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Effect of lenient versus strict rate control on cardiac remodeling in patients with atrial fibrillation data of the RACE II (RAte Control Efficacy in permanent atrial fibrillation II) study order 1mg propecia mastercard. Efficacy of three different ablative procedures to treat atrial fibrillation in patients with valvular heart disease: a randomised trial buy propecia 1 mg low price. Catheter ablation treatment in patients with drug- refractory atrial fibrillation: a prospective purchase propecia 5 mg on line, multi-centre cheap 5 mg propecia otc, randomized buy propecia 5 mg low price, controlled study (Catheter Ablation For The Cure Of Atrial Fibrillation Study). Analysis of cause-specific mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. The effect of rate versus rhythm control strategy on the left ventricular function in patients with persistent atrial fibrillation: Results of one year follow-up. Maintenance of sinus rhythm and survival in patients with heart failure and atrial fibrillation. Left atrial posterior wall isolation does not improve the outcome of circumferential pulmonary vein ablation for atrial fibrillation: a prospective randomized study. Rapid loading of sotalol or amiodarone for management of recent onset symptomatic atrial fibrillation: a randomized, digoxin-controlled trial. Rate control and quality of life in patients with permanent atrial fibrillation: the Quality of Life and Atrial Fibrillation (QOLAF) Study. Antiarrhythmic drug therapy after radiofrequency catheter ablation in patients with atrial fibrillation. A prospective randomized multicenter comparison on health-related quality of life: the value of add-on arrhythmia surgery in patients with paroxysmal, permanent or persistent atrial fibrillation undergoing valvular and/or coronary bypass surgery. Lenient versus strict rate control in patients with atrial fibrillation. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. Does intensity of rate-control influence outcome in atrial fibrillation? An analysis of pooled data from the RACE and AFFIRM studies. VERDICT: the Verapamil versus Digoxin Cardioversion Trial: A randomized study on the role of calcium lowering for maintenance of sinus rhythm after cardioversion of persistent atrial fibrillation. Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF): a randomized, multicentre, international trial. A randomized trial of prophylactic antiarrhythmic agents (amiodarone and sotalol) in patients with atrial fibrillation for whom direct current cardioversion is planned. Effects of diltiazem pretreatment on direct-current cardioversion in patients with persistent atrial fibrillation: a single-blind, randomized, controlled study. Mitral valve surgery plus concomitant atrial fibrillation ablation is superior to mitral valve surgery alone with an intensive rhythm control strategy. Control of heart rate versus rhythm in rheumatic atrial fibrillation: a randomized study. Control of rate versus rhythm in rheumatic atrial fibrillation: a randomized study. Prospective randomized comparison of left atrial and biatrial radiofrequency ablation in the treatment of atrial fibrillation. Pulmonary vein isolation combined with superior vena cava isolation for atrial fibrillation ablation: a prospective randomized study. Acute ventricular rate control in atrial fibrillation: IV combination of diltiazem and digoxin vs. Randomized study comparing combined pulmonary vein-left atrial junction disconnection and cavotricuspid isthmus ablation versus pulmonary vein- left atrial junction disconnection alone in patients presenting with typical atrial flutter and atrial fibrillation. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT). Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial.

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KANE The introduction of the randomized cheap 1mg propecia amex, double-blind discount 5mg propecia free shipping, clinical with a focus on specific domains such as negative symptoms trial was one of the major advances in the development of and cognitive dysfunction buy discount propecia 1mg. In the arena of psychotropic drug develop- of basic mechanisms should facilitate further treatment ad- ment this approach has proven to be of enormous value vances 1mg propecia amex, our current knowledge of pathophysiology remains in advancing a field in which laboratory tests and strictly limited 1mg propecia otc. Advances in imaging techniques and pharmacogen- objective methods for diagnosis and outcome assessment omics are also important potential developments on the are not currently available. Schizophrenia is a complex Each area of psychotropic drug development has its own illness affecting to varying degrees a range of functions, in- challenges in terms of rates of spontaneous remission, pla- cluding cognition, affect, behavior, mood, and motivation. Although there are core features of schizophrenia that involve percep- DESIGN ISSUES tion (hallucinations), cognition (attention, working mem- ory, etc. This has as the particular program of drug development. A drug de- important implications for the diagnostic process, which is velopment program needs to be comprehensive as well as also complicated by the fact that the evaluation of some adaptive so that early results can inform subsequent evalua- core features (e. Although even when a drug is marketed there are still on subjective reporting, the accuracy of which is potentially limitations in the amount of knowledge available to clini- influenced by the very symptoms themselves as well as by cians, several fundamental questions should have been at other social situational and personality variables. The tendency has been to conduct an tive treatments? Some of the most salient issues include dose finding; be given to those issues, and it is possible that multiple efficacy vs. It is hoped that new treatments will be developed adverse effects in specific subgroups (e. Dose-finding tolerability studies involving antipsychotic medications generally call for involvement of target patient J. Kane: Departmentof Psychiatry,HillsideHospital,GlenOaks,New York; Department of Psychiatry and Neuroscience, Albert Einstein College of populations earlier in the process than with other classes of Medicine, Bronx, New York. A variety of subject characteristics should be considered It is not always possible to accurately predict clinical in terms of inclusion and exclusion criteria. Specific deci- dosage requirements from preclinical studies; therefore, it sions will be influenced by the nature and goals of the partic- is important to establish a full range of tolerable dosages in ular trial. Age is often a basis for exclusion (either too young or too Drug development programs have been delayed and at times old). Age can certainly affect pharmacokinetics of particular abandoned because of inadequate dose-finding efforts in the drugs. The elderly are more likely to have comorbid medical early stages of development (1). In addition, it is not unusual conditions and be more sensitive to some adverse effects, for dosage recommendations to change after a drug is mar- and there are a variety of issues when young patients are keted. These and other factors have led to a It is also important to have sufficient data on absorption, paucity of subjects at the extreme age ranges in clinical trials. Sometimes attempts are made to study two or even Gender can be an important variable, and women are three phases in the same trial, but controversy surrounds often underrepresented in clinical trials. Patient characteristics may vary somewhat in terms are developed to extend clinical trial data, more accurate of desirability within specific trials, but overall the following documentation of race will be critical. Marital status can be a proxy for psychosocial adjustment and illness course, and may therefore be of prognostic signif- icance. Patient Characteristics Weight and body mass index have become an increasing It is important to be clear on whether or not patients are concern from a public health standpoint and because of the in a state of acute relapse or exacerbation as opposed to considerable weight gain observed with some psychotropic partial remission or a 'stable plateau' of chronic symptom- drugs and in particular several new-generation antipsychotic atology. At times investigators will withdraw patients from medications (2). The impor- acterize those patients most likely to benefit from specific tance of these different approaches is that they may result in treatments. Duration of illness and the duration of the cur- patients with very different degrees of drug responsiveness, rent episode can be important in helping to define popula- different patterns of baseline symptomatology, and varying tions in terms of drug responsivity as well as long-term degrees of 'stability' in baseline symptomatology. A current episode duration of more than 2 or 3 time course of response can be determined. However, given weeks could suggest that the patient is poorly or only par- the way that subjects must be ascertained and recruited for tially responsive to the treatments that have already been trials, it is likely that some treatment will have already been administered, or, alternatively that some other factor is com- administered.

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It has been surprising depends on the glial Na pump (38 discount 5 mg propecia overnight delivery,42–44) cheap propecia 1 mg free shipping, an anion to discover that glial cells release and express receptors for transporter that cotransports K and Na with Cl (43) a wide range of informational molecules order propecia 5mg line, including neuro- and Donnan forces that propel KCl into glial cells in the transmitters (22); this greatly expands the possibilities for face of elevated [K ] (42) (Fig 10 propecia 5mg overnight delivery. It has not been deter- o glial–neuronal interactions cheap propecia 5mg with amex. Indeed, astrocytes are in a posi- mined with certainty which of these mechanisms is quanti- tion to sense and modulate synaptic transmission through tatively most important for K uptake. The astrocyte Na the pervasive lamellar processes that surround synaptic con- pump, however, is exquisitely sensitive to elevations of tacts (7). Even a 1 mM increase in [K ] activates the Na o o pump in these cells indicating, perhaps, that this is the major mechanism of K sequestration (44). Neurons, of course, FUNCTIONS must eventually reaccumulate K lost during activity using their Na pump, but only glial cells show net accumulation Ion Homeostasis of K (Fig. It is interesting to note that the neuronal One of the best-established functions of astrocytes is regula- Na pump is not sensitive to small increases in [K ] and o tion of brain [K ]. Astrocytes are also likely to participate is probably activated mainly by increases in intracellular o in the regulation of extracellular pH, but this aspect of astro- [Na ] (45). In fact, under conditions of diminished energy supply, glial cells actually contribute K to the ECS, rather than take it up (49). Transmitter Synthesis Glutamate is one of the most common amino acids in the brain, present at millimolar concentrations in brain tissue homogenate. It is also the predominant excitatory neuro- transmitter (50). Only a small fraction of total brain gluta- mate is packaged for synaptic release and astrocytes are inti- mately involved in the synthesis of this crucial vesicular pool of glutamate. Although glutamate can be derived from neuron glucose metabolism, carbon-labeling experiments reveal that astro- FIGURE 10. Schematic representation of mechanisms of K cyte-derived glutamine is the principal precursor of synapti- uptake in astrocytes. K released by firing neurons is actively cally released glutamate (51,52). The synthesis and release accumulated by astrocytes in three ways. The sodium pump and an anion transporter both take up K ; the sodium pump relies of glutamine by astrocytes is part of a biochemical shuttle directly on the availability of ATP, whereas the anion transporter mechanism called the glutamate-glutamine cycle (53) (Fig is indirectly powered by the energy stored in the transmembrane 10. After release from the presynaptic terminal, glutamate Na gradient. The presence of channels for Cl and K , allow Donnan forces to produce KCl influx. These mechanisms along is taken up primarily by astrocytes (54,55). In the glial cell, with K spatial buffering (seetext), prevent [K ] from exceeding glutamate is converted to glutamine through the ATP-de- o 12 mM. Increases in [K ] are seen during neural activity as [K ] i o pendent enzyme glutamine synthetase, located exclusively increases. In fact, glutamine synthetase is localized to astrocytic processes surrounding glutamatergic synapses The idea that focal increases in [K ] could be redistrib- o uted by glial cells was introduced by Kuffler and colleagues (46). They realized that the selective K permeability of glia coupled with their low-resistance intercellular connections (mediated by gap junctions), would permit them to trans- port K from focal areas of high [K ] , where a portion o of the glial network would be depolarized, to areas of normal [K ] , where the glial network would have a near normal o membrane potential (46). Experiments suggest that under conditions of focal increases in [K ] , five times as much o K moves by way of glial cells as through the ECS, except where only very localized K gradients are involved (25). A further specialization that contributes to spatial buffering is a nonuniform distribution of K channels on a single cell. Because the end-foot of the Muller¨ cell, which abuts the vitreous humor of the eye, has the highest density of K channels, accumulated [K ] is pref- FIGURE 10. Scheme showing how astrocytes are involved in o erentially transported to the vitreous, which acts as a dis- glutamate metabolism and uptake. Only astrocytes contain the enzyme glutamine synthetase, which converts glutamate to glu- posal site. It is not known if nonuniform K channel distri- tamine in an ATP-requiring reaction.

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