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The apolipoprotein E ( APOE ) gene in humans contains two single-base polymorphisms in exon 4, which result in three common alleles, conventionally named epsilon2 , epsilon3 and epsilon4 . Numerous studies have shown an important association between the epsilon4 variant and an increased risk of Alzheimer's disease; other data suggest a possible linkage of APOE genetic heterogeneity with lipid profile and an increased risk of atherothrombotic stroke and coronary heart disease. APOE genotyping is therefore an increasingly common assay in laboratory medicine. The most widely used technique for APOE genotyping is based upon restriction isotyping, i.e., amplification of the fragment of exon 4 containing the most common sequence variations, followed by enzymatic digestion of the amplicon and fragments analysis by gel electrophoresis. We developed a novel, reliable and fast method that exploits the sensitivity and specificity of denaturing high-performance liquid chromatography in detecting single-nucleotide polymorphisms. We show that, in most cases, with a single chromatographic separation it is possible to correctly identify the six different APOE allelic patterns, without any manipulation after the polymerase chain reaction amplification. When compared to restriction isotyping, our method is much faster, less labor intensive and similarly inexpensive.
Hypertension is the most prevalent, treatable risk factor for diseases of the heart, brain and kidneys. In this review, we discuss advances in understanding of the genetics of blood pressure regulation, the development of hypertensive complications and the pharmacodynamics of antihypertensive drug responses. Discovery of single gene mutations that cause hypertension or hypotension in humans suggests that the common final pathway for regulation of blood pressure level is via alterations in renal sodium handling. Based on a working hypothesis that common genetic variations contributing to blood pressure variation in the population may also act on this same pathway, we summarize supporting evidence emerging from linkage and selected association studies of candidate genes--including those encoding components of the renin-angiotensin-aldosterone system, the epithelial sodium channel, adrenoceptors, G protein subunits, and other cellular signaling mediators and modifiers. We proceed to distinguish ischemic target organ complications due to arteriolosclerotic changes of the microvasculature from those due to atherosclerosis involving larger conduit and capacitance arteries. Using the example of subcortical white matter ischemia of the brain, we propose that interindividual variation in the arteriolosclerotic complications is more likely than atherosclerotic complications to be related to the same genetic (and environmental) mechanisms that contribute to hypertension. We conclude by summarizing the state-of-the-art of antihypertensive pharmacogenetics, which has succeeded in rejecting the null hypothesis that genetic variation does not influence blood pressure or protective target organ responses to drug therapy. In each of the three areas covered in this review, we indicate the many remaining obstacles to the routine clinical use of genetic measurements in the diagnosis, evaluation and treatment of hypertension.
OBJECTIVE: To increase weight gain in the first 28 days after birth for very low birth weight (VLBW) infants by isolating and sharing meaningful process differences between high- and low-weight-gain centers within a neonatal network. DESIGN/METHODS: We identified weight gain as an important target for improvement in 1999 for our national group practice of neonatologists. Site-specific average weight gain during the first 28 days was the primary outcome measure. Our target population was defined as inborn infants who survived and remained in the hospital of birth, whose birth weights were between 401 and 1500 g (VLBW), and who were >22 weeks' estimated gestational age. A team of 6 neonatologists and 1 nurse met, reviewed processes that might influence growth, and developed a structured observation guide for site visits. Weight gain data were obtained from an existing administrative database for the period January 1, 1997, through June 30, 1999. Centers were ranked and divided into upper, middle, and lower thirds. Seven team members visited 1 high- and 1 low-weight-gain center without being informed of the center's performance. Following the site visits, the team isolated 16 meaningful differences between high- and low-weight-gain sites. Meaningful differences were defined as processes observed in all or virtually all (for this project, 6 or 7 of 7 centers) of the high and none or virtually none (for this project, 0 or 1 of 7) of the low centers. The meaningful differences were distributed to our medical directors in August 2000 along with their site-specific weight-gain performance. To document the impact of sharing this material, we compared weight gain in a baseline period of January 1 through December 31, 1999 and a posteducational intervention period of January 1 through September 30, 2001. RESULTS: Compared with neonates admitted to our national neonatal practice in 1999, neonates admitted in 2001 were similar in birth weight, gestational age at birth, exposure to antenatal steroids, and male gender. Average daily weight gain during the first 28 days increased from 10.4 +/- 6 g for neonates cared for in 1999 to 12.5 +/- 6 g for neonates cared for in 2001. Thirty-nine of 51 (76%) units noted improvements, 4 were unchanged and 8 noted a decrease in average weight gain. Despite similar average lengths of stay, the average discharge weight for neonates sent home increased from 2.15 +/- 0.5 kg for 1999 to 2.29 +/- 0.5 kg for 2001. There were no differences in frequencies of mortality or major morbidities, including severe intraventricular hemorrhage, retinopathy, or necrotizing enterocolitis, between the 2 time periods. An increase in the use of continuous positive airway pressure was noted in the post implementation period. CONCLUSIONS: Variation in common processes can alter clinical outcomes. Although temporal trends in weight gain may be, in part, responsible for this trend, it appears that isolation and implementation of meaningful differences in processes can augment our desire to rapidly improve clinical outcomes.
Vocal amplitude, one of the crucial factors for the exchange of acoustic signals, has been neglected in studies of animal communication, but recent studies on song variation in Common Nightingales Luscinia megarhynchos have revealed new insights into its importance in the singing behavior of territorial birds. In nightingales song amplitude is not maximized per se, but is individually regulated according to the level of masking background noise. Also, birds adjust their vocal intensity according to social variables, as in male-male interactions. Moreover, during such interactions, males exploited the directionality of their songs to broadcast them in the direction of the intended receivers ensuring the most effective signal transmission. Studies of the development of this typical long-range signaling suggest that sound level is highly interrelated with overall developmental progression and learning, and thus should be viewed as an integral part of song ontogeny. I conclude that song amplitude is a dynamic feature of the avian signal system, which is individually regulated according to the ecological demands of signal transmission and the social context of communication.
Hypertension is a very prevalent cardiovascular (CV) disease risk factor in developed countries. All current treatment guidelines emphasise the role of nonpharmacological interventions, including physical activity, in the treatment of hypertension. Since our most recent review of the effects of exercise training on patients with hypertension, 15 studies have been published in the English literature. These results continue to indicate that exercise training decreases blood pressure (BP) in approximately 75% of individuals with hypertension, with systolic and diastolic BP reductions averaging approximately 11 and 8mm Hg, respectively. Women may reduce BP more with exercise training than men, and middle-aged people with hypertension may obtain greater benefits than young or older people. Low to moderate intensity training appears to be as, if not more, beneficial as higher intensity training for reducing BP in individuals with hypertension. BP reductions are rapidly evident although, at least for systolic BP, there is a tendency for greater reductions with more prolonged training. However, sustained BP reductions are evident during the 24 hours following a single bout of exercise in patients with hypertension. Asian and Pacific Island patients with hypertension reduce BP, especially systolic BP, more and more consistently than Caucasian patients. The minimal data also indicate that African-American patients reduce BP with exercise training. Some evidence indicates that common genetic variations may identify individuals with hypertension likely to reduce BP with exercise training. Patients with hypertension also improve plasma lipoprotein-lipid profiles and improve insulin sensitivity to the same degree as normotensive individuals with exercise training. Some evidence also indicates that exercise training in hypertensive patients may result in regression of pathological left ventricular hypertrophy. These results continue to support the recommendation that exercise training is an important initial or adjunctive step that is highly efficacious in the treatment of individuals with mild to moderate elevations in BP.
We designed a study to determine whether thickening or effacement of the anterior wall stripe of the left lower lobe bronchus on the lateral chest radiograph implies adjacent disease, as it does for the posterior wall stripe of the right bronchus intermedius. The anterior wall stripe of the left lower lobe bronchus originates from the inferior anterior aspect of the end-on left bronchus and descends in a gentle posteriorly convex curve. The left lower lobe bronchus was identified on routine lateral chest films in 86 of 90 consecutive patients who also had chest CT. In those cases the anterior wall stripe was measured and categorized on chest films. On the CT scans, the length of the left lower lobe bronchus and its relationship to the left lower lobe artery and left upper lobe, lingular, and lower lobe veins were assessed. The presence of adjacent disease was noted. A complete anterior wall stripe was seen in 59 of 86 cases. It was effaced by anterior soft tissue in 15 of 86 cases; in 12 of 86 cases only the superior 0.5-1.5 cm was effaced. A normal anterior wall stripe was as thick as 12 mm in one case, but was 6 mm or less in 90%. Shapes other than linear were common. Anatomic variation accounted for nearly all of these findings. There was no focal abnormality in the 12 cases with partial effacement or in nine of the 15 cases with complete effacement; disease was significant in only two of these six. We concluded that thickening or effacement of the anterior wall stripe is an unreliable sign of disease.
Stability of the glenohumeral articulation is dependent on the integrity of the rotator cuff, labrum, glenohumeral ligaments, capsular elements, and bony glenoid. The importance of the soft-tissue elements in maintaining stability has been well documented in the surgical literature but has only recently been introduced into the radiologic literature. The purpose of this essay is to illustrate the normal labrum, capsular complex, and glenohumeral ligaments, including common congenital variations as depicted by CT arthrography and MR imaging, and to describe the pathologic findings leading to shoulder instability.
A variety of focal processes and diffuse abnormalities are found predominantly in children. In addition, thoracic manifestations of trauma differ in children because of increased chest wall compliance. Familiarity with both these abnormalities as well as the common normal variations provides optimal imaging evaluation.
Vitamin D is known to modulate the immune system, and its administration has been associated with reduced risk of type 1 diabetes. Vitamin D acts via its receptor (VDR). Four single nucleotide polymorphisms (SNPs) of the VDR gene have been commonly studied, and evidence of association with type 1 diabetes has been reported previously. We sequenced the VDR gene region and developed its SNP map. Here we analyzed association of the 98 VDR SNPs in up to 3,763 type 1 diabetic families. First, we genotyped all 98 SNPs in a minimum of 458 U.K. families with two affected offspring. We further tested eight SNPs, including four SNPs associated with P < 0.05 in the first set and the four commonly studied SNPs, in up to 3,305 additional families from the U.K., Finland, Norway, Romania, and U.S. We only found weak evidence of association (P = 0.02-0.05) of the rs4303288, rs12721366, and rs2544043 SNPs. We then tested these three SNPs in an independent set of 1,587 patients and 1,827 control subjects from the U.K. and found no evidence of association. Overall, our results indicate that common sequence variation in the VDR gene has no major effect in type 1 diabetes in the populations tested.
AMP-activated protein kinase (AMPK) is a key molecular regulator of cellular metabolism, and its activity is induced by both metformin and thiazolidinedione antidiabetic medications. It has therefore been proposed both as a putative agent in the pathophysiology of type 2 diabetes and as a valid target for therapeutic intervention. Thus, the genes that encode the various AMPK subunits are intriguing candidates for the inherited basis of type 2 diabetes. We therefore set out to test for the association of common variants in the genes that encode three selected AMPK subunits with type 2 diabetes and related phenotypes. Of the seven genes that encode AMPK isoforms, we initially chose PRKAA2, PRKAB1, and PRKAB2 because of their higher prior probability of association with type 2 diabetes, based on previous reports of genetic linkage, functional molecular studies, expression patterns, and pharmacological evidence. We determined their haplotype structure, selected a subset of tag single nucleotide polymorphisms that comprehensively capture the extent of common genetic variation in these genes, and genotyped them in family-based and case/control samples comprising 4,206 individuals. Analysis of single-marker and multi-marker tests revealed no association with type 2 diabetes, fasting plasma glucose, or insulin sensitivity. Several nominal associations of variants in PRKAA2 and PRKAB1 with BMI appear to be consistent with statistical noise.
The described reference serum is characterized by: liquid human serum at "normal" level stored in frozen state at -80 degrees C; minimum damage of proteins; aseptic preparation; cryoprecipitate and excess fibrin removed; serum cleared by ultracentrifugation; pH at 7.2-7.6; available in sealed glass ampoules with inert gas (one ml serum in each); specified components among most frequently analyzed analytes; homogeneity assured and stability monitored; produced under strict rules for good manufacturing practices (GMP). The assigned values are traceable to reference measurement procedures and reference materials of highest achievable metrological level; according to the present proposal the maximum allowable uncertainty of the assigned value is based on biological variation (shared common reference intervals); the uncertainty should ideally not exceed 1/5 of the maximum allowable bias of results obtained on patients samples (even 1/2 would theoretically be acceptable and, for a practical guide approximately < 1% may suffice). The present document provides some guidance of how the reference serum could be established in practice. The document also indicates the use of the material and further extension of the concept. The present work is done as a NORDKEM project.
Sequential cerebrospinal fluid (CSF) pressure-volume studies were carried out in seven cats during the expansion at a constant rate of an epidural balloon. The same studies were performed in three control cats. Beginning after 20 minutes of inflation and continuing to the point of pupillary dilatation there was a progressive increase in the pressure-volume index (volume required to change intracranial pressure (ICP) by tenfold). During the course of balloon inflation, there was also a progressive increase in CSF elastance (instantaneous ICP change per unit change in CSE volume). At the point of pupillary dilatation there was a marked, abrupt increase in the pressure-volume index and an equally dramatic decrease in CSF elastance. The CSF outflow resistance increased to a variable extent during balloon inflation. The plot of the CSF pressure versus balloon volume (the mass lesion pressure-volume curve) was of the classical configuration with an initial relatively flat segment and a final steep segment. A hypothesis is presented that interprets the shape of the mass lesion pressure-volume curve in terms of changes occurring in the elastic properties of the tissues surrounding the CSF space and the volume of the CSF space. It is proposed that this hypothesis will explain most of the commonly observed variations in CSF pressure. Confusion regarding the ICP-volume relationships has arisen because of lack of specificity regarding which anatomical spaces are being perturbed.
Developmental venous anomalies (DVAs) are common congenital variations of normal venous drainage that are known for their benign natural history. Isolated cases of symptomatic DVAs with associated arteriovenous (AV) shunts have recently been reported. The present case, in which thrombosis occurred in a DVA involving an AV shunt, raises intriguing questions regarding the clinical characteristics of these lesions and can be used to argue in favor of considering such lesions to be arteriovenous malformations (AVMs). A 39-year-old man presented with acute thrombosis in a complex system of anomalous hemispheric venous drainage, which included two distinct DVAs, one of which involved an AV shunt. The hemodynamic turbulences induced by a communication between shunted and normal venous outflows were the possible predisposing factor of the thrombosis. Follow-up angiographic and magnetic resonance images revealed complete recanalization of the thrombosed vessel and provided a thorough visualization of the particular angioarchitecture of the DVA. Acute thrombosis within a DVA with an AV shunt has not been reported previously and, thus, this case can be added to other reports of complications that arise in this particular type of DVA. The authors hypothesize that the presence of an AV shunt in a DVA is a risk factor for aggressive clinical behavior of the anomaly, rendering those lesions prone to complications similar to AVMs. Although no treatment can be offered, the presence of an AV shunt in a DVA warrants close follow-up observation because such lesions may represent a particular subtype of AVM and, therefore, may exhibit an aggressive clinical behavior.
BACKGROUND: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear. OBJECTIVE: To evaluate the relation between VDR polymorphisms, BMD, and fractures. DESIGN: Prospective multicenter large-scale association study. SETTING: The Genetic Markers for Osteoporosis consortium, involving 9 European research teams. PARTICIPANTS: 26,242 participants (18,405 women). MEASUREMENTS: Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures. RESULTS: Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm2 for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model). LIMITATIONS: The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis. CONCLUSIONS: The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.
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This international compendium from the Organization for Economic Cooperation and Development Secretariat contains available data for the 24 Member countries for 1960 through 1987. The Federal Republic of Germany is listed as Germany. Tables are presented for expenditure on health, health care pricing trends, social protection and public participation, utilization of medical services and available personnel resources, selected variations in common medical care practice, selected health status indicators, and demographic and general economic background data. There may be some inconsistencies between the data presented in the articles in this issue and those in this data compendium. The articles were based on earlier versions of the Health Data File. As a result, revisions to the data in a number of countries, including Canada, France, Germany, and Italy, are not reflected in the articles. However, the changes are relatively minor and do not affect the results presented in the articles in any substantive way.
A vessel connecting the axillary or brachial artery to one of the forearm arteries was found in a 65 year old male cadaver, during the gross anatomy dissection of the upper extremity of 20 adult cadavers at the Department of Cellular Biology and Anatomy, Louisiana State University Medical Center. The right radial artery originated from the brachial artery nearly at the usual level and was connected to the axillary or brachial artery by a long slender anastomotic artery (vasa aberrantia). The anastomotic artery coursed under the medial side of the biceps muscle between the median and musculocutaneous nerves, and gave off two muscular branches to the biceps muscle. The anastomotic artery coursed between the median and musculocutaneous nerves in the arm, it passed to the forearm under the bicipital aponeurosis and connected the main radial artery on the radial side of the forearm. The anastomotic artery can be explained on the basis of its embryologic development and also ought to be distinguished from the other common arterial variations in the upper extremity.