The prevalence of adult onset wheeze: longitudinal study.
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Adolescent↗
Biomedical subjects
J Little
Publications and source records attributed to J Little.
Childhood cancer and neural tube defects.
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Brain Neoplasms↗
[Aspirin, non-steroidal anti-inflammatory agents and colonic carcinogenesis].
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Animals↗
Head and neck cancer: oral care during radiotherapy.
For patients with head and neck cancer who are compromised by the side-effects of radiotherapy, effective mouth care is essential. This article describes the detrimental effects of radiotherapy to the oral cavity and provides a practical guide to oral cleansing.
Head and Neck Neoplasms↗
The adenoma-carcinoma sequence and prospects for the prevention of colorectal neoplasia.
Colorectal adenomatous polyps are thought to be precursors of colorectal cancer. This article reviews the evidence for the adenoma-carcinoma sequence and possible interventions in regard to the prevention of colorectal cancer. Although there is no direct evidence to support the adenoma-carcinoma sequence, there is considerable indirect evidence from a range of epidemiological, histopathological, and molecular genetic studies. Sigmoidoscopy and fecal occult blood testing may offer the potential for secondary prevention, but screening based on either of these methods in the general population has not yet been shown conclusively to be effective and efficient. Although the importance of dietary factors in the etiology of colorectal lesions suggests that there may be potential for primary prevention through dietary modification or nutrient supplementation, few trials have been completed to date. Although observational studies suggest that the incidence of colorectal cancer may be reduced by as much as 50% by the use of aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs), further research is needed to determine the effects of individual NSAIDs and the appropriate prophylactic dose and to develop new NSAIDs with reduced gastrointestinal side-effects. Other strategies for primary prevention could focus on interventions to increase physical activity levels, to encourage smoking cessation, and to moderate alcohol consumption. Potential areas for further research are proposed.
Adenoma↗
Extended therapy with intravenous arginine butyrate in patients with beta-hemoglobinopathies.
BACKGROUND: Enhanced production of fetal hemoglobin lessens the severity of beta-thalassemia and sickle cell disease. Intravenous infusion of arginine butyrate can increase the number of reticulocytes containing fetal hemoglobin in patients with these disorders, and it has induced a substantial increase in hemoglobin in one patient with thalassemia. We therefore tested the efficacy of this agent in patients with beta-hemoglobinopathies. METHODS: We treated 10 patients with severe beta-thalassemia or sickle cell disease with arginine butyrate at an initial dose of 500 mg per kilogram of body weight per day (final dose, 2000 mg per kilogram per day), 6 days per week, for a mean (+/- SD) of 10 +/- 1.2 weeks (range, 9 to 13). A hematologic response was defined as an increase in the hemoglobin concentration of at least 2 g per deciliter in patients with thalassemia and as a twofold increase in the fetal hemoglobin concentration in patients with sickle cell disease. RESULTS: Increase in gamma-globin messenger RNA and in reticulocytes containing fetal hemoglobin but not in hemoglobin were observed in the patients with thalassemia. A small, unsustained increase in fetal hemoglobin was observed in two patients with sickle cell disease. Drug toxicity was minimal at standard doses. One patient had a grand mal seizure after inadvertently receiving 2000 mg of arginine butyrate per kilogram over a period of six hours. CONCLUSIONS: Ten weeks of intravenous arginine butyrate did not produce a hematologic response in 10 patients with either severe beta-thalassemia or sickle cell disease.
Adolescent↗
Treatment of angina pectoris in the community: is medical therapy given a chance?
OBJECTIVE: To describe the routine management of patients with chronic stable angina by GPs in Northern Ireland and the factors which they perceived affected the success of medical therapy. DESIGN: A questionnaire survey of all general practitioners in Northern Ireland (n = 962). SETTING: A survey conducted collaboratively by the Departments of Public Health Medicine in each of the four Health Boards in the province. Total population served, 1.5 million. MAIN OUTCOME MEASURES: The relationship between the perceived reasons for medical treatment failure and the stated referral and prescribing practice of the GPs. RESULTS: A total of 541 GPs replied; the response rate was 56%. The two most important reasons given for the perceived failure of medical therapy were (i) underlying disease progression and (ii) an adverse patient lifestyle such as smoking or obesity (cited as of primary importance by (i) 264 and (ii) 225 doctors respectively). The ranking differed significantly according to the doctor's propensity to prescribe triple therapy, with those doctors in the highest tertile of this distribution being less likely to cite the patient's lifestyle as a primary reason for treatment failure (chi-squared = 6.7, d.f. = 2, P = 0.035) and more likely to cite underlying disease progression as a primary reason (chi-square = 7.0, d.f. = 2, p = 0.031). The overall ranking of the primary reasons for referral differed significantly according to the proportion of patients given a trial of triple therapy and to the doctor's propensity to refer. Doctors who had given a greater proportion of their patients at least a trial of triple therapy (in the highest tertile of the distribution) were more likely to cite the need for revascularisation assessment as the primary reason (chi-square = 12.5, d.f. = 2, P = 0.0019). On the other hand, the need for further advice on medical therapy was generally ranked higher by those doctors who had given fewer of their patients at least a trial of triple therapy (chi-square = 7.3, d.f. = 2, P = 0.027). GPs who had referred fewer of their new patients to hospital were more likely to be those doctors with fewer patients given at least a trial of triple therapy. Doctors with a greater percentage of their patients managed primarily by a hospital specialist tended to have more who had had a trial of triple therapy for their symptoms. CONCLUSIONS: The results suggest the need for clearer definition for GPs of the place of revascularisation and of medical therapy for patients with stable angina.
Angina Pectoris↗
Expanding access to coronary artery bypass surgery: who stands to gain?
OBJECTIVE: To determine the perceptions of general practitioners (GPs) about the benefits of coronary artery bypass surgery, in terms of gains in life expectancy, for different groups of patients. DESIGN: A questionnaire survey of all GPs in Northern Ireland. SETTING: A survey conducted collaboratively by the departments of public health medicine in each of the four health boards in the province, serving a total population of 1.5 million. MAIN OUTCOME MEASURES: The median and mean gain in life expectancy perceived by groups of doctors for smoking and non-smoking male and female 55 year old patients. The percentage of 50 year old and 70 year old non-smoking patients considered likely to have their lives extended with bypass surgery. Differences were assessed using the Mann-Whitney U test for unpaired samples and the Wilcoxon signed rank tests for paired. RESULTS: 541 GPs replied (response rate 56%). The median (and mean) perceived gain in life expectancy after cardiac surgery for non-smoking 55 year old subjects was 120 (104) months for men and 120 (112) months for women (z = 6.42; P < 0.0001; Wilcoxon signed rank test). For male and female smokers of the same age, the perceived gains were 48 (47) and 60 (52) months respectively (z = 6.72; P < 0.0001; Wilcoxon signed ranks test), both figures being significantly different than for non-smokers. The median (and mean) percentage of patients that the doctors considered would have their lives extended by bypass surgery was 70 (64) of every 100 "young" patients and 40 (42) of every 100 "old" patients, (z = 16.2; P < 0.0001). CONCLUSIONS: These results point to a significant overestimation of the benefits of coronary artery bypass surgery by GPs in Northern Ireland and to a need to develop guidelines for referral.
Age Factors↗
Pharmacological characterization of a new class of nonpeptide neurokinin A antagonists that demonstrate species selectivity.
We examined the pharmacology of ZM253,270 and two representative examples of the pyrrolopyrimidines, a new class of nonpeptide, NK-2 receptor (NK-2R) antagonists. ZM253,270 competitively inhibited [3H]NKA binding to native or cloned NK-2R from hamster urinary bladder (Ki = 2 nM), but was a weaker (48-fold) inhibitor of [3H]NKA binding to cloned human NK-2R. A similar species selectivity was observed with less potent analogs of ZM253,270. The pyrrolopyrimidines demonstrated only marginal inhibition of [3H]SP binding to NK-1R in guinea pig lung membranes (Ki > 2 microM). In hamster trachea, ZM253,270 competitively antagonized the contractile response evoked by neurokinin A (NKA, -logKB = 7.5). In human bronchus, ZM253,270 was about 90-fold less potent as a competitive antagonist of NKA. The data from ligand binding assays in cloned receptors combined with functional receptor assays in airway smooth muscles, demonstrate that the nonpeptide antagonist ZM253,270 is selective for the NK2 receptor species that are prevalent in hamster, compared with those found in human tissues.
Animals↗
Photoaffinity labeling for evaluation of uridinyl analogs as specific inhibitors of rat liver microsomal UDP-glucuronosyltransferases.
The UDP-glucuronosyltransferases (UGT) involved in glucuronidation of endogenous and exogenous toxic compounds transfer the glucuronic acid residue from UDP-glucuronic acid (UDP-GlcUA), to various acceptor groups. A series of compounds that contain N-acyl phenylaminoalcohol derivatives linked to uridine or isopropylideneuridine were tested as UGT inhibitors. The potency of these inhibitors was determined by studying their effect on the photoaffinity labeling of rat liver microsomal UGTs by two photoaffinity probes, [beta-32P]5-azido-UDP-glucuronic acid (5N3UDP-GlcUA) and [beta-32P]5-azido-UDP-glucose (5N3UDP-Glc) and on the enzymatic formation of the two glucuronide conjugates (3-O- and carboxyl-specific) of lithocholic acid. All but one of the compounds tested proved to have an inhibitory effect on UGTs, both in the photoaffinity labeling system and in the enzymatic glucuronidation assay. In the photoaffinity labeling system, the inhibitors containing the isopropylidene moiety were less effective than their unprotected derivatives; however, the protected forms were, with one exception, more potent inhibitors of enzymatic activity. The photoaffinity labeling of UGTs with [beta-32P]5N3UDP-Glc was more susceptible to inhibition by all derivatives than that with [beta-32P]5N3UDP-GlcUA. The effect of one inhibitor, PP50B, on the two enzymatic activities involved in LA glucuronidation was extensively tested. A double-reciprocal plot suggested a competitive inhibition for UDP-GlcUA with an apparent Ki of 35 microM for LA 3-O-glucuronide formation and 94 microM for the carboxyl-linked glucuronide of the same substrate.
Affinity Labels↗
Resistance of the hookworms Ancylostoma ceylanicum and Necator americanus to intestinal inflammatory responses induced by heterologous infection.
Experiments were carried out to ascertain whether the acute inflammatory phase of the intestinal response of hamsters to infection with Trichinella spiralis would adversely affect hookworms in concurrently infected animals. The survival and growth of hookworms were unaffected. However, the presence of hookworms reduced the establishment of T. spiralis, the initial growth of female worms and their fecundity. The expulsion of T. spiralis was also significantly slower in concurrently infected animals and there was significant depression of the serum IgG antibody response to muscle stage and adult worm antigens of T. spiralis in concurrently infected animals. These results are discussed in relation to the chronicity of human hookworm infections.
Acute Disease↗
Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17.
Fourteen Caucasian families with 81 affected individuals have been assessed in which polycystic ovaries/male pattern baldness (PCO/MPB) segregates as an autosomal dominant phenotype (1). The gene CYP17, coding for P450c17 alpha (17 alpha-hydroxylase; 17/20 lyase) on chromosome 10q24.3 is the rate-limiting step in androgen biosynthesis. We have identified a new single base change in the 5' promoter region of CYP17 by heteroduplex analysis. This creates an additional SP1-type (CCACC box) promoter site, which may cause increased expression. This base change also creates a recognition site for the restriction enzyme MspA1 allowing a simple screening procedure. There is a significant association between the presence of this base change (A2) and the affected state for consecutively identified Caucasian women with PCO as compared either to consecutively matched controls (P = 0.03) with an odds ratio for those with at least one A2 allele of 3.57, or to a random population (P = 0.02) with an odds ratio of 2.50. Within the fourteen families, members with PCO or MPB have a significant association with the occurrence of at least one A2 allele compared to their normal relatives, with an odds ratio of 2.20 (P = 0.05). The base change does not cosegregate with the affected phenotype within the families showing association, demonstrating that this mutation of CYP17 does not cause PCO/MPB. Variation in the A2 allele of the CYP17 gene is a significant factor modifying the expression of PCO/MPB in families where it has been demonstrated to segregate as a single gene disorder, but it is excluded as the primary genetic defect.
Alleles↗
Exposure to passive smoking during pregnancy and childhood, and cancer risk: the epidemiological evidence.
There are relatively few studies on the association between environmental tobacco smoke (ETS) during pregnancy and childhood, and cancer in childhood, adolescence or adulthood. The associations between maternal smoking during pregnancy and childhood cancer have been studied intensively, but there is no clear association overall, or for specific sites. The association between childhood cancer and smoking by the father in the preconceptional period, and by either parent during the child's lifetime, has been little studied. Again, no clear associations have been identified. However, evidence from studies of exposure to known carcinogens from ETS, and of genotoxic effects indicates that any effect, if present, is expected to be weak, and therefore could not have been detected by most of the studies which have been performed, due to the small number of cases included. There is some consistency of association between ETS exposure in childhood and the risk of lung cancers in adulthood. There is therefore a need for further epidemiological studies on ETS exposure during pregnancy and childhood and the occurrence of cancers.
Adolescent↗
Is choice of general practitioner important for patients having coronary artery investigations?
OBJECTIVE: To determine whether particular sociodemographic characteristics of patients with stable angina affected their general practitioners' (GPs') decisions to refer them for revascularisation assessment. DESIGN: Postal questionnaire survey. SETTING: Collaborative survey by the departments of public health medicine in each of the four health boards in Northern Ireland, serving a total population of 1.5 million. SUBJECTS: All (962) GPs. MAIN MEASURES: The relation between GPs' referral decisions and patients' age, sex, employment status, home circumstances, smoking habits, and obesity. RESULTS: 541 GPs replied (response rate 56%). Most were "neutral" towards a patient's sex (428, 79%), weight (331, 61%), smoking habit (302, 56%), employment status (431, 80%), and home circumstances (408, 75%) in making decisions about referral. In assigning priority for surgery most were neutral towards the patient's sex (459, 85%), employment status (378, 70%), and home circumstances (295, 55%). However, most GPs (518, 95%) said that younger patients were more likely to be referred, and a significant minority were less likely to refer patients who smoked (202, 37%) and obese patients (175, 32%) and more likely to refer employed patients (97, 18%) and those with dependents (117, 22%) (compared with patients with otherwise comparable clinical characteristics); these views paralleled the priority which GPs assigned these groups. The stated likelihood of referral of young patients was independent of the GPs' belief in ability to benefit from revascularisation, but propensity to refer and perception of benefit were significantly associated for all other patient characteristics. CONCLUSION: GPs' weighting of certain characteristics in reaching decisions about referral for angiography is not uniform and may contribute to unequal access to revascularisation services for certain patient groups.
Age Factors↗
Isolation and characterization of neurokinin A receptor cDNAs from guinea-pig lung and rabbit pulmonary artery.
cDNA clones for NK-2 receptors (NK-2R) were isolated from guinea-pig lung (GPl) and rabbit pulmonary artery (Rpa) using a polymerase chain reaction based methodology. The GPl NK-2R consists of 402 amino acids and encodes a protein with a relative molecular mass of 45,097. The Rpa NK-2R consists of 384 amino acids and encodes a protein with a relative molecular mass of 43,169. The GPl and Rpa NK-2Rs share significant amino acid sequence homology amongst themselves (90.1%), as well as with human, bovine, hamster and rat NK-2 receptors. The two receptors were stably transfected into mouse erythroleukemia cells, high-speed membranes were prepared from induced cells and their pharmacological properties examined utilizing [3H]-NKA in a receptor-binding assay. [3H]NKA bound to both NK-2Rs with high affinity (KD = 2-7 nM) and saturable (Bmax = 633-9000 fmol/mg protein) manner which was inhibited by GTP analogs. Competition experiments with agonists demonstrated identical order of potency in both NK-2Rs; NKA > [Nle10]NKA(4-10) > [beta-Ala8]NKA(4-10) > > Substance P > > > Senktide. Similarly, an identical profile for both receptors was observed with selective NK-2 antagonists: SR48,968 > MEN10,376 > > R396. The rank order of antagonist affinity is consistent with that in cloned human NK-2R and the observations of NK-2 receptor pharmacology in native human, guinea pig and rabbit tissues.
Amino Acid Sequence↗
Expression of rat NK-2 (neurokinin A) receptor in E. coli.
With the goal of obtaining sufficient functional protein for structural analysis, rat neurokinin-2 receptor was produced in Escherichia coli by linking it to the periplasmic maltose-binding protein. As a first step, we present a biochemical and pharmacological investigation of the recombinant receptor. Western-blots showed that the fusion protein was associated with the membranes. The agonist [4,5-3H-Leu9]neurokinin A and the NK-2 antagonist [3H]SR48,968 bound to the receptor in a highly specific manner. Saturation binding of the [3H]agonist demonstrated a single class of receptors (KD = 10.5 nM, Bmax = 2.5 pmol/mg protein). The [3H]antagonist bound with higher affinity to a larger receptor population (KD = 0.2 nM, Bmax = 7.2 pmol/mg protein). Competition of [3H]agonist binding with other agonists demonstrated a potency order of: neurokinin A > [Nle10]NKA(4-10) = [beta-Ala8]NKA(4-10) >> substance P >>> senktide Against the [3H]antagonist, agonists were only partially inhibitory. Selective NK-2 antagonists inhibited binding of both [3H]ligands with an identical order of potency: SR48,968 >> R396 > MEN10,376, which is consistent with NK-2 receptor pharmacology in rat tissue.
ATP-Binding Cassette Transporters↗
Isolation and pharmacological characterization of a hamster urinary bladder neurokinin A receptor cDNA.
Functional cDNA clones for hamster neurokinin-2 receptor (NK-2R) were isolated from hamster urinary bladder using a polymerase chain reaction-based methodology. The hamster NK-2R consists of 384 amino acids with a relative molecular weight of 43,418. Hamster NK-2R shares significant amino acid sequence homology with other tachykinin receptors, particularly with rat, bovine, and human NK-2R (94.3, 84.4, and 86.5%, respectively). To examine the pharmacology of cloned hamster NK-2R, we transfected mouse erythroleukemia cells with this receptor, prepared high speed membranes, and studied the receptor properties utilizing the ligand [4,5-3H-Leu9]NKA in a receptor-binding assay. For pharmacological comparison, we also transfected the human NK-2R into mouse erythroleukemia cells. [3H]NKA bound to hamster NK-2R receptor in a protein-dependent, high affinity (Kd1 = 4.14 +/- 0.31 nM), saturable (Bmax1 = 679 +/- 26 fmol/mg of protein), and highly specific manner (89 +/- 2%). A smaller population (10% density) of lower affinity receptors (Kd2 = 150 +/- 92 nM), was also observed in competition experiments. [3H]NKA bound to the human receptor with significantly higher affinity and overall greater receptor density (Kd1 = 0.37 +/- 0.11 nM, Bmax1 = 234 +/- 175 fmol/mg of protein; Kd2 = 9.0 +/- 2 nM, Bmax2 = 1989 + 990 fmol/mg of protein). [3H]NKA binding to both hamster and human receptors was enhanced greatly by divalent cations, whereas GTP analogs weakly inhibited binding to hamster receptor, but potently inhibited binding to the human receptor. Competition experiments with agonists demonstrated binding to high and low affinity states of NK-2 receptors, with identical order of potency in hamster or human NK-2R; NKA > [Nle10]NKA(4-10) > [beta-Ala8]NKA(4-10) >> substance P >>> Senktide. However, remarkable differences were observed in studies with selective NK-2 antagonists (hamster, SR48,968 > L659,877 > R396 >> MEN10,376 versus human, SR48,968 > MEN10,376 > L659,877 > R396). The rank order of antagonist affinity is consistent with the observations of NK-2 receptor pharmacology in the native tissues.
Amino Acid Sequence↗
Effects of chronic lithium treatment on platelet PKC isozymes in Alzheimer's and elderly control subjects.
Patients with Alzheimer's disease (AD) have been reported to have abnormalities in peripheral cells similar to some of those found in the brain, including decreased levels of protein kinase C (PKC) in fibroblasts. Since increasing evidence suggests that lithium affects PKC function, we investigated the effects of 3 weeks of lithium administration on the immunolabeling of 4 PKC isozymes (alpha, beta, epsilon, and zeta) in particulate and soluble fractions from platelets of 7 patients with probable AD and 6 age-matched controls. AD patients had significantly less particulate or membrane-associated PKC zeta than normals during the placebo phase (P < 0.003). After 3 weeks of lithium treatment, AD patients had significantly less membrane-associated PKC alpha (P < 0.002), epsilon (P < 0.003), and zeta (P < 0.001) than normals. This is the first report of a difference in PKC in blood cells between AD and control subjects. These findings appear to indicate that some PKC isozymes may be differentially regulated in AD versus elderly controls, at least as evidenced in this peripheral cellular system.
Aged↗