Concurrent pharmacokinetic analysis of plasma cocaine and adrenocorticotropic hormone in men

The purpose of this study was to determine the covariance between plasma cocaine and ACTH pharmacokinetics. Twelve healthy male occasional cocaine users participated in a double blind study. Intravenous cocaine (0.2 mg/kg) or placebo was infused over 1 min, and samples for cocaine, ACTH and cortisol analysis were collected at 2, 4, 8, 12, 16, 20, 30, 40, 60, 80, 120, 180, and 240 min. Peak cocaine plasma levels averaged 101.2 +/- 14.6 ng/mL. ACTH increases were significantly correlated (P < 0.0001) with increases in plasma cocaine levels (r = 0.67; r2 = 0.44). Pharmacokinetic analysis showed that the t(max) (observed time to maximum concentration) values for cocaine (6.0 +/- 1.4 min) and ACTH (7.3 +/- 1.2 min) were almost identical. The area under the curve was calculated using the trapezoidal rule. The area under the curve for plasma cocaine was 6463 +/- 1070 ng/min x mL, and the area under the curve for ACTH was 1873 +/- 188 pmol/min x L. The mean half-life for plasma cocaine was 46.7 +/- 4.0 min, and that for ACTH was 35.8 +/- 5.1 min. Cardiovascular and subjective effect measures were correlated with concurrent increases in plasma cocaine and ACTH levels.     

The effect of dietary vitamin D3 on the intracellular calcium gradient in mammalian colonic crypts

A physiological gradient in intracellular calcium ([Ca2+]i) has been hypothesized to exist along the colonic crypt base-mouth axis, which may be involved in the regulation of colonocyte proliferation, differentiation and apoptosis. In addition [Ca2+]i may be modulated by dietary vitamin D3 which is thought to be protective against colorectal cancer. CF1 mice were maintained for 6 weeks on a defined diet containing either high or low vitamin D3. A colonic crypt base-mouth [Ca2+]i gradient of 201 +/- 79 nM (mean +/- SEM, P < 0.05) was observed in animals maintained on a high vitamin D3 diet and was abolished in mice maintained on a low vitamin D3 diet. The [Ca2+]i gradient was independent of extracellular calcium and elevated levels of [Ca2+]i observed in the basal regions of the crypt in animals maintained on low levels of vitamin D3 were also associated with an increase in intracellular calcium stores. Therefore, a [Ca2+]i gradient exists in colonic crypts and is dependent on dietary vitamin D3.     

Penile vibratory stimulation yields increased spermatozoa and accessory gland production compared with rectal electroejaculation in a neurologically intact primate (Saimiri boliviensis)

Assisted reproductive techniques require an efficient semen collection procedure in cases of ejaculatory dysfunction. Anejaculation may be of psychogenic or neurogenic origin but can be overcome with stimulatory techniques. Penile vibratory stimulation (PVS) therapy for anejaculation has recently emerged as an alternative to rectal probe electroejaculation (RPE) and more invasive testicular procedures. Comparison of the stimulatory procedures in neurologically intact subjects is not ethically possible due to the discomfort involved with electroejaculation, and comparison in spinal cord injured men may be compromised due to the intricate effects of chronic denervation on semen quality. We have previously shown the efficacy of PVS in a non-human primate, the squirrel monkey. A cross-over study design comparing semen collected by PVS and RPE was employed during the breeding season in which 15 donor males were divided into two groups. One group received PVS and the other RPE, then, three days later, treatments were reversed. Twelve of 15 animals responded to PVS (80%), all with spermatozoa in the ejaculate. Mean volume (436 +/- 90 microl), motility (80.6 +/- 4.3%), and total spermatozoa (32.8 +/- 10.2 x 10(6)) were significantly higher than in the semen after RPE. RPE resulted in ejaculation in all 15 animals with a semen volume of 205 +/- 25 microl, but fewer samples contained spermatozoa (9/15) resulting in a low total count (0.5 +/- 0.3 x 10(6)). The motility was reduced in those samples with spermatozoa (n = 9; 44.1 +/- 11.4%). Additionally, accessory gland activity was measured via the seminal vesicle and prostrate markers, fructose and citric acid, respectively. The PVS specimens had significantly more fructose (2.9 +/- 0.7 mg/ejaculate) and citric acid (0.46 +/- 0.14 mg/ejaculate) compared to RPE collected specimens (1.2 +/- 0.3 mg/ejaculate and 0.24 +/- 0.04 mg/ejaculate, respectively). In conclusion, PVS produces a much greater sperm yield and increased accessory gland secretion compared to RPE in our neurologically intact squirrel monkey model.     

Effect of truncated projections on defect detection in attenuation-compensated fanbeam cardiac SPECT

Na-nitrilotriacetic acid (Na3NTA) and Fe-nitrilotriacetic acid (FeNTA) have both been described to cause tumors in the urinary tract of rodents. However, these effects were observed using different modes of administration at extremely different dose levels and explained by different mechanisms. Whereas FeNTA causes an iron overload of cells and is genotoxic in various assays, Na3NTA is predominantly bound to zinc in vivo and thereby causes cytotoxic effects in the urinary tract. In contrast to FeNTA, Na3NTA requires high dose levels to produce tumors. The aim of this study was to compare the effects of Na3NTA and FeNTA on cellular proliferation, histopathology, lipid peroxidation, and 8-OH-2'-deoxyguanosine levels in the kidneys as well as on the urinary excretion of Ca, Fe, and Zn. For evaluation of DNA synthesis both compounds were administered for 1 or 4 weeks to 14-week-old male Wistar rats at a tumor causing dose, Na3NTA via the diet at 150 ppm and 20,000 ppm (approximately 9 and approximately 1000 mg/kg/day) and FeNTA i.p. at 25 mg/kg/day. An osmotic minipump, containing 20 mg/ml BrdU, was implanted subcutaneously 7 days before necropsy. Na3NTA showed nearly no effect on DNA replication after 1 week but a strong reaction after 4 weeks. The increase was 10- to 18-fold in different renal compartments. The enhancement of proliferation in the proximal tubules was nearly twice that in the distal tubules. In contrast, FeNTA caused DNA replication during the first week, and this was restricted to the proximal tubules. After 4 weeks there was an 18-fold increase in the outer stripe and no effect in the inner stripe of the outer medulla. The data presented give evidence to the assumption that both substances increase cell proliferation as a compensatory mechanism, causing different pattern of tubular proliferation in terms of time course and affected cell types. Both Na3NTA at 20,000 ppm and FeNTA led to increased lipid peroxidation, whereas increased levels of 8-OH-2'-deoxyguanosine were observed only after treatment with FeNTA. Urinary excretion of Zn was increased 30-fold after administration of 20,000 ppm Na3NTA but only 2-fold after administration of FeNTA. Urinary excretion of Ca and Fe remained unchanged after treatment with either Na3NTA and FeNTA. These results show that the Na3NTA-related proliferative effects are not mediated by an internal formation of FeNTA.     

Insights into the mechanism of catalysis by the P-C bond-cleaving enzyme phosphonoacetaldehyde hydrolase derived from gene sequence analysis and mutagenesis

Phosphonoacetaldehyde hydrolase (phosphonatase) catalyzes the hydrolysis of phosphonoacetaldehyde to acetaldehyde and inorganic phosphate. In this study, the genes encoding phosphonatase in Bacillus cereus and in Salmonella typhimurium were cloned for high-level expression in Escherichia coli. The kinetic properties of the purified, recombinant phosphonatases were determined. The Schiff base mechanism known to operate in the B. cereus enzyme was verified for the S. typhimurium enzyme by phosphonoacetaldehyde-sodium borohydride-induced inactivation and by site-directed mutagenesis of the catalytic lysine 53. The protein sequence inferred from the B. cereus phosphonatase gene was determined, and this sequence was used along with that from the S. typhimurium phosphonatase gene sequence to search the primary sequence databases for possible structural homologues. We found that phosphonatase belongs to a novel family of hydrolases which appear to use a highly conserved active site aspartate residue in covalent catalysis. On the basis of this finding and the known stereochemical course of phosphonatase-catalyzed hydrolysis at phosphorus (retention), we propose a mechanism which involves Schiff base formation with lysine 53 followed by phosphoryl transfer to aspartate (at position 11 in the S. typhimurium enzyme and position 12 in the B. cereusphosphonatase) and last hydrolysis at the imine C(1) and acyl phosphate phosphorus.     

Bone ingrowth behaviour of hydroxyapatite-coated,polyethylene-intruded and uncoated,sandblasted pure titanium implants in an infected implantation site: an experimental study in miniature pigs

We studied the dynamics of bone tissue ingrowth into the pores of hydroxyapatite-coated (plasma-spraying technique) and uncoated wire meshes of pure Ti in an infected implantation site. Samples of the test materials were implanted into the femora of 15 adult Göttingen minipigs. Just before implantation they were contaminated with Staphylococcus aureus. The pigs were killed after 4, 8, 12 or 24 weeks. Undecalcified ground sections of bone tissue were prepared and stained with toluidine blue for comparative histological evaluation. The hydroxyapatite-coated implants already demonstrated advanced new bone formation after 4 weeks. By 12 weeks most of the implant pores were filled with newly formed bone although all samples showed macro- as well as microscopic signs of persistent infection. Comparable reactions of the uncoated implants could be observed only after 24 weeks. Signs of degradation of the hydroxyapatite coating were seen in contact with soft tissue. This was more extensive in the infected than in the uninfected site. The results and possible clinical consequences are discussed.     

Acyl-CoA : cholesterol acyltransferase inhibitors from Magnolia obovata

In the course of a search for acyl-CoA : cholesterol acyltransferase (ACAT) inhibitors from natural sources, new types of ACAT inhibitors were isolated from the extract of Magnolia obovata leaves, and identified as obovatol, honokiol, and magnolol. The active compounds inhibit rat liver ACAT with IC50 values of 42, 71, and 86 microM, respectively.     

Comparison of echocardiography with magnetic resonance imaging in the assessment of the athlete's heart

AIM: The purpose of the study was to compare the accuracy of M-mode echocardiography and two different two-dimensional echocardiographic approaches in the assessment of left ventricular mass and volumes in endurance-trained and strength-trained athletes, using magnetic resonance imaging as reference standard. METHODS AND RESULTS: We studied 19 athletes and 10 untrained control subjects, M-mode and two-dimensional echocardiography were compared to magnetic resonance imaging. M-mode echocardiographic left ventricular mass was calculated using the Penn cube convention. Two-dimensional echocardiographic left ventricular mass was calculated using (1) the area-length method as proposed by the American Society of Echocardiography (ASE) and (2) as proposed by Reichek. The best correlation between magnetic resonance imaging and echocardiographic left ventricular mass and volumes was observed with the ASE two-dimensional echocardiographic method. The agreement between them (-3.4 +/- 7.6 g and 18.5 +/- 19.5 ml) was better than between Reichek two-dimensional echocardiography and magnetic resonance imaging (-39.4 +/- 15.4-g and 52.8 +/- 21.7 ml), and demonstrated less random difference than M-mode echocardiography and magnetic resonance imaging (3.2 +/- 21.1 g resp. 15.1 +/- 30.0 ml). CONCLUSION: We conclude that the ASE two-dimensional echocardiographic approach, when using magnetic resonance imaging as a reference standard, was the most accurate estimator of left ventricular mass and volumes in both controls and athletes.     

Safety and effectiveness of placement of pacemaker and defibrillator leads in the axillary vein guided by contrast venography

OBJECTIVE: To identify subjects with univentricular idiopathic structural and/or functional myocardial disorders (as defined) and to describe the characteristic features. DESIGN: Over a period of 4 years, 1993-1996, all adult subjects were obtained consecutively from a centralised referral cardiological service. The subjects had to fulfil a set of formulated diagnostic criteria for each isolated type of univentricular disease-symptomatic or asymptomatic. The subjects were diagnosed on the basis of clinical features, supported by electrocardiographic, radiological and echocardiographic evidence of lone ventricular disease, with a further definition of abnormalities based on appropriately selected standard left and right heart assessments, inter alia: (i) cardiac catheterisation, including coronary arteriography and pulmonary angiography; (ii) radio-isotope studies-mibiscan; (iii) ventilation perfusion scan; and (iv) laboratory tests to identify likely cause(s) of diffuse myocardial damage as well as to recognise nonspecific effects of tissue damage and organ dysfunction. SETTING: A referral cardiological service of a tertiary academic hospital, which provides a consultative service for inpatients and ambulatory cases. All subjects were studied on admission to hospital. PARTICIPANTS: A set of criteria was formulated for each category of lone ventricular myopathy. A total of 30 patients were thus identified and included in the study-men and women ranging in age from 18 years to 84 years, with an average of 48 years. All were investigated after admission to hospital by means of a detailed set of investigations that rigorously excluded overt or occult causes of diffuse myocardial damage and any severe myocardial dysfunction secondary to haemodynamic conditions. Seven patients with significant coronary artery disease were excluded. Any subject with pulmonary or systemic hypertension was also excluded. MAIN OUTCOME MEASURES: Total number of patients, number of patients in each subgroup were analysed by age, sex, clinical features, and by special investigation. The mode of presentation and electrocardiographic features were analysed separately. RESULTS: Twenty-two left ventricular and 8 right ventricular cases of lone ventricular cardiomyopathy were diagnosed. All but 1 patient with right ventricular disease were symptomatic and 5 subjects with left ventricular myopathy were incidentally discovered. There were 17 men and 13 women in the series. Of the 8 patients with right ventricular disease, 6 were women, while of the 22 patients with left ventricular cardiomyopathy, 15 were men. CONCLUSION: The study supports the previously described existence of lone ventricular idiopathic cardiomyopathy. Further studies are, however, indicated in order to define its prevalence and nature more accurately, as well as to describe any relationship with univentricular cardiomyopathies, and define the characteristics of each category and the possible evolutionary patterns. Right ventricular cardiomyopathy is a new entity which may pose difficult diagnostic challenges, while left ventricular disease is generally accepted as a stage in the clinical spectrum of classic idiopathic dilated cardiomyopathy.