October 15, 2009 — A new meta-analysis has found no benefit of lowering homocysteine with vitamin-B supplementation for either primary or secondary prevention of cardiovascular disease [1,2]. Dr Arturo J Martí-Carvajal (Iberoamerican Cochrane Network, Valencia, Venezuela) and colleagues publish their findings online October 7, 2009, in the Cochrane Database of Systematic Reviews.
"We found no evidence that homocysteine-lowering interventions, in the form of supplements of vitamin B6 (pyridoxine), B9 (folic acid), or B12 (cyanocobalamin), given alone or in combination at any dosage, compared with placebo or standard care, prevents myocardial infarction [MI] or stroke or reduces total mortality in participants at risk of or with established cardiovascular disease," they report.
Martí-Carvajal told heartwire the review was necessary despite the fact that trial after trial has failed to show a benefit of homocysteine-lowering therapy. Healthcare providers, consumers, researchers, and policy makers are inundated with unmanageable amounts of information, and it is unlikely they will all have the time to properly interpret this evidence and incorporate it into healthcare decisions, he said.
The new research provides "scientific proof . . . that folic acid, vitamin B12, and vitamin B6 do not work to prevent cardiovascular disease," he said, adding that his message to people would be: "Save your money." Doctors should advise their patients of this message and instead encourage them to quit smoking, exercise more, and monitor blood pressure, glucose, and lipids to reduce the risk of cardiovascular events, he stressed.
Antiplatelet function was diminished in PPI users, but cardiovascular outcomes were similar in PPI users and nonusers.
Consensus recommendations from cardiology and gastroenterology societies endorse the use of proton-pump inhibitors (PPIs) in patients who receive antiplatelet therapy and are at high risk for gastrointestinal bleeding (Am J Gastroenterol 2008; 103:2890). However, data from recent observational studies have suggested that PPI use might attenuate the antiplatelet effect of the thienopyridine clopidogrel in patients who receive it after an acute coronary syndrome (ACS) event. Moreover, one study identified a significantly higher composite rate of all-cause mortality and rehospitalization for ACS in patients who took both a PPI and clopidogrel than in those who took clopidogrel alone (JW Gastroenterol Mar 6 2009). To assess the effects of PPI use on both platelet function and cardiovascular endpoints, researchers retrospectively analyzed data from two industry-funded, randomized trials involving ACS patients treated with clopidogrel or another thienopyridine, prasugrel.
In the first trial, involving 201 patients scheduled to undergo percutaneous coronary intervention (PCI), 26% were taking a PPI at randomization. In the clopidogrel group, significantly more PPI users than nonusers experienced inadequate inhibition of platelet aggregation during the first day after clopidogrel administration, with a nonsignificant trend in that direction after 15 days of clopidogrel maintenance therapy. In the prasugrel group, the difference was significant after 15 days but was not consistent across time points during the first day after clopidogrel administration.
In the second trial, involving 13,608 participants who underwent PCI, 33% were taking a PPI at randomization. In both the clopidogrel and prasugrel groups, incidence of the primary endpoint of cardiovascular death, myocardial infarction, or stroke at 30 days did not differ significantly between PPI users and nonusers.
Comment: Platelet-function tests and data from observational studies might be factual, but they are not always accurate for extrapolation, as evident from recommendations by national societies and government agencies that PPIs and clopidogrel should not be coprescribed. The present findings, along with results from a recent prospective trial comparing omeprazole plus clopidogrel versus clopidogrel alone, show that concomitant PPI and thienopyridine use is not associated with adverse cardiovascular outcomes. Platelet assays and observational data are no substitutes for randomized controlled data. Gastroenterologists should be proactive in making sure that patients with an appropriate indication for PPI cotherapy neither stop nor avoid starting this therapy because of any misunderstanding of the PPI–clopidogrel interaction.
Published in Journal Watch Gastroenterology October 16, 2009
Citation(s):
O'Donoghue ML et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: An analysis of two randomised trials. Lancet 2009 Sep 19; 374:989.
Zeven procent studenten gebruikt ritalin voor plezier
Gepubliceerd: 12 oktober 2009 13:38 | Gewijzigd: 13 oktober 2009 09:56
Door onze redacteur Frederiek Weeda
Amsterdam. 12 oktober. Ruim 7 procent van de studenten aan vier onderzochte universiteiten gebruikt weleens ritalin (methylfenidaat) om niet-medische redenen. Ruim 3 procent gebruikt het om de concentratie te verbeteren tijdens een examenperiode, 5 procent gebruikt het voor de lol. Een klein deel gebruikt ritalin voor beide doeleinden.
Molecuulmodel van methylfenidaat (Ritalin).
Dit blijkt uit onderzoek van econoom Tjebbe van Meeteren, die 22 oktober afstudeert in marketing aan de Erasmus Universiteit Rotterdam. Het is het eerste onderzoek in zijn soort in Nederland. In de VS is al langer bekend dat tussen 2 en 20 procent van de studenten en professionals ritalin gebruiken om hun resultaten te verbeteren.
Van Meeteren ondervroeg 130 merendeels economiestudenten in Utrecht, Amsterdam, aan Nijenrode en in Rotterdam. Ze zeggen ritalin te kopen (circa 4 euro per pil) van kennissen of familie.
Ritalin is een medicijn dat op grote schaal door huisartsen en psychiaters wordt voorgeschreven voor patiënten met de psychiatrische stoornis ADHD. Het middel werkt ongeveer vier uur. Patiënten – veelal kinderen en tieners – slikken het om zich beter te concentreren op school en rustiger te worden. Vorig jaar slikten in Nederland ongeveer 200.000 kinderen ritalin of concerta, een duurder middel dat de hele dag werkt.
Ritalin is gebaseerd op amfetamine en verbetert de overdracht van bepaalde stoffen in de hersenen. De gebruiker wordt minder snel afgeleid en voelt minder behoefte aan nieuwe prikkelingen.
Van alle ondervraagde studenten (ook de niet-gebruikers) bleek bijna 47 procent op de hoogte te zijn van de effecten die ritalin kan hebben, schrijft Van Meeteren. Tachtig procent staat negatief tegenover het gebruik van ritalin om niet-medische redenen.
In totaal 12,5 procent van de studenten zegt ritalin het komende jaar te zullen gebruiken voor verbetering van de concentratie of voor recreatie. Het kleinste deel van deze groep (5 procent) wil ritalin slikken om zijn studieprestaties te verbeteren.
October 7, 2009 — A systematic review of the literature suggests that prestroke dementia is present in about 10% of patients before a first stroke, that 10% of patients develop dementia after a stroke, and that upward of 30% of patients develop dementia after a recurrent stroke.
Sarah T. Pendlebury, FPhil, and Peter Rothwell, FMedSci, from John Radcliffe Hospital, Oxford, United Kingdom, report a strong association between multiple strokes and poststroke dementia in an article published online September 24 in Lancet Neurology.
"It seems that the stroke itself and its complications are of paramount importance in the etiology of poststroke dementia," Dr. Pendlebury told Medscape Neurology.
Studies have shown that stroke unit care, now the gold standard for stroke treatment, provides better outcomes than general ward care, she added. "We would hypothesize that some of the better outcome is through better cognitive outcome through prevention of secondary insults such as hypoxia [and] hypotension and in better prevention of recurrent stroke."
Literature Confusing
Although there is "broad consensus" that stroke is associated with an increased risk for dementia, the results of previous studies of the prevalence of pre- and poststroke dementia have been conflicting, the authors write.
"The reported rates of prestroke, and even more for poststroke, dementia were very different between different studies, so it was very difficult to get a clear idea as a clinician as to what to expect for an individual patient with a stroke in terms of their outcome," Dr. Pendlebury added.
In this study, Dr. Pendlebury and Dr. Rothwell conducted a systematic review of studies on the subject published between 1950 and May 1, 2009, both to assess the heterogeneity of the published studies and to identify possible risk factors for pre- and poststroke dementia. The researchers identified 22 hospital-based and 8 population-based studies including 7511 patients in 73 eligible articles.
The pooled prevalence of prestroke dementia was higher in hospital-based studies, at 14.4% (95% confidence interval [CI], 12.0% – 16.8%), than in population-based studies, where it was 9.1% (95% CI, 6.9% – 11.3%).
For poststroke dementia, the incidence of dementia in the first year after a stroke was highly variable but ranged from 7.4% in population-based studies where prestroke dementia was excluded (95% CI, 4.8% – 10.0%) to 41.3% in hospital-based studies of patients with recurrent stroke that included those with prestroke dementia (95% CI, 29.6% – 53.1%).
Of the variance in these rates, 93% could be explained by differences in factors such as study setting and case mix, the authors note. The cumulative incidence of dementia after the first year was about 3% per year higher in hospital-based studies than would be expected on the basis of recurrent stroke alone, they add.
Factors strongly associated with prestroke dementia included medial temporal lobe atrophy, female sex, and a family history of dementia. Poststroke dementia, in contrast, was associated with characteristics and complications of the stroke itself, such the occurrence of seizures, hypoxia, or hypotension, for example, or the presence of multiple lesions in time and place, they write.
"After study methods and case mix are taken into account, reported estimates of the prevalence of dementia are consistent: 10% of patients had dementia before first stroke, 10% developed new dementia soon after first stroke, and more than a third had dementia after recurrent stroke," the authors conclude. "The strong association of post-stroke dementia with multiple strokes and the prognostic value of other stroke characteristics highlight the central causal role of stroke itself as opposed to the underlying vascular risk factors and, thus, the likely effect of optimum acute stroke care and secondary prevention in reducing the burden of dementia."
Limitations of the Literature
In an accompanying Reflection and Reaction article, Michael G. Hennerici, MD, from the University of Heidelberg, Germany, says the new findings "strengthen the association of post-stroke dementia with multiple strokes rather than with underlying vascular risk factors."
However, he notes, "most of the studies included were from the 1970s and 1980s when the emphasis was on concept of multi-infarct dementia and counting stroke recurrences rather than on investigation of distinct mechanisms in the development of pre-stroke and post-stroke dementia (eg, lesions in cortico-subcortical networks, disconnection syndromes, or overlapping cortical degeneration. Therefore, the authors' interpretation of the findings could be questioned nowadays."
"Above all," Dr. Hennerici writes, the current article, "shows the limitations of the available data to identify the most important, and possibly treatable active mechanisms of dementia and disability in elderly patients."
Stroke is not a homogeneous disease, and because the elderly have multimorbidity, the variability in stroke etiology and topography must be addressed in well-designed prospective trials using new technologies. One such trial already providing some of these answers, Dr. Hennerici writes, is the Leukoaraiosis and Disability Study, on which he is a coinvestigator. This study assesses the role of age-related white matter changes and conversion to dementia in patients free of dementia at entry.
Of 90 patients who developed dementia, only 13 had a new stroke; the other 37 patients who had incident stroke did not develop dementia (BMJ. 2009;339:b2477).
"This finding lends support to the notion of distinct, and hence potentially treatable, cumulative basic mechanisms (ie, white matter changes and hypertension) rather than to stroke in general for post-stroke dementia," Dr. Hennerici concludes. "Systematic treatment of hypertension represents the best available preventive strategy for both stroke and dementia in ageing people."
Dr. Pendlebury is supported by the Oxford Partnership Biomedical Research Center. The authors have disclosed no relevant financial relationships. Dr. Hennerici has disclosed that he was a coinvestigator on the Leukoaraiosis and Disability Study.
Lancet Neurol. Published online September 24, 2009.
AT SOUTH Lodge, Minsteracres, near Slaley, don’t be surprised if you hear the faint chanting of monkish voices, or sniff a whiff of incense. The Lodge lies on a hotbed of religious fervency, stoked for many generations.
South Lodge dates from the 1850s but Healey, the parish it stands in, was known in the Middle Ages as Temple Healey and was the property of that most legendary group of religious fundamentalists, the Knights Templar.
This 12th century order of warrior monks, whose fame was recently given fresh gloss by Da Vinci Code novelist Dan Brown, were supposed to be chaste and poor – as well as guarding the secret of the Holy Grail.
But far from being poverty-stricken, the Knights Templar were actually canny businessmen who owned land worth millions. As well as the south Northumberland parish known as Temple Healey, Temple Houses at Haydon Bridge was probably in the Knights Templar portfolio too.
But those mighty knights, like most other church landlords, lost out in Henry VIII’s 16th century Reformation, and Minsteracres seems to have lain fallow for a while.
Then the estate found new owners just as motivated by religion as were the Knights Templar – the Silvertops, who were to become one of the North’s greatest Catholic dynasties.
Henry VIII’s little disagreement with Catholicism didn’t have quite the same impact in the North of England as in the South. At a safe distance from the centre of government, many powerful Northern families felt quite secure to carry on with their bells and smells, importing family priests from the Continent and building impressive private chapels.
The Radcliffes of Dilston near Corbridge had made a big noise on behalf of the Old Faith in both Jacobite rebellions, sacrificing two family heads for Catholic pretenders old and young.
The Swinburnes of Capheaton and the Erringtons of Beaufront were also active Papists.
The Silvertops were making an impact by the late 1700s, when their modest mining interests began to hit the mother lode. Like the Knights Templar, the Silvertops knew how to make money, and they used their growing income to help pay for chapels, establish missions and retreats, and train young priests.
And early in King George III’s era, Albert Silvertop bought Minsteracres.
The estate originally consisted of a handful of cottages and a few fields, but by the time Albert’s heir George died in 1789, he could be described as a gentleman who “accumulated an ample fortune, honourably got”.
George built a Catholic mission at Barleyhill, which must have been on or near the site of the later South Lodge.
It was George’s son John who built Minsteracres mansion, lavishly equipping it with the best quality Regency furnishings and must-have innovations like bathrooms and those new-fangled water closets.
It took more than 20 servants – a small army of tweenies and under-butlers, footmen, gardeners and grooms – to run the Silvertop home, and the estate had expanded to more than 2,000 acres.
John’s son, another George, was famous for visiting Bonaparte at Elba, and for bringing back some prize plants to beautify the Minsteracres gardens.
George had no children, so the Silvertop line should have ended when he died in 1849. Luckily George’s heir Henry Charles Englefield was happy to change his name to Silvertop to keep the dynasty going.
Henry Charles Silvertop built the South Lodge around 1850, and not far away he placed Minsteracres’ lovely church of St Elizabeth, two years later.
His wife, Elizabeth Silvertop, chose to dedicate the £11,000 family chapel to her namesake – a particularly fervent 13th century saint, St Elizabeth of Hungary.
St Elizabeth was apparently the sort of turbulent teenager whose parents one pities. She married at 14, refused to wear decent clothes or eat properly, and her preferred chums were people suffering from gruesome diseases – the more suppurating sores the better.
It was probably anorexia which snatched St Liz away, aged just 24, and she had only one dirty smock to be buried in. But even this most saintly of patrons could not, it seems, protect the Silvertop family from ill fortune.
Just a few years after the chapel was completed, Elizabeth died in childbirth. Her son and heir Henry Thomas died aged just 40, from botulism after eating a bad tin of salmon he’d bought in Newcastle, and her younger son Arthur was killed at the Battle of Jutland in World War One. Henry Thomas’s sons Francis and William both died on the fields of Flanders.
The Second World War was no less cruel to the Silvertops. Arthur Silvertop’s only son David was killed in Holland while commanding the 3rd Battalion the Royal Tank Regiment. The city of Antwerp honoured this dashing Silvertop by naming a street after him.
The last male heir of the dynasty was Charles Arthur Silvertop, just three months old when his father Francis was killed.
Charles Arthur decided in 1949 to sell Minsteracres, but Catholic piety still guided the Silvertops. The great house, the church, the stables and 60 acres of land went to the Order of Passionist Monks for £20,000. It is still a retreat and a base for several charities.
The remainder of the estate, including 15 farms with associated cottages, and 5,000 acres of land, was sold to the industrialist Charles Cookson. The South Lodge was no longer in Silvertop hands.
l South Lodge is for sale through Foster Maddison of Priestpopple, Hexham.
Department of Genetics, North Carolina State University, Raleigh, NC, USA. aedwards5@vcu.edu
BACKGROUND: Aggressive behavior in animals is important for survival and reproduction. Identifying the underlying genes and environmental contexts that affect aggressive behavior is important for understanding the evolutionary forces that maintain variation for aggressive behavior in natural populations, and to develop therapeutic interventions to modulate extreme levels of aggressive behavior in humans. While the role of neurotransmitters and a few other molecules in mediating and modulating levels of aggression is well established, it is likely that many additional genetic pathways remain undiscovered. Drosophila melanogaster has recently been established as an excellent model organism for studying the genetic basis of aggressive behavior. Here, we present the results of a screen of 170 Drosophila P-element insertional mutations for quantitative differences in aggressive behavior from their co-isogenic control line. RESULTS: We identified 59 mutations in 57 genes that affect aggressive behavior, none of which had been previously implicated to affect aggression. Thirty-two of these mutants exhibited increased aggression, while 27 lines were less aggressive than the control. Many of the genes affect the development and function of the nervous system, and are thus plausibly relevant to the execution of complex behaviors. Others affect basic cellular and metabolic processes, or are mutations in computationally predicted genes for which aggressive behavior is the first biological annotation. Most of the mutations had pleiotropic effects on other complex traits. We characterized nine of these mutations in greater detail by assessing transcript levels throughout development, morphological changes in the mushroom bodies, and restoration of control levels of aggression in revertant alleles. All of the P-element insertions affected the tagged genes, and had pleiotropic effects on brain morphology. CONCLUSION: This study reveals that many more genes than previously suspected affect aggressive behavior, and that these genes have widespread pleiotropic effects. Given the conservation of aggressive behavior among different animal species, these are novel candidate genes for future study in other animals, including humans.
Genetic approaches to dissecting complex traits in animal models increasingly use transcript levels as a molecular phenotype and as validation for predictions of gene function. A recent study in BMC Biology using these approaches shows the complexity of the genetic contribution to aggressive behavior in Drosophila.
Genetic investigation of quantitative behavioral traits
Neuropsychiatric geneticists are now focusing considerable attention on the investigation of quantitative human behavioral traits, postulating that such phenotypes could be more straightforward to genetically map than neuropsychiatric disorders. Such syndromes are among the most complex of human traits, a fact that may explain why efforts to elucidate their etiology have been singularly unsuccessful. Although quantitative phenotypes may be simpler than clinically heterogeneous diseases, there is still little evidence that human behavioral quantitative trait loci (QTL) will be easy to identify. For this reason there is a tremendous appeal in using the powerful tools available for genetic investigation of simple model organisms; genes implicated in behavioral variation in flies or worms can then be targeted for various forms of analysis in mammals, including humans. This strategy depends on the identification of suitable measures of behavior in simple systems. Circadian rhythms are a classic example. Investigations of clock mutants in Drosophila led to the discovery of the first circadian rhythm gene, period, and ultimately to cellular pathways underlying circadian behavior [1]; this line of investigation was subsequently successfully extended in rodents as well as humans [2].
Aggressive behavior is another complex behavioral trait that can be efficiently modeled in Drosophila [3,4]. Yet, as recently reported by Edwards et al. [5], aggressive behavior in flies results from the action of numerous genes, reflects extensive pleiotropy, and is significantly influenced by molecular processes outside the nervous system. Perhaps circadian rhythm phenotypes will prove more an exception than the rule; when it comes to behavior, a simple system does not guarantee simple genetics.
Utility of fly models of complex behavior
Given the observation that aggressive behavior in flies has such an apparently complex genetic basis, it is worth reviewing the motivations for using such a behavioral genetic model. In humans it is a given that most behavioral traits involve interactions between numerous genetic loci in the context of multiple, mostly unquantified environmental influences. No strategies implemented so far have been sufficiently powerful to overcome the challenge represented by this degree of complexity, and the systematic genome-wide mapping of human behavioral QTL is, therefore, still a nascent endeavor. This fact alone could account for interest in investigation of behavioral pheno types in virtually all widely used animal genetic models, including Drosophila. Given the functional analogies of tissues, organs and organ systems as well as the considerable conservation of neurobehavioral traits and of a high proportion of gene counterparts between human and fly [6], identification of Drosophila behavioral QTL is useful for informing studies in other organisms, including humans [7]. Elucidation of the molecular basis of a specific trait such as aggressive behaviour in Drosophila could answer several questions of generalized importance: which genes of unknown function, gene functions and pathways may contribute to the trait? How many genes are implicated in a single complex behavior? What is their effect on the trait in terms of magnitude and specificity?
The particular strength of the Drosophila model for behavioral investigation is its suitability for various experi mental genetic approaches. It is ideal for artificial selection for a target trait (such as aggressive behavior) and for genetic modification of candidate genes. In addition, it offers diverse complex behavioral and neuroanatomical phenotypes that can be efficiently quantified to study the putative pleiotropy of candidate genes. For example, a quantitative aggression phenotype has been assayed by scoring aggressive encounters among male files that were exposed to a food droplet after 90 minutes of food depri vation [4,5]. In Drosophila it is also particularly straight forward to control variations in environmental influences that might influence behaviors, a factor that adds substantially to the power to identify genes that influence quanti tative traits, especially genes contributing a small amount of the trait variance.
Genes implicated in aggressive behavior
As Drosophila has a short generation time and controlled mating is easy, it is possible to perform artificial selection by repeatedly selecting individuals that show extreme scores for behavioral measures. Resulting divergent lines with high or low aggressive behavior show significant differ ences in gene expression for as much as 10% of the fly genome [4]. It is likely that genetic variants directly regulate only a relatively small fraction of the genes contributing to the transcriptional response to selection for aggres sive behavior; rather, most of these genes are co-regulated in response to causal genes [8]. Nevertheless, the observation that a substantial fraction of the Drosophila genome may be related to aggressive behavior raises interest in determining whether specific genes are directly involved in the trait, in quantifying the magnitude of their effect, and in evaluating whether these genes also contribute to other traits.
The effect of a candidate gene on a complex trait in an animal model can be directly established by functional analysis – for example, by inducing mutation in a candidate gene and then quantifying relevant phenotypes. Unlike QTL mapping, which establishes relations between a phenotype and specific underlying causative genetic variants, mutational analysis discovers the function of candidate genes and elucidates the molecular mechanisms for such functions. The advantage of mutational analysis is that it tests a role of a candidate gene on a defined isogenic background, facilitating the detection of subtle mutational effects. For mutational analysis Edwards et al. [5] used P-element insertional mutant fly lines to investigate the effects of a large series of novel candidate genes that had not been previously implicated in aggressive behavior. These genes were selected solely on the basis of gene expression measures obtained after artificial selection for this trait [4] or their known involvement in other complex behavioral traits. Functional evidence supported a role in aggressive behavior of a large fraction (almost 40%) of these novel candidate genes, but mutations in them exert only small or moderate effects on aggression level [5].
This observation supports the suggestion that the genetic architecture of complex behavior may be remarkably similar in organisms as neurobiologically simple as Drosophila and as complex as humans [9]. There is now a consensus that human neurobehavioral diseases mainly reflect the effects of large numbers of genetic variants of relatively small effect and, therefore, that genetic dissection of such traits will require investigation of samples of considerable size. The findings of Edwards et al. [5] imply that a similar expectation may hold for QTL mapping of aggressive behaviors in humans. Identifying the functional importance of so many variants will obviously be more straightforward in flies than in humans, and progress in dissecting human traits may depend on the degree to which they reflect molecular mechanisms similar to those in their Drosophila counterparts.
Organismal phenotypes and pleiotropic action of behavioral genes
One of the most interesting findings to emerge from the investigation of aggression in Drosophila concerns the size and localization of mutation-induced expression changes. Edwards et al. [5] found that relatively small transcript-level alterations (twofold or less) noticeably affect behavior. Their observation suggests that, in considering intermediate phenotypes for behavioral traits, it would be unwise to ignore transcripts showing a low magnitude of expression alterations. Their results also remind us that an arbitrary division between the brain and the remainder of the body may be unhelpful in efforts to understand complex behavior. Investigations of the spatial expression pattern of wild-type and mutant genes, using decapitated flies, indicated that significant differences between wild-type and mutated genes occurred for all tested genes; however, for the majority of such genes significant differences were detected in the bodies but were not observed in the heads [5]. Accordingly, investigations of human behavioral traits should probably pay greater attention than is typically the case at present to gene expression patterns in peripheral tissues and more vigorously evaluate other types of molecular phenotypes (such as endocrine markers) as intermediate phenotypes. Indeed, the observations in the fly are consistent with, for example, the confirmed role of hormonal regulation in the development and function of the nervous system as well as in levels and types of aggressive behavior in various species, including non-human primates and humans.
A single gene may generate pleiotropy by contributing to a variety of traits. There is existing – although not abundant – evidence that a single gene or even a single genetic variant related to neuropsychiatric diseases may contribute to diverse cognitive and neuroanatomical phenotypes. For example, PER3 is implicated in a rare human circadian rhythm disorder called delayed sleep phase syndrome, but it is also associated with several other circadian phenotypes and with cognitive measures, such as performance tasks assessed during sleep deprivation and brain responses to a working memory task assessed using functional magnetic resonance imaging [2]. A striking observation reported by Edwards et al. [5] is that, in flies, a very large fraction of mutations introduced in genes related to aggressive behavior produce extremely pleiotropic effects, affecting various complex traits. Among the most interesting of these traits are quantitative changes in brain morphology observed in mutants' mushroom bodies. These structures were previously implicated in aggressive behavior in Drosophila and show many parallels to an analogous mammalian brain structure, the hippocampus, which also has an important role in behavior [10]. The observation of pleiotropy of particular genes with respect to related traits (such as aggressive behavior and neuroanatomical phenotypes) may provide an important form of corroboration of the role of a given gene in contributing to complex behavioral traits.
Demonstrations of the importance of pleiotropy in the genetic regulation of behavioral variation also provide support for approaches using human genetic mapping that attempt to take advantage of pleiotropy by identifying various intermediate phenotypes (endophenotypes) that link genes and disease. An endophenotype-centered approach has two major potential advantages over genetic mapping of disease phenotypes themselves. First, it is hypothesized that endophenotypes are more directly associated with genetic variation than is disease. Second, unlike disease, endophenotypes can be investigated as quantitative traits and are, therefore, more readily studied in animal models.
The findings of Edwards et al. [5] indicating novel candidate genes and cellular processes for aggressive behavior in the fly model provide useful information about the biology of behavioral traits and also suggest new loci and pathways for studies in other organisms, including humans. The increasing sense that a universal feature of complex behavior may be the contribution of numerous genetic variants of small effect may influence experimental design in human genetic studies of behavioral traits. Furthermore, although it is often assumed that the genetic complexity of the behavioral traits mostly reflects the complexity of the central nervous system, Edwards et al. [5] demonstrated the importance of also considering genes that act mainly in the periphery. Finally, the extensive pleiotropy of behaviorally important genes observed in the fly model may suggest that their human orthologs exert similarly widespread phenotypic effects. These conclusions are not comforting for those attempting to dissect human behaviors genetically, but they offer a reminder that sustained investigation of simple model systems is critically important to these efforts.
To what extent does statin therapy for lowering cholesterol levels also hinder appropriate hormone production and function? Cholesterol is the starting point for various needed compounds, including testosterone. If the substrate levels are too low, don't we interfere with hormone production?
Response from Darrell T. Hulisz, PharmD Associate Professor, Department of Family Medicine, Case Western Reserve University School of Medicine, University Hospitals, Case Medical Center, Cleveland, Ohio
Recent consensus guidelines recommend increasingly aggressive treatment of low-density lipoprotein cholesterol (LDL-C) to targets lower than previous values to improve patient outcomes.[1] For example, in very high-risk patients, such as those with established cardiovascular disease plus multiple risk factors (eg, diabetes, smoking, metabolic syndrome), an LDL-C goal of <>[1] Recent evidence from clinical trials, such as Treating to New Targets (TNT), also suggests that using higher doses of atorvastatin to achieve lower LDL-C targets can decrease subsequent coronary interventions and revascularization procedures.[2] However, there is concern that lowering LDL-C to very low thresholds may decrease hormone synthesis, as free intracellular cholesterol is necessary for adequate gonadal and adrenal steroid hormonal production.
Various studies have examined the effects of lipid-lowering agents on endogenous steroid synthesis.[3-10] These studies have focused mainly on hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins. Statins decrease hepatic cholesterol synthesis by competitive inhibition of HMG-CoA.
An early study of 26 men was conducted to determine the long-term effects of pravastatin or simvastatin on steroidogenesis under basal and maximal adrenal and testicular stimulation.[3] Subjects were followed up to 36 months with no adverse changes observed in adrenocortical and testicular steroidogenesis, even under glandular stimulation. Similarly, a 1-year controlled study showed that up to 80 mg/day of atorvastatin yielded an average of 57% decrease in LDL-C but was not associated with any adverse effects on adrenal function under basal and maximal stimulation.[4]
Dobs and colleagues[5] studied simvastatin 80 mg/day vs placebo in 81 men over 12 weeks to determine drug effect on adrenal and gonadal steroidogenesis. There were small but nonsignificant declines in pooled total, free, and bioavailable testosterone associated with simvastatin, relative to placebo. However, there was no compensatory increase in follicle-stimulating hormone (FSH) or luteinizing hormone (LH) levels. Likewise, basal and stimulated cortisol production was unaffected by simvastatin.
To address whether reproductive hormonal changes are seen in women receiving lipid-lowering drugs, a cross-sectional analysis of the Women's Ischemia Syndrome Evaluation (WISE) was conducted.[6] The WISE trial enrolled 453 women with coronary risk factors undergoing coronary angiography for suspected ischemia. While the majority of women were postmenopausal, premenopausal and perimenopausal women were also enrolled. Only 27% (n = 121) received a statin. Levels of total estradiol, progesterone, estrone, FSH, LH, and bioavailable estradiol were measured and compared between statin and nonstatin users. Overall, the use of statins was not associated with lower reproductive hormone levels. Even in women with very low LDL-C targets <>
A small study of atorvastatin treatment in both men (n = 16) and postmenopausal women (n = 8) with type 2 diabetes examined drug effect on gonadal and adrenal hormone levels.[7] All patients had mild-to-moderate dyslipidemia and received atorvastatin 20 mg/day for 3 months. Measurements of cortisol and various sex hormone levels were compared at baseline and at the end of the 3-month trial. Use of atorvastatin resulted in no clinically significant difference in adrenal or gonadal hormone production. However, no placebo group was used.
A more recent study of 74 men with dyslipidemia evaluated the effects of statins on sex steroids, autonomic function, libido, and erectile function.[8] All subjects received atorvastatin 40 mg/day over a 12-month period. Mean LDL-C level at 12 months of treatment was 95.6 mg/dL. Hormone levels for prolactin, testosterone, LH, estradiol, and dehydroepiandrosterone-sulfate (DHEA-S) were obtained at baseline and at 6 and 12 months, as were parameters to assess autonomic and erectile function. With the exception of a statistically significant decrease in DHEA-S levels, no hormonal changes were associated with statin use. Autonomic changes were not significant, and erectile function improved on statin therapy, relative to baseline. The clinical implications of the decreased DHEA-S levels observed from baseline are unknown.
One cross-sectional study of 355 men with type 2 diabetes receiving a variety of statins showed an association with statin use and lower total testosterone levels, but not bioavailable or free testosterone levels.[9]
Most of the aforementioned trials did not focus specifically on the effect of lower LDL-C targets (<>[10] studied 160 men with coronary heart disease who received either high-dose atorvastatin (up to 80 mg/day) to a target LDL-C <> 100 mg/dL. Patients were stratified according to cardiac risk factors. At the end of 12 weeks, mean LDL-C in the high-dose group was 77 mg/dL. There were no significant alterations in free and total testosterone, sex hormone-binding globulin, FSH, or LH. The authors concluded that high-dose atorvastatin, given to achieve lower LDL targets, appears to be as safe as conventional doses with respect to gonadal steroidogenesis. However, this study was not placebo controlled for ethical reasons and was of short duration.
In conclusion, there remains a theoretical concern that HMG-CoA inhibitors -- and perhaps other lipid-lowering drugs -- may slightly blunt adrenal and/or gonadal steroid production. The balance of studies that examined this hypothesis have shown little or no effect, however, although most studies have not treated patients to targets <>
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice. It is associated with substantial morbidity and mortality, owing to a significantly increased risk for stroke, thromboembolic events, heart failure (HF), impaired cognitive function, as well as an impaired quality of life.[1-6] According to data from the Framingham study, the lifetime risk of developing AF is approximately 1 in 4 for white men and women aged 40 years and older.[7] Although more common in individuals with underlying structural heart disease, the lifetime risk for AF remains high (1 in 6) even in individuals without prior congestive heart failure (CHF) or myocardial infarction (MI).[7] The risk for AF increases with age; the vast majority of individuals with AF (approximately 70%) are between the ages of 65 and 85 years. Although the age-adjusted prevalence of AF is higher in men than in women,[8] approximately 60% of the patients with AF who are older than 75 years of age are women, accounting for the greater longevity of women.[5]
The prevalence and incidence of AF have increased considerably over the past 2 decades, especially in North America and Western Europe.[9] According to a study that assessed community-based trends in AF incidence, the incidence of AF grew 12.1% between 1980 and 2000.[10] Assuming the increased age-adjusted trends prevail, the authors estimated that the prevalence of AF in the United States could reach as high as 15.9 million by 2050.[10]
This study and others attribute the increased prevalence of AF to the advancing age of the population, improved survival from MI and CHF, as well as to greater awareness by clinicians (and, in turn, more diagnoses).[9-11] In addition, the number of patients with new-onset AF has also steadily risen, independent of the increasing prevalence of known AF risk factors.[5]
In parallel with a growing incidence and prevalence of AF is the rate of hospitalizations for patients with AF. AF is the most common arrhythmia, with more than 461,000 hospital discharges annually.[12] A study of hospitalized Medicare patients also found that the costs of hospitalization for AF as a comorbidity are significantly higher in patients admitted without AF of the same age and sex.[13] Overall, prevention of AF and treatment of patients with AF and other associated cardiovascular comorbidities may help reduce the significant burden associated with AF.
To better understand the burden of AF and the need for increased awareness and prevention programs, the following review discusses factors and conditions known to increase the risk for AF, the influence of AF on outcomes in patients with other comorbidities, particularly stroke, and new data suggesting that secondary prevention of AF may reduce morbidity and mortality associated with the arrhythmia.
NEW YORK (Reuters Health) Sep 28 - There is "compelling evidence" for a benefit of statins in chronic obstructive pulmonary disease (COPD), but the evidence is not yet strong enough to expand statin indications beyond vascular protection, Canadian researchers report in the September issue of the journal Chest.
In addition to a proven role in lowering high cholesterol levels, statins also have anti-inflammatory and immunomodulatory pleiotropic effects postulated to be beneficial in COPD, Dr. John Swiston, from the University of British Columbia, Vancouver, and colleagues note in their report.
In a systematic review, Dr. Swiston's team analyzed nine studies that evaluated the effect of statins in COPD patients. Only one was an interventional randomized controlled trial, however. The other 8 were retrospective cohorts, case-control studies, or epidemiologic analyses.
Individually and collectively, the studies showed benefit from statins in a number of COPD-specific outcomes, including lung function and exercise capacity, COPD exacerbation rates, COPD-related hospital admissions and intubations, and COPD-related mortality.
The researchers emphasize, however, that due to a lack of data from randomized controlled trials, the current evidence is not enough to support a change in clinical practice.
"Multiple observational studies in the setting of biological plausibility paints a compelling picture but is not sufficient to justify routine clinical use of statins for COPD patients," Dr. Swiston noted in an email to Reuters Health.
"However, the current literature is sufficient to ethically and financially justify large, well designed randomized controlled prospective studies. These types of studies, if properly carried out, will provide stronger evidence either supporting or refuting the utility of statins as part of medical therapy for COPD," Dr. Swiston added.
He and his colleagues conclude, "A therapeutic intervention that positively affected outcomes, such as hospitalization and mortality rates in patients with COPD, potentially could have a huge beneficial impact on the individual, social, and economic consequences of this disease."
September 24, 2009 — A new analysis of the Anglo-Scandinavian Cardiac Outcomes Trial--Blood Pressure Lowering Arm (ASCOT-BPLA) shows that the amlodipine (Norvasc, Pfizer)-based arm of the study remained superior to the beta-blocker arm, even when resting heart rate was taken into account [1].
The study was published in the September 22, 2009 issue of the Journal of the American College of Cardiology.
The findings mean that "there is no reason to believe that beta blockers should be used earlier on in the treatment of hypertension on the basis of heart rate," lead author Dr Neil R Poulter (Imperial College London, UK) told heartwire. He said many cardiologists have had "a hindbrain belief" that "if there is a touch of tachycardia, beta blockers are the right drugs to use in hypertension management." But prior to this analysis, there had been no data from randomized controlled trials available to assess the impact of this advice on patient outcomes, he noted.
"We thought, if it's true that a touch of tachycardia should push you toward beta blockers, we'd be able to see that in ASCOT," Poulter added. Noting that the ASCOT-BPLA study–-reported in 2005--confirmed the superiority of an amlodipine-based regimen over an atenolol-based regimen, "we looked to see whether, if you started with tachycardia, was that still the case?" he noted. "The bottom line is, yes, it is. Pulse rate should not be the determinant of what drugs you use in hypertension."
These findings "reinforce the UK guidelines that state that, in primary prevention, beta blockers should be kept to a much later stage of intervention," Poulter says.
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