By K. Spike. University of Louisiana at Monroe.
Propagation of foreign DNA sequences before it can become a reality purchase levitra plus no prescription. First purchase generic levitra plus line, and most important levitra plus 400 mg visa, linked to a herpes simplex virus origin of replication. In: Gluzman stability of transgene expression must be achieved. Cold Spring Harbor, NY: Cold not only stability but also inducibility and regulatibility of Spring Harbor Laboratory Press, 1982:199–204. The herpes simplex virus amplicon: analyses of cis-acting replication functions. Proc Natl Acad Sci USA 1985; transgene product is often critical. Site-specific cleavage/packaging the gene(s) of interest but also appropriate regulators or of herpes simplex virus DNA and the selective maturation of 20: Gene Delivery into the Brain Using Viral Vectors 261 nucleocapsids containing full-length viral DNA. Proc Natl Acad sion patterns of CNS gene transfer by an adeno-associated virus Sci USA 1982;79:1423–1427. Effects of gamma replication-defective mutant of herpes simplex virus type 1. J irradiation on the transduction of dividing and nondividing cells Virol 1992;66:2952–2965. Efficient transfer, integra-¨ tors: potential applications to human gene therapy and neuronal tion, and sustained long-term expression of the transgene in adult physiology. Helper virus-free transfer of USA 1996;93:11382–11388. Highly efficient and sustained¨ Virol 1996;70:7190–7197. HSV-1 vectors using an IE 2 deletion mutant and quantitative 30. Gene therapy study of expression in cultured cortical cells. Behavioral effects and gene delivery in a rat model of hol Depend 1998;51:13–22. Repeated exposures intensify rather than diminish the nant herpes simplex virus alters the functional properties of AMPA receptors. Overexpression in ity to acquisition of amphetamine self-administration. Brain Res neurons of human presenilin-1 or a presenilin-1 familial Alzhei- 1990;514:22–26. The neural basis of drug craving: tyrosine hydroxylase. Molecular and cellular basis of addic- simplex virus amplicon vector. A hybrid herpesvirus infectious vector based on Rev Neurosci 1994;17:31–108. Epstein-Barr virus and herpes simplex virus type 1 for gene trans- 39. RNA editing of brain gluta- fer into human cells in vitro and in vivo. J Virol 1996;70: mate receptor channels: mechanism and physiology. Drugs of abuse and amplicon vectors extend transgene expression in human glioma stress increase the expression of GluR1 and NMDAR1 glutamate cells. Gene transfer into hepato- tations among cross-sensitizing agents. J Neurosci 1996;16: cytes mediated by helper virus free HSV/AAV hybrid vectors. Gene transfer to the tral tegmental area dopamine neurons to glutamate after repeated nigrostriatal system by hybrid herpes simplex virus/adeno-associ- administration of cocaine or amphetamine is transient and selec- ated virus amplicon vectors. Hum Gene Ther 1999;10: tively involves AMPA receptors. Dopamine transmission in the initiation bility of persistent adenovirus vectors in the brain: peripheral and expression of drug- and stress-induced sensitization of motor exposure to vector leads to renewed inflammation, reduced gene activity. Immune responses of opiate reward and aversion within the midbrain identified to transgene-encoded proteins limit the stability of gene expres- sion after injection of replication-defective adenovirus vectors. The role of excitatory amino acids in behavioral sensiti- ated virus vectors into the central nervous system. Molecular mechanisms of drug reinforce- systems for gene transfer. Lentiviruses as gene transfer agents for delivery to 46. Differential and persistent expres- Nature 1999;401:272–276. Repeated cocaine and related drugs in nucleus accumbens shell and frontal cortex. Amphetamine self-administration and relapse of cocaine-seeking behavior. J and cocaine induce drug-specific activation of the c-fos gene in Neurosci 1998;18:1848–1859. Cyclic AMP stimulates somato- opiate-induced c-fos mRNA expression patterns in the rat fore- statin gene transcription by phosphorylation of CREB at serine brain: comparisons between acute drug treatment and a drug 133. Conditioned place preference challenge in sensitized animals. AP-1 complex composed of altered Fos-like proteins in brain by 60. Dynorphin is a specific en- chronic cocaine and other chronic treatments. Neuron 1994;13: dogenous ligand of the kappa opioid receptor. Sensitization to the behavioral effects of long-term neural and behavioral plasticity. Brain Res 1999; of cocaine: modulation by dynorphin and kappa-opioid receptor 835:10–17. From motivation to action: Curr Opin Neurobiol 1999;9:305–313. SCHAFER Pharmacologic agents often biochemically interact with ditis elegans, and the fruit fly Drosophila melanogaster. These multiple receptor or channel proteins, and induce multiple organisms share a number of advantages that make them changes in cellular physiology and signal transduction.
The currently hibit the splicing of E10 presumably by blocking the associa- known tau gene mutations in FTDP-17 kindreds are listed tion of snRNA with the splice site (151 buy cheapest levitra plus,154) order levitra plus cheap online. The S305N mutation has also frequent than previously recognized buy levitra plus 400 mg with mastercard. However, the S305S mutation, which increases the be pathogenic by one or more abnormalities in tau proteins, 4R/3R ratio like the S305N mutation, has been demon- and at present, two mechanisms have been proposed to me- strated to weaken the 5′ splice site (161). Another potential diate the effects of these mutations based on recent molecu- regulatory element might be an exon-splicing enhancer lar and biochemical analyses (111,154,159,166). The first (ESE) or exon-splicing silencer (ESS) element within E10 mechanism involves perturbations of the alternative splicing adjucent to the following intron (159). The N279K muta- of E10 by mutations in E10 or around the 5′ splice site in tion is thought to augment the ESE and consequently cause the intron following E10, thereby resulting in an altered an increase in the 4R/3R ratio of tau isoforms because of ratio of 4R tau to 3R tau proteins. The second pathogenic the fact that it raises the purine content of this purine-rich mechanism directly impairs the ability of tau to bind to domain (i. The silent mutation 4R/3R ratio of brain tau isoforms has been demonstrated L284L is likely to disturb the ESS (159), but it also is possi- in brains of FTDP-17 patients with mutations clustered ble that this mutation augments the effects of the ESE. The altered splicing of the 4R/3R tau isoform ratio is likely to produce an excess FIGURE 94. The muta- tion sites are depicted on the long- est tau isoform. The alternatively spliced inserts are indicated as gray boxes and MT-binding repeats are shown as black boxes. Sequences in intron 10, which form a stem-loop structure, are presented in lower case. Such models are abnormal increase of free tau may result in the formation of also expected to be useful for assessing methods of early insoluble tau aggregates and consequently neurodegenera- diagnosis and the effectiveness of therapeutic agents for the tion. The second hypothetical pathogenic mechanism to ac- The strategies for making animal models that recapitulate count for brain degeneration in FTDP-17 owing to other tauopathies are summarized in the following and include: tau gene mutations suggests that these mutations directly cause deficits in the abilities of tau to bind to MTs and 1. Selection of DNA constructs to be expressed in the CNS promote assembly and stability of MTs. This disease mecha- of the model, and the use of cDNA or genomic DNA nism has been linked to several tau gene missense mutations tau constructs is a straightforward strategy to induce ac- including: G272V, K280, P301L, P301S, V337M cumulations of tau in the CNS of experimental animals. On Indeed, tau cDNAs or minigenes have been used to over- the other hand, the mutations that increase E10 splicing express specific tau isoform(s), and cause an imbalance do not have similar effects on the functions of tau (111, of the tau isoform profile similar to that seen in human 159). Nonetheless, a loss of the binding ability of tau to tauopathies. Further, animal models engineered to ex- MTs may produce an increase in the levels of free tau pro- press human genomic tau DNA using bacterial artificial teins in the neuronal cytoplasm, and this could promote chromosome (BAC) or a P1-derived artificial chromo- their fibrillogenesis. Mutant tau proteins are also likely to some (PAC) containing the entire tau gene may be in- accelerate the accumulation of insoluble tau filaments formative for elucidating the biochemistry (including within neurons. This notion has been supported by several E10 splicing) and neuropathology (including emergence studies of the in vitro assembly of tau filaments, which also of tau deposits) in animals with and without a tau gene demonstrated that tau filament formation is enhanced by mutation. Other possible strategies to generate animal heparin using recombinant G272, P301L, V337M, and models of tauopathies are to express proteins that regu- R406W tau mutant proteins compared to wild-type tau late the phosphorylation of tau proteins, or to express protein (172,173). Moreover, mutations in exons other APP, PS-1, and PS-2 in tau transgenic (Tg) animals to than those in E10 (i. Overexpression of tau without mutation to assess the nary data to account for the differential effects of these mu- effects of excess tau proteins in the cytoplasm of neurons tations, additional studies are needed to fully elucidate how and glia on the formation of tau aggregates. Further, the generation of tau DNA with mutations that The discovery of tau gene mutations pathogenic for FTDP- alter the splicing of E10 to produce animal models would 17 indicates that genetic abnormalities directly influence be informative using the entire gene or minigene of the levels or functions of tau proteins, thereby resulting human tau. However, the phenotypes of these mutant in the aggregation of insoluble tau and neurodegeneration. Use of neuron-specific promoters including the Thy-1, in FTDP-17 syndromes that vary from patient to patient 3-hydroxy-3-methylglutaryl coenzyme A reductase by analyzing human cases because of the following reasons: (HMG-CoA) and prion protein (PrP) promoters to gen- (a) limited sample size of kindreds with each mutation; (b) erate tau pathology in neurons, whereas animals showing the difficulty of conducting biochemical and pathologic glial tau pathology can be developed by using glia-spe- studies in early stages of the disease; and (c) the possibility cific promoters including glial fibrillary acid protein that several additional but as yet unknown environmental (GFAP) promoter for astrocytes and 2′,3′-cyclin-nucleo- and/or genetic factors might modify the biochemical and tide phosphodiesterase (CNP) and myelin basic protein clinicopathologic phenotype of FTDP-17. Accordingly, an- (MBP) promoters for oligodendrocytes. Tg animals with imal models that reproduce tauopathies are required for genomic DNA are generally driven by endogenous pro- better understanding of the central roles played by tau ab- moters. Hence, this Tg mouse Thy-1 promoter was reported in 1995 (174), followed by is thought to be a good model for age-related neurodegener- a study of tau Tg mice expressing the shortest tau isoform ation in tauopathies, and it is useful for studying the time (T44 or fetal tau, 3R0N tau) driven by the HMG-CoA course of CNS degeneration in a human tauopathy. In these studies, somatodendritic spheroidal tau inclusions in these tau Tg mice have also overexpression of human tau was observed using anti-phos- been shown to contain neurofilaments (NFs) and tubulin. However, these Tg mice did not show This colocalization of tau and NFs is found in the inclusions tau aggregates in any of the CNS regions nor other tauopa- of ALS/PDC spinal cord. Further studies using these tau thy-like phenotypic changes, probably owing to the low Tg mice crossed with NF-knockout mice could be informa- expression level of the transgene product. Filamentous tau tive by determining whether or not NFs promote the forma- aggregates have been observed in the spinal cord and brain- tion of tau aggregates, and whether or not tau can form stem of tau Tg mice generated by using a transgene consist- aggregates in the absence of NFs. Tau Tg mice with the T40 transgene combined with the This Tg mouse showed approximately ninefold more tau Thy-1 promoter have been developed recently (177,178). The tau aggregates in the colocalization of tau and NFs has also observed in these this Tg mouse are spheroidal inclusions in proximal axons, inclusions. Axonal degeneration and corresponding pheno- and they showed an increase in number with aging, consis- typic changes were found in these Tg mice, and thus they tent with an age-dependent increase in the extent of tau may be regarded as models of neurodegenerative tauopathies phosphorylation and an age-dependent decrease in the solu- with increased 4R tau. In addition, these 4R tau Tg mice bility of overexpressed human tau. In addition, this tau Tg showed somatodendritic tau expression to a greater extent than 3R tau Tg mice. This suggests that the difference in affected brain areas between 4R tau and 3R tau Tg mice as well as the effect of predominant tau isoforms on the distribution of pathology should be analyzed by using tau Tg mice with the same promoter and a similar expression level of human tau. To date, only a few genomic tau Tg mice using PAC and BAC have been generated, and they have shown a so- matodendritic pattern of phosphorylated tau expression (179). Although all of the mentioned tau Tg mice have shown a somatodendritic tau expression that resembles the 'pretangles' in AD, none of them have developed NFTs containing a -pleated sheet structure that can be recog- nized by thioflavin-S and Congo red. In fact, overexpressed tau in the cytoplasm and processes of neurons is rather dif- fuse and does not show a filamentous structure by EM (179). One possible method to generate NFTs in tau Tg mice would be to use a mutant tau gene construct to de- crease the ability of tau to regulate MTs. Another method would be to follow tau Tg mice showing an age-related FIGURE 94. Spheroidal tau deposits in the spinal cord of tau increase of tau pathology to vary advanced ages. Tg mice over-expressing the shortest human tau isoform. A: Low power field of the spinal cord section of a 6-month-old Tg mouse One of the major goals in developing animal models is stained with anti-tau antibody T14.
This may not be incorporated in to the other models buy levitra plus 400 mg amex. Therefore they may have estimated higher cost savings purchase 400 mg levitra plus mastercard. In our model order levitra plus with a mastercard, we do not include long- term costs or health gain for patients with proteinuria but GFR >60. The GDG considered that multisystem diseases with the potential to involve the kidney, such as SLE, were clearly risk factors for CKD. The evidence principally assessed demographic and behavioural risk factors for CKD but in addition it was recognised that diabetes and cardiovascular disease, particularly ischaemic heart 70 5 Classification and early identification disease, chronic heart failure, peripheral vascular disease and cerebrovascular disease are all risk factors for CKD. The GDG noted that the increased prevalence of CKD seen in the NHANES studies (1988–1994 compared with 1999–2004) was associated with an increased prevalence of diagnosed diabetes and hypertension. The cost-effectiveness evidence suggests that testing for CKD in high-risk groups (such as those with hypertension or diabetes) is highly cost-effective. However, for over 55s without additional risk factors, the prevalence of CKD with proteinuria was too low for testing to be cost-effective. Although specific evidence for drug-induced nephrotoxicity was not considered, the GDG noted that both acute and chronic use of drugs known to be potentially nephrotoxic can lead to CKD. The use of certain agents such as lithium and calcineurin inhibitors should be monitored and the GDG considered that long-term chronic use of NSAIDs should prompt an annual GFR check. The GDG did not consider the evidence about smoking, alcohol intake, abnormal lipids, obesity (in the absence of metabolic syndrome), lower socioeconomic status and ethnicity strong enough to recommend that people in these groups should be tested for CKD. There was uncertainly regarding the significance of a family history of CKD but the GDG recommended that people with a family history of stage 5 CKD or hereditary kidney disease should be considered at risk of having CKD. GDG consensus was that those with structural renal tract disease, multiple and recurrent renal calculi and urinary outflow tract obstruction should be considered at risk of having CKD. The GDG also recommended that people found incidentally to have haematuria or proteinuria on opportunistic medical testing should be considered at risk of having CKD. Check GFR at least annually in people receiving long-term systemic non-steroidal anti-inflammatory drug (NSAID) treatment. R25 Offer people testing for CKD if they have any of the following risk factors: q diabetes q hypertension q cardiovascular disease (ischaemic heart disease, chronic heart failure, peripheral vascular disease and cerebral vascular disease) q structural renal tract disease, renal calculi or prostatic hypertrophy q multisystem diseases with potential kidney involvement, e. R26 In the absence of the above risk factors, do not use age, gender, or ethnicity as risk markers to test people for CKD. In the absence of metabolic syndrome, diabetes or hypertension, do not use obesity alone as a risk marker to test people for CKD. The clinical features and course of CKD are dependent on a number of factors including the underlying cause, severity and associated conditions of the underlying cause. Although the classification of CKD into 5 stages has been widely adopted, it has been criticised as not being sufficiently sophisticated for clinical needs. The existing classification is neither staged according to age, nor according to level of proteinuria. All patients, regardless of age, gender and proteinuria/albuminuria are considered to have at least moderately severe CKD when their GFR is <60 ml/min/1. A further criticism of the existing classification of CKD has been the suggestion that loss of GFR is a feature of ageing and that many people classified as stage 3 CKD are merely exhibiting a normal ageing process. The effects of normal ageing on renal function are controversial. Data from some studies suggest that the decline in GFR with increasing age may be largely attributable to comorbidities such as hypertension and heart failure. Loss of renal function may not, therefore, be an inevitable consequence of ageing. However, controversy over what constitutes normality in the group with the highest prevalence of CKD makes defining what constitutes progression even more difficult. Consideration must also be given to the inherent biological and analytical variation associated with estimation of GFR from serum creatinine measurements. The power of this study was undermined by a high drop-out rate in the macro- albuminuria, impaired renal function, and haematuria groups, although the authors noted that the baseline characteristics of those who were lost to follow-up were NS different from subjects who completed follow-up. GFR was measured by iothalamate clearance in 365 potential living kidney donors163 or by inulin clearance in 141 healthy subjects who had a nephrectomy. This was evident in the lower GFR values in apparently healthy people (mean GFR=111 ml/min/1. As this was a retrospective analysis of medical records, there was no detail on how often GFR was measured. The cross-sectional Biomedical Nijmegen Study measured eGFR (MDRD) in apparently healthy men and women (N=3732) and in men and women with comorbid conditions (N=2365). Limitations of this study included: q a questionnaire, rather than a clinical examination, was used to assess the health of participants q GFR was estimated with the MDRD equation and creatinine was measured only once q the GFR decline was inferred from cross-sectional data, rather than from a longitudinal follow-up. The younger and older healthy subjects were matched for body weight. This study was limited by the small sample size and it did not address rate of GFR decline. In the first study,166 the decline in creatinine clearance with increasing age was assessed in healthy males (N=548). In a follow-up study,158 the decline in creatinine clearance over time in healthy males (N=254) was compared with creatinine clearance decline in men with renal/urinary tract disease (N=118) or 74 6 Defining progression of CKD with hypertensive/oedematous disorders (N = 74). The effect of increasing blood pressure on creatinine clearance was also examined. An observational study (N=10,184, mean age 76 years, 2 years follow-up) examined GFR decline over time in older (>66 years old) males and females stratified by GFR. The decline in GFR in diabetics was compared with non-diabetics. Regression analysis of GFR normalised to body surface area was significant for age (p<0. After age 60, creatinine clearance declined steeply. This data suggests that macroalbuminuria is a better predictor of GFR decline than low baseline GFR. Renal function decreased more rapidly as mean arterial pressure (MAP) increased. Mean GFR was NS different between older healthy and older hypertensive people. Few participants in this older cohort experienced a rapid progression of CKD (decline in GFR >15 ml/min/1. Mean GFR (inulin clearance) was significantly lower in older people with heart failure (92 ml/min/1. The longitudinal studies contained mixed populations in that not all participants were followed up for the full duration of the study.
Timothy Walsh: Columbia University College of Physicians & Sur- such as self-induced vomiting or laxative abuse buy levitra plus australia. Following onset disturbed eating behavior abuse buy levitra plus 400mg without a prescription, and overt family conflict in comparison to those with waxes and wanes over the course of several years in a high the restricting subtype of AN order levitra plus online pills. Personality traits of marked percentage of clinic cases. Approximately 30% of remitted perfectionism, conformity, obsessionality, constriction of women relapse into BN symptoms. These traits typically appear in advance of the onset PERSISTENT PSYCHOLOGICAL of illness and persist even after long-term weight recovery, DISTURBANCES AFTER RECOVERY indicating they are not simply epiphenomena of acute mal- nutrition and disordered eating behavior (8–11). People who have an ED often have a variety of symptoms Individuals with BN remain at normal body weight, al- aside from pathologic eating behaviors. Physiologic symp- though many aspire to ideal weights far below the range of toms include an abundance of neuroendocrine, autonomic, normalcy for their age and height. The core features of BN and metabolic disturbances (see the following). Psychologi- include repeated episodes of binge eating followed by com- cal symptoms include depression, anxiety, substance abuse, pensatory self-induced vomiting, laxative abuse, or patho- and personality disorders. Determining whether such symp- logically extreme exercise, as well as abnormal concern with toms are a consequence or a potential cause of pathologic weight and shape. The DSM-IV has specified a distinction feeding behavior or malnutrition is a major methodologic within this group between those individuals with BN who issue in the study of EDs. It is impractical to study EDs engage in self-induced vomiting or abuse of laxatives, di- prospectively because of their low incidence, early age of uretics, or enemas (purging type), and those who exhibit onset, and difficulty of premorbidly identifying those who other forms of compensatory action such as fasting or exer- will develop an ED. However, subjects can be studied after cise (nonpurging type). Beyond these differences, it has been long-term recovery from an ED. The assumed absence of speculated (12) that there are two clinically divergent confounding nutritional influences in recovered ED women subgroups of individuals with BN differing significantly in raises a possibility that persistent psychobiological abnor- psychopathologic characteristics: a so-called multi-impul- malities might be trait-related and potentially contribute to sive type, in whom BN occurs in conjunction with more the pathogenesis of this disorder. A limited number of stud- pervasive difficulties in behavioral self-regulation and affec- ies have investigated people who have recovered from AN tive instability; and a second type whose distinguishing fea- and BN. Although the definition of recovery from an ED tures include self-effacing behaviors, dependence on exter- has not been formalized, investigators tend to include peo- nal rewards, and extreme compliance. Individuals with BN ple formerly ill with AN after they are at a stable and healthy of the multi-impulsive type are far more likely to have histo- body weight for months or years and have not been mal- ries of substance abuse and display other impulse control nourished or engaged in pathologic eating behavior during problems such as shoplifting and self-injurious behaviors. For BN, investigators tend to in- Most cases of AN emerge during the period of adoles- clude subjects who have been abstinent from binge eating cence, although the condition can be observed in children. Some investigators include Whether or not prepubertal onset of the illness confers a criteria of normal menstrual cycles and a minimal duration more or less ominous prognosis is not known. In addition, they have social introversion, into adulthood. Ten percent of people with AN pursue a overly compliant behavior, and limited social spontaneity chronic, unremitting course; the remaining 10% of those as well as greater risk avoidance and harm avoidance. The frequency of binge episodes, their duration, and the Similarly, people who have recovered from BN continue to amount of food consumed during any one episode all vary be overly concerned with body shape and weight, display considerably among patients. Age of onset is somewhat abnormal eating behaviors, and report dysphoric mood more variable in BN than AN, with most cases developing (14–17). Recovered AN and BN women have increased during the period from mid- to late adolescence through perfectionism; their most common obsessional target symp- the mid-twenties. Follow-up studies of clinical samples 5 to toms are the need for symmetry and ordering/arranging. In general, pathologic eating roleptics for AN because of their notoriety for causing behavior and malnutrition appears to exaggerate the magni- weight gain in other patient populations (29). Thus, the intensity of these symp- report suggested that olanzapine administration was associ- toms is less after recovery but the content of these concerns ated with weight gain and maintenance as well as reduced remains unchanged. The persistence of these symptoms agitation and resistance to treatment in 2 women with AN after recovery raise the possibility that the disturbances are (30). Several drugs have been tested because of anecdotal premorbid traits that contribute to the pathogenesis of AN reports of their effects on stimulating appetite. Clonidine was also found to have no therapeu- PHARMACOLOGIC TREATMENT OF tic effect on increasing weight restoration as compared to ANOREXIA NERVOSA placebo (32), even with doses that affected hemodynamic parameters. Most medication trials in AN have been conducted with When underweight, patients with anorexia nervosa have inpatients in an attempt to accelerate restoration of weight. Still, delayed gastric emptying could perpetuate the mood or anorectic attitudes. A wide variety of psychoactive disorder in some patients by limiting the quantity of food medications, such as L-dopa (18), phenoxybenzamine (19), that may be comfortably eaten. Most studies of prokinetic diphenylhydantoin (20,21), stimulants (22), and naloxone drugs in AN have been limited to parenteral preparations (23), have been administered to people with anorexia ner- or experiments with small uncontrolled groups of patients vosa in open, uncontrolled trials. In a controlled trial, cisapride (37) was no better medications have been claimed to be beneficial, but none than placebo in improving gastric emptying, although some of these observations has been confirmed under double- subjective measures of distress during meals and measures blind, controlled conditions. Few studies of medication using rigorous double-blind In summary, these medication trials have been of short placebo-controlled trials have been reported in patients with duration and focused on whether medication produces ad- AN. In contrast to the positive claims from open trials, ditive benefit to an established treatment program. Few fol- results from double-blind trials have been limited, for the low-up studies have examined whether medication treat- most part. Double-blind studies, at most, report marginal ment produces lasting benefit. A new generation of studies success in treatment of specific problems such as improving has begun to focus on whether medication can prevent re- the rate of weight gain during refeeding, and disturbed atti- lapse after patients leave to a structured treatment setting. Use of Antidepressants in AN One problem with determining the efficacy of pharma- cotherapy in AN is that often medications have been given There has been controversy as to whether AN and major in association with other therapies. Thus, it may be unclear depressive disorders share a common diathesis; however, whether it was the medication or therapy that resulted in critical examination of clinical phenomenology, family his- improvement. Furthermore, the primary criterion for im- tory, antidepressant response, biological correlates, course provement has often been weight gain, not a normalization and outcome, and epidemiology yield limited support for of thinking and reduction in fears of being fat. Still, the high frequency of mood tant to emphasize that treatment in structured settings, such disturbances associated with this disorder resulted in trials as inpatient units, even without medication, succeeds in of drugs such as amitriptyline (41–43), and lithium (44). Thus, it may be difficult to prove that an active medi- compared with the effects of placebo. However, relapse within For more that 50 years (45), investigators have suggested 1 year after successful inpatient weight restoration is very that AN shares similarities with obsessive-compulsive disor- common (25). In fact, patients with AN have a high prevalence ported that only 23% of the patients had a good outcome of obsessive-compulsive symptoms or disorders (46–48), as at 1 year after discharge despite intensive outpatient individ- well other anxiety disorders (49). Controlled trials of the neuroleptics pimozide (27) and Individuals with a past history of AN display evidence of sulpiride (28) have suggested limited effects in accelerating increased serotonin (51) activity that persists after long-term weight gain or altering anorectic attitudes for some patients weight recovery. In addition, women who recover from AN for part of the study, but overall drug effect was marginal.
Winter Depression Following our discovery of bright light suppression of mela- tonin production in humans (23) 400mg levitra plus sale, researchers began to treat Pineal Pharmacology depressed patients with bright light (24) discount levitra plus online. Drugs that a diary he had kept over for over 13 years (25) purchase levitra plus 400mg with visa. Since 2,000- stimulate and block 2-adrenergic receptors also have the light was effective in suppressing melatonin production, we predictable effects on melatonin production. For example, assumed that this intensity would have other chronobiologic clonidine decreases melatonin production in humans (11), effects as well. Kern responded to a regimen of 2,000- whereas yohimbine increases it (18). Chapter 129: Circadian Sleep and Mood Disorders 1881 Timing of Light The Light Phase Response Curve The next step in the course of our work was to address the circadian phase-shifting effects of light. A phase advance (shift to an earlier time)results from light exposure between the middle of the night and morning. A phase delay (shift to a later time)results from light exposure between the evening and middle of the night. These phase shifts are greatest in the middle of the night. During the day there are decreased responses to light. Each point represents the mean concentration of melatonin ( stan- Wever, who previously was the driving force behind the dard error) for six subjects. A paired t-test, comparing exposure importance of social cues, published a study in 1983, dem- to 500 lux with exposure to 2,500 lux, was performed for each onstrating that continuous bright light during the day had data point. A two-way analysis of variance with repeated mea- sures and the Newman-Keuls statistic for the comparison of a more potent effect on the human circadian system than means showed significant differences between 0230 and 0400 (*, did ordinary-intensity light (30). Right: Effect of different light intensities on melatonin secretion. Symbols: (o) 500 lux; (x) 2,500 lux; ( ) 1,500 lux; and ( ) Phase-Typing Circadian Rhythm Disorders asleep in the dark. Science 1980; Our much less elegant anecdotal report the same year indi- 210:1267–1269, with permission. We proposed that there were two types of circadian disor- We exposed him to bright light at these times, because ani- ders, the phase-delayed and phase-advanced types (Table mals tell time of year by the interval between the twilight 129. Most white light sources have this Phase-Advanced Type Phase-Delayed Type wavelength, which is in the middle of the scotopic spectral distribution. Rods, not cones, are most sensitive at this wavelength; Adjusting to night work Readjusting to off-work however, the precise retinal photoreceptors that mediate Winter depression chronobiologic effects of light have not yet been identified. The following year we showed that—holding the man group (39). Morning light was shown to be more anti- sleep/wake cycle constant—we could shift the melatonin depressant than evening light; however, evening bright light rhythm (a biological marker that we had proposed would was shown to be more effective than evening dim light. It be ideal for assessing circadian phase position in humans) should be noted, though, that there was no control for the by shifting the light/dark cycle (31,32). Signifi- cantly, the Terman group made the important suggestion The Phase Shift Hypothesis for Winter that 10,000 lux could be used for a shorter duration than Depression the 2,000- to 2,500-lux light that had been the previous When we proposed 'phase typing' circadian disorders (29), standard. Accordingly, we hypothesized that the optimum light for most patients. Some studies have shown that morn- time for bright light exposure was in the morning, which ing light is more effective than evening light (40,41); would provide a corrective phase advance. We further hy- whereas other studies showed that they are equally effective pothesized that morning light would advance the circadian (42). We also expressed of the former compared to the latter. According to their 'photon counting' hy- with the amount of phase advance. We had previously pothesis, light at any time of day should be antidepressant, shown this relationship with patients exposed to 30 minutes as long as light of sufficient duration and intensity was used versus 120 minutes of morning light (50), which has the (38). As Charmane Eastman has shown, the pla- cebo response is a major component to light treatment (51). Whether or not a specific mechanism for this can be found (e. We further suggest that dim light begin 1 hour before patients in the winter compared to the summer, particularly blood sampling (61). A third hypothesis, suggested by Charles salivary collections. In the early 1980s, we thought that plasma melatonin sam- pled every 30 to 60 minutes might be able to show differ- ences in circadian phase position between individuals and Low Melatonin Producers to monitor the phase-shifting effects of bright light (31,32). When there is a the time when melatonin levels begin to increase. Circadian Amplitude Sighted People It is not clear if the overnight melatonin profile is a good marker for the amplitude of its endogenous circadian pace- In sighted people, we reduced the dose to. Furthermore, it is not clear if circadian amplitude produces melatonin levels of the same order of magnitude is as important as circadian phase, in that an amplitude that occur physiologically. As opposed to previous studies disturbance has yet to be shown. Moreover, no technique of melatonin (which used higher doses and gave melatonin has been shown to enhance circadian amplitude or to relia- in the late afternoon or evening), we administered melato- bly diminish it. The jury is out over whether or not sup- nin at different times. In each trial we gave melatonin on pressing amplitude is important for bright light to cause four consecutive days, and the results were the first unequiv- phase shifts (65,66). That melatonin causes phase shifts op- at least three types of blind people: normally entrained, posite to those of light should not be surprising, because entrained at an abnormal phase, and free-running [blind melatonin appears to be a chemical signal for darkness. Of the million or Circadian Time so legally blind in the United States, about 200,000 are totally blind. Because 'lights phase with their preferred sleep time. The clock times in the tonin in the afternoon/evening. The timing of light and melatonin administration is best done with reference to circadian time rather than clock a few hours later or earlier, depending on how much the time. The role of habitual wake time (not the wake time on a particular day) melatonin and light in the human circadian system. For example, a person who habitually Kalsbeek A, Romijn H, et al, eds. Circadian Time and Zeitgeber Time occurs on average 14 hours after wake time. Therefore, the advance zone of the by the light/dark cycle in a relatively delayed phase position. Schematic diagram of the light and melatonin on advanced and delayed sleep phase syndromes. Chronobiol Int 1998; The use of melatonin has allowed us to conduct a further 15:71–83.
These findings suggest that amiodarone appears to be better than dronedarone or sotalol order levitra plus 400 mg free shipping, but no different from propafenone (low strength of evidence) purchase levitra plus in united states online. Studies assessing recurrence of AF Study Sample Time Point Results P-Value Size (N) Kochiadakis buy levitra plus 400 mg amex, 214 2 years Amiodarone: 33. Amiodarone + Verapamil: 20% Amiodarone + Flecainide + Verapamil: 21% Verapamil) p=0. Flecainide + Verapamil) 256 Katritsis, 2003 90 12 months Bisoprolol: 46% p=0. Three of the studies compared amiodarone with sotalol, and statistical comparisons were either not performed or treatments were not found to be statistically significantly 180,181,241 different. In one study, amiodarone was compared with sotalol or propafenone and no 230 statistical analyses were done. In another study amiodarone was compared with dronedarone 224 but no statistical analyses were done Differences in followup, comparisons, and findings resulted in insufficient strength of evidence for this outcome. Studies reporting all-cause mortality as an outcome Study Sample Time Point Results P-Value Size (N) 230 Roy, 2000 403 Mean followup 468 days Amiodarone: 4% NR Sotalol or propafenone: 4% Anonymous, 256 5 years (mean followup 3. Three studies compared amiodarone with sotalol and found no difference between these 180,241,260 treatment arms. In one study, there was no statistically significant difference in 241 arrhythmic death between those receiving amiodarone vs. Another study reported 2 percent of patients in the amiodarone group had sudden death and 3 180 percent in the sotalol group (no statistical test reported), while the third study reported no 260 deaths in either treatment arm due to proarrhythmia or sudden death. In the study comparing amiodarone with either sotalol or propafenone, 1. There was a low strength of evidence rating for there being no difference between evaluated pharmacological agents. CV Hospitalizations 230 No studies reported generally on CV hospitalizations. One study compared the proportion of patients with AF hospitalizations between amiodarone and either sotalol or propafenone. The rate of AF hospitalization was lower with amiodarone than with sotalol or propafenone (14% vs. In addition, the mean number of days to AF hospitalization was lower with amiodarone than with sotalol/propafenone (0. Control of AF symptoms 230 One study assessed control of AF symptoms using the Atrial Fibrillation Severity Scale (AFSS) and found no statistically significant difference in mean scores between amiodarone versus sotalol or propafenone arms (12. Quality of Life 180,230 Two studies reported outcomes related to quality of life. One study comparing amiodarone with sotalol found no significant changes in quality-of-life scores for any treatment group during the 1 year of followup except for a significant decrease in the mental health score 180 for patients on amiodarone, which differed significantly from those on sotalol (p=0. The 230 other study compared treatment with amiodarone versus treatment with either sotalol or 230 propafenone and found that all quality-of-life measures improved during 3 months of followup, but these improvements did not differ by treatment arm (low strength of evidence). In the study comparing amiodarone with either sotalol or propafenone, patients on sotalol or propafenone experienced a greater number of strokes and intracranial hemorrhages than did those on amiodarone (9 vs. In a study comparing amiodarone with sotalol, there was no significant difference between treatment arms for the number of minor or major stroke episodes per person-year (0. Composite Outcome (Recurrence of AF or Adverse Drug Effect) Five studies assessed a composite outcome of recurrence of AF or adverse drug event (Table 224,258-261 258,261 19). Two studies compared sotalol with propafenone, two compared amiodarone 259,261 260,261 with propafenone, two compared amiodarone with sotalol, and one compared 224 amiodarone with dronedarone. In several of these comparisons, statistical analyses were not conducted. Both studies comparing sotalol with propafenone found that patients on propafenone had a lower rate of the composite outcome than did patients on sotalol at 12–30 months; however, 258,261 statistical analyses comparing these rates were not done. In one of these studies a statistical analysis was done to compare the mean monthly rate of progression to AF or adverse drug effects. The rate among those on propafenone was significantly lower than the rate among those 261 on sotalol (4. In the two studies comparing amiodarone with propafenone, the proportion of patients with the composite outcome was higher in patients receiving propafenone versus amiodarone except 261 in one study at 24 months; however, statistical analyses were not done for any of these 259,261 comparisons. Both studies also assessed the mean monthly progression to AF or adverse drug effects and found a lower rate with amiodarone than with propafenone; however, the difference was not statistically significant in either study (amiodarone 3. Rates of the composite outcome were higher in those receiving sotalol versus amiodarone except at 1 month (see Table 19), but statistical analyses were not reported. The mean monthly rate of progression to AF or adverse drug events was statistically significantly lower for amiodarone as compared with sotalol in both studies (see Table 19). In the study comparing amiodarone with dronedarone, there was a statistically significantly higher rate of recurrence of AF or premature drug discontinuation due to side effects or lack of efficacy at 1 year among those on dronedarone compared with amiodarone (HR 1. Studies reporting a composite outcome of recurrence of AF or adverse drug effect Study Sample Time Point Results P-Value Size (N) Kochiadakis, 186 1 month Amiodarone: 28% NR 260 2000 Sotalol: 13% 12 months Amiodarone: 41. Propafenone) Kochiadakis, 254 12 months Sotalol: 50% NR 258 2004 Propafenone: 59% Mean monthly progression Sotalol: 5. Arrhythmic death (including sudden cardiac arrest) and all- cause mortality are described above as separate outcomes. Of these 11 studies, 5 incorporated adverse drug events resulting in drug discontinuation into a composite outcome with recurrence 224,258-261 of AF to assess the effectiveness of the drug(s). These studies had a more robust method of collecting adverse drug event information than other studies. The method of collecting adverse drug events and the definitions of adverse drugs varied between studies, making comparison between studies and summaries of studies challenging. In these 2,747 patients, only 7 proarrhythmias were reported (1 in a patient 245,258,269 receiving propafenone and 6 in patients receiving sotalol). Tachycardia was reported in 3 230,259 patients (2 receiving propafenone, and 1 receiving either sotalol or propafenone). Bradycardia was one of the more commonly reported adverse drug reactions, reported in 161 patients in 9 studies (73 on dronedarone, 61 on amiodarone, 15 on sotalol, 2 on propafenone, 3 224,230,241,245,258-261,269 on bisoprolol, and 7 on either sotalol or propafenone). Hypothyroidism or hyperthyroidism were reported in 5 studies that included 668 patients with amiodarone, 138 patients with propafenone, 136 with sotalol, 249 with dronedarone, and 202 with either sotalol or 224,230,259-261 propafenone. Hypothyroidism was reported in 29 patients with amiodarone and 2 patients with dronedarone. Hyperthyroidism was reported in 20 patients with amiodarone. Results in Specific Subgroups of Interest Six studies report outcomes by treatment arm for subgroups of patients based on characteristics such as age, sex, type of AF, duration of AF, left atrial size, and presence of heart 180,230,258-261 disease. With few exceptions, the results of primary outcomes did not change by 180,230,260,261 subgroup. In one of these, the probability of remaining in sinus rhythm continued to be significantly greater among patients without ischemic heart disease on amiodarone compared with sotalol (p<0.