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We have a baseline condition which is scrambled? and we would like to know how the condition of interest faces? di? If we now click somewhere outside the box prehypertension in young adults 100mg lasix for sale, a default name will be assigned to this e? Enter -50 in the left box and 300 in the right box to select the segment -50 to 300 ms relative to the presentation of the visual stimulus hypertension categories buy lasix 100mg otc. You can choose whether you want to remove low-frequency drifts of the data at sensor level heart attack kiss the way we were goodbye discount lasix express. Otherwise select the number of discrete cosine transform terms you want to remove blood pressure kidney disease buy lasix 40mg cheap. It is possible to change the detrend? and subsample? values or the time window and press Display? again to see what e? The idea is that the main features of the time-frequency image can be repre sented by a small number of components with? You cannot know in advance what the optimal number of components for your data is hypertension pathophysiology purchase 100mg lasix with amex. If you are happy with your data selection blood pressure journal pdf cheap lasix 100 mg, the subsampling and the detrending terms, you can click on the > (forward) button, which will bring you to the next stage electromagnetic model. From this part, you can press the red < button to get back to the data and design part. The onset-parameter determines when the stimulus, presented at 0 ms peri-stimulus time, is assumed to trigger the cortical induced response. Because the propagation of the stimulus impulse through the input nodes causes a delay, we found that the default value 43. Note, that it is possible to enter more than one number in the onset[s] (ms)? box. If you have not used the input dataset for 3D source reconstruction before you will be asked to specify the parameters of the head model at this stage. In each of these square matrices you specify a connection from a source area to a target area. Note that all connections in the model should be at least linear, so if you think some connection should be present in the model, the corresponding button in this matrix should be on. Also the buttons on the leading diagonal of the matrix are always on because each node in the model has a linear intrinsic connection with negative sign. To the right of the linear connectivity matrix there is a nonlinear connectivity matrix. The idea here is the same, just remember to enable the corresponding linear connection as well. It is actually recommended to always make the intrinsic connections non-linear unless there is a good theoretical reason not to do it. Since we are mainly interested in non-linearities in the extrinsic connections we would like to be over-conservative and? It is usually not square, and in the case of a single input, as we have here, is reduced to a column vector. The entries of this vector specify which areas receive the external input (whose onset time we speci? We will start by specifying the model with nonlinear forward and backward connections (FnBn) and with e? Below these buttons there are controls for specifying the parameters of the wavelet transform for computing the time-frequency decomposition. We will keep the default frequency window 4 to 48 Hz and increase the number of wavelet cycles to 7. You can press the Wavelet transform button to preview the time-frequency plots and optimize the parameters if necessary before inverting the model. In the Matlab command window, you will see each iteration print an expectation-maximization iteration number, free energy F, and the predicted and actual change of F following each iteration step. Here you can also see whether the activity picked up by the minor modes is noise, which is helpful for optimizing the number of modes. These matrices are obtained by multiplying the between-mode matrices estimated with the frequency pro? The arrangement of the matrices corresponds to arrangements of the buttons in the connectivity matrices above. This representation is useful for diagnostics when something is wrong with the inversion, but the physiological interpretation is less straightforward. If you are analyzing a group of subjects you can then enter these images into parametric statistical tests to? You will see, at the top, a bar plot of the log-model evidences for all models 43. At the bottom, you will see the posterior probability, for each model, given the data. By convention, a model can be said to be the best among a selection of other models, with strong evidence, if its log-model evidence exceeds all other log model evidences by at least 3. In our case the FnBn model is superior to the other models as was found in the original paper [22] for a di? A weakly coupled oscillator approach is used to describe dynamic phase changes in a network of oscillators. If you have been following the previous chapters of this tutorial, these should already be available in the dataset. On the right-hand side enter the trial indices 1 2 for the face? and scrambled? evoked responses (we will model both trial types). The sub-trials option makes it possible to select just a subset of trials for the analysis (select 2 for every second trial, 3 for every third etc. You can now click on the > (forward) button, which will bring you to the next stage electromagnetic model. This is appropriate when the channels already contain source data either recorded directly with intracranial electrodes or extracted. Generally, if you have not used the input dataset for 3D source reconstruction before you will be asked to specify the parameters of the head model at this stage. After source reconstruction (using a pseudo-inverse approach), source data is bandpass? It can take up to an hour to estimate the model parameters depending on the speed of your computer. The Sin(Data)-Region i option will show the sin of the phase data in region i, for the? The Coupling(As) and Coupling(Bs) buttons display the estimated endogenous and modulatory activity shown in Figure 44. These can then be changed by an amount bij as shown in the modulatory parameter matrices. In this case it is possible to specify more generic phase interaction functions, such as arbitrary order Fourier series. The generative model now reports coherence and signal covariance as well as complex spectral densities (from which the former are derived). The rodent was presented with a white noise auditory input for several minutes at each anaesthetised level and time series recordings were obtained for the entire epoch. We demonstrate in this chapter the consistency of the model comparison and conditional parameter estimates across di? The smaller this value, the greater the gain on this cell population due to the modulation. These three subpopulations are connected with intrinsic coupling parameters (which can be found in spm fx mnn nmda). Lateral, inter-hemispheric connections are modelled with a postsynaptic response that is elicited in all layers. This outperformed a model comprising the same two neural masses with the same extrinsic connections but where the e? The conversion script can be altered to suit your own conditions/sampling parameters. Since we are interested in the anaesthetized trials we enter [1 2 3 4] under the trials label and Iso 1. Right: Data time series for two intracranial electrode recordings from 25000 to 30000 msec. Bottom: conditional probability for each model assuming equal priors on model space. You will see at the top, a bar plot of the log-model evidences for all models (Figure 45. The bottom panel displays the conditional probability, for each model assuming equal priors on model space. By convention, a model can be said to be the best among a selection of other models, with strong evidence, if its log-model evidence exceeds all other log-model evidences by at least 3. As neuronal process requires extra delivery of oxygen, this hemodynamic change provides a marker of under lying neuronal activity. However, due to complex relationships between neurodynamic and hemodynamic processes, functional con nectivity often di? In the second session, the subjected was instructed to perform kinesthetic imagery of the same hand movement, but without moving the hand. Select yes? to average the optical density signal across trials, and then specify averaging window length [secs] for each experimental condition. You can refer to sensor positions shown in Figure 1: Optode and Channel Positions. Middle: Regions receiving driving input (eg, motor tasks encoding the occurrence of motor execution and motor imagery tasks). It is also suggested that Native Space versions of the tissues in which you are interested are also generated. Segmentation can require quite a lot of memory, so if you have large images (typically greater than about 256? The next step is to estimate the nonlinear deformations that best align them all together [4]. This is achieved by alternating between build ing a template, and registering the tissue class images with the template, and the whole procedure is very time consuming. If you run multiple Dartel sessions, then it may be a good idea to have a unique template basename for each. Template generation incorporates a smoothing procedure [10], which may take a while (several minutes). Note that the earlier iterations usually run faster than the later ones, because fewer time-steps? are used to generate the deformations. The whole procedure takes (in the order of) about a week of processing time for 400 subjects. There is a further complication in that a smoothing procedure is built into the averaging. This essentially involves pushing each voxel from its position in the original image, into the appropriate location in the new image keeping a count of the number of voxels pushed into each new position. The results of the pushing procedure are analogous to Jacobian scaled (?modulated?) data. There are several advantages of having more accurate spatial normalisation, especially in terms of achieving more signi? The objectives of spatial normalisation are:??To transform scans of subjects into alignment with each other. For this reason, warping is now combined with smoothing, in a way that may be a bit more sensible than simply warping, followed by smoothing. The end result is essentially the same as that obtained by doing the following with the old way of warping??Create spatially normalised and modulated? (Jacobian scaled) functional data, and smooth. This should mean that signal is averaged in such a way that as little as possible is lost. More accurate within-subject alignment between functional and anatomical scans should allow more of the bene? Similarly, the spatial transforms do not incorporate any masking to reduce artifacts at the edge of the? If this step is unsuccessful, then some pre-processing of the anatomical scan may be needed in or der to skull-strip and bias correct it. If segmentation is done before coregistration, then the functional data should be moved so that they align with the anatomical data. Generally, the procedure would begin by registering with a smoother template, and end with a sharper one, with various intermediate templates between. Running this option is rather faster than Run Dartel (create Template), as templates are not created. This can be achieved by running Dartel so that both images are matched with a common template, and composing the resulting spatial transformations. This can be achieved by aligning them both with a pre-existing template, but it is also possible to use the Run Dartel (create Template) option with the imported data of only two subjects. Suppose the image of one subject has been manually labelled, then this option is useful for transferring the labels on to images of other subjects. This section explains how a sequence of processing steps can be run at once without Matlab programming. A batch describes which modules should be run on what kind of data and how these modules depend on each other. Compared to running each processing step interactively, batches have a number of advantages: Documentation Each batch can be saved as a Matlab script. Thus, a saved batch contains a full description of the sequence of processing steps and the parameter settings used. Unattended execution Instead of waiting for a processing step to complete before entering the results in the next one, all processing steps can be run in the speci? Error reporting If a batch fails to complete, a standardised report will be given in the Matlab command window.

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Douglas Dean blood pressure pills buy discount lasix 100mg online, An Examination of Infra-Red and Ultra-Violet Techniques to Test for Changes in Water Following the Laying-On of Hands arrhythmia future cure cheap lasix 100 mg with mastercard. Spottiswoode blood pressure medication green capsule buy lasix 100mg visa, Infrared Spectra Alteration in Water Proximate to the Palms of Therapeutic Practitioners pulse pressure 50 40 mg lasix otc. William Braud and Marilyn Schlitz arteria innominada order lasix in india, "A Methodology for the Objective Study of Transpersonal Imagery fetal arrhythmia 32 weeks cheap 40 mg lasix with visa," Journal of Scientific Exploration, 3(1), 1989. Psychological methods, in general, have not been designed to test for scientific anomalies and extraordinary claims. If anything, a close examination of the methodological rigor used in psi research might tend to create doubts about the validity of a great deal of research in psychology as well as other behavioral and social sciences. In a table of random numbers, all of the numbers occur with a frequency approximating chance expectation. We can be certain that a table of random numbers meets the various statistical tests that have been devised for randomness. However, since such tables are published and generally available in libraries there is always a risk that "random" target sequences could be predicted by someone who obtained access to the random number table being used in a particular study. The best of these devices rely on random sources which are quantum mechanical in nature, such as electronic white noise or radioactive decay. Due to the uncertainty principle in quantum mechanics, the output of such devices in theoretically unpredictable; they are thus the most random sources known to nature. Ironically, it is entirely possible, however, that a truly random source will provide a short-term output that fails the statistical tests for randomness mentioned above. Thus, a genuinely random target sequence can be problematic if it mimics the properties of a non-random sequence. A test subject who receives trial by trial feedback in such a situation might make inferences that happen to match the random output. Therefore, the ideal experiment must not only be derived from a true random source; it must also meet post hoc tests for randomnicity. Such tests will also detect more serious sources of bias that may develop within electronic or mechanical apparatus designed to generate random events. The main concern is that subjects will learn the characteristics of previous target sequences, and use this information to infer the characteristics of future target sequences. Or, subjects may simply have a personal bias towards some targets that, coincidently, matches the patterns that emerge in a non-random sequence. If a critical procedure such as randomization broke down, this raises the possibility that there were other breakdowns, or failures to carry out the experimental plan. If random number tables are used, the application procedures must be fully described. This is particularly important when untrained assistants are asked to generate target sequences. Electronic random event generators should employ a switching system to correct for possible systematic bias. However, there is always the possibility that the output bias could, in some manner, correlate with the switching sequence itself. Schmidt, at a 1974 research meeting at the Foundation for Research on the Nature of Man, suggested doing this by incorporating the Rand Corporation random number tables into such a switching system. In spite of this importance, there is no way to theoretically ensure that such control runs are immune from psychokinetic influence. This makes it all the more important to introduce systematic controls, especially as a guard against short-term generator bias. One means of systematically controlling for generator bias is to randomly pair control and experimental trials. To what extent can one make allowances for non-random target sequences and salvage an experiment which is flawed in this respect? This is an extremely important question because (a) pure randomness is an ideal which can never truly be reached in the real world; and (b) valid random procedures may, in fact, produce target sequences which in retrospect do not appear random i. In other words a genuinely random sequence of sufficient length will have many subsequences which do not appear random. Such randomness tests should be conducted in the actual experimental environment with all peripheral equipment attached. Ultimately, of course, at least one experimenter who 333 designs the study will have to know the arrangements. It should be mentioned that some Schmidt generators have been tested by generating sequences of over a million trials, and have shown no evidence of either short or long-term bias. Hence the problem is not a severe one with a well-designed generator which has been thoroughly tested. As early as 1895, psychologists described "unconscious whispering" in the laboratory and wwere even able to show that senders in telepathy experiments could give auditory cues to their recievers quite unwittingly. Many researchers in the early years of experimental psychology and psi research gave early warnings on the dangers of unintentional cueing. In designing experiments to prevent sensory leakage, experimenters cannot assume that there are no tricksters present among the subjects. Precautions must be taken that would prevent the most skilled of tricksters or magicians from succeeding in obtaining normal sensory information about the targets. Experimental reports must clearly describe the relative location of subjects and targets. Subjects must not be present at any time while the target materials are being prepared. Chemist George Price suggested, in his 1955 Science article advocating the presumption of fraud, that a metal container be used with a cover welded on and photomicrographs taken of the welds. Even with such precautions a clever subject, using advanced technology, under unobserved circumstances could devise ways of penetrating such a device. Thus it is simply better not to allow the subjects to have unobserved access to containers with target materials. James Davis, of the Institute for Parapsychology in Durham, North Carolina, has observed that a subject who has access to the computer, knows the data format, and has sufficient programming knowledge, might subvert experimental precautions. This might be in terms of subtle audio or electromagnetic signals that could aid a sensitive individual in distinguishing different targets. In telepathy experiments one must exclude the possibility that the subject learns about the targets indirectly, through cues from the agent. Thus any individual with information regarding the targets must not be within auditory or visual range of the subject. This often means that putting subject and agent in adjacent rooms is insufficient. Furthermore, any communication between subject and agent with regard to timing of trials. Experimenter cueing can be eliminated by keeping experimenters blind as to target order. In order to insure experimenter blindness with regard to targets, experimenters should have no sensory contact with individuals who are aware of the target order. In free response experiments with independent judges, it is also essential that the judges be shielded from all sensory cues just as if they were subjects. In addition, judges must be provided with no sensory cues whatsoever regarding the order of the various calls made by subjects. If such cues are provided, judges may succeed in time-ordering both the target and the response sets, thus contaminating the judging process with additional logically derived information. Providing feedback in a "closed deck" target pool situation reduces, in effect, the degrees of freedom of the final target (even if the total pool is unknown to the subject) and thus may be a source of experimental contamination. This may occur if subjects avoid producing imagery related to any targets for which imagery has already been provided. Both judges and percipients may detect creases, marks, smudges, temperature differences or other artifacts that result if actual targets have been handled and then mixed in 335 with targets from a pool for judging. Handling cues may also result when targets placed in envelopes are opened and then resealed or placed in new envelopes, as has sometimes been done. Some researchers deal with this issue by never working with well-known "psychics" and by insisting that all subjects participate anonymously in their studies. Although many phenomena were apparently observed, none of these manifested under well-controlled conditions. Eventually, researchers suspected fraud and set up hidden cameras which succeeded in revealing blatantly fraudulent activities. When confronted with this evidence of his deception, the subject denied that his activities has been fraudulent. However, several months later he confessed that he was a practicing magician "who had wished to see if it were possible for a magician to pose successfully as a psychic in a laboratory. Psi researchers are somewhat vulnerable to this type of invasion, because in attempting to establish conditions conducive to the alleged phenomena they wish to investigate they attempt to establish good rapport and thus avoid treating experimental subjects with suspicion. Human nature is often unpredictable; this is sometimes the case with regard to fraudulent and criminal activity, especially when it occurs in the absence of apparent motive. Some subjects may simply get a kick out of fooling experimenters (especially when researchers have claimed fraudproof conditions). In one clever incident, a research study conducted at Harvard University, the agent and percipient were 100 feet apart, with four closed doors separating their rooms. The student subjects used a confederate hidden in one of the rooms to aid in passing a signal. The system was so successful that the percipient was able to guess the correct color of a deck of playing cards, on all 52 attempts. The researcher, George Estabrooks was initially fooled, even though he knew that cheating would be attempted. Often shielding characteristics change over time, as modifications are made to experimental rooms. Some experimenters have attempted to control for fraud by locking subjects into experimental rooms during testing. Naturally, this control would be of little success if the subject is skilled at picking locks. Readers interested in developing a more detailed knowledge of the many ways in which fraud may be committed to create the illusion of psychic functioning will want to study the literature of professional magic. Recording Error the possibility of unconscious errors in the recording of experimental data has been observed in psi research since the 1930s. If targets and responses are recorded manually, this must be done by individuals who are blind (or unaware) as to the correct targets in order to preclude unconscious errors. When automated equipment is used, it is critical to good experimental design that automated equipment be subject to periodic tests, during the course of an experiment, to ensure that the equipment functions as it was intended to function. When computers are used to record psi targets and responses, it is important that the paper printout be kept in its original continuous condition, in order to prevent misplacement of some records. In the event that computer printout paper becomes severed, the paper sheets should be prenumbered. The classification must be blind and would ordinarily be completed before psi testing is conducted. Ideally, the basis for classification into high and low scorers should be made public in full detail to the research community before any testing begins. Fixed response alternatives or a preplanned scoring system are essential for such classifications. In all aspects of data handling, such as computing various statistical parameters from raw data, automated analysis is preferable. If analysis is done manually, it is advantageous that the scorer or statistician be blind as to the various experimental conditions and hypotheses in order to avoid inadvertent bias. Statistical/Methodological Violations Some critics claim that experiments should compare psi scores with scores obtained in some sort of control conditions, rather than simply with the expected statistical means. The reason for this is not that the predictions of probability theory are being called into question but rather because a control group may 337 tend to benefit from any otherwise undetected, non-psi sources of information related to methodological flaws, recording errors or sensory leakage. The problem with this approach, however, is that it is not possible to devise a control condition that would be identical to the experimental condition in every way except that it would eliminate possible psi communication. This dilemma would seem to place a limit on the degree of precision which is possible to attain in psi research. A clever card-counter, such as those who sometimes use the system to win at Blackjack in Las Vegas, can increase the certainty of their guesses on the final cards in a deck. Independence, of course, is not violated when using an "open" sequence in which targets are chosen from a much larger universe. Multiple responses for a single target cannot be evaluated using statistical tests that assume independence of responses. If there is a sufficient number of responses, the data can be analyzed by the Greville method, which accounts for the stacking effect. In remote-viewing experiments, violations of independence have arisen even when a single judge is asked to rank a small number of targets against an equal number of responses. The judge may, under these conditions, be influenced in assigning a rank or rating to a given target by the memory of how he or she assigned ranks or ratings to other targets. The assumptions used in most statistical tests are violated if optional stopping is used. The Princeton method of converting free-response information to binary data avoids this criticism. Statistical tests are not accurate if researchers are free to censor data which does not support their hypotheses. This sometimes occurs by the use of post hoc decisions as to whether a study will be reported as an informal, preliminary demonstration or as part of an experiment. Ideally all formal psi experiments should be registered, in advance, specifying the total number of trials, runs, subjects, etc. Then all data from those experiments should be reported, regardless of the outcome.

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Because viruses require host cell machinery to replicate, it was originally thought that any action interfering with viral replication would also necessarily kill host cells. However, the strategy of targeting enzymes unique to viruses has since yielded several safe and effective therapies. Today, the indications for the use of antiviral drugs include the treatment of active viral disease, as well as for prophylactic (for uninfected but at-risk individuals) and preemptive (infected but asymptomatic) therapies. Despite these successes, cellular toxicity remains an important therapeutic consideration, as adverse effects limit the successful use of many antiviral drugs. Although the devastating consequences of untreated disease allow a higher threshold for acceptable side effects, poorly tolerated agents still lead to higher rates of noncompliance and inconsistent drug exposure that, in turn, lead to further development of resistant strains. Amantadine, Rimantadine: the Adamantanes Amantadine and rimantadine are structurally related tricyclic amines that bind to the M2 protein found in the nucleocapsid membrane of in? This protein is an ion channel that allows protons to cross the membrane barrier, thereby acidifying the cytoplasm. This drop in pH enables viral uncoating, a step necessary to initiate viral replication (4). Treatment is effective in reducing the duration of illness by about one day if given within two days of the onset of symptoms (5,6). Prophylaxis for high-risk individuals is indicated for those who cannot tolerate the in? Amantadine is not metabolized systemically and is excreted by the kidneys largely unchanged; rimantadine is metabolized extensively by the liver prior to renal clearance. Side effects are similar with both drugs, but are typically less severe with rimantadine. A major area of concern with the use of the adamantanes has been the rise of viral resistance to these drugs. While infection of the treated index case typically resolves despite the development of resistant strains, transmission of the strain to others often results in failure of drug prophylaxis for household contacts (9). Zanamivir, Oseltamivir: the Neuraminidase Inhibitors Zanamivir and oseltamivir are structurally similar compounds that work by competitively binding neuraminidase, a surface glycoprotein that is common to both in? Neuraminidase is essential for the release and spread of newly formed virus, making this enzyme an attractive target for inhibiting viral replication. It also facilitates the migration of virus through mucous, allowing spread through the respiratory tract. Zanamivir is a synthetic competitive inhibitor, while oseltamivir is an ethyl ester prodrug that is converted to its active form by hepatic esterases. Peramivir, another similar compound, is an additional promising drug currently undergoing clinical trials. Zanamivir and oseltamivir have both been shown to be effective in the prophylaxis and treatment of in? Prophylaxis with zanamivir or oseltamivir reduces the rate of infection by up to 79% and 75?85%, respectively (12?18). Treatment with zanamivir within two days of the onset of symptoms lessens the severity of disease and shortens the duration of symptoms by an average of one day (19). Similarly, oseltamivir treatment started within one to two days of disease onset ameliorates symptoms and reduces duration by 1 to 1. In a retrospective evaluation of managed care databases, patients treated with oseltamavir had decreased hospitalization rates and respiratory complications (22). Zanamivir requires administration by oral inhalation due to its poor oral bioavailability. Zanamivir is generally well tolerated, but some patients experience exacerbation of reactive airways disease with treatment (23,24). Renal dose adjustment is rarely needed despite the fact that the unchanged compound is excreted via the kidneys. In contrast, oseltamivir is well tolerated orally, with over 90% of the drug converted to its active metabolite (21). Side effects are rare and mild, and typically consist of nausea and vomiting (25). Rare case reports of delirium and abnormal behavior in children taking oseltamivir, mostly in Japan, have prompted revision in the warning label of the drug (26). The development of viral resistance to zanamivir is rare; however, widespread resistance of the H1N1 in? Point mutations in the viral genome (H274Y) alter the active site of neuraminidase and block binding of the drug (27). Ribavirin is no longer used because of the lack of improvement in clinical end points such as duration of hospitalization or required oxygen therapy (30?32). Intravenous ribavirin is used in the treatment of Lassa fever, while an oral formulation is used to treat hepatitis C in conjunction with pegylated interferon-. Inhaled drug reaches therapeutic levels in the respiratory mucosa with only small amounts absorbed sys temically. The oral bioavailability of ribavirin is about 40% (33), whereas intravenous therapy achieves approximately ten times higher peak concentrations. Less than a third of systemically administered drug passes through the urine unchanged, with an additional one-third of the drug excreted as metabolites (33). Side effects of the inhaled form include mild conjunctivitis, rash, and bronchospasm. Fortunately, over the past 30 years several drug therapies have emerged that have proven to be safe and effective. Acyclovir is taken up preferentially by infected cells and is ini tially phosphorylated by the viral enzyme thymidine kinase. This monophosphate form is then diphosphorylated by host cellular enzymes to the active triphosphate form. Prophylactic or suppressive therapy can be used in patients with recurrent genital infections as well as to prevent reactivation of herpes labialis (35?41). Acyclovir can be given intravenously, topically, or orally with less than 30% bioavailability (42). Drug distribution is good with penetration to kidney, lung, liver, and cardiac tissue as well as to skin lesions. Acyclovir is primarily excreted by the kidney, necessitating dose adjustment in patients with renal insuf? Acyclovir has shown to be a safe drug with minimal side effects relative to other antiviral drugs. The oral form is generally well tolerated with only mild associated gastrointestinal upset. Standard courses of therapy have not been shown to cause bone marrow suppression in adults, although neutropenia has been observed in neonates undergoing high-dose therapy (43,44). Acyclovir is expressed in breast milk and crosses the placenta, but association with congenital defects has not been demonstrated. The most serious adverse effects of acyclovir are nephrotoxicity and neurotoxicity. Renal dysfunction is reversible and is typically worse in settings of dehydration. Neurotoxicity is also worse in dehydrated patients, and can manifest as seizures, lethargy, confusion, hallucinations, delirium, and extrapyramidal signs. The poor oral bioavailability of acyclovir led to the development of valacyclovir, which is its L-valine ester prodrug. Its indications are the same as those for acyclovir, although it should not be used for life-threatening conditions where accurate monitoring of levels is necessary. It is similarly phosphorylated by viral thymidine kinase and subsequently converted to its active form, penciclovir triphosphate. Famciclovir is the diacetyl ester prodrug of penciclovir and confers 70% bioavailability (49). It is excreted by the kidney and thus requires dose adjustment in patients with renal insuf? Famciclovir is tolerated well with minimal side effects with headache and gastrointestinal upset being most common. Ganciclovir, Valganciclovir Ganciclovir is a synthetic analogue of 2 -deoxyguanosine structurally similar to acyclovir. Cellular enzymes subsequently phosphory late the monophosphate derivate to yield the active triphosphate compound. Prophylaxis with ganciclovir is used in transplant recipients, and preemptive therapy is used routinely in seropositive posttransplant patients (51?54). The oral form has poor bioavailability, with less than 10% drug absorption (55,56). The drug is excreted by the kidneys, necessitating drug dose adjustment in patients with renal insuf? Hematologic toxicity occurs in up to a third of recipients and most commonly includes neu tropenia, although thrombocytopenia and anemia can also be observed. For this reason, close monitoring of the complete blood count is necessary to detect early bone marrow suppression. Fever, liver function abnormalities, and rash are less likely but have also been observed. Valganciclovir is the L-valine ester prodrug of ganciclovir that is rapidly metabolized after oral administration. Its oral bioavailability is improved to 60%, and is further increased by administration with food (57). It has similar indications and resistance mechanisms as ganci clovir and offers an effective alternative to intravenous ganciclovir. Neutropenia, anemia, and headache are seen in some recipients, but nausea and diarrhea are more common adverse effects (58). Initial phosphorylation by a viral enzyme is not necessary as the compound already has a monophosphate group. Host cellular enzymes subsequently phosphorylate the drug, resulting in the active form. Its potential therapeutic role has been tested in other clinical situations as well. Because of its poor oral bioavailability, cidofovir is used primarily in its intravenous formulation. Ninety percent of the drug is excreted by the kidneys, thus necessitating dose adjustment in patients with renal insuf? Despite its broad activity, the clinical utility of cidofovir is limited by its potential for severe renal toxicity. Aggressive intravenous hydration, co-administration of probenecid, and avoidance of other nephrotoxic drugs minimizes the risk, yet nephrotoxicity still causes the discontinuation of cidofovir in 25% of patients. Other side effects include neutropenia, fever, myalgias, nausea, and hair loss, but it is its renal toxicity that renders the drug a therapy of last resort. Foscarnet Foscarnet is a pyrophosphate analogue and the only antiherpes drug that is not a nucleoside or nucleotide analogue. Because of the severity of its associated adverse effects, foscarnet is typically reserved as a potent therapeutic option in select situations. Foscarnet is available only as an intravenous formulation due to its poor oral bioavail ability (20%). It is cleared renally, and thus requires dose adjustment in patients with renal insuf? Nephrotoxicity and electrolyte disturbances are the major side effects associated with foscarnet. Serum creatinine elevations of up to threefold are observed in about half of the recip ients. Risk factors for renal dysfunction include preexisting renal disease and concurrent use of other nephrotoxic drugs. In addition, factors such as hydration status and manner of infusion also affect nephrotoxicity (71). Renal toxic effects are typically reversible within two to four weeks of discontinuing therapy. Hypocalcemia is seen in up to a third of patients, and can result in seizures, tetany, and arrhythmias. Other adverse effects include fever, nausea, vomiting, hepatic dysfunction, and cytopenias. But because the drug undergoes phosphorylation by cellular kinases, there is signi? Patients should be monitored for side effects such as occlusion of the puncta and keratinization of lid margins. Chronic infections often lead to cirrhosis and hepatocellular carcinoma, and are a leading cause for liver transplantations in the United States. Current therapeutic regimens designed to clear infection and prevent late sequelae involve the use of nucleoside and nucleotide analogues, as well as immune modulators. Lamivudine can be used alone or in combination with other medications such as interferon for the treatment of chronic hepatitis B infection. Treatment with lamivudine requires long-term oral administration, and is generally well tolerated. Adverse reactions include headache, fatigue, nausea, vomiting, diarrhea, peripheral neuropathy, and hair loss. Adefovir Adefovir is a nucleotide analogue of adenosine monophosphate that is administered orally as its prodrug, adefovir dipivoxil. Adefovir has approximately 60% oral bioavailability and is excreted by the kidneys and therefore requires dose adjustment in patients with impaired renal function. Adefovir is generally well tolerated, with headache, pharyngitis, abdominal pain, and peripheral neuropathy being the most commonly reported side effects.

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