Clinical diaries: a compelling necessity.
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Appointments and Schedules↗
Biomedical subjects
B Jackson
Publications and source records attributed to B Jackson.
Effect of bradykinin on NaCl transport in the medullary thick ascending limb of the rat.
The aim of the present study was to determine whether bradykinin affects NaCl reabsorption in the medullary thick ascending limb of the loop of Henle. At 10(-8) M, bradykinin significantly inhibited Cl- transport in the in vitro microperfused rat medullary thick ascending limb by 67% (P < 0.01). This inhibitory effect could be totally prevented by preincubating tubules with the bradykinin B2 receptor antagonist N alpha-adamantaneacetyl-D-Arg-[Hyp3,Thi5,8,D-Phe7]brady kinin (10(-6) M). In contrast, the bradykinin B1 receptor agonist des-Arg9 bradykinin (10(-6) M) had no effect on Cl- transport. Bradykinin caused transient increases in intracellular Ca2+ concentration, which could be blocked by the bradykinin B2 receptor antagonist, but could not be reproduced with the bradykinin B1 receptor agonist. These data suggest that the natriuretic and diuretic effect of bradykinin in vivo is due, at least in part, to a bradykinin B2 receptor-mediated inhibition of NaCl reabsorption in the medullary thick ascending limb of the loop of Henle.
Animals↗
Effect of membrane environment on inhibition of acyl-CoA:cholesterol acyltransferase by a range of synthetic inhibitors.
The effect of the membrane environment of acyl-CoA:cholesterol acyl transferase (ACAT), an important intracellular enzyme of cholesterol metabolism, on the properties of a range of inhibitors of varying potencies was studied. ACAT activity from rat liver was solubilised with 3% deoxycholate (97% solubilised activity). After dilution into cholesterol/phosphatidylcholine liposomes (molar ratio 0.35), the assay of this reconstituted system showed linearity with protein and time. Saturation with oleoyl-CoA was achieved at 10 microM. Comparison of the potency of the ACAT inhibitors in the reconstituted assay and in a microsomal assay revealed a relationship between the lipid content of the assay and the inhibitory activity for potent inhibitors of ACAT (CI976, CL277,082, YMI7E and DuP128). This relationship was unrelated to lipophilicity of the drugs. Octimibate, lovastatin and progesterone, none of which is a potent ACAT inhibitor but which have all been described as ACAT inhibitors in the literature, all had low potencies in both assay systems. These results suggest that the lipid concentration must be taken into account when comparing potencies of ACAT inhibitors. The present data also indicate that some compounds which inhibit cholesterol esterification may do so by an indirect mechanism.
Anilides↗
Adenine nucleotide binding and photoincorporation in Glanzmann's thrombasthenia platelets.
Adenosine 5'-(1-thiotriphosphate) (ATP alpha S) binds to about 25,000 high affinity sites in platelets (Kd approximately 3 nM), competes fully in inhibiting the binding of ADP and, despite the absence of a specific photoactivatable substituent, is directly photoincorporated into a specific 18 kDa domain beginning at Tyr-198 in the alpha chain of glycoprotein IIb (GPIIb alpha) following ultraviolet irradiation of fresh unfixed platelets (Greco et al. (1991) J. Biol. Chem. 266, 13627-13633). 8-azido ATP has now been shown to have similar binding parameters (Kd 8 nM, 20,000 sites/platelet) but, in this case, photoincorporation occurred equally in GPIIb and GPIIIa. To determine the possible function of GPIIb alpha in ADP-induced activation, platelets were isolated from two Glanzmann's thrombasthenia patients whose platelets contain approximately 6% of normal levels of GPIIb. ADP and ATP alpha S bound to intact, formaldehyde-fixed Glanzmann's platelets at high affinity sites with dissociation constants of approximately 30 nM and approximately 2 nM, respectively. Both nucleotides also bound to low affinity sites with dissociation constants of approximately 2 microM: these values are similar to those obtained with control platelets. ATP alpha S antagonized the shape ADP-induced shape change response of Glanzmann's platelets (EC50 5 microM) indicating that it bound to the P2T (ADP) receptor. However, photoincorporation was low (approximately 7% of control) similar to their content of GPIIb alpha. These results show that ADP binding and photoincorporation are occurring at different sites on the platelet surface but suggest that the ADP binding site may be located in proximity to GPIIb alpha.
Adenine Nucleotides↗
Summary of the workshop on passive immunotherapy in the prevention and treatment of HIV infection. The Passive Antibody Workshop Participants.
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Clinical Trials as Topic↗
The response of the skeleton to physical training: a biochemical study in horses.
In this study we tested the hypothesis that exercise induces an adaptive response in the developing skeleton which may be monitored in vivo by measuring biochemical markers of bone metabolism. The effects of exercise on two biochemical markers of bone formation were determined; the carboxy-terminal propeptide of type I procollagen (PICP), and the bone-specific isoenzyme of alkaline phosphatase (BAP), and one putative marker of resorption, the pyridinoline crosslinked telopeptide domain of type I collagen (ICTP). All three markers were measured for a year in 2-year-old thoroughbred horses exercised three times a week on a treadmill, and values compared to a control group of age-matched animals. Levels of all three markers fell in both exercised and control groups over the 12-month period reflecting normal age changes. However, there were differences between groups in the pattern of this decrease. When expressed as a percentage of baseline values, BAP was higher (p < 0.05) at 2 months and both BAP and the PICP were higher at 4 months (p < 0.01 and p < 0.05, respectively) in the exercised group, reflecting an increase in bone turnover in this group in the early stages of training. PICP levels were also elevated in the exercised group at 10 months and this result indicates an increase in bone turnover at this time. The changes in ICTP were different; at 2 months, levels were higher in exercised animals than in controls, but there was no significant difference between the two groups at 4 and 6 months. After 8 months, ICTP levels in the exercised group increased returning to near baseline values at 10 months.(ABSTRACT TRUNCATED AT 250 WORDS)
Alkaline Phosphatase↗
A cost analysis of a case management system for infants with chronic illnesses and developmental disabilities.
Service coordination has long been a documented need of children with disabilities. The purpose of this study was to examine the costs associated with providing a comprehensive system of service coordination for hospitalized infants and toddlers with special health care needs and their families. Coordination costs were evaluated across seven functions including (a) determining eligibility for services, (b) identifying and arranging evaluations, (c) providing support to families, (d) making referrals to outside agencies, (e) exchanging information among service providers and families, (f) maintaining follow-up contact, and (g) determining discharge from the program. Results indicated that the service coordination function of providing family support was the most time-consuming task area, followed by the functions of exchanging information and maintaining follow-up contact. Costs also varied with the medical diagnosis and the child's age. Consistent with this variability, the diagnostic category and/or possibly the length of hospitalization was a better correlate of total cost of service coordination per child than was the number of months served. The complexity of the family's social and financial situation also appeared to be related to cost per month of service.
Case Management↗
Age related changes in biochemical markers of bone metabolism in horses.
Biochemical markers of bone metabolism were analysed in serum samples obtained from 60 horses with no history of orthopaedic disease (age 3 months-20 years). Serum levels of the carboxyterminal propeptide of type I procollagen (PICP), a marker of bone formation and the pyridinoline cross linked telopeptide domain of type I collagen (ICTP), a putative marker of bone resorption, were measured by radioimmunoassay (RIA). Serum levels of the bone specific isoenzyme of alkaline phosphatase (BALP), another marker of bone formation, were measured by a wheatgerm agglutinin affinity (WGA) method. Total alkaline phosphatase levels were also determined. Serum levels of PICP were significantly correlated with bone ALP (r = 0.78, P < 0.0001) and ICTP (r = 0.87, P < 0.0001). ICTP levels also correlated significantly with bone ALP (r = 0.81, P < 0.0001). However, total alkaline phosphatase did not correlate significantly with PICP, ICTP and BALP in horses over 1 year of age. There was an inverse correlation between serum levels of all biochemical markers and age of animals, with the most significant changes seen over the first 2 years. In animals less than 1 year of age, the reference ranges (mean +/- s.d. 1.96) were as follows: PICP 1216-2666 micrograms/l, ICTP 13.8-26.7 micrograms/l, bone ALP 134-288 u/l and total ALP 223-498 u/l. In 2-year-olds, the equivalent reference ranges were: PICP 550-1472 micrograms/l, ICTP 7.96-22.8 micrograms/l, bone ALP 32.7-125 u/l and total ALP 134-238 u/l.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Characterisation of angiotensin converting enzyme from different rat vascular beds.
The tissue renin angiotensin system may play a role in cardiovascular pathophysiology. Angiotensin converting enzyme in tissues is now a target for pharmacological inhibition. It is therefore important to determine whether ACE is evenly distributed throughout the vascular tree and whether the enzyme has the same characteristics in different vascular beds. We have thus measured angiotensin converting enzyme density in three functionally different vascular beds with three different methods: the enzyme kinetic assay, a radioligand binding assay and in vitro autoradiography. All three methods demonstrated a significantly higher binding density and activity of ACE in resistance arteries from the mesenteric vascular bed of rats than in microvessels from the brain, or in a conduit artery, the aorta. The dissociation constant (Kd) of the enzyme-radioligand complex was the same in the three functionally different vessel types. Radioligand displacement studies for ACE from plasma and the mesenteric vessels in vitro utilizing a panel of different ACE inhibitors have shown a similar rank order of inhibitory potency suggesting that catalytic sites of ACE were the same in plasma and the mesenteric microvessels. In vivo, the enzyme inhibition in plasma, mesenteric and brain vessels measured by enzyme kinetic and radioligand binding assay were well correlated. There was a similar degree of inhibition between different vessels and tissues (mesenteric vessels, aorta, kidney, left ventricle and coronaries) measured by in vitro autoradiography.
Angiotensin-Converting Enzyme Inhibitors↗
Doppler sonographic studies on the ophthalmic and central retinal arteries in the gravid woman.
The aim of this study was to establish normative data as gestation advances for pulsed Doppler evaluation of both the ophthalmic artery and the central retinal artery. After measuring intraocular pressure and blood pressure, pulsed Doppler ultrasonographic examination was performed on the ophthalmic and central retinal arteries in both eyes of 125 normal pregnant women. Nomograms, with 95% prediction intervals, have been generated for the Doppler indices, reflecting blood flow in both the ophthalmic and the central retinal arteries. The use of this technique in the management of pregnancy induced hypertension can now be better evaluated.
Blood Pressure↗
Technetium-99m-sestamibi scintimammography of breast lesions: clinical and pathological follow-up.
UNLABELLED: Mammography and physical examination combined have a sensitivity of 85% for the detection of breast carcinoma. Mammography also has a positive predictive value of 15%-30%. The aim of this study was to evaluate the usefulness of scintimammography using 99mTc-sestamibi as a complementary technique to mammography for the detection of breast carcinoma to improve mammography's sensitivity and specificity. METHODS: We studied 100 consecutive patients (mean age 48.3 +/- 10.8 yr) who had 106 lesions warranting biopsy (67 lesions) or fine needle aspiration cytology (FNA) (39 lesions) of the breast. There were 85 palpable and 21 nonpalpable lesions. The size of the lesions on the mammograms were moderate (2.3 +/- 1.8 x 1.9 +/- 1.5 cm). Each patient received 20 mCi 99mTc-sestamibi intravenously. Five and 60 min postinjection, planar breast images in the lateral prone position were obtained. An anterior erect projection was then obtained to visualize the axilla and, if needed, a posterior oblique prone projection. RESULTS: Scintimammography was true-positive in 30 lesions with biopsy-confirmed breast carcinoma; it was true-negative in 65 lesions subsequently proved to be benign. There were nine breast lesions with benign findings in which the scintimammography result was positive (false-positive scintimammography) for cancer. Finally, two lesions with pathologically proven carcinomas demonstrated a negative scintimammographic result. Therefore, in this group, the sensitivity of scintimammography was 93.7% with a specificity of 87.8%; the positive predictive value was 76.9%. The negative predictive value was 97%. CONCLUSION: Scintimammography is a highly sensitive test that improves the specificity of conventional mammography for the detection of breast carcinoma.
Biopsy, Needle↗
Axillary metastasis from occult breast carcinoma: diagnosis and management.
Axillary metastasis from carcinoma of an unknown primary site is an uncommon and difficult problem. When biopsy of an enlarged axillary node reveals adenocarcinoma, the most likely site (in a female patient) is the ipsilateral breast. From January 1977 to December 1986, 10 patients (eight female, two male) were treated at the University of Mississippi Medical Center for axillary metastasis from carcinoma of unknown primary. Two male patients (ages 60 and 63) were believed to have lung primaries. Both had evidence of distant metastasis at initial diagnosis and died 2 and 7 months after presentation. Of the eight women (ages 40-72, mean 56.5 years), seven developed breast abnormalities between 6 and 39 months (mean: 15 months) after initial diagnosis, and two of these underwent modified radical mastectomy. No primary site was identified in the eight women. Two women had evidence of distant metastases at initial presentation. All patients have died with disease at a mean of 42 months (range: 2-93 months). In contrast with other reported series, the outcome of patients with occult breast carcinoma presenting as axillary adenopathy was not favorable.
Adenocarcinoma↗
Separation of immunomodulatory and cholesterol-lowering activities of heterocyclic azaspiranes.
Azaspiranes are novel immunomodulators which are effective in a variety of autoimmune diseases. One azaspirane analog, SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine dihydrochloride), caused a decrease in total serum cholesterol in dogs after oral administration. To determine whether an effect on cholesterol was common to this class of compounds, the immunomodulatory activity was compared with the cholesterol-lowering activity of six azaspirane analogs. The compounds were given to beagles at a dose of 1 mg/kg p.o. for 28 days, and the effect on serum cholesterol was determined. The results from this study showed a clear dissociation between the immunomodulatory and hypocholesterolemic activities of these compounds. Studies performed to determine the mechanism of the decrease in serum cholesterol caused by SK&F 105685 indicated that it was not due to inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase or acyl-CoA:cholesterol acyltransferase activities, or to a potentiation of cholesterol-7 alpha-hydroxylase activity. In addition, analysis by gas chromatography of the nonsaponifiable sterol fraction in dog plasma after treatment with SK&F 105685 or SK&F 106333 showed a decrease in cholesterol and an accumulation of lathosterol and an unknown sterol, indicating that the conversion of these sterols is inhibited and cholesterol synthesis is blocked at these steps. SK&F 105685 affected the sterol profile in human hepatoblastoma cells (Hep G2) in a similar way. Characterization of the unknown sterol by gas chromatography and mass spectrometry indicated that the unknown sterol is very similar to cholesterol and lathosterol, but its identity has yet to be established. These results show that the hypocholesterolemic effects of azaspiranes are related to inhibition of one or more of the final steps in the biosynthetic pathway of cholesterol.
Animals↗
Phencyclidine inhibits epinephrine-stimulated platelet aggregation independently of high affinity N-methyl-D-aspartate (NMDA)-type glutamatereceptors.
The psychotomimetic analgesic phencyclidine (PCP), which binds to a high affinity site on the neuronal N-methyl-D-aspartate (NMDA)-sensitive glutamate receptor, has previously been found to bind to platelets with high affinity and to specifically delay the onset of epinephrine-stimulated platelet aggregation (Jamieson et al. (1992) Biochem. J. 285, 35-39). We have now shown that the rank order of binding affinities of 14 synthetic PCP analogs at the high affinity binding site on platelets does not parallel the rank order of their affinities in binding to rat brain membranes, indicating that the high affinity PCP binding sites in platelets is distinct from the neuronal NMDA receptor. The order of potency of six of these analogs in delaying the onset of epinephrine-stimulated platelet aggregation also did not parallel the rank order of their binding affinities for platelet or brain binding sites. These data indicate that the ability of PCP analogs to inhibit epinephrine-stimulated aggregation is not related to their ability to bind to the high affinity platelet PCP binding site. Furthermore, (+)MK-801, which binds to the same high affinity binding site in neurons as does PCP, failed to inhibit epinephrine-stimulated platelet aggregation, further suggesting that the site at which PCP acts in platelets is not related to the NMDA-type glutamate receptor. Further studies showed that 5-HT2 receptors and effects on platelet secretion are not involved in PCP-mediated inhibition of epinephrine-induced platelet aggregation.
Adenosine Diphosphate↗
Structural constraints of inhibitors for binding at two active sites on somatic angiotensin converting enzyme.
Angiotensin converting enzyme active sites from rat plasma, lung, kidney and testis were assessed by comparative radioligand binding studies under physiological chloride conditions. Displacement of [125I]Ro 31-8472 from somatic and plasma angiotensin converting enzyme by angiotensin converting enzyme inhibitors of different structure indicated two binding sites (perindoprilat: high affinity carboxyl site, KDC 18 +/- 6 pM), and a single high affinity binding site on testis angiotensin converting enzyme (KDC 20 +/- 1 pM). Displacement of [125I]351A from plasma, somatic and testis angiotensin converting enzyme occurred at a single high affinity binding site. Reduction in affinity at the amino binding site of somatic angiotensin converting enzyme was related to an increased side chain size (lung KDA (pM): Ro 31-8472 175 +/- 38, lisinopril 2205 +/- 1832, and 351A 2271 +/- 489), or hydrophobicity of the competing unlabelled angiotensin converting enzyme inhibitor (lung KDA (pM): quinaprilat 1267 +/- 629 and perindoprilat 824 +/- 6). This trend was reversed at the carboxyl binding site of plasma, somatic and testis angiotensin converting enzyme. Bradykinin hydrolysis by lung angiotensin converting enzyme was inhibited in a similar manner by cilazaprilat or quinaprilat (F = 0.64, F-test based on the extra sum-of-squares principle; P > 0.05), indicating the angiotensin converting enzyme carboxyl active site predominates in bradykinin cleavage. The data demonstrate that the two binding sites on native plasma and somatic angiotensin converting enzyme are of potentially different functional and structural nature, suggesting they may have different substrate specificities.
Angiotensin-Converting Enzyme Inhibitors↗
The human immunodeficiency virus and nonmenstrual toxic shock syndrome: a female case presentation.
Toxic shock syndrome (TSS) generally is associated with tampon use among menstruating women. Descriptions from the early 1980's detailed this sudden, multisystem, frequently fatal disease. The bacterial agent, Staphylococcus aureus produced exotoxins, which were quickly identified as the cause of TSS as well as a host of other systemic, bacterial infections. While S. aureus has become one of the more common bacterial pathogens in patients with Acquired Immune Deficiency Syndrome (AIDS), staphylococcal toxin-related disorders rarely have been reported in individuals infected with Human Immunodeficiency Virus (HIV) or individuals diagnosed with AIDS. To date all published cases of TSS attendant with HIV involved homosexual, hemophiliac, or drug injecting male patients. This report describes a woman infected with HIV and diagnosed with the classic array of symptoms found in toxic-shock syndrome, and provides information specific to women and their experience with HIV infection.
AIDS-Related Opportunistic Infections↗
Haemodynamic, renal and hormonal responses to enalkiren in four patients with post-surgical oliguria.
1. The haemodynamic and hormonal responses of four patients with acute post-surgical oliguria (urine output < 0.5 mL/kg per h) were measured in response to the renin inhibitor enalkiren. Enalkiren was infused at 0.01 up to 0.1 mg/kg per h for up to 4 h. 2. Enalkiren infusion was associated with a progressive fall in blood pressure, clinically significant in three of the four patients. Systemic vascular resistance fell in proportion to blood pressure fall. Cardiac output and pulse rate remained unchanged. Effective renal plasma flow rose in all four cases (236 +/- 19 to 327 +/- 38). There was no change in urine flow rate, or urinary sodium excretion. 3. Plasma renin activity (ng angiotensin I/mL per h) fell from 1.9 +/- 0.5 to 0.02 +/- 0.01 (P < 0.04), plasma angiotensin II (pg/mL) fell from 104 +/- 93 to 7.7 +/- 1.5, and plasma aldosterone (ng/dL) fell from 32 +/- 8 to 21 +/- 9 (P = 0.03) at the highest infusion dose. 4. Enalkiren inhibited plasma renin activity with reduced plasma angiotensin II and aldosterone concentrations. This was associated with vasodilation, reduced blood pressure and maintained cardiac output. There was no beneficial effect on renal function in these patients with post-surgical oliguria.
Aldosterone↗
Genotypic influence on plasma dipeptidyl carboxypeptidase-1 activity in hypertensives.
1. Plasma dipeptidyl carboxypeptidase-1 (DCP1; angiotensin I-converting enzyme, kininase II; EC 3.4.15.1) tracks with the deletion allele in genotypes of a 287 bp insertion/deletion (I/D) polymorphism of its gene, DCP1, in healthy Caucasian populations. The aim of the present study was to see whether genotype has a similar influence on plasma DCP1 in hypertensives. 2. The study involved 35 Caucasian patients with severe, familial essential hypertension, who were not being treated with DCP1 inhibitors, and 94 normotensives. Genotyping for the I/D polymorphism was performed by polymerase chain reaction and plasma DCP1 activity was measured by rate of hydrolysis of both [3H]-Hip-Gly-Gly and Hip-His-Leu. 3. Plasma DCP1 activity (nmol Gly-Gly/min per mL; mean +/- s.e.m.) was 67 +/- 2, 82 +/- 4 and 91 +/- 6 in II, ID and DD hypertensives, respectively, which was similar to values of 68 +/- 4, 82 +/- 3 and 94 +/- 3 in normotensives (P = 0.0001 by one-way analysis of variance). Results for the His-Leu assay indicated similar tracking with genotype. 4. The Michaelis constant (mumol Hip-Gly-Gly/mL; mean +/- s.e.m., n = 10) for DD subjects was the same as for II subjects (10.6 +/- 1.6 vs 11.1 +/- 2.3; P = 0.86). 5. In conclusion, in severely hypertensive Caucasian subjects, plasma DCP1 activity is subject to a similar genotypic influence in hypertensives as has been reported previously in normotensives. Furthermore, the plasma DCP1 enzyme itself appears to be functionally similar for each genotype.
Female↗