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Biomedical subjects

J A Lowe

Publications and source records attributed to J A Lowe.

At least 19 recordsLinked to original sources
PubMed2005

The effects of climate change on storm surges around the United Kingdom.

Coastal flooding is often caused by extreme events, such as storm surges. In this study, improved physical models have been used to simulate the climate system and storm surges, and to predict the effect of increased atmospheric concentrations of greenhouse gases on the surges. In agreement with previous studies, this work indicates that the changes in atmospheric storminess and the higher time-average sea-level predicted for the end of the twenty-first century will lead to changes in the height of water levels measured relative to the present day tide. However, the details of these projections differ somewhat from earlier assessments. Uncertainty in projections of future extreme water levels arise from uncertainty in the amount and timing of future greenhouse gas emissions, uncertainty in the physical models used to simulate the climate system and from the natural variability of the system. The total uncertainty has not yet been reliably quantified and achieving this should be a priority for future research.

Climate↗
PubMed2002

Predictions of extreme precipitation and sea-level rise under climate change.

Two aspects of global climate change are particularly relevant to river and coastal flooding: changes in extreme precipitation and changes in sea level. In this paper we summarize the relevant findings of the IPCC Third Assessment Report and illustrate some of the common results found by the current generation of coupled atmosphere-ocean general circulation models (AOGCMs), using the Hadley Centre models. Projections of changes in extreme precipitation, sea-level rise and storm surges affecting the UK will be shown from the Hadley Centre regional models and the Proudman Oceanographic Laboratory storm-surge model. A common finding from AOGCMs is that in a warmer climate the intensity of precipitation will increase due to a more intense hydrological cycle. This leads to reduced return periods (i.e. more frequent occurrences) of extreme precipitation in many locations. The Hadley Centre regional model simulates reduced return periods of extreme precipitation in a number of flood-sensitive areas of the UK. In addition, simulated changes in storminess and a rise in average sea level around the UK lead to reduced return periods of extreme high coastal water events. The confidence in all these results is limited by poor spatial resolution in global coupled models and by uncertainties in the physical processes in both global and regional models, and is specific to the climate change scenario used.

Altitude↗
PubMed1999

The scope of unmet maternal health needs in pediatric settings.

OBJECTIVE: Previous work has focused attention on the prevalence of specific maternal health problems known to affect children, such as smoking or depression. However, the cumulative health burden experienced by mothers and the potential for a practical pediatric health services response have not been examined. The aims of this study were to characterize: 1) the prevalence and cumulative burden of maternal health behaviors and conditions, 2) maternal access to a source of comprehensive adult primary care, and 3) maternal perceptions of a pediatric role in screening and referral. METHODS: We surveyed 559 consecutive women bringing a child 18 months of age or less to one of four pediatric primary care sites between July 1996 and May 1997. The pediatric sites included one outpatient program in an academic hospital, one in a community health center, and two in-staff model practices of a managed care organization (these last two were combined for analysis). The self-administered questionnaire contained previously validated questions to assess health behaviors and conditions (smoking, alcohol abuse, depression, violence, risk for unintended pregnancy, serious illness, self-reported health) and access to care (regular source, regular provider, health insurance, care delayed or not received). Maternal attitudes toward a pediatric role in screening and referral were also elicited. RESULTS: In the three settings, response rates ranged from 75% to 84%. The average age of the women ranged from 25.1 to 32. 1 years and the average age of the children ranged from 6.5 to 8.0 months. Across the settings, the percentage of women reporting at least one health condition (66%-74%) was similarly high, despite significant demographic differences among sites. Many women reported more than one condition (31%-37%); among all women who smoked, 33% also screened positive for alcohol abuse, 31% for emotional or physical abuse, and 48% for depression. Access to comprehensive adult primary care was variable with 23% to 58% of women reporting one or more barriers depending on the site. Across all sites, >85% of mothers reported they would "not mind" or "would welcome" a pediatric role in screening and referral. CONCLUSIONS: Two-thirds of women bringing their children for pediatric care had health problems regardless of the site of care. Many women also reported substantial barriers to comprehensive health care. Most women reported acceptance of a pediatric role in screening and referral. Given the range and depth of maternal health needs, strategies to connect or reconnect mothers to comprehensive adult primary care from a variety of pediatric settings should be explored.

Adult↗
PubMed1998

CB1 receptor antagonist precipitates withdrawal in mice exposed to Delta9-tetrahydrocannabinol.

Although tolerance to cannabinoids has been well established, the question of cannabinoid dependence had been very controversial until the discovery of a cannabinoid antagonist, SR141716A. The objective of this study was to develop and characterize a mouse model of precipitated withdrawal indicative of cannabinoid dependence. Using a dosing regimen known to produce pharmacological and behavioral tolerance, mice were treated with Delta9-tetrahydrocannabinol (Delta9-THC) twice a day for 1 wk. SR141716A administration after the last Delta9-THC injection promptly precipitated a profound withdrawal syndrome. Typical withdrawal behavior was an increase in paw tremors and head shakes that was accompanied with a decrease in normal behavior such as grooming and scratching. Of the three Delta9-THC regimens tested, daily Delta9-THC injections of 10 and 30 mg/kg produced the greatest number of paw tremors and head shakes and the least number of grooms after challenge with SR141716A. Precipitated withdrawal was apparent after 2, 3, 7 and 14 days of treatment based on an increase in paw tremors in Delta9-THC-treated mice as compared with vehicle-treated mice. These findings are consistent with SR141716A-precipitated withdrawal in rats. Moreover, these results suggest that mice are a viable model for investigating dependence to cannabinoids.

Analysis of Variance↗
PubMed1997

Characterization of non-peptide antagonist and peptide agonist binding sites of the NK1 receptor with fluorescent ligands.

Ligand recognition of the NK1 receptor (substance P receptor) by peptide agonist and non-peptide antagonist has been investigated and compared by the use of fluorescent ligands and spectrofluorometric methods. Analogues of substance P (SP) labeled with the environment-sensitive fluorescent group 5-dimethylaminonaphthalene-1-sulfonyl (dansyl) at either position 3, 8, or 11 or with fluorescein at the Nalpha position were synthesized and characterized. Peptides modified at the alpha-amino group or at positions 3 or 11 conserved a relatively good affinity for NK1 and agonistic properties. Modification at position 8 resulted in an 18, 000-fold decrease in affinity. A fluorescent dansyl analogue of the non-peptide antagonist CP96,345 was prepared and characterized. The quantum yield of fluorescence for dansyl-CP96,345 was much higher than for any of the dansyl-labeled peptides indicating that the micro-environment of the binding site is more hydrophobic for the non-peptide antagonist than for the peptide agonists. Comparison of collisional quenching of fluorescence by the water-soluble hydroxy-Tempo compound showed that dansyl-CP96,345 is buried and virtually inaccessible to aqueous quenchers, whereas dansyl- or fluoresceinyl-labeled peptides were exposed to the solvent. Anisotropy of all fluorescent ligands increased upon binding to NK1 indicating a restricted motional freedom. However, this increase in anisotropy was more pronounced for the dansyl attached to the non-peptide antagonist CP96,345 than for the fluorescent probes attached to different positions of SP. In conclusion, our data indicate that the environment surrounding non-peptide antagonist and peptide agonists are vastly different when bound to the NK1 receptor. These results support recent observations by mutagenesis and cross-linking work suggesting that peptide agonists have their major interaction points in the N-terminal extension and the loops forming the extracellular face of the NK1 receptor. Our data also suggest that neither the C terminus nor the N terminus of SP appears to penetrate deeply below the extracellular surface in the transmembrane domain of the receptor.

Animals↗
PubMed1997

Cardiovascular effects of cholecystokinin-4 are mediated by the cholecystokinin-B receptor subtype in the conscious guinea pig and dog.

Panicogenic effects in humans of the selective cholecystokinin (CCK(B)) receptor agonist, cholecystokinin tetrapeptide (CCK4), have been reported to correlate with increases in heart rate (HR) and mean arterial pressure (MAP). Previous investigators have demonstrated that the nonselective CCK(A) and CCK(B) receptor agonist, sulfated cholecystokinin octapeptide, also produces increases in HR and mean arterial pressure. The purpose of our study is to determine if the cardiovascular changes induced by CCK4 are mediated by the CCK(A) or CCK(B) receptor subtype using selective CCK antagonists for both receptor subtypes. The rank order of potency of the CCK receptor antagonists affecting CCK4-induced HR and mean arterial pressure changes in the guinea pig corresponded to the rank order of potency for blockade of the CCK(B) receptor binding in rat cortex, phosphatidyl inositol turnover in AR 4-2J rat pancreatoma cells and inhibition of pentagastrin-induced acid secretion in the rat. The changes induced by CCK4 on HR, but not mean arterial pressure, appear to be species dependent as reflected by a decrease in the HR in the guinea pig and an increase in the dog. Nonetheless, the results from the antagonist studies indicate that the cardiovascular responses to CCK4 in both the guinea pig and dog are mediated by the CCK(B) receptor subtype.

Animals↗
PubMed1996

Design of novel cholecystokinin-B receptor ligands based on the 'double-ring system' approach.

A structurally novel series of cholecystokinin-B (CCK-B) receptor ligands has been designed and synthesized based on the 'double ring system' theory of receptor recognition. Compounds 2b-cis and 2g-cis from this 1-amino-2-benzyltetralin series show modest CCK-B receptor affinity, with IC50 values of 48.5 nM and 39.0 nM, respectively. The results are discussed in the context of ongoing efforts to identify the CCK-B receptor binding site for nonpeptide ligands.

Binding Sites↗
PubMed1996

3-Benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents.

A series of substituted phenethyl derivatives of 3-benzisothiazolylpiperazine incorporating potent D2 and 5-HT2A antagonist activity was investigated as an approach to a novel atypical antipsychotic agent. The in vitro profile of 8e from this series is a combination of D2 receptor affinity comparable to the typical antipsychotic agent haloperidol and a 5-HT2A/D2 ratio comparable to the atypical agent clozapine. In vivo 8e possesses activity consistent with an efficacious antipsychotic agent with less tendency to induce extrapyramidal side effects in man.

Amphetamine↗
PubMed1996

Effects of the cannabinoid CB1 receptor antagonist SR141716A on the behavior of pigeons and rats.

SR141716A (Sanofi Recherche), a pyrazole derivative with high affinity for rat and human CB1 cannabinoid receptors, has recently been reported to reverse biochemical, physiological and behavioral effects induced by cannabinoid agonists. The present experiments characterized the activity of SR141716A (SR) in behavioral procedures designed to assess its antagonistic and intrinsic effects on unconditioned behavior and on complex learned behaviors. Six adult male pigeons were trained to discriminate injections of 0.56 mg/kg delta 9-tetrahydrocannabinol (delta 9-THC) from vehicle under a two-key, fixed-ratio schedule of food reinforcement. SR (IM) produced a nearly complete blockade of THC-appropriate responding occasioned by the training dose without inducing significant changes in session response rates, but also produced partial substitution for delta 9-THC when administered alone. In another group of pigeons trained under a multiple schedule of signaled and unsignaled fixed consecutive number (FCN) responding, SR had little effect on accuracy, but delta 9-THC produced dose-related decreases in accuracy under both schedule components. SR was also evaluated in acoustic startle procedures in rats. SR produced little effect either on startle amplitude or prepulse inhibition of acoustic startle. In contrast, the potent cannabinomimetic CP-55, 940 produced large decreases in startle responses elicited by 120 dB [A] broad-band noise. These decreases were completely reversed by SR (10 mg/kg, IP). In concurrent measures, SR blocked the hypothermic effect CP-55,940. These results suggest that SR is an effective antagonist of the psychoactive effects of cannabinoids.

Animals↗
PubMed1996

BIRMA-K3, a new monoclonal antibody for CD34 immunophenotyping and stem and progenitor cell assay.

A murine monoclonal antibody with specificity for the CD34 antigen has been produced and designated BIRMA-K3. The antibody characterized as IgG1(kappa) has been shown to react with KG-1a cells following treatment of the cells with glycoprotease enzyme, indicating reactivity with the class III epitope of CD34. It was possible to show that class I and class II anti-CD34 antibodies were not able to inhibit binding of BIRMA-K3. Investigation of FITC-labeled as well as PE-labeled BIRMA-K3 resulted in a clear cut-off staining of acute leukemias and CD34+ cell counts in patients submitted to high-dose chemotherapy and stem cell transplantation. The results obtained correlate strongly with those from HPCA-2, the Becton-Dickinson class III antibody.

Animals↗
PubMed1996

Photoaffinity labeling of the human substance P (neurokinin-1) receptor with [3H2]azido-CP-96,345, a photoreactive derivative of a nonpeptide antagonist.

An azido derivative of [3H2](2S, 3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl) methyl)-1-azabicyclo[2.2.2]octon-3-amine (CP-96,345), a potent nonpeptide antagonist of the substance P (SP) (neurokinin-1) receptor, was synthesized and shown to have an affinity for the human SP receptor similar to that of the parent compound, CP-96,345. When Chinese hamster ovary cells expressing the human SP receptor were photolabeled with this compound and analyzed with the use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography, several radioactive bands were observed, including a major band centered at molecular mass 80 kDa, the expected value for the SP receptor expressed in Chinese hamster ovary cells. Only the labeling of the 80-kDa protein was specific: nonradiolabeled CP-96,345 but not its optical enantiomer, CP-96,344 was a potent inhibitor of photoincorporation. SP prevented photolabeling only at concentrations higher than expected from its binding affinity but similar to those shown in a competition binding assay to displace radioiodinated analogue of CP-96,345. Antiserum generated against a synthetic peptide corresponding to the carboxyl terminus of the human SP receptor immunoprecipitated only the 80-kDa photoaffinity labeled protein, confirming that it is the human SP receptor. Interestingly, a second antiserum that was generated against the third extracellular loop of the G protein-coupled receptor no longer immunoprecipitated the receptor when covalently labeled with [3H2]azido-CP-96,345. This result indicates either that attachment of the antagonist modified the antigenic region directly, suggesting involvement of this domain in the binding of CP-96,345, or that the loss of recognition by the antiserum is secondary to a change in conformation induced by the covalent attachment of the antagonist at a different site.

Affinity Labels↗