Distinct and overlapping expression patterns of ligands for Eph-related receptor tyrosine kinases during mouse embryogenesis

Recent studies have implicated Eph-related receptor tyrosine kinases and their membrane-bound ligands in restricting or stimulating the movement of cells and axons. Members of these large families of receptors and ligands fall into two major binding specificity classes, in which the GPI-anchored subgroup of ligands can each bind to all members of a subgroup of receptors, whereas the transmembrane ligands interact with a distinct subgroup of receptors. Analysis of expression patterns is therefore important in order to understand which receptor-ligand interactions occur in vivo. We have cloned mouse orthologues of five members of the ligand family and analysed in detail their developmental expression, in comparison with each other, and with the receptor specificity class they can interact with. We find that B61, AL-1/RAGS, LERK4, and ELF-1, members of the GPI-anchored subgroup of ligands, have both distinct and overlapping aspects to their expression in early mesoderm, somites, and branchial arches; in complex, dynamic patterns in the limb; and in spatial domains and specific neurons in the CNS. Similarly, Elk-L is expressed in hindbrain segments, the roof plate, and floor plate, which overlaps with that of other transmembrane ligands, but has distinct expression in somites. The expression domains of ligands are complementary to those of the corresponding receptors in a number of tissues, including the midbrain, hindbrain, and differentiating limbs, consistent with potential roles in restricting cell movement. In addition, we find that there are some overlaps in expression of receptors and ligands, for example in somites and the early limb. Taken together with previous studies showing that Eph-related receptors also have distinct but overlapping expression patterns, these data indicate that each ligand may have stage- and tissue-specific interactions with an individual member or multiple members of the receptor family.     

Exposure to chlorine gas: effects on pulmonary function and morphology in anaesthetised and mechanically ventilated pigs

We report on a child with a 'new' syndrome characterized by multiple congenital anomalies, mental retardation, sensorineural deafness, talon cusps of upper central incisors, growth retardation, bilateral symmetrical digital anomalies mainly in the form of preaxial brachydactyly and hyperphalangism of digits I-III. Because he had a similarly affected brother and his parents were cousins we suggest autosomal recessive inheritance, X-linked recessive inheritance cannot be excluded. Differential diagnosis from other syndromes with preaxial brachydactyly and hyperphalangism is presented.     

Double dissociation of the behavioural effects of R(+) 7-OH-DPAT infusions in the central and basolateral amygdala nuclei upon Pavlovian and instrumental conditioned appetitive behaviours

Dopaminergic cell bodies located within the ventral mesencephalon innervate the amygdaloid complex, a region critically involved in the attribution of affective significance to environmental stimuli. Recently, we have shown that post-session intra-amygdala administration of a D3 dopamine receptor agonist enhances selectively the acquisition of an appetitive conditioned response. In the present study, we have investigated the potential involvement of the central nucleus and the basolateral nuclei of the amygdala in mediating this effect. Thus, rats were trained to associate an arbitrary stimulus (CS+) with the availability of 10% sucrose reward. Post-session infusions of the D3 receptor-preferring agonist, R(+) 7-OH-DPAT, were made into either the central nucleus or basolateral nuclei. Acquisition of a conditioned approach response was enhanced by R(+) 7-OH-DPAT infusions within the central nucleus, but not within the basolateral nuclei. Drug infusions into either region failed to affect approach behaviour elicited by presentation of a control stimulus (CS-), explicitly unpaired with sucrose reward. The effects of pre-test infusions of R(+) 7-OH-DPAT on the instrumental properties of the stimuli were then determined. Rats were presented with two novel levers, depression of one lever resulted in presentation of the CS+, while presentation of the CS- was contingent upon depression of the other lever. Rates of response upon each lever as well as the ability of the conditioned stimuli subsequently to elicit conditioned approach behaviour were recorded. Data revealed a double dissociation of the effects of R(+) 7-OH-DPAT on the expression of the Pavlovian and instrumental properties of the reward-related stimulus. Thus, within the central nucleus R(+) 7-OH-DPAT dose-dependently attenuated expression of the conditioned approach response, but had no effect upon instrumental responding maintained by the conditioned reward. In contrast, within the basolateral nuclei, R(+) 7-OH-DPAT had no effect upon expression of conditioned approach behaviour, but abolished selectively the ability of the reward-associated stimulus to support the acquisition of a novel instrumental response. Hence, these data indicate that distinct regions of the amygdaloid complex process distinct aspects of conditioned appetitive behaviours.     

Hepatic structure-pharmacokinetic relationships: the hepatic disposition and metabolite kinetics of a homologous series of O-acyl derivatives of salicylic acid

1. The hepatic disposition and metabolite kinetics of a homologous series of O-acyl (acetyl, propionyl, butanoyl, pentanoyl, hexanoyl and octanoyl) esters of salicylic acid (C2SA, C3SA, C4SA, C5SA, C6SA and C8SA, respectively) was determined using a single-pass, in-situ rat liver preparation. 2. The hepatic venous outflow profiles for the parent esters and the generated metabolite, salicylic acid (SA) were analysed by HPLC. Non-parametric moments analysis was used to determine the area under the curve (AUC'), mean transit time (MTT) and normalized variance (CV2) for the parent esters and generated SA. 3. Pregenerated SA ([14C]-salicylic acid) was injected into each liver with the parent ester to determine its distribution characteristics. 4. The overall recovery of ester plus metabolite was 89% of the ester dose injected and independent of the ester carbon number, suggesting that ester extraction was due to hepatic metabolism to salicylic acid. 5. The metabolite AUC' value increased directly with the lipophilicity of the parent ester (from 0.12 for C2SA to 0.95 for C8SA). By contrast, the parent AUC' decreased with the lipophilicity (from 0.85 for C2SA to zero for C8SA). The metabolite MTT value also showed a trend to increase with the lipophilicity of the parent ester (from 15.72 s for C3SA to 61.97 s for C8SA). However, the parent MTT value shows no significant change across the series. 6. The two-compartment dispersion model was used to derive the kinetic parameters for parent ester, pregenerated SA and generated SA. Consequently, these parameters were used to estimate the values of AUC', MTT and CV2 for the parent ester and metabolite. The moments values obtained using the two-compartment dispersion model show similar trends to the corresponding moments values obtained from the outflow profiles using a non-parametric approach. 7. The more lipophilic aspirin analogues are more confined to the portal circulation after oral administration than aspirin due to their more extensive hepatic elimination avoiding systemic prostacyclin inhibition. Given that aspirin's selectivity as an anti-thrombotic agent has been postulated to be due to selective anti-platelet effects in the portal circulation, the more lipophilic and highly extracted analogues are potentially more selective anti-thrombotic agents than aspirin.     

Audit and its impact in the management of early prostatic cancer

An analysis was made of a prospective database of 614 men with newly diagnosed carcinoma of the prostate who presented between January 1978 and December 1990; 3-monthly updates were available on their clinical, haematological and biochemical parameters and 6-monthly updates on chest X-rays, bone scans and skeletal X-rays. It was found that 107 men (mean age 73.5 years) had early disease at presentation. Their management was based on regular surveillance and the treatment deferred until disease progression or development of symptoms. The audit of outcome measured various clinical events. Four patients (3.7%) developed local failure, 11 (10.3%) developed bone metastases, 3 (2.8%) died of cancer with a median survival of 6.3 years, and 34 (31.8%) died of intercurrent disease with a median survival of 2.6 years. The observed survival for 12 years of the whole group was similar to the expected survival for an age-matched population in Scotland. The standardised mortality ratio was 81 (95% confidence limits 57-112).