Striatal [18F]fluorodopa utilization after COMT inhibition with entacapone studied with PET in advanced Parkinson's disease

The effect of peripheral catechol-O-methyltransferase (COMT) inhibition with entacapone on striatal uptake of 6-[18F]fluoro-L-dopa (FDOPA) was studied with PET both without and with entacapone in fifteen advanced parkinsonian patients and six healthy controls. Entacapone significantly enhanced the fraction of unmetabolized FDOPA in plasma from 16% to about 50% at 80 minutes after FDOPA injection in all subjects. The striatal to occipital ratios and the striatal FDOPA uptake, expressed as a modified decarboxylation coefficient (k3R0), was significantly increased in healthy controls, whereas in parkinsonian patients the increase was significant only in the caudate. On the other hand, the influx constant (Ki) decreased significantly in the caudate and putamen in parkinsonian patients; in healthy controls the Ki remained virtually unchanged. Effective peripheral COMT inhibition markedly increased the fraction of FDOPA in plasma and thus its availability in the brain for decarboxylation both in patients and control subjects. However, the change in striatal FDOPA uptake was modest in the advanced parkinsonian patients as compared to that in control subjects, because of the advanced disease, decreased storage capacity, or both.     

Analyzing the evolution of the opioid/orphanin gene family

Advances in molecular biology have made it possible to rapidly obtain the amino acid sequence of neuropeptide precursors-either by cloning and sequencing the cDNA that encodes the precursor, or by reconstructing the arrangement of exons and introns in a neuropeptide-coding gene through genomic approaches. The databases generated from these molecular approaches have been used to design probes to identify the cells that express the gene, or to ascertain the rate of expression of the gene, and even to predict the post-translational modifications that can generate functional neuropeptides from a biologically inert precursor. Although the power of these approaches is substantial, it is appreciated that a gene sequence or an mRNA sequence reflects the potential products that may be assembled in a secretory cell. To understand the functional capabilities of the secretory cell, the molecular genetics approaches must be combined with procedures that actually characterize the end-products generated by the secretory cell. Recent advances in two-dimensional gel electrophoresis and mass spectrometry now make it possible to analyze neuropeptides from a relatively small amount of tissue. These procedures can reveal novel end-products, tissue-specific endoproteolytic cleavage events, and developmental shifts in post-translational processing schemes. A gene family that illustrates all of these processes and the advantages of combining genomics with proteomics is the opioid/orphanin gene family.     

Haemodynamic effects of four months' mefruside therapy in hypertensive patients

The haemodynamic changes after 4 months' mefruside therapy in 13 patients with essential hypertension have been studied. Intraarterial BP was significantly reduced both at rest supine and during standardized leg exercise in sitting position. The reduction was caused mainly by a decrease in cardiac output in about half of the patients and mainly by a decrease in total peripheral vascular resistance in the remainder. Thus, for the total material there was no significant change in either cardiac output or total peripheral vascular resistance. At rest, however, there was a significant decrease in storke volume (p less than 0.05) and an increase in heart rate (p less than 0.05). On changing from supine to sitting position, the average systolic and diastolic pressures increased before and decreased after therapy, the differences being significant. The results indicate that the hypotensive effect of long-term saluretic therapy is accomplished by a decrease in cardiac output and/or peripheral vascular resistance, with large interindividual variations.     

Comorbidity between abuse of an adult and DSM-III-R mental disorders: evidence from an epidemiological study

The nonuniform distribution of thrombocytes in a microvessel is considered in terms of a previously advanced phenomenological theory, which describes the relationship between the mean blood velocity and thrombus growth rate.     

Effect of ethinyl estradiol-dienogest combination on serum androgen concentrations

Antiandrogens or progestins with an antiandrogenic component usually have only a weak antigonadotropic activity. It is thus possible that the antiandrogenic effect on the cellular level is cancelled or at least reduced by an increased ovarian androgen production. The aim of the four submitted clinical studies of the progestin and antiandrogen dienogest alone (0.5-2 mg/day) or of a combined regimen of ethinylestradiol (0.03 mg) plus dienogest (2 mg) (EE/DNG) was to examine the influence on the serum androgen and SHBG concentrations as well as on the serum FSH, LH, progesterone and 17 beta-estradiol concentrations in young women. Like the progesterone derivatives, dienogest has a relatively low antigonadotropic activity. Inhibition of ovulation is mainly produced by peripheral mechanisms such as the reduction of preovulatory 17 beta-estradiol secretion. Dienogest alone has no significant effects on the serum SHBG and androgen concentrations. Unlike this, the combination of EE plus DNG markedly increases SHBG concentrations (to 2.1-3.7 fold the basal levels). The decrease in serum androgens with total testosterone (by 17 and 40%), free testosterone (by 48 and 54%) and dehydroepiandrosterone sulfate (by 51%) corresponds to the values shown in the literature for other oral contraceptives with modern progestins. EE/DNG does not affect the serum concentrations of 5 alpha-dihydrotestosterone (DHT), although the marker of the peripheral transformation from T to DHT, androstanediol glucuronide, is distinctly reduced (by 38%). In a double-blind comparison no differences are found between EE/DNG and a regimen combining 0.02 mg of ethinylestradiol and 0.150 mg of desogestrel. Solely the SHBG concentrations, with EE/DNG, as expected, are significantly higher. In a sequential regimen, dienogest, chlormadinone acetate and desogestrel (progestins without binding to SHBG) enhance the inhibitory effect of ethinylestradiol sulfonate on free testosterone, whereas norethindrone acetate and levonorgestrel (progestins with a strong binding to SHBG) reduce this effect of the estrogen significantly. These results exclude the possibility that the very distinct antiandrogenic effect of dienogest on a cellular level is neutralised or reduced by an increased systemic supply of androgen.     

Dynamic effects on the lumbar spinal canal: axially loaded CT-myelography and MRI in patients with sciatica and/or neurogenic claudication

STUDY DESIGN: In patients with sciatica or neurogenic claudication, the structures in and adjacent to the lumbar spinal canal were observed by computed tomographic myelography or magnetic resonance imaging in psoas-relaxed position and during axial compression in slight extension of the lumbar spine. OBJECTIVES: To determine the mechanical effects on the lumbar spinal canal in a simulated upright position. SUMMARY OF BACKGROUND DATA: For years, functional myelographic investigation techniques were shown to be of value in the evaluation of suspected encroachment of the spinal canal. Since the advent of computed tomography and magnetic resonance imaging, there have been few clinical and experimental attempts that have imitated these techniques. The data indicate that the space within the canal is posture dependent. METHODS: Portable devices for axial loading of the lumbar spine in computed tomographic and magnetic resonance examinations were developed. Fifty patients (94 sites) were studied with computed tomographic myelography, and 34 patients (80 sites) with magnetic resonance in psoas-relaxed position followed by axial compression in slight extension. The dural sac cross-sectional area at L2 to S1, the deformation of the dural sac and the nerve roots, and the changes of the tissues surrounding the canal were observed. RESULTS: In 66 of the investigated 84 patients, there was a statistically significant reduction of the dural sac cross-sectional area in at least one site during axial compression in slight extension. Of the investigated patients, 29 passed the borderlines for relative (100 mm2) or absolute stenosis (75 mm2) in 40 sites. In 30 patients, there was deformation of the dural sac in 46 sites. In 11 of the patients investigated with magnetic resonance imaging, there was a narrowing of the lateral recess in 13 sites, during axial compression in slight extension. CONCLUSIONS: Axial loading of the lumbar spine in computed tomographic scanning and magnetic resonance imaging is recommended in patients with sciatica or neurogenic claudication when the dural sac cross-sectional area at any disc location is below 130 mm2 in conventional psoas-relaxed position and when there is a suspected narrowing of the dural sac or the nerve roots, especially in the ventrolateral part of the spinal canal in psoas-relaxed position. The diagnostic specificity of the spinal stenosis will increase considerably when the patient is subjected to an axial load.     

Obesity and thrombotic vascular diseases

Obesity may either be unspecific as indicated by an increased body mass index (BMI) or due to an abnormal fat-distribution as indicated by an increased waist-to-hip ratio (WHR). The latter is frequently associated with deteriorations of glucose tolerance, hypertriglyceridaemia and hypertension (the metabolic syndrome), a syndrome which is among the strongest risk factors of ischemic heart disease. It is important to note that visceral obesity is a frequent feature of the polycystic ovary syndrome. Also, weight gain after menopause is often associated with a particular increase of the WHR. Obesity as indicated by an increased BMI (> 30 kg/m2) is a weak but easily detectable risk marker of venous thrombotic disease. This risk needs to be considered in clinical practice since obesity was shown to enhance the power of precipitating risk factors of venous disease such as pregnancy, surgery or estrogen treatment.     

Pitfalls in clinical recognition and a novel operative approach for hypertrophic cardiomyopathy with severe outflow obstruction due to anomalous papillary muscle

BACKGROUND: Ventricular septal myotomy/myectomy (Morrow procedure) is the standard surgical option for severely symptomatic patients with hypertrophic cardiomyopathy (HCM) and marked basal obstruction to left ventricular outflow due to mitral valve systolic anterior motion. In some patients, however, congenital malformations of the mitral apparatus may be responsible for outflow obstruction; the failure to recognize this morphology before operation could have adverse consequences. METHODS AND RESULTS: We recently evaluated 2 patients with obstructive HCM operated on at Mayo Medical Center in 1997 who demonstrated direct anomalous papillary muscle insertion into the anterior mitral leaflet, producing muscular midcavity obstruction. This anomaly is potentially identifiable with echocardiography by exaggerated anterior displacement of hypertrophied papillary muscles within the left ventricular cavity and the direct continuity between papillary muscle and anterior leaflet associated with a rigid motion pattern of the mitral apparatus. Echocardiographic diagnosis, however, was confused in both patients by the association of systolic anterior motion of the mitral valve, probably produced by freely mobile margins of the mitral leaflet unencumbered by papillary muscle insertion, and in 1 patient probably representing a second and more basal level of obstruction. Because outflow tract morphology was judged unsuitable for conventional myotomy/myectomy, a novel surgical strategy was designed to remove the outflow gradient in which an extensive myectomy trough (wider at its apical than basal extent) was created within the ventricular septum to papillary muscle level; also, in 1 patient, attachment of anterolateral papillary muscle with the lateral free wall was partially severed to increase mobility of the mitral apparatus. After surgery, both patients reported substantial relief of symptoms and improved exercise tolerance and also showed reduced or abolished basal outflow obstruction. CONCLUSIONS: In HCM, outflow obstruction due to anomalous papillary muscle insertion directly into anterior mitral leaflet is challenging to identify but should always be contemplated before operative intervention. This important (but often unsuspected) congenital malformation may require alternative surgical strategies to standard myotomy/myectomy, similar to those described here.     

Cytokine-induced inhibition of bone matrix proteins is not mediated by prostaglandins

Interleukin-1 (IL-1) and tumor necrosis factor (TNF), two pleiotropic cytokines produced in inflammatory processes, inhibit bone matrix biosynthesis and stimulate prostanoid formation in osteoblasts. In the present study, the importance of prostaglandin formation in IL-1 and TNF-induced inhibition of osteocalcin and type I collagen formation has been examined. In the human osteoblastic cell line MG-63, IL-1 alpha (10-1000 pg/ml), IL-1 beta (3-300 pg/ml) and TNF-alpha (1-30 ng/ml) stimulated prostaglandin E2 (PGE2) formation and inhibited 1,25(OH)2-vitamin D3-induced osteocalcin biosynthesis as well as basal production of type I collagen. Addition of PGE2 or increasing the endogenous formation of PGE2 by treating the cells with arachidonic acid, bradykinin, Lys-bradykinin or des-Arg9-bradykinin, did not affect osteocalcin and type I collagen formation in unstimulated or 1,25(OH)2-vitamin D3-stimulated osteoblasts. Four non-steroidal antiinflammatory drugs, indomethacin, flurbiprofen, naproxen and meclofenamic acid, inhibited basal, IL-1 beta- and TNF-alpha-stimulated PGE2 formation in the MG-63 cells without affecting IL-1 beta- or TNF-alpha-induced inhibition of osteocalcin and type I collagen formation. In isolated, non-transformed, human osteoblast-like cells, IL-1 beta and TNF-alpha stimulated PGE2 formation and concomitantly inhibited 1,25(OH)2-vitamin D3-stimulated osteocalcin biosynthesis, without affecting type I collagen formation. In these cells, indomethacin and flurbiprofen abolished the effects of IL-1 beta and TNF-alpha on prostaglandin formation without affecting the inhibitory effects of the cytokines on osteocalcin biosynthesis. These data show that IL-1 and TNF inhibit osteocalcin and type I collagen formation in osteoblasts independently of prostaglandin biosynthesis and that non-steroidal antiinflammatory drugs do not affect the effects of IL-1 and TNF on bone matrix biosynthesis.     

International River Basins of the World

It is becoming acknowledged that water is likely to be the most pressing environmental concern of the next century. Difficulties in river basin management are only exacerbated when the resource crosses international boundaries. One critical aid in the assessment of international waters has been the Register of International Rivers a compendium which listed 214 international waterways that cover 47% of the earth's continental land surface. The Register, though, was last updated in 1978 by the now defunct United Nations Department of Economic and Social Affairs. The purpose of this paper is to update the Register in order to reflect the quantum changes that have taken place over the last 22 years, both in global geopolitics and in map coverage and technology. By accessing digital elevation models at spatial resolutions of 30 arc seconds, corroborating at a unified global map coverage of at least 1:1 000 000, and superimposing the results over complete coverage of current political boundaries, we are able to provide a new register which lists 261 international rivers, covering 45.3% of the land surface of the earth (excluding Antarctica). This paper lists all international rivers with their watershed areas, the nations which share each watershed,their respective territorial percentages, and notes on changes in or disputes over international boundaries since 1978.