Glostrup Hospital

BACKGROUND: Intensified multifactorial intervention - with tight glucose regulation and the use of renin-angiotensin system blockers, aspirin, and lipid-lowering agents - has been shown to reduce the risk of nonfatal cardiovascular disease among patients with type 2 diabetes mellitus and microalbuminuria. We evaluated whether this approach would have an effect on the rates of death from any cause and from cardiovascular causes. METHODS: In the Steno-2 Study, we randomly assigned 160 patients with type 2 diabetes and persistent microalbuminuria to receive either intensive therapy or conventional therapy; the mean treatment period was 7.8 years. Patients were subsequently followed observationally for a mean of 5.5 years, until December 31, 2006. The primary end point at 13.3 years of follow-up was the time to death from any cause. RESULTS: Twenty-four patients in the intensive-therapy group died, as compared with 40 in the conventional-therapy group (hazard ratio, 0.54; 95% confidence interval [CI], 0.32 to 0.89; P=0.02). Intensive therapy was associated with a lower risk of death from cardiovascular causes (hazard ratio, 0.43; 95% CI, 0.19 to 0.94; P=0.04) and of cardiovascular events (hazard ratio, 0.41; 95% CI, 0.25 to 0.67; P<0.001). One patient in the intensive-therapy group had progression to end-stage renal disease, as compared with six patients in the conventional-therapy group (P=0.04). Fewer patients in the intensive-therapy group required retinal photocoagulation (relative risk, 0.45; 95% CI, 0.23 to 0.86; P=0.02). Few major side effects were reported. CONCLUSIONS: In at-risk patients with type 2 diabetes, intensive intervention with multiple drug combinations and behavior modification had sustained beneficial effects with respect to vascular complications and on rates of death from any cause and from cardiovascular causes. (ClinicalTrials.gov number, NCT00320008.)

This study, which is a part of the initiative 'Lifting The Burden: The Global Campaign to Reduce the Burden of Headache Worldwide', assesses and presents all existing evidence of the world prevalence and burden of headache disorders. Population-based studies applying International Headache Society criteria for migraine and tension-type headache, and also studies on headache in general and 'chronic daily headache', have been included. Globally, the percentages of the adult population with an active headache disorder are 46% for headache in general, 11% for migraine, 42% for tension-type headache and 3% for chronic daily headache. Our calculations indicate that the disability attributable to tension-type headache is larger worldwide than that due to migraine. On the World Health Organization's ranking of causes of disability, this would bring headache disorders into the 10 most disabling conditions for the two genders, and into the five most disabling for women.

A set of related medical disorders that lack a proper classification system and diagnostic criteria is like a society without laws. The result is incoherence at best, chaos at worst. For this reason, the International Classification of Headache Disorders (ICHD) is arguably the single most important breakthrough in headache medicine over the last 50 years. The ICHD identifies and categorizes more than a hundred different kinds of headache in a logical, hierarchal system. Even more important, it has provided explicit diagnostic criteria for all of the headache disorders listed. The ICHD quickly became universally accepted, and criticism of the classification has been minor relative to that directed at other disease classification systems. Over the 20 years following publication of the first edition of the ICHD, headache research has rapidly accelerated despite sparse allocation of resources to that effort. In summary, the ICHD has attained widespread acceptance at the international level and has substantially facilitated both clinical research and clinical care in the field of headache medicine.

Post-translational modifications (PTMs) occur on almost all proteins analyzed to date. The function of a modified protein is often strongly affected by these modifications and therefore increased knowledge about the potential PTMs of a target protein may increase our understanding of the molecular processes in which it takes part. High-throughput methods for the identification of PTMs are being developed, in particular within the fields of proteomics and mass spectrometry. However, these methods are still in their early stages, and it is indeed advantageous to cut down on the number of experimental steps by integrating computational approaches into the validation procedures. Many advanced methods for the prediction of PTMs exist and many are made publicly available. We describe our experiences with the development of prediction methods for phosphorylation and glycosylation sites and the development of PTM-specific databases. In addition, we discuss novel ideas for PTM visualization (exemplified by kinase landscapes) and improvements for prediction specificity (by using ESS--evolutionary stable sites). As an example, we present a new method for kinase-specific prediction of phosphorylation sites, NetPhosK, which extends our earlier and more general tool, NetPhos. The new server, NetPhosK, is made publicly available at the URL http://www.cbs.dtu.dk/services/NetPhosK/. The issues of underestimation, over-prediction and strategies for improving prediction specificity are also discussed.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Abbreviations ACE: angiotensin-converting enzyme; BP: blood pressure; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; ESC: European Society of Cardiology; ESH: European Society of Hypertension; ET: endothelin; IMT: carotid intima-media thickness; JNC: Joint National Committee; LVH: left ventricular hypertrophy; LVM: left ventricular mass; PDE-5: phosphodiesterase-5; PPAR-γ: peroxisome proliferators-activated receptor-γ; PWV: pulse wave velocity; SBP: systolic blood pressure; WHO: World Health Organization. Introduction In the 2 years since the publication of the 2007 guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) [1], research on hypertension has actively been pursued and the results of new important studies (including several large randomized trials of antihypertensive therapy) have been published. Some of these studies have reinforced the evidence on which the recommendations of the 2007 ESH/ESC guidelines were based. However, other studies have widened the information available in 2007, modifying some of the previous concepts, and suggesting that new evidence-based recommendations could be appropriate. The aim of this document of the ESH is to address a number of studies on hypertension published in the last 2 years in order to assess their contribution to our expanding knowledge of hypertension. Furthermore, some critical appraisal of the current recommendations of the ESH/ESC, as well as of other guidelines, might be a useful step toward the preparation of a third version of the European guidelines in the future. The most important conclusions are summarized in boxes. The points that will be discussed are reported in Box 1.Box. 1Assessment of subclinical organ damage for stratification of total cardiovascular risk The 2007 ESH/ESC guidelines recommend total cardiovascular risk be evaluated in each patient to decide about important aspects of treatment: the blood pressure (BP) threshold at which to commence drug administration, the target BP to be reached by treatment, the use of two-drug combinations as the initial treatment step, and the possible addition to the antihypertensive treatment regimen of lipid-lowering and antiplatelet agents [1]. Among the criteria to assess total cardiovascular risk, the European guidelines consider subclinical organ damage to be a very important component, because asymptomatic alterations of the cardiovascular system and the kidney are crucial intermediate stages in the disease continuum that links risk factors such as hypertension to cardiovascular events and death. On the basis of a number of criteria (prognostic importance, prevalence in the population, availability and cost of the assessment procedures, etc.), the 2007 European guidelines considered detection of organ damage as important for the diagnostic and prognostic evaluation of hypertensive patients. They further subdivided the different types of organ damage into (1) those that can be identified by relatively simple and cheap procedures [electrocardiogram, serum creatinine, estimated glomerular filtration rate (eGFR), and measurement of urinary protein excretion in order to detect microalbuminuria or proteinuria], which were thus regarded as suitable for routine search in the whole hypertensive population, and (2) those that require more complex procedures or instrumentations (echocardiogram, carotid ultrasonography, pulse wave velocity), which were for this reason only recommended for a more in-depth characterization of the hypertensive patient. Since then, other studies have added useful information on the importance of detecting subclinical organ damage in the hypertensive population, strengthening the recommendation to use the most easily available and the least costly procedures in the routine examination of individuals with hypertension. Heart A few recent papers have revived interest in the of the to the risk of cardiovascular In a a new of left ventricular the of left ventricular that is on and has been reported to be to cardiovascular The for and Furthermore, in the the have reported that in hypertensive with left individuals at risk of cardiovascular cardiovascular and for a very recent on the in as with left ventricular and of cardiovascular events hypertension is by risk for each evidence is available on the of as by of interest because of to more and and A has information more and hypertensive with left ventricular left ventricular left ventricular in of the left ventricular and and the risk of as large as that of with left ventricular in on population, the left ventricular and for and only in the risk with has been by other In a on a of hypertensive for with a of and cardiovascular events and with for cardiovascular risk factors Furthermore, a of hypertensive in the that cardiovascular events about more in with a or more with those with a this in the population, with a to in cardiovascular and were for a large number of and BP A in the risk more risk the The of carotid and with cardiovascular discussed in the 2007 guidelines, has been further by which have that carotid cardiovascular events of BP and and this for the at the carotid and for the at the of the carotid that by the at the and by the carotid prognostic in addition to that of prognostic of carotid has been reported in a of of the of cardiovascular which for about years has on the prognostic of arterial In the population, pulse wave with a in the risk of a cardiovascular Furthermore, of for cardiovascular events has been in for years of and wave such as BP and have been as of cardiovascular events in recent studies In in of these studies of and hypertensive only and cardiovascular for cardiovascular risk and carotid However, be that in most available the of BP pressure which the BP be considered in the of hypertensive in of further new the evidence on the prognostic of that available at the of the 2007 guidelines [1]. 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The 2007 European guidelines hypertensive with subclinical organ damage those with a total cardiovascular is further by more recent evidence on the contribution of subclinical and damage to the total cardiovascular to subclinical of the by some of the studies that in hypertensive of the is with of cardiovascular events to or in years in years has been reported for for with in the in the hypertensive of the with a of cardiovascular events of with the in evidence for In the of the Health the of cardiovascular events the carotid or more and and in those with in the In the hypertensive of the the of and cardiovascular events in years carotid in the third and or at least been In with in the or the cardiovascular events in In hypertensive the of cardiovascular events or more and in those with in the and Furthermore, asymptomatic disease as by a has been to be in with of cardiovascular events in years and recent evidence that in hypertensive subclinical organ damage is with a risk of cardiovascular events of or has been reported some years that by a serum more is with a of cardiovascular events or more In the recent of hypertensive a with cardiovascular events of about in with Furthermore, in the hypertensive by the of disease in years in the of microalbuminuria and of only in in the the of cardiovascular events in only in those individuals in microalbuminuria in the with in the of these hypertension. 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BACKGROUND AND PURPOSE: In 2005, we presented for the first time overall estimates of annual costs for brain disorders (mental and neurologic disorders) in Europe. This new report presents updated, more accurate, and comprehensive 2010 estimates for 30 European countries. METHODS: One-year prevalence and annual cost per person of 19 major groups of disorders are based on 'best estimates' derived from systematic literature reviews by panels of experts in epidemiology and health economics. Our cost estimation model was populated with national statistics from Eurostat to adjust to 2010 values, converting all local currencies to Euros (€), imputing cost for countries where no data were available, and aggregating country estimates to purchasing power parity-adjusted estimates of the total cost of brain disorders in Europe in 2010. RESULTS: Total European 2010 cost of brain disorders was €798 billion, of which direct health care cost 37%, direct non-medical cost 23%, and indirect cost 40%. Average cost per inhabitant was €5.550. The European average cost per person with a disorder of the brain ranged between €285 for headache and €30 000 for neuromuscular disorders. Total annual cost per disorder (in billion € 2010) was as follows: addiction 65.7; anxiety disorders 74.4; brain tumor 5.2; child/adolescent disorders 21.3; dementia 105.2; eating disorders 0.8; epilepsy 13.8; headache 43.5; mental retardation 43.3; mood disorders 113.4; multiple sclerosis 14.6; neuromuscular disorders 7.7; Parkinson's disease 13.9; personality disorders 27.3; psychotic disorders 93.9; sleep disorders 35.4; somatoform disorder 21.2; stroke 64.1; and traumatic brain injury 33.0. CONCLUSION: Our cost model revealed that brain disorders overall are much more costly than previously estimated constituting a major health economic challenge for Europe. Our estimate should be regarded as conservative because many disorders or cost items could not be included because of lack of data.

BACKGROUND: Few population studies addressed the prognostic significance of aortic pulse wave velocity (APWV) above and beyond other cardiovascular risk factors. METHODS AND RESULTS: We studied a sex- and age-stratified random sample of 1678 Danes aged 40 to 70 years. We used Cox regression to investigate the prognostic value of APWV, office pulse pressure (PP), and 24-hour ambulatory PP while adjusting for mean arterial pressure (MAP) and other covariates. Over a median follow-up of 9.4 years, the incidence of fatal and nonfatal cardiovascular end points, cardiovascular mortality, and fatal and nonfatal coronary heart disease amounted to 154, 62, and 101 cases, respectively. We adjusted for sex, age, body mass index, MAP measured in the office (conventional PP and APWV) or by ambulatory monitoring (24-hour PP), smoking, and alcohol intake. With these adjustments, APWV maintained its prognostic significance in relation to each end point (P<0.05), whereas office and 24-hour PP lost their predictive value (P>0.19), except for office PP in relation to coronary heart disease (P=0.02). For each 1-SD increment in APWV (3.4 m/s), the risk of an event increased by 16% to 20%. In sensitivity analyses, APWV still predicted all cardiovascular events after standardization to a heart rate of 60 beats per minute, after adjustment for 24-hour MAP instead of office MAP, and/or after additional adjustment for the ratio of total to HDL serum cholesterol and diabetes mellitus at baseline. CONCLUSIONS: In a general Danish population, APWV predicted a composite of cardiovascular outcomes above and beyond traditional cardiovascular risk factors, including 24-hour MAP.

BACKGROUND: Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights. OBJECTIVE: To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion. METHODS: A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived. RESULTS: The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1-3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient. Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10). CONCLUSIONS: The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA.

Of all 30-, 40-, 50-, and 60-year-old inhabitants of Glostrup, a suburb of Copenhagen, 82% (449 men and 479 women) participated in a general health survey, which included a thorough physical examination relating to the lower back. The examination was constituted of anthropometric measurements, flexibility/elasticity measurements of the back and hamstrings, as well as tests for trunk muscle strength and endurance. The reproducibility of the tests was found to be satisfactory. Twelve months after the physical examination 99% of the participants completed a questionnaire sent by mail concerning low back trouble (LBT) in the intervening period. The prognostic value of the physical measurements was evaluated for first-time experience and for recurrence or persistence of LBT by analyses of the separate measurements and discriminant analyses. The main findings were that good isometric endurance of the back muscles may prevent first-time occurrence of LBT in men and that men with hypermobile backs are more liable to contract LBT. Recurrence or persistence of LBT was correlated primarily to the interval since last LBT-episode: the more LBT, the shorter the intervals had been. Weak trunk muscles and reduced flexibility/elasticity of the back and hamstrings were found as residual signs, in particular, among those with recurrence or persistence of LBT in the follow-up year.

OBJECTIVE: We propose new classification criteria for Sjögren's syndrome (SS), which are needed considering the emergence of biologic agents as potential treatments and their associated comorbidity. These criteria target individuals with signs/symptoms suggestive of SS. METHODS: Criteria are based on expert opinion elicited using the nominal group technique and analyses of data from the Sjögren's International Collaborative Clinical Alliance. Preliminary criteria validation included comparisons with classifications based on the American–European Consensus Group (AECG) criteria, a model-based “gold standard”obtained from latent class analysis (LCA) of data from a range of diagnostic tests, and a comparison with cases and controls collected from sources external to the population used for criteria development. RESULTS: Validation results indicate high levels of sensitivity and specificity for the criteria. Case definition requires at least 2 of the following 3: 1) positive serum anti-SSA and/or anti-SSB or (positive rheumatoid factor and antinuclear antibody titer >1:320), 2) ocular staining score >3, or 3) presence of focal lymphocytic sialadenitis with a focus score >1 focus/4 mm2 in labial salivary gland biopsy samples. Observed agreement with the AECG criteria is high when these are applied using all objective tests. However, AECG classification based on allowable substitutions of symptoms for objective tests results in poor agreement with the proposed and LCA-derived classifications. CONCLUSION: These classification criteria developed from registry data collected using standardized measures are based on objective tests. Validation indicates improved classification performance relative to existing alternatives, making them more suitable for application in situations where misclassification may present health risks.

BACKGROUND: This study examined the impact of virtual reality (VR) surgical simulation on improvement of psychomotor skills relevant to the performance of laparoscopic cholecystectomy. METHODS: Sixteen surgical trainees performed a laparoscopic cholecystectomy on patients in the operating room (OR). The participants were then randomized to receive VR training (ten repetitions of all six tasks on the Minimally Invasive Surgical Trainer-Virtual Reality (MIST-VR)) or no training. Subsequently, all subjects performed a further laparoscopic cholecystectomy in the OR. Both operative procedures were recorded on videotape, and assessed by two independent and blinded observers using predefined objective criteria. Time to complete the procedure, error score and economy of movement score were assessed during the laparoscopic procedure in the OR. RESULTS: No differences in baseline variables were found between the two groups. Surgeons who received VR training performed laparoscopic cholecystectomy significantly faster than the control group (P=0.021). Furthermore, those who had VR training showed significantly greater improvement in error (P=0.003) and economy of movement (P=0.003) scores. CONCLUSION: Surgeons who received VR simulator training showed significantly greater improvement in performance in the OR than those in the control group. VR surgical simulation is therefore a valid tool for training of laparoscopic psychomotor skills and could be incorporated into surgical training programmes.

BACKGROUND: Calcitonin gene-related peptide (CGRP) may have a causative role in migraine. We therefore hypothesized that a CGRP-receptor antagonist might be effective in the treatment of migraine attacks. METHODS: In an international, multicenter, double-blind, randomized clinical trial of BIBN 4096 BS, a highly specific and potent nonpeptide CGRP-receptor antagonist, 126 patients with migraine received one of the following: placebo or 0.25, 0.5, 1, 2.5, 5, or 10 mg of BIBN 4096 BS intravenously over a period of 10 minutes. A group-sequential adaptive treatment-assignment design was used to minimize the number of patients exposed. RESULTS: The 2.5-mg dose was selected, with a response rate of 66 percent, as compared with 27 percent for placebo (P=0.001). The BIBN 4096 BS group as a whole had a response rate of 60 percent. Significant superiority over placebo was also observed with respect to most secondary end points: the pain-free rate at 2 hours; the rate of sustained response over a period of 24 hours; the rate of recurrence of headache; improvement in nausea, photophobia, phonophobia, and functional capacity; and the time to meaningful relief. An effect was apparent after 30 minutes and increased over the next few hours. The overall rate of adverse events was 25 percent after the 2.5-mg dose of the drug and 20 percent for the BIBN 4096 BS group as a whole, as compared with 12 percent for placebo. The most frequent side effect was paresthesia. There were no serious adverse events. CONCLUSIONS: The CGRP antagonist BIBN 4096 BS was effective in treating acute attacks of migraine.

Calcitonin gene-related peptide (CGRP) has been detected in increased amounts in external jugular venous blood during migraine attacks. However, it is unknown whether this is secondary to migraine or whether CGRP may cause headache. In a double-blind crossover study, the effect of human alphaCGRP (2 microg/min) or placebo infused intravenously for 20 min was studied in 12 patients suffering from migraine without aura. Headache intensity was scored on a scale from 0 to 10. Two patients were excluded due to severe hypotension and one because she had an infection. In the first hour median peak headache score was 1.0 in the halphaCGRP group vs. 0 in the placebo group (P < 0.01). During the following 11 h all patients experienced headaches after halphaCGRP vs. one patient after placebo (P = 0.0004). The median maximal headache score was 4 after CGRP and 0 after placebo (P = 0.006). In three patients after halphaCGRP, but in no patients after placebo, the delayed headache fulfilled the IHS criteria for migraine without aura. As intravenous administration of halphaCGRP causes headache and migraine in migraineurs, our study suggests that the increase in CGRP observed during spontaneous migraine attacks may play a causative role.

Chemokines direct tissue invasion by specific leukocyte populations. Thus, chemokines may play a role in multiple sclerosis (MS), an idiopathic disorder in which the central nervous system (CNS) inflammatory reaction is largely restricted to mononuclear phagocytes and T cells. We asked whether specific chemokines were expressed in the CNS during acute demyelinating events by analyzing cerebrospinal fluid (CSF), whose composition reflects the CNS extracellular space. During MS attacks, we found elevated CSF levels of three chemokines that act toward T cells and mononuclear phagocytes: interferon-gamma-inducible protein of 10 kDa (IP-10); monokine induced by interferon-gamma (Mig); and regulated on activation, normal T-cell expressed and secreted (RANTES). We then investigated whether specific chemokine receptors were expressed by infiltrating cells in demyelinating MS brain lesions and in CSF. CXCR3, an IP-10/Mig receptor, was expressed on lymphocytic cells in virtually every perivascular inflammatory infiltrate in active MS lesions. CCR5, a RANTES receptor, was detected on lymphocytic cells, macrophages, and microglia in actively demyelinating MS brain lesions. Compared with circulating T cells, CSF T cells were significantly enriched for cells expressing CXCR3 or CCR5. Our results imply pathogenic roles for specific chemokine-chemokine receptor interactions in MS and suggest new molecular targets for therapeutic intervention.

Many important decisions on hypertension management must currently be taken without the support of evidence&#13;\nfrom large randomized controlled trials. The following issues appear in urgent need to be approached by simply&#13;\ndesigned trials.&#13;\n(1) Should antihypertensive drugs be prescribed to all patients with grade 1 hypertension, even when total&#13;\ncardiovascular risk is relatively low or moderate? Because of the very low rate of cardiovascular events&#13;\nexpected in these patients, a placebo-controlled trial using intermediate endpoints such as signs of organ&#13;\ndamage of recognized prognostic importance would be feasible, ethical, and clinically relevant.&#13;\n(2) Should antihypertensive drugs be prescribed to the elderly with grade 1 hypertension, and should antihypertensive&#13;\ntreatment achieve a goal of below 140/90mmHg also in the elderly? These trials could make use&#13;\nof hard cardiovascular outcomes and could be placebo-controlled.&#13;\n(3) Should antihypertensive drug treatment be started in diabetic patients or in patients with previous cerebrovascular&#13;\nor cardiovascular disease when BP is still in the high normal level, and should BP goal be below 130/&#13;\n80mmHg in these patients? These issues can be approached by placebo-controlled trials because no trial&#13;\nevidence is still available on the benefit of lowering high normal BP or of achieving BP goals below 130/&#13;\n80mmHg.&#13;\n(4) What are the lowest safe BP values to achieve by treatment in different clinical conditions? This issue should&#13;\nbe approached by trials comparing more or less intense BP-lowering treatment strategies in patients with&#13;\ndifferent cardiovascular risk levels.&#13;\n(5) Are lifestyle measures known to reduce BP also capable of reducing morbidity and mortality in hypertension?&#13;\nA controlled randomized trial using intermediate endpoints (organ damage) would be feasible and desirable&#13;\nin patients with high normal BP or grade 1 hypertension.

In 74 adult patients suffering from various renal diseases, the total [51Cr]EDTA plasma clearance (Cl) was compared to the [51Cr]EDTA clearance obtained on assuming a one-pool system (Cl1). Cl1 always exceeded Cl, and the relative difference increased with increasing clearance values. An equation for correction is given. The method for determining Cl1 is very simple and suitable for clinical routine examinations.

The trigeminal nerve and its projections to the intracranial vasculature — the trigeminovascular system — are at the nexus of migraine. Identification of the mechanisms that trigger signals in this system have led to targeted treatments and preventive therapies for migraine.

BACKGROUND: Depression has been shown to adversely affect the prognosis of patients with established coronary artery disease, but there is comparatively little evidence to document the role of depression in the initial development of coronary disease. METHODS AND RESULTS: Study participants were 409 men and 321 women who were residents of Glostrup, Denmark, born in 1914. Physical and psychological examinations in 1964 and 1974 established their baseline risk factor and disease status and their level of depressive symptomatology. Initial myocardial infarction (MI) was observed in 122 participants, and there were 290 deaths during follow-up, which ended in 1991. A 2-SD difference in depression score was associated with relative risks of 1.71 (P = .005) for MI and 1.59 (P < .001) for deaths from all causes. These findings were unchanged after we controlled for risk factors and signs of disease at baseline. There were no sex differences in effect sizes. CONCLUSIONS: High levels of depressive symptomatology are associated with increased risks of MI and mortality. The graded relationships between depression scores and risk, long-lasting nature of the effect, and stability of the depression measured across time suggest that this risk factor is best viewed as a continuous variable that represents a chronic psychological characteristic rather than a discrete and episodic psychiatric condition.

Cortical spreading depression (CSD) and depolarization waves are associated with dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells, increased energy metabolism and changes in cerebral blood flow (CBF). There is strong clinical and experimental evidence to suggest that CSD is involved in the mechanism of migraine, stroke, subarachnoid hemorrhage and traumatic brain injury. The implications of these findings are widespread and suggest that intrinsic brain mechanisms have the potential to worsen the outcome of cerebrovascular episodes or brain trauma. The consequences of these intrinsic mechanisms are intimately linked to the composition of the brain extracellular microenvironment and to the level of brain perfusion and in consequence brain energy supply. This paper summarizes the evidence provided by novel invasive techniques, which implicates CSD as a pathophysiological mechanism for this group of acute neurological disorders. The findings have implications for monitoring and treatment of patients with acute brain disorders in the intensive care unit. Drawing on the large body of experimental findings from animal studies of CSD obtained during decades we suggest treatment strategies, which may be used to prevent or attenuate secondary neuronal damage in acutely injured human brain cortex caused by depolarization waves.