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Biomedical subjects

G Rennie

Publications and source records attributed to G Rennie.

11 recordsLinked to original sources
PubMed2001

Molecular cloning and functional characterization of MCH2, a novel human MCH receptor.

Melanin-concentrating hormone (MCH) is involved in the regulation of feeding and energy homeostasis. Recently, a 353-amino acid splice variant form of the human orphan receptor SLC-1 () (hereafter referred to as MCH(1)) was identified as an MCH receptor. This report describes the cloning and functional characterization of a novel second human MCH receptor, which we designate MCH(2), initially identified in a genomic survey sequence as being homologous to MCH(1) receptors. Using this sequence, a full-length cDNA was generated with an open reading frame of 1023 base pairs, encoding a polypeptide of 340 amino acids, with 38% identity to MCH(1) and with many of the structural features conserved in G protein-coupled receptors. This newly discovered receptor belongs to class 1 (rhodopsin-like) of the G protein-coupled receptor superfamily. HEK293 cells transfected with MCH(2) receptors responded to nanomolar concentrations of MCH with an increase in intracellular Ca(2+) levels and increased cellular extrusion of protons. In addition, fluorescently labeled MCH bound with nanomolar affinity to these cells. The tissue localization of MCH(2) receptor mRNA, as determined by quantitative reverse transcription-polymerase chain reaction, was similar to that of MCH(1) in that both receptors are expressed predominantly in the brain. The discovery of a novel MCH receptor represents a new potential drug target and will allow the further elucidation of MCH-mediated responses.

Amino Acid Sequence↗
PubMed2001

The neuroprotective agent sipatrigine (BW619C89) potently inhibits the human tandem pore-domain K(+) channels TREK-1 and TRAAK.

We have cloned and functionally expressed the human orthologue of the mouse TRAAK gene. When cDNA for hTRAAK is expressed in either Xenopus oocytes or HEK293 cells it forms a K(+)-selective conductance and hyperpolarises the resting membrane potential. Quantitative mRNA expression analysis using Taqman revealed that hTRAAK mRNA is predominantly present in the central nervous system where it exhibits a regionally diverse pattern of expression. Like the related channel TREK-1, the activity of TRAAK was potentiated by arachidonic acid. The neuroprotective agent sipatrigine (10 microM) inhibited both hTREK-1 (73.3+/-4.4%) and hTRAAK (45.1+/-11.2%) in a reversible, voltage-independent manner. Inhibition of both channels was dose-dependent and for TREK-1 occurred with an IC(50) of 4 microM. The related compound lamotrigine, which is a better anticonvulsant but weaker neuroprotective agent than sipatrigine, was a far less effective antagonist of both channels, producing <10% inhibition at a concentration of 10 microM.

Amino Acid Sequence↗
PubMed2001

Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery.

Potassium channels are amongst the most heterogeneous class of ion channels known and are responsible for mediating a diverse range of biological functions. The most recently described family of K+ channels, the 'two pore-domain family', contain four membrane spanning domains and two pore-forming domains, suggesting that two channel subunits associate to form a functional K+ pore. Several sub-families of the two pore domain potassium channel family have been described, including the weakly inward rectifying K+ channel (TWIK), the acid-sensitive K+ channel (TASK), the TWIK-related K+ channel (TREK) and the TWIK-related arachidonic acid stimulated K+ channel (TRAAK). However, comparison of the mRNA expression of these channels has been difficult due to the differences in methods used and the species studied. In the present study, we used a single technique, TaqMan semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), to investigate the mRNA distribution of all currently known two pore potassium channels in human central nervous system (CNS) and peripheral tissues. TWIK-1 and the TWIK-1-like channel KCNK7 were predominantly expressed in the CNS, in contrast to TWIK-2 which was preferentially expressed in peripheral tissues such as pancreas, stomach, spleen and uterus. TASK-1 was expressed in the CNS and some peripheral tissues, whereas TASK-2 was exclusively expressed in the periphery except for mRNA expression observed in dorsal root ganglion and spinal cord. In addition, mRNA expression of the recently identified TASK-3, was almost completely exclusive to cerebellum with little or no mRNA detected in any other tissues. TREK-1 and TRAAK mRNA expression was predominantly CNS specific in contrast to the closely related TREK-2, which was expressed in both CNS and peripheral tissues. Studying the mRNA expression profiles of known two pore domain K+ channels will aid in the understanding of the biological roles of these channels. Furthermore, identification of common areas of expression may help identify which channels, if any, associate to form heteromeric K+ channel complexes.

Central Nervous System↗
PubMed1999

Functional domains of the SYT and SYT-SSX synovial sarcoma translocation proteins and co-localization with the SNF protein BRM in the nucleus.

The t(X;18)(p11.2;q11.2) chromosomal translocation commonly found in synovial sarcomas fuses the SYT gene on chromosome 18 to either of two similar genes, SSX1 or SSX2, on the X chromosome. The SYT protein appears to act as a transcriptional co-activator and the SSX proteins as co-repressors. Here we have investigated the functional domains of the proteins. The SYT protein has a novel conserved 54 amino acid domain at the N-terminus of the protein (the SNH domain) which is found in proteins from a wide variety of species, and a C-terminal domain, rich in glutamine, proline, glycine and tyrosine (the QPGY domain), which contains the transcriptional activator sequences. Deletion of the SNH domain results in a more active transcriptional activator, suggesting that this domain acts as an inhibitor of the activation domain. The C-terminal SSX domain present in SYT-SSX translocation protein contributes a transcriptional repressor domain to the protein. Thus, the fusion protein has transcriptional activating and repressing domains. We demonstrate that the human homologue of the SNF2/Brahama protein BRM co-localizes with SYT and SYT-SSX in nuclear speckles, and also interacts with SYT and SYT-SSX proteins in vitro. This interaction may provide an explanation of how the SYT protein activates gene transcription.

Amino Acid Sequence↗
PubMed1998

Skin irritation potential of mixed surfactant systems.

Virtually all current detergent formulations contain mixtures of surfactants. Our experience and test data on these formulations, which is in agreement with that of many others, has shown that in use the formulations exhibit lower acute irritation potential than predicted by simple summation of the irritation potential of the individual actives. Using the criteria of the Dangerous Preparations Directive (EC Directive 88/379/EEC), many of these formulations classify as irritant in the neat state, with consequent labelling requirements. Such classification is based on addition of irritant components giving a total concentration which exceeds a nominal threshold. In this study, mixtures of surfactants were tested by application to a panel of 31 human volunteers for up to 4 hr, using the technique established for the assessment of acute skin irritation potential. The positive control, sodium dodecyl sulfate (SDS) at 20% concentration, gave an 84% positive response. Dimethyl dodecyl amido betaine (DDAB) at the same concentration gave a 94% response. However, a combination of 20% of each of these surfactants in the same panellists gave a response of only 44%--a significant reduction in the irritation potential. A further test conducted with a mixture of 10% SDS and 10% DDAB in a second panel gave a 31% positive response compared with a 94% positive response to the 20% SDS control in that panel. These results clearly demonstrate that the acute irritation potential of mixed surfactants cannot be predicted by simple summation of the irritation potential of the component substances. Initial results of the mechanistic investigation indicate that the reduced irritation induced by the mixed surfactant systems correlates with a reduced critical micelle concentration (CMC). However, the reduced CMC itself seems not to be responsible for the lowered irritation, since these experiments were conducted at concentrations well above the CMC. It is proposed that the critical event leading to skin irritation is binding to skin protein and that in mixed surfactant systems, the individual surfactants exhibit less affinity for this protein.

Betaine↗
PubMed1989

Is captopril effective in controlling blood pressure when administered once daily? An assessment using 24-h ambulatory blood pressure monitoring.

Twelve patients with essential hypertension receiving captopril monotherapy or captopril in conjunction with a diuretic had their 24-h blood pressure profiles monitored using an automatic, non-invasive ambulatory method. The study examined the efficacy of once a day versus twice a day administration of the ACE inhibitor in controlling blood pressure. Six untreated subjects with borderline hypertension were also studied using the same monitoring equipment and with the same frequency, to act as controls because of the possibility of repeated use of the device causing a 'familiarisation' effect. The results obtained indicated that if anything, the once daily dosing produced marginally better blood pressure values. The amplitude of the diurnal blood pressure variation was reduced on a 'second-wearing' of the monitoring equipment suggesting some degree of familiarisation with the apparatus.

Adult↗
PubMed1988

Malignant transformation of solar keratoses to squamous cell carcinoma.

1689 people aged 40 years and over were examined over a 5-year period to determine the incidence of malignant transformation of solar keratoses. They were seen on 2 consecutive years on 4267 occasions; a total of 21,905 solar keratoses were present on the first visit. A squamous cell carcinoma (SCC) developed within 12 months on 28 of the 4267 occasions. Where accurate mapping of both SCCs and pre-existing solar keratoses was available, it was found that 10/17 (60%) SCCs arose from a lesion diagnosed clinically as a solar keratosis in the previous year and the other 7 (40%) SCCs on what had been clinically normal skin 12 months previously. The risk of malignant transformation of a solar keratosis to SCC within 1 year was less than 1/1000. The cost-effectiveness of treating all solar keratoses to prevent the development of SCC is questionable.

Aged↗
PubMed1988

The relationship of basal cell carcinomas and squamous cell carcinomas to solar keratoses.

Six thousand four hundred sixteen people aged 40 years and over from three different locations in Victoria (Australia) were examined on the hands, forearms, head, and neck for the presence of solar keratoses and basal (BCCs) and squamous cell carcinomas (SCCs). Analysis of the relationship between these tumors revealed that the factors which predicted the likelihood of developing a solar keratosis were essentially the same as those that predicted the likelihood of developing a BCC and/or an SCC. These were age, sex, years of residence in Australia, indoor or outdoor occupation, tanning ability, propensity to sunburn, and location of residence. The presence of a coexisting solar keratosis was necessary for the development of an SCC in contrast to the development of a BCC. The findings suggest that unlike BCCs, the majority of SCCs in light-exposed areas may arise from preexisting solar keratoses. Whereas the prevalence of BCCs and SCCs was relatively constant in the three locations, the prevalence of solar keratoses differed markedly in direct relation to the degree of isolation. This suggests that solar keratoses are a more sensitive indicator of sunlight exposure than invasive carcinoma.

Adult↗
PubMed1985

Factors influencing pregnancy rates following in vitro fertilization and embryo transfer.

In 831 patients having 1533 in vitro fertilization treatments, pregnancy rates were examined in relation to clinical and laboratory factors. Pregnancy rates were significantly affected by the month and year of treatment, the age of the patient, the type of ovarian stimulation, the use of human chorionic gonadotropin, the number of eggs collected, the number of eggs fertilized, the number of embryos developed, and the number of embryos transferred. The most important factors determining pregnancy rates were the number of oocytes collected and the number of embryos transferred. The low pregnancy rate when only one egg was collected raises the problem of how to predict and manage such a patient in a current or future treatment cycle.

Adult↗
PubMed1983

Selection of high fertility donors for artificial insemination programmes.

One hundred and seventy-seven semen donors were used in an artificial insemination service using frozen semen over a 4 year period. Although the donors were selected for good semen quality, pregnancy rates varied markedly from less than five to greater than 20 pregnancies per 100 treatment cycles. When the characteristics of the 25 most fertile and 25 least fertile donors were compared, only sperm morphology was significantly different. Sperm concentration and motility before and after thawing of semen were similar in the two groups as were the proportions of adverse prognostic factors in the recipients. It is concluded that using more stringent criteria for selection of donors on the basis of sperm morphology and discarding donors who do not produce pregnancies within 12 cycles should improve overall pregnancy rates.

Adolescent↗