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Another measure discussed below purchase geriforte 100 mg with amex, depend not only on airways of current interest is FEF25–75% geriforte 100 mg amex, which is the resistance, but also on lung volumes. It is considered to measure effects in the exhales as rapidly as possible as much as small airways. Illustration of some spirometric measurements 366 TEXTBOOK OF CLINICAL TRIALS A full spirometric manoeuvre consists of various predicted formulas have been obtained measurement of the inspiratory part also. There are a number of If performed correctly, the spirometric test is such formulae available, generally depending on highly reproducible but somewhat effort-depen- demographic variables like race, gender, age and height. FEV1 is less dependent that these measures cannot be anything but than FVC, since it only needs maximum effort for rather approximative ones, since the predicted 1 s. The direct measurement of airway resistance normal values are not exact counterparts to (Raw), which is done in the body box, is effort- the unknown lung function without disease! In special Another disease characteristic obtained from situations, however, the assessment of resistance lung function measurements is the reversibility. This is an index obtained from a very simple PEF is much more effort-dependent than FEV1, single-dose monitoring experiment: we measure but it can also be measured by a much cheaper FEV1, give a rapid-acting β2-agonist and wait apparatus than a spirometer. The meter is often provided to the patients for classical reversibility is then obtained as self-monitoration at home. Instructions are then reversibility given to fill in a diary card and to contact the healthcare service when PEF has dropped for a FEV1(after) − FEV1(before) = 100 × few consecutive days below prespecified levels. FEV1(before) In the same way, PEF can be monitored with this A value in excess of 15% was previously consid- simple device in a long-term study by recording, ered indicative of reversible airways obstruction, often twice daily, in a diary card. The basis for There is a diurnal variation in FEV1 and these numbers is somewhat unclear – it is prob- other lung function measurements. Lung function measurements can be followed Upper Airway Function Tests in order to assess effects, but also to characterise disease severity. Therefore a lung function parameter cannot be They are however much less used, since symptom judged on an absolute scale – an FEV1 of 2. A measure of disease two different techniques: posterior rhinomanome- severity would be the ratio of the actual FEV1 try in which values are obtained by probes placed and the would-be, and unmeasurable, FEV1 in the mouth, and anterior rhinomanometry in the patient should have without the obstructive which a device in the nose is used. As a remedy for the latter cated, and expensive methods for assessing nasal RESPIRATORY 367 patency rely on the measurement of peak nasal is declared at a timepoint t if there is a 15% flow either on inspiration (PNIF) or expiration increase compared to baseline at that time. We do not discuss these methods in any on such a concept, we can define: the time of further detail. The ending of effect occurs For asthma studies, there are a number of at the timepoint on the polygonal approximation experimental designs to measure various aspects which is followed by at least two observations of the therapeutic effect based on objective lung below the line E = 1. In most real-life cases that will suffice and if no measurement was found this is FEV1, but the discussion is not restricted below the line, censor the end of effect to the last to this case. The duration is then the time from We can group the designs in two groups: either onset of action to end of effect. This is not appropriate, since lung function has a clear diurnal variation. Single Dose Monitoring It might be a reasonable approximation for a few hours, the perceived time of clinical efficacy of This type of experiment is simple. Consider one a short-acting β2-agonist, but will produce an individual on one occasion when this experiment incorrect result if used for a longer period. We first take a baseline measure- fact, there are studies in which a patient receiving ment, E0, give the study drug and then follow placebo as treatment has had a definite increase lung function at predetermined timepoints after in lung function already on the first measurement study drug administration. This provides us with after treatment administration (changes in the an approximation of a response curve E(t), where means – not individual spurious events), so the we use E(0) = E0 (though technically it was use of baseline as a reference when declaring obtained at a timepoint t<0). The two most important measures As the name suggests, a responder is a subject derived from the curve E(t)are who responds to the treatment. The discussion above curve (of the polygonal approximation we implies that this is not necessarily a good way have observed to the response curve) divided to go. However, since asthma is not a stable disease, these must be We can also compute tmax, the time at which taken simultaneously.

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Duplicate publication Magazines and newspapers compete against each other generic geriforte 100mg fast delivery, and therefore consider it quite wrong for an author to offer the same article to more than one publication at a time geriforte 100 mg on line. However, in these markets it is usually considered acceptable to write a similar article for a non-competing market (a newspaper for doctors and a journal for nurses, for instance). To avoid inadvertently biting the hand that you are asking to feed you, it makes sense to tell both editors what you are doing. When it comes to writing for journals, the matter gets rather more complicated. Journal editors feel aggrieved if they publish an article that has appeared elsewhere. Also, since publication is now used as a key performance indicator (see CV), many people feel that it is 38 DUPLICATE PUBLICATION cheating to get two sets of points for one piece of work (see also salami publication). There is a clear solution for writers: under no circumstances should you send the same article to more than one editor at a time, nor should you revamp a published original scientific article and send it to another journal. There is a trickier issue, which is whether authors can write the same – or a similar – scientific article in two different languages. It seems reasonable that someone who has written an interesting article in one language should be allowed to communicate to those who speak (only) another. However, the author should make it absolutely clear what is being done: he or she should refer to the previous paper, thereby putting everything in the open and enabling the editor to make a decision in full view of the facts. This is why many people find it useful to read aloud (preferably to themselves, quietly) what they have written. Easy reading Something we all value, unless we happen to be doing the writing at the time (see effective writing). Editing See books, editing of; copy-editor; editor; macro- editing; micro-editing; subeditor; technical editor. It is a key position, and editors find themselves co-ordinating a web of activities: • ensuring that the publication has enough funds to keep publishing; • gathering and presenting material; 39 THE A–Z OF MEDICAL WRITING • setting deadlines and ensuring that they are met; • making sure that readers receive their copies, and so on. Sometimes, particularly on small publications or newsletters, the same person will be editor and subeditor, but there is a clear difference between the two roles. Find out where the limits of your power will be – to whom will you report and under what circumstances can you be fired? This is particularly important if you are being appointed by a professional (as opposed to a commercial) organization (see editorial freedom, editorial integrity). Find out what they want from you, and be sure to let them know when you achieve it. Publications work if they meet the needs of a definable group of people – the readership. One of the first tasks of the editor is to decide in his or her mind what this group is – and what distinguishes them from other groups. A large part of the job consists of deciding what goes in and where, and you must make these decisions rationally. To do this, you need to have a clear idea of (a) where your publication is going, (b) how you will get there, and (c) how you will know when you do. Make sure all those involved (from owners to readers to contributors) know all this (see mission). Unless you reject contributions, you are working as a clerical assistant, not an editor. Unless you have contribu- tions from others, you are writing a pamphlet, not editing a publi- cation. The key is motivation – enthusing them with your view of the future and helping them to share in the rewards. These could be vulgar financial ones – or something less tangible such as job satisfaction, praise, and a feeling of teamwork. Readers nowadays are unlikely to expect that your publication consists solely of the Truth, but they do have the right to assume that the articles are honestly written, and that they have been chosen on merit and not because money or some other favours have secretly changed hands.

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The strength of synaptic efficacy between parallel fibers and The cerebellum participates in the seamless Purkinje cells may set the force and timing of synthesis of complex cheap geriforte 100mg line, multijoint movements muscle contractions geriforte 100 mg discount. Pure cere- sensorimotor skill in the rat leads to an increase bellar lesions, for example, cause upper ex- in the number of synapses between parallel tremity ataxia that decompose the coordination fibers and Purkinje cells, and these changes last for reaching between the elbow and shoulder. These actions may contribute activity in the contralateral anterior and bilat- more to modifying performance than to learn- eral paramedian cerebellar lobules. The posterior allel arrangements also hold for the cerebellar parietal cortex, a multimodal integrating region projections to the ventrolateral nucleus of the that receives projections from the dentate nu- thalamus. One loop connects M1-pons-dorsal cleus,122 is also more active, perhaps as it dentate nucleus-cerebellar cortex-thalamic processes visual data about the target and pro- ventrolateral nucleus-M1. These loops, like late to postural control and upper extremity ac- those of the basal ganglia, help sort out valid tions, the cerebellum also plays a major role in and invalid cues for initiating and planning locomotion. Damage to its medial structures, movements, which is mostly a dentate nucleus including the fastigium, disturbs standing and and frontal lobe circuit function. The detection and correction of any mismatch Lateral lesions that include the dentate alter between intended and actual movements are voluntary multijoint movements. Balance functions of the interpositus nucleus and spin- deficits vary with the location of the lesion. Postural control is managed Damage to the anterior vermis affects antero- by the fastigial nucleus with its vestibular and posterior sway. The olivocerebellar system lonodular lobe damage causes sway in all di- functions as an oscillatory circuit that can gen- rections and poor tandem walking. Neurons of the fasti- spinal and brain stem motor regions, inform the gial and interpositus nuclei burst primarily cerebellar cortex of the place and rate of move- during the flexor phase of stepping. These fibers put the motor bellum receives inputs from alpha and gamma intention generated by the cerebral cortex into motor neurons and Ia interneurons, as well as the context of the status of the body at the time from segmental dorsal root afferents. An fMRI study, for example, rons project to the cerebellar cortex from the demonstrated independent activation of sepa- contralateral lateral funiculus and burst during rate cerebellar regions during a task of visual locomotion, reflecting activity in spinal central attention and during motor performance. Spinoreticulocerebellar pathways also the hot spot for attention, but a sustained mo- carry bilateral information predominantly from tor task did not. The neocere- tems as it acquires new information and builds bellum monitors the outcome of every move- internal models based on previous experience ment and optimizes movements using pro- for the analysis and smooth control of actions. Given the great compu- A careful neuropsychologic evaluation often re- tational interest the cerebellum has in the de- veals aspects of frontal lobe-like dysfunction in tails of afferent information from joints and patients who have lesions within the cerebel- muscles, rehabilitation therapies for walking lar network. The from the internal and external world as well as sorts of motor functions that the cerebellar in- all processed sensorimotor information from puts and outputs attend to, such as timing and the spinal cord, cerebellum, basal ganglia, and error correction for accuracy as the hand ap- substantia nigra. The thalamic nuclei are not proaches an object, are especially important for passive relays. They almost certainly perform patients to practice when a lesion undermines distributed, parallel processing of sensory in- motor control. All thalamic Cognitive Functions relay nuclei respond to excitatory inputs with The cerebellum is also a node in the distrib- either tonic or burst firing. The burst pattern uted neural circuits that subserve aspects of may play a role in attending to a stimulus. The cerebel- Separate channels are maintained within the lum influences at least a few prefrontal regions somatic sensory and motor thalamus for cuta- via thalamic projections and through the den- neous sensation, for slowly adapting and rap- tate nucleus. Thus, individual channels of the thal- planning, initiation, and execution of move- amocortical projections control separate func- ments, and the verification of willed actions tional units of motor cortex which, in turn, and thoughts. The rostral cingulate, septal nu- independently influence the basal ganglia, clei, hippocampus, and amygdala provide lim- cerebellum, and other subcortical motor nu- bic connections to the cerebellum. This divergence of projections pro- duces convergence of a variety of thalamic in- HAND FUNCTIONS puts to targets. Why would so many thalamic cells with similar receptive fields converge onto Rudimentary synergistic movements such as the same assemblies of cortical neurons? One opening and closing the hand persist after a thought is that information about a cutaneous pyramidectomy, probably through the activity stimulus requires cells only in a single recep- of the descending rubrospinal, vestibulospinal, tive field to respond, but a moving stimulus and reticulospinal systems. When learning a motor ments, especially movements related to feed- skill, coding across a population leads to tem- ing. This thalamic mediated more individuated a movement, the greater the activity-dependent plasticity induces rapid cor- amount of corticomotoneuronal activity needed tical reorganization (see Experimental Case to superimpose control on subcortical centers Studies 1–4).

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This switch from promotion to inhibi- growth purchase geriforte 100 mg otc, synaptogenesis discount geriforte 100 mg visa, and neurotransmis- tion makes some sense in that the physiologic sion. These proteins promote the survival of inhibition by myelin prevents spontaneous ab- mature neurons and axons, participate in normal sprouting of axons late in development. They also act on neuronal, astrocytic, the best studied molecules, but it is worth men- and oligodendroglial precursors to mediate tioning others in the context of potential targets stem cell differentiation and proliferation. Oligodendrocytes produce These growth factors are part of the complex MAG, Nogo-A, and chondroitin sulfate proteo- system of chemical messengers and receptors glycans. Oligodendrocyte precursors produce that tie cells together depending on the con- the proteoglycans phosphacan, neurocan and text of the situation in the milieu. Reactive astrocytes produce ephrins, pro- these extraordinary molecules continues to un- teoglycans including neurocan and NG-2, ker- fold. Microglia produce tenascin, nitric ment and in adult PNS and CNS tissue. The better known mem- 2–6 lists the better characterized growth fac- brane-associated inhibitors in myelin that have tors, their presynaptic and postsynaptic recep- been neutralized by antibodies to allow axonal tors, and some of the locations in which they growth in animal studies include MAG and at have been detected. The signaling pathway for least one of its proteolytic fragments and Nogo, the classic neurotrophins, nerve growth factor also present in several forms. Neuronal Properties Affected by Neurotrophic Factors Proliferation, differentiation and survival of precursors. Synaptic modulation: formation, function, rearrangements; long-term potentiation and depression. For exam- Synaptic activity may help regulate the syn- ple, following a ventral rhizotomy, NGF re- thesis and transport of the neurotrophins and ceptors reappear on motoneurons after having their receptors. The phospho- that neurotrophins given exogenously may aid tyrosine residues, in turn, serve as binding sites neural repair. Clinicians will soon be trying to for signaling proteins in the cytoplasm. When translate the modest successes of researchers these proteins are phosphorylated, a cascade of in using neurotrophic factors to manipulate effectors modify gene expression and protein stem cells into neurons and oligodendrocytes synthesis, making substances such as cy- and regenerate axons through the hostile mi- toskeletal proteins that allow axons to extend. The cytoplasmic effectors also have rapid ac- tions on synaptic transmission and neuronal ex- citability that do not require genes to be turned Neurogenesis on, such as the association of BDNF and LTP in learning, reviewed in Chapter 1. Thus, the New neurons and glia are generated in the adult mammalian brain, including primates. Some, 1990s, techniques that label proliferating cells, such as leukemia inhibitory factor (LIF), up- such as use of the synthetic thymidine analogue regulate another growth factor, in this instance called bromodeoxyuridine (BrdU), with mark- NT-3. Others, such as the family of fibroblast ers for specific cell types such as neurons and growth factors or bone morphogenic proteins oligodendrocytes led to the identification of (BMPs), include from 15 to 20 members. The immunophilins act on one type of FK-binding protein for immuno- Embryonic stem cells (ES cells) derived from suppression and on other types that lead to the inner cell mass of embryos at the blasto- neuroprotective and regenerative actions. The commonly used in people to prevent organ term neural stem cell refers to cells of the nerv- transplant rejection. FK506 acts on neurons af- ous system that divide and self replicate Table 2–6. Localization of a Sample of Growth Factors Growth Factor Receptor PNS Neurons CNS Neurons CLASSIC NEUROTROPHINS Nerve Growth Factor (NGF) trkA, p75 Sympathetic, trigeminal, Cholinergic basal forebrain, dorsal horn nociceptors medial septal, striatum Brain-Derived Neurotrophic trkB, p75 Vestibular, auditory, Cortex, hc, cholinergic basal Factor (BDNF) retinal ganglion, forebrain, cortex, mechanoreceptors striatum, -motoneurons Neurotrophin-3 (NT-3) trkC, p75 Nodose, enteric, trigeminal, Cortex, hc, cholinergic basal auditory, proprioceptors forebrain, striatum; oligodendrocyte Neurotrophin-4/5 (NT-4/5) trk B, p75 Retinal ganglion, sensory -motoneurons CYTOKINES Ciliary Neurotrophic CNTF- Parasympathetic, sensory Cholinergic basal forebrain, Factor (CNTF) hc, and cortical moto- neurons, striatum; oligodendrocyte precursor Leukemia Inhibitory LIF- Cortex, and cortical Factor (LIF) motoneurons; glia FIBROBLAST GROWTH FACTORS FGF-1 (acidic) trk FGF Cortex, brainstem, cord FGF-2 (basic) trk FGF Retinal ganglion Cortex, cholinergic basal forebrain, dopaminergic; stem cell differentiation TRANSFORMING GROWTH FACTOR- (TGF) Glial-Derived Neurotrophic trk RET Sensory and cortical motoneurons; Factor (GDNF) dopaminergic Bone Morphogenic Neuronal, cholinergic cell Proteins (BMP) Neurturin differentiation EPIDERMAL GROWTH FACTORS (EGF) trk EGF Cortex, hc; dopaminergic; stem cell differentiation TGF- trk EGF Schwann cell receptors Dopaminergic; hc Neuroregulins trk Erb Schwann cell; neuro- Glia; synapse muscular junction INSULIN-LIKE GROWTH FACTORS (IGF) IGF-1 trk and Glucose utilization; Cortex, -motoneurons, hc; ATP sympathetic, trigeminal, oligodendrocyte; hc dorsal root; muscle; neurogenesis Schwann cells IGF-2 Glycine Sensory, sympathetic PLATELET-DERIVED GROWTH Stem cell differentiation FACTOR (PDGF) Continued on following page 96 Biologic Adaptations and Neural Repair 97 Table 2–6. Multipotential pro- cursor cells toward a particular neural type genitor cells are a further step along the path such as a dopaminergic neuron has been much of differentiation into cell lines with more re- less reliable, so far, than coaxing dopamine stricted fates. This issue genitor cells such as neuroblasts and glioblasts, is at the heart of the political and ethical de- which differentiate into neurons and glia, bate about the use of embryonic cells in neu- respectively. The difficulty in prede- Stem cells can be isolated in vitro and ex- termining what a potentially mulipotent or panded with epidermal growth factor (EGF), precursor cell may be coaxed to become fuels LIF, and FGF into neurospheres. Proving that the debate about the need to experiment with cells in the bunch-of-grapes-like neurosphere embryonic blastocyst or germinal cells. In vitro, neurospheres can be differenti- isolated and expanded from fetal germ tissue ated by manipulations into the following cell ES cells and maintained for more than a year types: under the influence of neurotrophins (Geron 1. An astrocyte lineage by ciliary neuro- tain markers for GABA and tyrosine hydroxy- trophic factor (CNTF), some of the BMPs, lase for monaminergic activity. The markers in multi- which offers another potential source of potent cells or precursors for neurons, oligo- cells for implantation. Over time, neural stem cells ers, and the type of stem that identifies a rose can change their propensity to encode neuro- as a rose. Until a definitive panel of genetic genesis over gliogenesis and may respond dif- and protein markers is developed, the poten- 98 Neuroscientific Foundations for Rehabilitation tial for ex vivo and in vivo manipulations of precursors.

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