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1.  Characterization of propranolol-resistant (-)-[125I]-cyanopindolol binding sites in rat soleus muscle. 
British Journal of Pharmacology  1993;109(2):344-352.
1. The characteristics of a propranolol-resistant (-)-[125I]-cyanopindolol (CYP) binding site in rat soleus muscle were determined. 2. Saturation studies performed on homogenates of rat soleus muscle showed two phases of (-)-[125I]-CYP binding, a high affinity site (KD1 30.5 +/- 16.3 pM, Bmax 9.4 +/- 1.38 fmol mg-1 protein) and a lower affinity site (KD2 522.5 +/- 29.1 pM, Bmax 62.19 +/- 11.76 fmol mg-1 protein, n = 4). 3. In rat soleus muscle homogenates labelled with (-)-[125I]-CYP (500 pM), (-)-propranolol competition curves were biphasic with pKD values of 8.30 +/- 0.19, and 5.33 +/- 0.08, n = 7. 4. Competition between (-)-[125I]-CYP (500 pM) and (+/-)-tertatolol, (+/-)-nadolol, (+/-)-alprenolol, (+/-)-CYP, and (-) and (+)-pindolol showed that these compounds competed for binding at the propranolol-resistant site with affinities lower than those displayed at typical beta-adrenoceptors. The atypical beta-adrenoceptor agonists BRL 37344, SR58611A and ICI D7114 and the partial agonist (+/-)-CGP 12177 also competed for (-)-[125I]-CYP binding. 5. Stereoselectivity was demonstrated for the stereoisomers of alprenolol and tertalolol. The (-)-isomers of alprenolol and tertalolol had higher affinity than their corresponding (+)-isomers (3.1 and 2.6 fold respectively). These low stereoselectivity values are a characteristic of atypical beta-adrenoceptors. 6. The beta-adrenoceptor agonists, (-)-adrenaline, (-)-isoprenaline and (-)-noradrenaline, all showed lower affinity than the atypical beta-adrenoceptor agonists and competition curves appeared biphasic in nature.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC2175712  PMID: 8102926
2.  Prevention of renal scarring from pyelonephritis in nonhuman primates by vaccination with a synthetic Escherichia coli serotype O8 oligosaccharide-protein conjugate. 
Infection and Immunity  1993;61(12):5214-5218.
Rhesus monkeys were vaccinated with a synthetic Escherichia coli serotype O8 oligosaccharide-protein conjugate. Using our experimental pyelonephritis monkey model, we tested whether such immunization was protective against the renal damage from inflammation following experimental infection with a P-fimbriated O-antigenically homologous E. coli strain. The vaccination did not significantly alter the duration of bacteriuria or interfere with the infection. However, the vaccine was efficient in renal protection, as vaccinated animals showed significantly less intratubular infiltration of neutrophils (P < 0.02) and the degree of renal scarring was also significantly less in these animals (P > 0.005) than in the control animals. Total kidney involvement in the vaccinated animals was 16.9%, compared with 32.5% in the control animals (P = 0.07).
PMCID: PMC281303  PMID: 8225595
3.  Cost analysis of early discharge after hip fracture. 
BMJ : British Medical Journal  1993;307(6909):903-906.
OBJECTIVE--To ascertain the economic impact of an early discharge scheme for hip fracture patients. DESIGN--Population based study comparing costs of care for patients who had "hospital at home" as an option for rehabilitation and those who had no early discharge service available in their area of residence. SETTING--District hospital orthopaedic and rehabilitation wards and community hospital at home scheme. PATIENTS--1104 consecutively admitted patients with fractured neck of femur. 24 patients from outside the district were excluded. MAIN OUTCOME MEASURES--Cost per patient episode and number of bed days spent in hospital. RESULTS--Patients with the hospital at home option spent significantly less time as inpatients (mean of 32.5 v 41.7 days; p < 0.001). Those patients who were discharged early spent a mean of 11.5 days under hospital at home care. The total direct cost to the health service was significantly less for those patients with access to early discharge than those with no early discharge option (4884 pounds v 5606 pounds; p = 0.048). CONCLUSIONS--About 40% of patients with fractured neck of femur are suitable for early discharge to a scheme such as hospital at home. The availability of such a scheme leads to lower direct costs of rehabilitative care despite higher readmission costs. These savings accrue largely from shorter stays in orthopaedic and geriatric wards.
PMCID: PMC1679043  PMID: 8241853
4.  Expression and characterization of glycophospholipid-anchored human immunodeficiency virus type 1 envelope glycoproteins. 
Journal of Virology  1993;67(9):5279-5288.
Four chimeric human immunodeficiency virus type 1 (HIV-1) env genes were constructed which encoded the extracellular domain of either the wild-type or a cleavage-defective HIV-1 envelope glycoprotein (gp160) fused at one of two different positions in env to a C-terminal glycosyl-phosphatidylinositol (GPI) attachment signal from the mouse Thy-1.1 glycoprotein. All four of the constructs encoded glycoproteins that were efficiently expressed when Rev was supplied in trans, and the two cleavable forms were processed normally to gp120 and a chimeric "gp41." The chimeric glycoproteins, in contrast to the wild-type glycoprotein, could be cleaved from the surface of transfected cells by treatment with phosphatidylinositol-specific phospholipase C, indicating that they were anchored in the plasma membrane by a GPI moiety. These GPI-anchored glycoproteins were transported intracellularly at a rate only slightly lower than that of the full-length HIV-1 glycoprotein and were present on the cell surface in equivalent amounts. Nevertheless, all four glycoproteins were defective in mediating both cell-cell and virus-cell fusion as determined by syncytium formation in COS-1-HeLa-T4 cell mixtures and trans complementation of an env-defective HIV-1 genome.
PMCID: PMC237926  PMID: 8102410
5.  Age, sex, and temporary resident originated prescribing units (ASTRO-PUs): new weightings for analysing prescribing of general practices in England. 
BMJ : British Medical Journal  1993;307(6902):485-488.
OBJECTIVE--To derive demographic weightings to replace the existing system of prescribing units used in analysing prescribing by general practitioners in England. DESIGN--The prescribing data for one year from a sample of 90 practices in 80 family health service authority areas were used to calculate the relative frequency with which items were prescribed, for each sex, in nine age bands and for temporary residents. Data on the variation in cost per item by age and sex then allowed estimates to be made of the relative costs for these groups. Integer values for both the item based and cost based weightings were obtained by conversion to optimal integer scales. MAIN OUTCOME MEASURES--Item based and cost based weightings for each of the 18 age-sex groups and for temporary residents. The cost based weightings were considered more appropriate to the context in which the new system was to be used. RESULTS--Prescribing costs increased noticeably, for both sexes, in the middle years (ages 35-64). Compared with the existing system, the cost based weightings (ASTRO-PUs) gave greater weight to patients aged 45 and over, especially those in the 55-64 age band, at the expense of younger patients. Children under 5 received twice as many items as those aged 5-14, but the inexpensiveness of their drugs made the cost based weightings of the two groups equal. Similarly, women were generally given more items than men, but at a lower average cost per item, which reduced differences between the sexes in the cost based weightings. Costs for patients aged 75 and over, compared with those aged 65-74, were higher only for women. CONCLUSIONS--The cost based weightings proposed are believed to reflect the present distribution of prescribing costs, in relation to age and sex, in English general practice. They are intended for use in analyses at practice level.
PMCID: PMC1678776  PMID: 8305014
6.  Protective anti-idiotype antibodies in the primate model of pyelonephritis. 
Infection and Immunity  1993;61(6):2289-2295.
The adherence of P-fimbriated Escherichia coli to a receptor containing alpha-D-Gal-(1-4)-beta-D-Gal (Gal-Gal) on urothelial cells is an important pathogenic mechanism in the development of pyelonephritis. Antibodies (Ab1) that had been produced by immunization with Gal-Gal conjugated with bovine serum albumin were specifically purified and used to stimulate the production of anti-idiotypic antibodies (Ab2) in cynomolgus monkeys (Macaca fascicularis). While sera from all of the Ab2-producing monkeys contained antibodies reactive with Ab1 and P-fimbriae, not all of the sera inhibited P-fimbrial binding to the Gal-Gal receptor. On the basis of the inhibition of binding, Ab2-producing monkeys were divided into two groups, termed reactive and nonreactive. The reactive and nonreactive Ab2-producing monkeys, together with a group of control monkeys, were challenged with a renal inoculation with P-fimbriated Escherichia coli. Hematologic, immunologic, microbiologic, and pathologic data were compared among the three groups. The reactive monkeys, whose Ab2 in serum inhibited binding between P-fimbriae and the Gal-Gal receptor, were protected against renal damage compared with the control group. The nonreactive group shared some parameters with the reactive group but overall developed renal damage comparable to that of the controls.
PMCID: PMC280847  PMID: 8099064
7.  Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts. 
Journal of Clinical Investigation  1993;91(3):950-960.
In normal human pregnancy, invasion of the uterus and its arterial system by cytotrophoblasts extends through the entire decidua and the adjacent third of the myometrium. Our previous work showed that during the first trimester of pregnancy, invasion is accompanied by a marked change in the expression of cell adhesion molecules by invasive cytotrophoblasts. In the pregnancy disorder preeclampsia, cytotrophoblast invasion is limited to the superficial decidua, and few arterioles are breached. The purpose of this study was to determine whether cytotrophoblast expression of adhesion molecules in this disorder is also abnormal. Placental bed biopsy specimens from normal pregnancies and those complicated by preeclampsia were stained with anti-integrin antibodies. The results showed that adhesion molecule switching by invasive cytotrophoblasts is abnormal in preeclampsia, which suggests that this subpopulation of trophoblast cells fails to differentiate properly. A likely result is that the delicate balance of adhesive interactions that normally permit cytotrophoblast invasion is tipped in favor of those which restrain this process, with the net effect of shallow uterine invasion.
PMCID: PMC288047  PMID: 7680671
8.  Hyperphosphataemia after enemas in childhood: prevention and treatment. 
Archives of Disease in Childhood  1993;68(2):233-234.
The case of a child with severe hyperphosphataemia and symptomatic hypocalcaemia secondary to retention of phosphate administered through an antegrade continence enema is reported. Caution should be exercised with the use of phosphate enemas and prompt action taken to remedy retention. The use of glucose with insulin in the emergency management of acute hyperphosphataemia is discussed.
PMCID: PMC1029243  PMID: 8481047
9.  Oral piritrexim, an effective treatment for metastatic urothelial cancer. 
British Journal of Cancer  1993;67(2):388-390.
Piritrexim is a lipid-soluble inhibitor of dihydrofolate reductase (DHFR) that enters tumour cells rapidly by passive diffusion, cannot be polyglutamated, and is as effective as methotrexate in inhibiting DHFR. Bioavailability after oral dosing is approximately 75%. We performed a phase II study with oral piritrexim in non-chemotherapy pretreated patients with metastatic urothelial cancer. Thirty-three patients were treated with 25 mg three times daily for 5 consecutive days, repeated weekly, with provision for dose escalation or reduction according to the toxicity observed. Of 29 evaluable patients, one patient achieved a complete response of 19+ weeks duration, and ten patients achieved a partial response with a median duration of 22 weeks (range 16-48), for a total response rate of 38%. Piritrexim was generally well tolerated, with myelosuppression as the major toxicity, that frequently required dose modification. We conclude that piritrexim appears to be an active agent in patients with metastatic urothelial cancer when administered as a 5-day, low-dose oral schedule. It would be attractive to investigate the combination of piritrexim and cisplatin.
PMCID: PMC1968166  PMID: 8431372

Results 1-9 (9)