By O. Yussuf. Washington & Jefferson College.

These docking proteins bind to the receptor phos- activates a GDP-GTP exchange factor effective 50mg penegra, such as SOS buy generic penegra 50 mg on-line, which discount 100 mg penegra with mastercard, phorylation sites by SH2 domains (PLC- ) or PTB domains (IRS and Shc). The three pathways shown here are as follows: (1) The PLC- in turn, activates Ras through GTP binding. This initiates (2) PI-3-Kinase (PI-3-K), comprising an 85-kd regulatory subunit and a 100-kd catalytic subunit, generally becomes activated by a cascade in which Raf activates MEK (from MAPK or ERK binding to an insulin receptor substrate (IRS)–like adaptor pro- kinase), and then MEK phosphorylates and activates ERKs tein, which interacts with the receptor and then activates signal- (26). ERKs, also known as mitogen-activated protein kinase ing proteins. IRS proteins also bind other signaling molecules such as Fyn and Syp. The PI-3-K then activates AKT and p70 S6-kinase (MAPKs), are abundant, multifunctional, intracellular ki- (p70 S6K). AKT has an antiapoptotic effect through actions on nases with many different cellular activities. Activated Rasthen turnson thecascade of hydroxylase, transcription factors, regulators of protein kinases including Raf, MEK, and erks (also known as MAP kinases). Each of these pathways In cells in vitro, ERKs have been shown to mediate neuron then exerts a number of nuclear and nonnuclear actions with short- and long-term consequences for the cells. ERKs have been shown to be important in hippo- campal long-term potentiation in brain slices (31). Some phosphorylated receptor, they become activated. The mech- effects of ERK activation are very rapid, whereas others are anisms by which they are activated are not entirely clear. Often they, too, become phosphorylated on tyrosine resi- dues. In addition, their recruitment to the membrane or into signaling complexes plays a role in the initiation of their PLC- CASCADE activity (22,23). Activation of each of these NT-signaling proteins triggers distinct downstream cascades of target en- A second NT-signaling pathway involves PLC- activation zymes and other biological effects. Like the better-understood PLC- , PLC- cleaves diversity of neurotrophic factor receptors, they seem to trig- phosphatidylinositol phosphates into diacylglycerol and ger only a few well-conserved types of downstream signaling inositol phosphates. Among the best characterized of the pathways nase C (PKC), whereas inositol-1,4,5-tris phosphate releases include the Ras/extracellular signal regulated kinase (ERK) intracellular stores of calcium. Intracellular calcium can pathway, the phosphotidylinositol-3′-OH-kinase (PI-3-K) exert numerous effects from the activation of Ca2 /calmo- 210 Neuropsychopharmacology: The Fifth Generation of Progress dulin–dependent protein kinases to the production of cyclic INTERACTION OF NEUROTROPHIN adenosine monophosphate through some adenylyl cyclases. SIGNALING CASCADES All these are known to have powerful effects on neurons. Unlike PLC- , which is regulated by heterotrimeric G-pro- Numerous levels of complexity have been found in the tein–coupled receptors, PLC- is regulated by tyrosine downstream signaling pathways of the NT receptors. PLC- contains SH-2 and SH-3 do- K has been shown to contribute to ERK activation by Ras- mains. When bound to tyrosine phosphorylated receptors, dependent and Ras-independent process pathways (36,38, it is recruited to the membrane and becomes phosphory- 42). Ras can contribute to activation of AKT, and both lated, which activates its PLC activity. Virtually nothing is SHC and IRS can bind to the same phosphorylated tyrosine known about the role of PLC- in the intact brain, although site, although with differing affinities (43). PLC- can acti- it is likely to exert important effects on neuronal function. PI-3-K CASCADE In addition, most of these proteins exist in multiple isoforms arising either from different genes or differential splicing of Somewhat less well understood is the PI-3-K pathway the same gene. These isoforms are differentially expressed (35–37). The complement of They are heterodimers of a catalytic subunit and a regula- signaling proteins and adaptors would be expected to deter- tory subunit. The subunit contains SH-2 and SH-3 mine the effects of the NT on particular populations of domains. When bound to phosphorylated tyrosines, the neurons. Regulation of these proteins may influence plastic- subunit activates the catalytic activity of the subunit. Furthermore, this complex- phosphorylates phosphatidylinositol on the 3′-hydroxl ity of expression and cross-talk allows tremendous opportu- group (distinct from the 4′,5′ phosphorylated forms men- nity for potential sites of therapeutic intervention. Furthermore, PI-3-K has been shown to pos- sess protein kinase activity and can bind Ras (38). The PI-3-K lipid product, phosphotidylinositol-3′-phosphate, REGULATION OF NEUROTROPHIN activates at least two protein kinases, AKT and S6-kinase.

It may manifest as discomfort penegra 50 mg line, pulling at intravenous and bladder catheters generic 50 mg penegra overnight delivery, tracheal and nasogastric tubes discount 50mg penegra with visa, shouting, aggressive behavior, extreme restlessness, and confusion (Schnakers 2007). Pain is particularly common and often unrecognized because of General Neurological Treatment Strategies | 91 confusion and the difficulties with communication in the aphonic, aphasic or paralyzed patient. Clinical assessment may direct attention through finding of profuse sweating, sustained tachycardia and blood pressure fluctuations, and dilated pupils. Most patients will require sedation but there is a natural reluctance to sedate patients with an evolving CNS disorder (McMillian 2011). The first line of management is to reassure and calm the patient, ensuring a quiet environment and normal diurnal cycle. Next, there should be careful nursing and treatment of the underlying causes, including positioning, splinting, bed cages, catheterization, and physical treatments. In spite of reluctance to sedate patients with an evolving CNS disorder, sedative medications are mandatory and must be used, when indicated, to reduce pain, distress, and anxiety. Also they may be used to help patient toleration of tracheal tubes, IPPV, tracheal suction, and physiotherapy. Patients with neurologically-induced respiratory failure often require prolonged periods of mechanical ventilation in the NICU, and it is not desirable to keep such patients continuously sedated throughout their stay (Jacobi 2002). Furthermore, assessment of their condition and subsequent weaning is impossible when sedated. However, during periods of cardiorespiratory instability, raised ICP, and in cases of intubation, sedation may be essential. In the ICU environment, however, medications are often needed to calm patients. As many as 30 different medications are used, and the agents most frequently used are midazolam, olanzapine, propofol, lorazepam and opioid analgesics (Jacobi 2002). Bedside approach to the agitated patient Assess and manage immediate threat to life (airway, breathing, circulation and temperature). Assess pain by querying the patient about pain, and assess for noxious stimuli after measurement of pain score. Correct any identified causes, and if the patient is hemodynamically unstable, give fentanyl 25-100 µgm IV q5-15 minutes until 92 | Critical Care in Neurology desired effect is achieved, or hydromorphone 0. When patients have been on sedative and analgesic drug infusions for longer than 24 hours and begin to recover, daily interruptions of drug infusions for a time period sufficient to allow awakening is recommended (Blanchard 2002). Role of Rehabilitation Rehabilitation is a reiterative active, educational, problem- solving process, focused on the patient disability. The operational characteristics of rehabilitation services comprise a multidisciplinary group of people who work together towards common goals for each patient, involve and educate the patient and family in the process, have relevant expertise and experience (knowledge and skills) and can, between them, resolve most of the common problems faced by patients (Arnow 1993). The stages of rehabilitation involve general assessment to identify the nature and extent of the patient problems and the factors relevant to their solution, goal setting, then intervention, which may include treatments that affect the process of change and support (care), which maintain life and safety, and finally evaluation to check on the effects of the intervention. The aims of rehabilitation are to maximize the participation of the patient in his/her social setting, minimize the pain and distress experienced by the patient and family and/or carers (Collen 1990). The development of models for disability has fostered and clarified discussion about the nature of rehabilitation. Definition of rehabilitation refers to the operational characteristics of a rehabilitation service (structure), how rehabilitation service works (process) and the aims of rehabilitation services (outcome). Three specific core skills are particularly associated with rehabilitation: General Neurological Treatment Strategies | 93 1. An ability to set realistic but challenging goals in both the short and long term, a skill that depends upon an accurate evaluation of the likely prognosis and scope for effective intervention. An ability to participate in teamwork, working co-operatively with a group of other experts towards agreed common goals (Cunningham 2000). However, recent research, mostly related to stroke, does support various hypotheses. First, there is now evidence that even quite small levels of intervention can have powerful and specific effects. There is also some evidence of a dose response relationship between therapeutic input and outcome. Third, patients should be encouraged to seek review of medication at regular intervals, perhaps every 6 months, especially for drugs that have cognitive side effects and either slow or hinder the process of recovery. Use drugs to treat specific impairments like gabapentin to improve visual acuity when nystagmus is present, and a dopamine agonist (such as bromocriptine) to ameliorate the reduced initiation after frontal lobe damage. Acute-onset disability is often considered the easiest to manage, because recovery occurs and may be complete (Wade 2000). Diagnostic Findings in Cerebral Death Brain death is the irreversible cessation of cerebral functions. Cerebral death, which is of medico-legal importance, cannot be accurately assessed on the basis of a criterion related to a single functional system. It is basically characterized by the absence of three main brain functions: 94 | Critical Care in Neurology (1) Cerebral activity known as “cerebral responsivity” (2) Vital functions (3) Cephalic reflexes Cephalic reflexes are mediated by the cranial nerves, and are considered as important indicators of the integrity of the brainstem, as absence of the cephalic reflexes are essential for considering the diagnosis of brain death, yet they differ in importance as a criterion of death.

The critical comparison purchase penegra 50 mg fast delivery, CS unpaired versus to regions that mediate fight-or-flight responses and away CS cheap penegra 50 mg otc, revealed activation in anterior cingulate order 100mg penegra with mastercard, bilateral in- from widespread heteromodal cortical areas, as a neural sub- sular, parietal, supplementary motor, and premotor cortex. A time by event type interaction revealed that fMRI signal in amygdala decreased over time in the CS unpaired condition Structural Imaging Findings relative to the CS condition. These researchers also found conditioning- Bremner and colleagues (21) found that right hippocampal related hippocampal activation that declined over time. In addition, the PTSD group exhibited poorer performance on a standard measure of ver- Summary bal memory, and their percent retention scores on this test Taken together, functional imaging studies in healthy were directly correlated with right hippocampal volume human subjects extend findings from animal research. Gurvits and colleagues (58) used mMRI activity in limbic and paralimbic regions, whereas other ter- to study seven Vietnam combat veterans with PTSD, seven ritories of heteromodal association cortex exhibit decreased Vietnam combat veterans without PTSD, and eight nonvet- activity. However, similar patterns of limbic and paralimbic erans without PTSD. These investigators found signifi- activation may be observed in association with other emo- cantly smaller hippocampal volumes bilaterally for the tional states, and hence this general profile should not be PTSD group in comparison with both control groups. Exposures to unpleasant, Across the 14 veterans, hippocampal volume was inversely arousing, or threat-related stimuli often produce detectable correlated with extent of combat exposure and PTSD symp- amygdala responses, which can be associated with enhanced tom severity. Habi- been reported in mMRI studies of PTSD resulting from tuation can be observed in widely distributed brain regions, childhood abuse. Bremner and colleagues (22) found 12% Chapter 65: Structural and Functional Imaging of Anxiety and Stress Disorders 957 smaller left hippocampal volumes in 17 adult survivors of age and dendritic atrophy in the CA3 region (117). More- childhood abuse with PTSD than in 21nonabused compar- over, chronic stress during development is capable of inhib- ison subjects. Stein and colleagues (134) found 5% smaller iting normal cellular proliferation within the hippocampus, left hippocampal volumes in 21adult survivors of childhood a process mediated by glucocorticoids and glutamatergic sexual abuse (most of whom had PTSD) than in 21non- transmission by an N-methyl-D-aspartate receptor–depen- abused comparison subjects. Furthermore, total hippocam- dent excitatory pathway (57). However, the PTSD cortisol levels and decreased hippocampal volumes have also group had smaller intracranial and cerebral volumes than been found in patients with major depressive disorder (25). The hippocampus is also involved in the modulation of the Taken together, the results of structural neuroimaging hypothalamic-pituitary-adrenal (HPA) axis, and lesions to studies of adult samples suggest that PTSD is associated hippocampus appear to increase the release of glucocorti- with reduced hippocampal volume, which, in turn, may coids during stress (43,60); this, in turn, may further dam- be associated with cognitive deficits and PTSD symptom age the hippocampus (116). Although the extent of traumatic exposure may be Although these findings may have great relevance to anxi- correlated with hippocampal volume, it appears that differ- ety and stress disorders, the picture is complicated by the ences between PTSD and control groups cannot be ex- finding that cortisol levels are characteristically reduced, plained by traumatic exposure alone (58). Stress, Glucocorticoids, and the Functional Imaging Findings Hippocampus Semple and colleagues used PET to study six patients with In this review about neuroimaging of anxiety and stress combat-related PTSD and comorbid substance abuse versus disorders, it is worth elaborating on the potential relation- seven normal control subjects (125). For example, with the control group, the PTSD group exhibited greater sustained, fatal social stress in vervet monkeys was associated rCBF during both task conditions within orbitofrontal with degeneration of neurons in the CA3 region of the cortex. In the pro- mersion stress in rats was related to structural damage to voked versus control condition, patients exhibited increased hippocampus (CA3 and CA2 fields) and deceased local CBF rCBF within anterior cingulate cortex, right orbitofrontal, in hippocampus (42). Interpreta- coids is associated with hippocampal damage in both rats tions of this initial study, with regard to the pathophysiology and primates. Using a similar paradigm and a comparison group, Shin Woolley and colleagues found that daily corticosterone in- and colleagues studied eight women with childhood sexual jections decreased dendritic branching and length in the abuse–related PTSD and eight matched trauma-exposed CA3 region of the rat hippocampus (145). However, a group-by-condition inter- implanted in hippocampus) was related to neuronal shrink- action revealed that the control group manifested a 958 Neuropsychopharmacology: The Fifth Generation of Progress significantly greater rCBF increase within anterior cingulate These results suggest that PTSD may be characterized by cortex than did the PTSD group, whereas the PTSD group amygdala hyperresponsivity to general threat-related stim- showed significantly greater rCBF increases within anterior uli, consistent with our neurocircuitry model of PTSD. Bremner and colleagues (20) also used script-driven imagery and PET to study rCBF in ten female survivors of childhood sexual abuse with Imaging Studies of Neurochemistry PTSD and 12 without PTSD. Consistent with the findings Schuff and colleagues used mMRI and MRS to study seven of Shin et al. Although these investigators found a nonsignificantly in the PTSD group. Liberzon and col- PTSD and 11 healthy comparison subjects without histories leagues (76) used SPECT to study rCBF in 14 Vietnam of maltreatment (37). The PTSD group had lower NAA/ veterans with PTSD, 11 veteran control subjects, and 14 creatine ratios in pregenual anterior cingulate gyrus. In separate scanning sessions, subjects result is consistent with those of symptom provocation PET listened to combat sounds and white noise. In the combat studies (20,23,129), which have reported failure to activate sounds versus white noise comparison, all three groups anterior cingulate in PTSD. Yohimbine administration was associated with increased anxiety and panic symptoms , as well as wide- spread decreases in cerebral glucose metabolism in the Summary PTSD group. Taken together, data from neuroimaging studies are consis- Shin and colleagues studied seven patients with combat- tent with the current neurocircuitry model of PTSD that related PTSD and seven matched trauma-exposed control emphasizes the functional relationship among the amygdala, subjects without PTSD in the context of a PET cognitive hippocampus, and medial prefrontal cortex. Subjects were required to make volumes and NAA levels appear to be decreased in persons judgments about pictures from three categories: neutral, with PTSD. These findings dovetail with animal research general negative, and combat-related.

How- two coding sequences must be placed in frame with each ever discount penegra 100 mg without a prescription, the use of adenovirus vectors continues to be restricted other buy discount penegra 100 mg on line. However order penegra 50mg amex, the added benefit of being able to track by the robust host immune response that they elicit (21, the subcellular location of the transgene product makes this 22). Foreign TRANSFER INTO NEURONS genes are cloned into easy-to-manipulate amplicon vectors that can be packaged directly into viral particles as head- Despite the problems that remain with the HSV-1 vector, to-tail repeats in the presence of the helper virus, with no it is a gene delivery system that has come of age. In addition, intermediate recombination step required. This enables numerous alternative and increasingly user-friendly means rapid construction of a large number of recombinant vectors of gene transfer into the brain are now available (Table simultaneously, and is particularly useful for those who are 20. Adenovirus vectors, like HSV-1 vectors, infect post- doing mutation analysis, and who wish to work with multi- mitotic cells and can enter a broad range of mammalian ple genes. Such ease of cloning is not possible with the cell types. They have the additional advantages that they genomic HSV and adenovirus vectors. Direct in vivo transfer of genes into the brain has been achieved using not only herpes virus and adenovirus vectors, but also adeno-associated virus vectors (see refs. COMPARISON OF VIRUSES USED TO review) and lentivirus vectors (see ref. In MANIPULATE GENE EXPRESSION IN THE BRAIN contrast to other viral vectors, adeno-associated virus vectors Advantages Disadvantages do not cause an immune response or toxicity. Interestingly, the ability of adeno-associated virus vectors to transduce Herpesvirus vectors and express transgenes is not equivalent in all regions of the Broad host and cell type range Occasional cytotoxicity brain (26,27). Only in some regions will neurons bind and Episomal (no possibility of Lack of persistence of insertional activation of host expression internalize the virus, with resultant long-term expression. Long-term expression of -galac- of foreign DNA tosidase and GFP was observed in rat neurons for at least High level of expression of 9 months following intracerebral injection of the vectors, foreign genes within hours Can be concentrated to high titers with no sign of tissue pathology or immune response (28, Helper virus–free stocks possible 29). Progress has been made in achieving biosafety with Adenovirus vectors these vectors, by eliminating viral sequences nonessential Broad mammalian host and Elicits host immune for transduction. To date, the delivery of recombi- cell type range 4. One of the most success- Lentivirus vectors ful uses of this strategy has been in the field of addiction Integrates into host chromosome Can accommodate only research. Exposure to drugs of abuse causes many changes 6–8 kb of foreign DNA in gene expression within the brain. A major challenge in Expression is persistent Low titers addiction research is to determine which of these changes Potent human pathogen have a direct influence on behavior. In the case of addiction, it is thus trols their function. High expression of GluR1 favors the possible to mimic certain aspects of the drug-exposed state formation of Ca2 -permeable (GluR1-homomeric) AMPA without ever administering the drugs themselves. Examples of this subunit contains a motif that blocks Ca2 conductance behavioral changes in addiction that may result from drug- (38). Because repeated drug exposure is known to selectively induced alterations in biology (gene expression) are compul- increase the electrophysiologic responsiveness of VTA dopa- sive drug use (drug-taking) and craving (drug-seeking). However, this question is difficult to ad- Addiction Circuitry dress using traditional methods. For example, AMPA ago- nists and antagonists cannot be used to study the relation- Much research on the neuronal circuitry involved in drug ship between GluR1 expression and sensitized drug addiction has focused on the mesolimbic dopamine (DA) responses because they affect AMPA receptor function gen- system. However, the neural It was first necessary to determine if viral-mediated eleva- events that mediate the acute rewarding effects of abused tions in GluR1 expression within the VTA would increase drugs are not understood, nor are the neuroadaptations that sensitivity to the locomotor-stimulating effects of morphine, presumably underlie the transition from occasional drug use a hallmark of behavioral sensitization (36,42). Furthermore, increased activity in rats given HSV- enon that may contribute to the addiction process (36). GluR1 was seen only in response to morphine, and was This altered sensitivity is presumably a consequence of al- not evident after saline. The transient nature of the HSV- tered gene expression, and the VTA-NAc circuitry is a logi- mediated elevations in transgene expression allowed the be- cal starting point for biobehavioral studies. Because several havioral adaptations to be correlated with the time course robust and reliable drug-induced neuroadaptations have of GluR1 expression: when morphine was given only on been discovered within this circuitry (37), it has been the days 7 and 8 after microinjection—when elevations in focus of gene transfer studies in which the behavioral signifi- GluR1 expression had dissipated—the rats that were given cance of altered gene expression has been assessed. To date, HSV-GluR1 were no longer more sensitive to the stimulant the biobehavioral significance of three specific, drug-in- effects of morphine. When some rats given HSV-GluR1 duced changes in gene expression have been studied using were tested with morphine on days 3 to 4 and on days 7 viral-mediated gene transfer—the ability of drugs (cocaine, to 8, significant increases in sensitivity to the locomotor- morphine) (a) to increase expression of the AMPA (gluta- stimulating effects of the persisted in rats given HSV- mate) receptor subunit GluR1 in VTA, (b) to alter expres- GluR1, despite the fact that GluR1 labeling in the VTA sion of GluRs in the NAc, and (c) to increase the activity had dissipated. Thus when morphine is given while GluR1 of the transcription factor CREB (cAMP response element expression in the VTA is elevated, increased sensitivity to binding protein) in the NAc. These data suggest that altered expression of GluR1 in the VTA underlies, at least in part, the development and GluRs in the VTA expression of sensitized behavioral responses to morphine.