1.1-3.2 °C) after 30 mg AZD1386 and 4.0 °C (CI: 3.0-5.0 °C) after 95 mg. Heat analgesia persisted for 2.5 h. Pain thresholds to the other stimuli were unaffected by AZD1386. 50% reported 'feeling cold' and body temperature increased in all subjects exposed to 30 and 95 mg AZD1386 (mean increase 0.4±0.3 °C and 0.7±0.3 °C, respectively, P<0.05). CONCLUSIONS: AZD1386 increased oesophageal and skin heat pain thresholds and had a safe adverse-event profile. This drug class may have a potential for treatment of GERD.

A model of healing of Los Angeles grades C and D reflux oesophagitis: is there an optimal time of acid suppression for maximal healing?

BACKGROUND: In patients with Los Angeles (LA) grade C or D oesophagitis, a positive relationship has been established between the duration of intragastric acid suppression and healing. AIM: To determine whether there is an apparent optimal time of intragastric acid suppression for maximal healing of reflux oesophagitis. METHODS: Post hoc analysis of data from a proof-of-concept, double-blind, randomized study of 134 adult patients treated with esomeprazole (10 or 40 mg od for 4 weeks) for LA grade C or D oesophagitis. A curve was fitted to pooled 24-h intragastric pH (day 5) and endoscopically assessed healing (4 weeks) data using piecewise quadratic logistic regression. RESULTS: Maximal reflux oesophagitis healing rates were achieved when intragastric pH >4 was achieved for approximately 50-70% (12-17 h) of the 24-h period. Acid suppression above this threshold did not yield further increases in healing rates. CONCLUSION: After 4 weeks' acid-suppressive therapy for LA grade C or D oesophagitis, successful healing appears to reach a threshold above which improvements are unlikely to be achieved despite an increase in number of hours with intragastric pH >4.

Investigation of boundary conditions for biomimetic HA deposition on titanium oxide surfaces.

To improve the clinical outcome of metal implants, i.e. earlier loading and reduction of the incidence of revision surgery, better bone bonding ability is wanted. One method to achieve this is to change the surface chemistry to give a surface that facilitates bone bonding in vivo, i.e. a bioactive surface. Crystalline titanium oxide has recently been proven to be bioactive in vitro and is an interesting option to the more common hydroxylapatite (HA) coatings on implants. A materials possible in vitro bioactivity is tested through soaking in simulated body fluid and studies of possible HA formation on the surface. For bioactive materials, the formed HA layer can also be used as a coating. The aim of the current paper is to investigate some boundary conditions for HA formation on crystalline titanium oxide surfaces regarding influence from coating thickness, soaking time and soaking temperature. The influence from soaking time and temperature on the HA growth were investigated on oxidised Ti samples, (24 h at 800 degrees C) resulting in a rutile surface structure. The oxidised samples were tested at three temperatures (4, 37 and 65 degrees C) and four times (1 h, 1 day, 1 week and 4 weeks). The influence from titanium coating thickness on the HA growth was investigated via depositing thin films of crystalline titanium dioxide on Ti plates using a reactive magnetron sputtering process. Four different PVD runs with coating thicknesses between 19 and 74 nm were tested. The soaking temperature had an effect on the HA formation and growth on both rutile surfaces and native oxide on Ti substrates. Higher temperatures lead to easier formation of HA. It was even possible, at 65 degrees C, to grow HA on native titanium oxide from soaking in PBS. The coating quality was better for HA formed at 65 degrees C compared to 37 degrees C. All PVD-coatings showed HA growth after 1 week in PBS at 37 degrees C, thus even very thin coatings of crystalline titanium oxide coatings are bioactive.

A comparison of normalization methods for high density oligonucleotide array data based on variance and bias.

MOTIVATION: When running experiments that involve multiple high density oligonucleotide arrays, it is important to remove sources of variation between arrays of non-biological origin. Normalization is a process for reducing this variation. It is common to see non-linear relations between arrays and the standard normalization provided by Affymetrix does not perform well in these situations. RESULTS: We present three methods of performing normalization at the probe intensity level. These methods are called complete data methods because they make use of data from all arrays in an experiment to form the normalizing relation. These algorithms are compared to two methods that make use of a baseline array: a one number scaling based algorithm and a method that uses a non-linear normalizing relation by comparing the variability and bias of an expression measure. Two publicly available datasets are used to carry out the comparisons. The simplest and quickest complete data method is found to perform favorably. AVAILABILITY: Software implementing all three of the complete data normalization methods is available as part of the R package Affy, which is a part of the Bioconductor project http://www.bioconductor.org. SUPPLEMENTARY INFORMATION: Additional figures may be found at http://www.stat.berkeley.edu/~bolstad/normalize/index.html

Endocrine and behavioral traits in low-avoidance Sprague-Dawley rats.

In the present series of experiments, we have examined the endocrine profile of two stable colonies of Sprague-Dawley rats, here labeled Stock A, and Stock B, differing markedly in their ability to acquire a conditioned avoidance response. On separate occasions, the animals were subjected to five daily sessions (approximately 20 trials per 15 min session) of conditioned avoidance training, measurements of startle reactivity to an auditory stimulation and open-field spontaneous locomotor activity observations. The experiments were concluded by taking blood samples for later analysis of plasma glucose and plasma levels of the following hormones: insulin, gastrin, CCK, glucagon, somatostatin, oxytocin and corticosterone. The low-performing Stock B animals were characterized by [1] being more reactive to sensory stimulation: higher startle amplitude and shorter startle latency; [2] having higher plasma insulin and corticosterone levels, whereas plasma gastrin and oxytocin were significantly lowered and a strong tendency for a decrease also in plasma CCK. There were no differences in spontaneous locomotor activity between the two substrains. Taking total variability in avoidance performance into account, there was a statistically significant positive correlation between plasma oxytocin, as well as gastrin, levels and avoidance performance. The evidence obtained here, and in other laboratories, suggests that the Stock B animals display hormonal changes indicative of a submissive-defensive reaction pattern. Thus, the avoidance acquisition deficits displayed by the present Sprague-Dawley stocks A and B, are in all probability caused by emotional reactions when challenged with external stimuli requiring active responding.

[Decreasing number of orchiectomies in prostatic cancer. Results of 9-year registration of the disease are reviewed]. / Allt färre orkiektomier vid prostatacancer. Resultat av nio års regional registrering av sjukdomen redovisas.

There are several controversies regarding the management of prostate cancer. Whether curative treatment (e.g. radiotherapy and total prostatectomy) prolongs survival remains uncertain. Conservative management is beset with such unresolved issues as the effect on tumour progression of early instituted hormonal treatment and of treatment deferral. Since the outcome of the different types of treatment is unclear the value of screening and early detection remains uncertain. Owing to such issues as these, and the divergent views on prostate cancer, there is an urgent need of auditing. To co-ordinate prostate cancer care in the South-east Region of Sweden, a local management programme with principles for investigation and treatment has been used since 1987. An important feature of the programme is a register containing information on all cases of prostate cancer in the region, including the patient's national registration number, date of diagnosis, basis of diagnosis (cytology, pathology), tumour stage, histological grade, first line treatment, and date and cause of death. Secondary treatment has also been recorded since 1990, and treatment with prostate specific antigen since 1992. From 1987 to 1995, a total of 5,939 cases of prostate cancer were registered, the annual total increasing from 531 to 779 in 1993, after which there was a slight overall decrease but a small increase in the proportion of local tumours. The proportion of incidental tumours followed the same pattern as the transurethral prostatectomy rate in the region. M- and N-categorisation were done to a greater extent in the under-70 than in the over-70 age group. Orchidectomy is rapidly being replaced by treatment with GnRH (gonadotrophin-releasing hormone) analogues. Over the 9-year period, the total prostatectomy rate decreased from 12.5 to 4.6 per cent. All units responsible for prostate cancer care in the south-east region regularly receive processed updates from the register providing information on diagnostic and therapeutic methods used and their effect on mortality, thus providing a basis for improving the quality of prostate cancer care. Starting in 1997, a similar registration system is to be extended to cover the entire country.