Dynamic species interactions associated with the range-shifting marine gastropod Mexacanthina lugubris.

Globally, species are undergoing range shifts in response to climate change. However, the potential impacts of climate-driven range shifts are not well understood. In southern California, the predatory whelk Mexacanthina lugubris has undergone a northward range shift of more than 100 km in the past four decades. We traced the history of the whelk's range shift and assessed potential effects using an integrated approach, consisting of field surveys, as well as feeding and thermotolerance experiments. We found that at sites where Mexacanthina and native species co-occurred, native whelks distributions peaked lower in the intertidal. In laboratory experiments, we found that the presence of Mexacanthina led to reduced growth in native whelks (Acanthinucella spirata). Additionally, the range-shifting whelk was able to tolerate higher temperatures than common native species (A. spirata and Nucella emarginata), suggesting further impacts as a result of climate warming. Many species are likely to undergo range shifts as a coping mechanism for changing climatic conditions. However, communities are unlikely to shift as a whole due to species-specific responses. By studying the impacts of range-shifting species, like Mexacanthina, we can better understand how climate change will alter existing community structure and composition.

The challenge for innovation in direct restorative materials.

During the past 50 years, a series of key UN conferences have established a framework to minimize human health risks from environmental exposures to key chemicals. In January 2013, more than 140 countries agreed to the text of new treaty to minimize Hg effects on the environment (the Minamata Convention). Dental caries is omnipresent around the globe, affecting 60% to 90% of school children and most adults, and producing discomfort that affects quality of life. Dental amalgam is frequently used to treat carious lesions and its use releases mercury into the environment. The best way to avoid the use of dental amalgam is to emphasize caries prevention. Alternatives to amalgam are suitable in some applications, but no replacement for amalgam has been found for large posterior restorations. For any restorative material, safety and environmental impacts are part of clinical risk assessment. Safety is freedom from unacceptable risks. Risk is a combination of probability of exposure and severity of harm. Best management practices are crucial to manage dental amalgam, but these impose additional that are disproportionately more for developing countries. The Minamata Convention seeks a phase-out of all mercury-based products except dental amalgam, where a phase-down is the present goal. For dentistry, the most important focus is the promotion of caries prevention and research on new materials.

Symbiont genotype influences holobiont response to increased temperature.

As coral reefs face warming oceans and increased coral bleaching, a whitening of the coral due to loss of microalgal endosymbionts, the possibility of evolutionary rescue offers some hope for reef persistence. In tightly linked mutualisms, evolutionary rescue may occur through evolution of the host and/or endosymbionts. Many obligate mutualisms are composed of relatively small, fast-growing symbionts with greater potential to evolve on ecologically relevant time scales than their relatively large, slower growing hosts. Numerous jellyfish species harbor closely related endosymbiont taxa to other cnidarian species such as coral, and are commonly used as a model system for investigating cnidarian mutualisms. We examined the potential for adaptation of the upside-down jellyfish Cassiopea xamachana to increased temperature via evolution of its microalgal endosymbiont, Symbiodinium microadriaticum. We quantified trait variation among five algal genotypes in response to three temperatures (26 °C, 30 °C, and 32 °C) and fitness of hosts infected with each genotype. All genotypes showed positive growth rates at each temperature, but rates of respiration and photosynthesis decreased with increased temperature. Responses varied among genotypes but were unrelated to genetic similarity. The effect of temperature on asexual reproduction and the timing of development in the host also depended on the genotype of the symbiont. Natural selection could favor different algal genotypes at different temperatures, affecting host fitness. This eco-evolutionary interaction may be a critical component of understanding species resilience in increasingly stressful environments.

Thirty-Day Mortality for Proximal Femoral Fractures Treated at a U.K. Elective Center with a Site-Streaming Policy During the COVID-19 Pandemic.

COVID-19 led to the reconfiguration of U.K. orthopaedic trauma services because surgical capacity was threatened in acute centers. We report the 30-day mortality of proximal femoral fractures in older adults treated at an elective orthopaedic center. METHODS: Patients >60 years old who presented with a proximal femoral fracture to any of 4 sites in the regional trauma network were transferred to our elective center for emergency surgery. Care was modeled according to the National Institute for Health and Care Excellence guidelines, and efforts were made to treat all patients within 36 hours. Data were collected prospectively, and mortality outcomes were recorded. RESULTS: Of the 192 patients who presented to the elective orthopaedic center, 167 were treated there. The median age of the latter patients was 88 years (interquartile range, 83 to 79 years). The median Charlson Comorbidity Index was 4 (interquartile range, 4 to 6). The median time from emergency department admission to surgical treatment was 24.5 hours (interquartile range, 18.8 to 34.7 hours). The 30-day rate of mortality was 10.2%. A total of 29 (17.4%) tested positive for COVID-19 during their admission, of whom 10 died, for a case-fatality rate of 34.5%. There were no significant differences in age (p = 0.33) or Charlson Comorbidity Index (p = 0.13) between patients who tested positive and those who did not. There was no significant difference in age between those who tested positive and died and those who tested positive and did not die (p = 0.13), but there was a significant difference in Charlson Comorbidity Index between those subgroups (p = 0.03). CONCLUSIONS: During a pandemic, an elective orthopaedic center can be reconfigured to a surgical center for older patients with proximal femoral fractures with acceptable health-care quality outcomes. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Marine phosphorite deposits and the nitrogen cycle.

We have attempted to demonstrate a possible relationship between phosphorite deposition and an increase in marine denitrification. The studies of others indicate that major phosphorite deposits are often associated with black shales and accumulated during only a few epochs of geologic history. Some of these epochs were also marked by mass extinctions of organisms. Such events are not as precisely nor as strongly correlated as we would like. Nevertheless, the correlations are strong enough to encourage further consideration of the effects of possible changes in the rate of denitrification within ancient oceans on the origin of phosphorite deposits, the extinctions of marine organisms, variations in the overall level of biological activity, and temporal fluctuations in the organic carbon content of sedimentary rocks (36).

The structure of GABPalpha/beta: an ETS domain- ankyrin repeat heterodimer bound to DNA.

GA-binding protein (GABP) is a transcriptional regulator composed of two structurally dissimilar subunits. The alpha subunit contains a DNA-binding domain that is a member of the ETS family, whereas the beta subunit contains a series of ankyrin repeats. The crystal structure of a ternary complex containing a GABPalpha/beta ETS domain-ankyrin repeat heterodimer bound to DNA was determined at 2. 15 angstrom resolution. The structure shows how an ETS domain protein can recruit a partner protein using both the ETS domain and a carboxyl-terminal extension and provides a view of an extensive protein-protein interface formed by a set of ankyrin repeats. The structure also reveals how the GABPalpha ETS domain binds to its core GGA DNA-recognition motif.

Geochemistry of bed and suspended sediment in the Mississippi river system: provenance versus weathering and winnowing.

Stream-bed sediment for the size fraction less than 150 microm, examined in 14,000 samples collected mostly from minor tributaries to the major rivers throughout the Mississippi River drainage system, is composed of 5 mineral fractions identified by factor analysis-Al-silicate minerals, quartz, calcite and dolomite, heavy minerals, and an Fe-Mn fraction. The Al-silicate fraction parallels its distribution in the regolith, emphasizing the local sediment source as a primary control to its distribution. Quartz and the heavy-mineral fraction, and associated trace elements, exhibit a complementary distribution to that of the Al-silicate fraction, with a level of enrichment in the bed sediment that is achieved through winnowing and sorting. The carbonate fraction has a distribution suggesting its dissolution during transport. Trace elements partitioned onto the Fe-Mn, possibly amorphous oxyhydride, fraction are introduced to the streams, in part, through human activity. Except for the heavy-mineral fraction, these fractions are identified in suspended sediment from the Mississippi River itself. Although comparison of the tributary bed sediment with the riverine suspended sediment is problematic, the geochemistry of the suspended sediment seems to corroborate the interpretation of the geochemistry of the bed sediment.

Ancient deep-sea sponge grounds on the Flemish Cap and Grand Bank, northwest Atlantic.

Recent studies on deep-sea sponges have focused on mapping contemporary distributions while little work has been done to map historical distributions; historical distributions can provide valuable information on the time frame over which species have co-evolved and may provide insight into the reasons for their persistence or decline. Members of the sponge family Geodiidae are dominant members of deep-sea sponge assemblages in the northwestern Atlantic. They possess unique spicules called sterrasters, which undergo little transport in sediment and can therefore indicate the Geodiidae sponge historical presence when found in sediment cores. This study focuses on the slopes of Flemish Cap and Grand Bank, important fishing grounds off the coast of Newfoundland, Canada, in international waters. Sediment cores collected in 2009 and 2010 were visually inspected for sponge spicules. Cores containing spicules were sub-sampled and examined under a light microscope for the presence of sterrasters. These cores were also dated using X-radiographs and grouped into five time categories based on known sediment horizons, ranging from 17,000 years BP to the present. Chronological groupings identified Geodiidae sponges in four persistent sponge grounds. The oldest sterrasters were concentrated in the eastern region of the Flemish Cap and on the southeastern slope of the Grand Bank. Opportunistic sampling of a long core in the southeastern region of the Flemish Cap showed the continuous presence of sponge spicules to more than 130 ka BP. Our results indicate that the geodiids underwent a significant range expansion following deglaciation, and support a contemporary distribution that is not shaped by recent fishing activity.

Assignment of Empirical Mode Decomposition Components and Its Application to Biomedical Signals.

OBJECTIVES: Empirical mode decomposition (EMD) is a frequently used signal processing approach which adaptively decomposes a signal into a set of narrow-band components known as intrinsic mode functions (IMFs). For multi-trial, multivariate (multiple simultaneous recordings), and multi-subject analyses the number and signal properties of the IMFs can deviate from each other between trials, channels and subjects. A further processing of IMFs, e.g. a simple ensemble averaging, should determine which IMFs of one signal correspond to IMFs from another signal. When the signal properties have similar characteristics, the IMFs are assigned to each other. This problem is known as correspondence problem. METHODS: From the mathematical point of view, in some cases the correspondence problem can be transformed into an assignment problem which can be solved e.g. by the Kuhn-Munkres algorithm (KMA) by which a minimal cost matching can be found. We use the KMA for solving classic assignment problems, i.e. the pairwise correspondence between two sets of IMFs of equal cardinalities, and for pairwise correspondences between two sets of IMFs with different cardinalities representing an unbalanced assignment problem which is a special case of the k-cardinality assignment problem. RESULTS: A KMA-based approach to solve the correspondence problem was tested by using simulated, heart rate variability (HRV), and EEG data. The KMA-based results of HRV decomposition are compared with those obtained from a hierarchical cluster analysis (state-of-the-art). The major difference between the two approaches is that there is a more consistent assignment pattern using KMA. Integrating KMA into complex analysis concepts enables a comprehensive exploitation of the key advantages of the EMD. This can be demonstrated by non-linear analysis of HRV-related IMFs and by an EMD-based cross-frequency coupling analysis of the EEG data. CONCLUSIONS: The successful application to HRV and EEG analysis demonstrates that our solutions can be used for automated EMD-based processing concepts for biomedical signals.

Diagnosis of tubular injury in renal transplant patients by a urinary assay for a proximal tubular antigen, the adenosine-deaminase-binding protein.

Two murine monoclonal antibodies (URO-4 and URO-4a)--which detect different epitopes of a proximal tubular cell glycoprotein antigen, the adenosine-deaminase-binding protein (ABP)--have been formatted into a sandwich enzyme immunoassay for detection of ABP in the urine. Serial urine samples from 34 renal transplant patients during the first six months posttransplant were analyzed to determine the correlation of this test with clinical rejection and cyclosporin (CsA) nephrotoxicity. In 29/29 acute rejection episodes the ABP level was elevated, beginning 1-7 days prior to treatment of rejection. Eighteen patients were treated for rejection with courses of OKT3 or antithymocyte globulin: 0/6 whose ABP level fell to normal during therapy had rerejection; 10/12 whose ABP level remained elevated had rerejection within 7 days of therapy completion. Of 15 patients treated with CsA, 7 had no rejection or drug toxicity; all 7 had normal ABP levels. The remaining 8 had CsA nephrotoxicity, all in association with elevated ABP levels that rapidly fell to normal with decreased CsA dose. An additional 7 patients with creatinine elevations more than 6 months posttransplant were studied: 5 had chronic vascular changes on biopsy, no response to increased immunosuppression, and normal ABP levels; 2 had a cellular infiltrate on biopsy, response to increased immunosuppression, and elevated ABP levels. We conclude that the urinary ABP assay provides information useful in the management of renal transplant patients with acute and chronic rejection and CsA toxicity.

In vitro and in vivo profile of SB 206553, a potent 5-HT2C/5-HT2B receptor antagonist with anxiolytic-like properties.

1. SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2 ,3-f]indole) displays a high affinity (pK1 7.9) for the cloned human 5-HT2C receptor expressed in HEK 293 cells and the 5-HT2B receptor (pA2 8.9) as measured in the rat stomach fundus preparation. SB 206553 has low affinity for cloned human 5-HT2A receptors expressed in HEK 293 cells (pK1 5.8) and (pK1 < 6) for a wide variety of other neurotransmitter receptors. 2. SB 206553 appears to be a surmountable antagonist of 5-HT-stimulated phosphoinositide hydrolysis in HEK 293 cells expressing the human 5-HT2C receptor (pKB 9.0). 3. The compound potently (ID50 5.5 mg kg-1, p.o., 0.27 mg kg-1, i.v.) inhibited the hypolocomotor response to m-chlorophenylpiperazine (mCPP), a putative model of 5-HT2C/5-HT2B receptor function in vivo. 4. At similar doses (2-20 mg kg-1, p.o.) SB 206553 increased total interaction scores in a rat social interaction test and increased punished responding in a rat Geller-Seifter conflict test. These effects are consistent with the possession of anxiolytic properties. 5. SB 206553 also increased suppressed responding in a marmoset conflict model of anxiety at somewhat higher doses (15 and 20 mg kg-1, p.o.) but also reduced unsuppressed responding. 6. These results suggest that SB 206553 is a potent mixed 5-HT2C/5-HT2B receptor antagonist with selectivity over the 5-HT2A and all other sites studied and possesses anxiolytic-like properties.

Characterization of SB-269970-A, a selective 5-HT(7) receptor antagonist.

The novel 5-HT(7) receptor antagonist, SB-269970-A, potently displaced [(3)H]-5-CT from human 5-HT(7(a)) (pK(i) 8.9+/-0.1) and 5-HT(7) receptors in guinea-pig cortex (pK(i) 8.3+/-0.2). 5-CT stimulated adenylyl cyclase activity in 5-HT(7(a))/HEK293 membranes (pEC(50) 7.5+/-0.1) and SB-269970-A (0.03 - 1 microM) inhibited the 5-CT concentration-response with no significant alteration in the maximal response. The pA(2) (8.5+/-0.2) for SB-269970-A agreed well with the pK(i) determined from [(3)H]-5-CT binding studies. 5-CT-stimulated adenylyl cyclase activity in guinea-pig hippocampal membranes (pEC(50) of 8.4+/-0.2) was inhibited by SB-269970-A (0.3 microM) with a pK(B) (8.3+/-0.1) in good agreement with its antagonist potency at the human cloned 5-HT(7(a)) receptor and its binding affinity at guinea-pig cortical membranes. 5-HT(7) receptor mRNA was highly expressed in human hypothalamus, amygdala, thalamus, hippocampus and testis. SB-269970-A was CNS penetrant (steady-state brain : blood ratio of ca. 0.83 : 1 in rats) but was rapidly cleared from the blood (CLb=ca. 140 ml min(-1) kg(-1)). Following a single dose (3 mg kg(-1)) SB-269970 was detectable in rat brain at 30 (87 nM) and 60 min (58 nM). In guinea-pigs, brain levels averaged 31 and 51 nM respectively at 30 and 60 min after dosing, although the compound was undetectable in one of the three animals tested. 5-CT (0.3 mg kg(-1) i.p.) induced hypothermia in guinea-pigs was blocked by SB-269970-A (ED(50) 2.96 mg kg(-1) i.p.) and the non-selective 5-HT(7) receptor antagonist metergoline (0.3 - 3 mg kg(-1) s.c.), suggesting a role for 5-HT(7) receptor stimulation in 5-CT induced hypothermia in guinea-pigs. SB-269970-A (30 mg kg(-1)) administered at the start of the sleep period, significantly reduced time spent in Paradoxical Sleep (PS) during the first 3 h of EEG recording in conscious rats.

Drugs for the prevention of peptic ulcer recurrence.

The treatment of chronic peptic ulcer involves the treatment of acute exacerbations and the complications, and the prevention of ulcer recurrence. Several drugs accelerate the initial healing of ulcer and include the H2-receptor antagonists (cimetidine and ranitidine), colloidal bismuth, sucralfate, pirenzepine, carbenoxolone sodium, prostaglandins, high dose antacids and trimipramine. The long term management of ulcer involves the use of drugs and, in selected patients, surgery. Drugs used in this context include H2-receptor antagonists, pirenzepine, sucralfate and probably prostaglandins when further trial evidence is available. Regimens of long term drug treatment include intermittent treatment and maintenance treatment. The former consists of no active treatment after the ulcer is healed and the treatment of each acute exacerbation when it occurs, this treatment involving any one of the several drug routines mentioned above. If exacerbations are frequent (i.e. more than 2 to 3 years), maintenance therapy with H2-receptor antagonists, pirenzepine or sucralfate is advised. If the ulcer recurs despite long term treatment, it may be healed again using the healing dose of the above agents, and maintenance therapy recommenced if the remission induced by maintenance therapy was several years. If the remission was short, surgery should be advised.

Incidence of duodenal ulcer healing after 1 week of proton pump inhibitor triple therapy for eradication of Helicobacter pylori. The Lansoprazole Helicobacter Study Group.

BACKGROUND: A number of clinical studies have assessed the efficacy of short-term twice-daily Helicobacter pylori eradication regimens but few have investigated the proportion of patients in whom duodenal ulcer disease was healed with these regimens. AIM: To compare the safety and efficacy of four 1-week H. pylori eradication regimens in the healing of H. pylori associated duodenal ulcer disease. METHODS: Following endoscopic confirmation of duodenal ulcer disease and a positive CLO test, patients underwent a 13C-urea breath test to confirm H. pylori status. Treatment with one of four regimens: LAC, LAM, LCM or OAM, where L is lansoprazole 30 mg b.d., A is amoxycillin 1 g b.d., M is metronidazole 400 mg b.d., C is clarithromycin 250 mg b.d., and O is omeprazole 20 mg b.d., was assigned randomly to those patients who were H. pylori positive, with 62 (LAC), 64 (LAM), 61 (LCM) and 75 (OAM) patients in each treatment group. Follow-up breath tests and endoscopies were performed at least 28 days after the end of treatment. RESULTS: Duodenal ulcer disease was healed 28 days after treatment in 53/62 (85.5%) patients who were treated with LAC, 52/64 (81.3%) of patients treated with LAM, 49/61 (80.3%) of patients treated with LCM and 60/75 (80.0%) of patients treated with OAM (intention-to-treat analysis, n = 262, assumed unhealed if no follow-up endoscopy was performed). All the treatments were of similar efficacy (P = 0.85, chi-squared test) with regard to the healing of duodenal ulcer disease. CONCLUSIONS: The four 1-week treatment regimens were equally effective in healing H. pylori associated duodenal ulcer disease.

Chronic administration of the 5-HT3 receptor antagonist BRL 43694; effects on reflex epilepsy and social behaviour of the Mongolian gerbil.

The 5-HT3 receptor antagonist BRL 43694 was administered in drinking fluid to Mongolian gerbils, previously selected for their propensity to exhibit seizures on mild stimulation, for 11 days at doses of 1.5 micrograms/kg, 150 micrograms/kg and 1 mg/kg daily, while controls received tap water. Effects upon behaviour during encounters under white light with an untreated resident gerbil were assessed using ethological procedures. Effects upon seizure susceptibility and severity were also examined. All doses of BRL 43694 significantly increased the time spent by gerbils in the social activity "attend", and acts of social investigation involving physical contact between animals were significantly increased only by the highest dose of 1 mg/kg, as was occurrence of the specific element, "groom". The duration of flight was increased in gerbils receiving the drugs at 1.5 micrograms/kg. The treatment had no effect upon seizure susceptibility or severity. It is suggested that BRL 43694 increases the sensitivity of gerbils to their social environment. At the lower dose this was seen as an increase in flight, at all doses it was associated with increase of the social activity "attend" and at the high dose it was manifested as an increase in active social interaction. Further investigations are required to assess the relevance of these findings to the purported anxiolytic activity of 5-HT3 receptor antagonists.

Effect of SB 200646A, a 5-HT2C/5-HT2B receptor antagonist, in two conflict models of anxiety.

SB 200646A is the first selective 5-HT2C/5-HT2B receptor antagonist and has previously been observed to have anxiolytic-like properties in the rat social interaction test. In the present study the effects of the compound in two conflict models of anxiety, the rat Geller-Seifter and marmoset conflict test, were examined. In the rat Geller-Seifter test, suppressed responding was increased by all doses of SB 200646A between 5 and 40 mg/kg PO when given 1 h pretest. Unsuppressed responding was slightly increased only at 10 mg/kg PO. Suppressed responding was also increased by the benzodiazepine anxiolytic, chlordiazepoxide, at 1, 2.5 and 5 mg/kg PO 1 h pretest. Unsuppressed responding was modestly increased by chlordiazepoxide only at 5 mg/kg PO. In the marmoset conflict test marmosets were trained to lever press for a palatable food reward. Lever pressing was subsequently suppressed by air puffs. In this procedure suppressed responding was increased by both the benzodiazepine anxiolytic diazepam at 2 and 5 mg/kg PO and SB 200646A after 10 and 20 mg/kg PO. Both treatments caused small increases in unsuppressed responding at 2 and 20 mg/kg PO respectively. Taken together with the previous effects of SB 200646A in the rat social interaction test, this is compelling evidence that 5-HT2C/2B receptor antagonists may possess anxiolytic properties.

Clozapine enhances breakpoint in common marmosets responding on a progressive ratio schedule.

RATIONALE: Motivational effects of psychotropic drugs may contribute to their therapeutic profile and progressive ratio (PR) schedules provide a method of measuring these effects in animals. OBJECTIVE: Determine effects of selected antipsychotic, psychotomimetic, anxiolytic and antidepressant drugs on PR performance in common marmosets. METHOD: Marmosets were trained to lever press for banana milkshake reinforcement using a PR schedule, in which the number of lever presses to achieve successive reinforcements increased by one until responding ceased (breakpoint). RESULTS: Clozapine administered intramuscularly (0.01-2 mg/kg IM; 30 min pretreatment time (ptt) or by oral gavage (0.1-4 mg/kg PO; 60 min ptt) significantly increased the breakpoint. Independent tests of fluid consumption failed to show enhanced fluid intake after clozapine pretreatment, suggesting this effect was not due to drug induced polydipsia. Neither haloperidol (0.005-0.1 mg/kg PO; 60 min ptt) nor risperidone (0.0025-0.05 mg/kg PO; 60 min ptt) altered breakpoint. Olanzapine (0.01-1 mg/kg PO; 60 min ptt) significantly enhanced the breakpoint at 0.05 mg/kg PO, but the effect was not robust. Amphetamine (0.2-2 mg/kg SC; 30 min ptt) significantly reduced the breakpoint at 2 mg/kg and fluoxetine (0.1-1 mg/kg PO; 60 min ptt) was without effect. Diazepam significantly increased the breakpoint at 0.5 mg/kg PO. Drug-induced polydipsia might play a role in this response as independent tests showed increased fluid consumption following diazepam. CONCLUSIONS: These results demonstrate that, unlike other antipsychotics, clozapine over a wide dose range increased the motivational state of marmosets to respond for banana milkshake. This motivational aspect of clozapine's actions may contribute to its unique clinical profile and the PR procedure may provide a method for detecting novel antipsychotics with a clozapine-like profile.

BRL 46470A: a highly potent, selective and long acting 5-HT3 receptor antagonist with anxiolytic-like properties.

The novel 5-HT3 antagonist, BRL 46470A (endo-N-(8-methyl-8-azabicyclo [3.2.1]oct-3-yl)2,3-dihydro-3,3 dimethyl-indole-1-carboxamide, hydrochloride), has been investigated in a series of in vitro and in vivo tests, including the effect of the drug in models of anxiolysis. In classical tests for 5-HT3 receptor antagonism, BRL 46470A was shown to antagonise 5-HT3 mediated responses in the guinea-pig ileum [pA2 8.3 +/- 0.5, slope 0.98 +/- 0.20, mean +/- SEM (5)], the rabbit isolated heart (pA2 10.1 +/- 0.1, slope 1.2 +/- 0.2, n = 5) and the rat Bezold-Jarisch model (ID50 0.7 microgram/kg IV +/- 0.1, n = 8), with a long duration of action (> 3 h). BRL 46470A selectively displaced [3H]-BRL 43694 from 5-HT3 binding sites in rat brain membranes (Ki 0.32 nM +/- 0.04, n = 4) without displacing (at concentrations greater than 1 microM) a wide variety of ligands binding to other neurotransmitter receptors, opioid receptors and to neurotransmitter gated ion channel complexes. In vivo, BRL 46470A showed anxiolytic-like activity in two animal models predictive of antianxiety effects-elevated X-maze and social interaction in rats. In both models, BRL 46470A showed significant activity over a wide dose-range following both oral (0.0001-0.1 mg/kg PO) and systemic administration. The unique level of potency of BRL 46470A was apparent in the rat social interaction test and was shown to be 100 fold more potent than the 5-HT3 receptor antagonist ondansetron, with no evidence of a bell-shaped dose response curve over 4 orders of magnitude.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparative overview of the adverse effects of antiulcer drugs.

During the past 2 decades, great advances have been made in the treatment of ulcer disease. This has involved the development of new drugs that are not only well tolerated, but are relatively inexpensive. The lack of significant adverse effects has revealed a degree of tolerability that, to write a review of the adverse effects, poses a difficult task. Most of the adverse effects are related to an excessive reaction to the relevant pharmacological characteristic that mediates the therapeutic response. The drug dosage can be reduced, freeing the patient of the adverse reaction, but leaving behind a background activity adequate to produce a therapeutically beneficial effect. The adverse effects of H2-antagonists fall into 2 groups. Firstly, there are poorly defined symptoms that have a prevalence similar to that in the community; these include headache, giddiness, dizziness, fatigue, constipation and diarrhoea. Secondly, they may delay the metabolism of drugs metabolised by the the cytochrome P450 system, and rarely be androgenic. Many antacids and the site-protective agent sucralfate contain aluminium, which can be absorbed, producing elevation of serum aluminium levels. In view of the possible association of aluminium with Alzheimer's disease, anxiety has arisen as to whether aluminium from these sources may, in those on prolonged treatment, cause Alzheimer's disease. However, the evidence so far indicates that aluminium is not a risk factor for Alzheimer's disease. The association of gastric cancer with achlorhydria has led to the fear that long term use of potent acid inhibitors may cause cancer. This fear has been accentuated by the observation that some rats, given omeprazole over their lifetime, developed carcinoid tumours of the stomach. However, enthusiastic research, both clinical and epidemiological, indicates that drug-induced achlorhydria is unlikely to be a problem in humans. Site protective agents have a role in certain conditions such as pregnancy where the systemic effect of a drug may produce adverse effects.

Dose-response effects of orexin-A on food intake and the behavioural satiety sequence in rats.

Although intracerebroventricular (i.c.v.) administration of orexin-A has been reported to stimulate food intake and/or feeding behaviour in rats, mice and goldfish, little attention has thus far been paid to its effects on normal patterns of feeding. In the present study, a continuous monitoring technique was used to characterise the effects of this novel neuropeptide on the microstructure of rat behaviour during a 1-h test with palatable wet mash. Particular attention was devoted to the behavioural satiety sequence, in which feeding is followed by grooming and resting. Although results confirmed the hyperphagic effects of orexin-A (3.33-30.0 microg i.c. v.), gross behavioural analysis failed to reveal any reliable effects of peptide treatment on eating, drinking, sniffing, grooming, resting, locomotion or rearing. However, microstructural analysis revealed behavioural effects of orexin-A that are both dose- and time-dependent. At lower doses (3.33-10.0 microg), orexin-A primarily delayed behavioural satiety, i.e. the normal transition from eating to resting. In contrast, the 30 microg dose initially induced a sedative-like effect, significantly suppressing eating and other active behaviours for the first 15-20 min of the test period. This sedative-like effect resulted in a phase-shifting of the entire behavioural sequence with higher than control levels of eating, grooming, locomotion, rearing and sniffing observed over the second half of the test session. Present findings illustrate the advantages of microstructural behavioural analysis and suggest that the hyperphagic response to low doses of orexin-A results largely from a delay in behavioural satiety while that seen in response to high doses may occur in rebound to initial behavioural suppression. Further studies will be required to confirm the identity of the specific orexin receptors (i.e. OX(1) or OX(2)) involved in mediating the dose-dependent behavioural effects reported.