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By O. Hogar. The Sage Colleges.

However cheap rocaltrol 0.25 mcg visa, in addition we were sensitive to the particularities of each service redesign attempt studied discount rocaltrol 0.25mcg line. Here we used onward referral – a snowball research technique – in order to include informed and diverse perspectives appropriate to the situation buy rocaltrol 0.25 mcg cheap. For each service redesign attempt researched buy discount rocaltrol 0.25 mcg line, a set of interviewees was agreed with a senior sponsor of the research collaboration within the CCG. The selection of each sample was guided by the need to include the actors who had played a key role in initiating, shaping and evaluating the course of the service redesign event. This typically meant that clinical leads, programme managers and project managers, as well as some of the clinicians, were involved. In several cases we were also able to include patient representatives who had been involved in the service innovation (e. In recognition of the multilayered nature of health-care reform, it was necessary to look upwards and outwards to the wider context, including area, regional and national policies and institutions which had an impact on the service areas under focal scrutiny. Thus the institutional settings usually had fuzzy boundaries which extended across primary, secondary, administrative, regulatory, professional and educational institutions. Theoretical sampling allows the clarification of the relationships among multiple constructs. We used this approach in order to identify further interviewees in each case, to ensure exposure to data from informants who could add to an accumulative and iterative body of knowledge about relevant issues. The range of informants evolved with the emergent theory. First, we conducted pre-entry documentary analysis drawing on a wide range of sources. Second, we conducted face-to-face semistructured interviews. Although interviews can be a highly efficient and effective research tool, it is recognised that they also present the challenge that bias may arise because of the efforts of image-conscious informants. This challenge was mitigated through the use of multiple interviews among diverse informants who were likely to view the issues and events from different standpoints. Some of the interviews were conducted with both researchers present, other interviews with just one researcher. In the main, interviews were recorded and transcribed. The researchers drew on a semistandard interview schedule comprising semistructured interview questions. These had to be adapted to the varying situations including, for example, the subject of the service redesign under scrutiny and the role and vantage point of the interviewee. The semistructured interview schedule was adapted accordingly. Appendix 4 shows a typical example of one such interview guideline. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 15 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. PROJECT DESIGN AND METHODOLOGY Case study data analysis As mentioned, members of the research team worked in pairs for each main case study. These subteams undertook the first stage of each data analysis process. In this way a coherent narrative of the flow of events within each case could be constructed. This was combined with a descriptive account of the issues and challenges encountered by the actors involved. These first-level reports used a common framework: (1) context, (2) focus and narrative of the case, (3) clinical leadership themes emerging and (4) emerging ideas for cross-case comparisons. The first three sections of these initial draft reports were fed back to informants in the case studies concerned, as a way of validating the accuracy of the data collected and the descriptive interpretations made. Next, the first-level case reports were discussed, in turn, at a monthly series of research team meetings.

J Psychol 1987;121: nificantly more research is needed to diminish the gap in 533–538 discount rocaltrol 0.25 mcg with mastercard. Psychopathol- ogy in pathological gamblers seeking treatment order 0.25 mcg rocaltrol free shipping. J Gambling Stud illnesses and to optimize treatment strategies for the large 1996;12:67–81 cheap rocaltrol 0.25 mcg line. Compulsive behaviors and obsessive-compulsive disorder (OCD): lack of a relationship between OCD buy rocaltrol 0.25mcg fast delivery, eating disorders, and gambling. Hollander has received research support and/or served spectrum disorders. American Psychiatric Association Committee on Nomenclature 1990;85:1389–1394. Diagnostic and statistical manual of mental disor- 23. Washington, DC: American Psychiatric Associa- E, ed. Gambling and spirituality: a new anthropological 24. Cunningham-Williams RM, Cottler LB, Compton WM 3rd, both sexes, who had sacrificed their health, wealth, and honor at et al. Taking chances: problem gamblers and mental health the gaming tables. Legalization of crimes disorders—results from the St. Louis Epidemiologic Catchment against the moral order: results from the 1995 United States Area Study. Pathological R impulse control disorders not elsewhere classified: clinical gambling among methadone patients. Drug Alcohol Depend characteristics and relationship to other psychiatric disorders. Treatment of obsessive-compulsive spectrum dis- ments or counter-attractions? Body dysmorphic disorder, pathologi- erans for pathologial gambling. Gambling, alcohol, and other drugs: preva- 56[Suppl 4]:7–12; discussion, 13. Relationship between impulsivity and compulsivity: adult population, 1994. Washington, DC: American Psy- erans for pathological gambling. Neuropsychological assessment of atten- 1738 Neuropsychopharmacology: The Fifth Generation of Progress tion problems in pathological gamblers. Gradients of mono- personality and pathological gambling. J Gambling Behav 1989; amine metabolites and cortisol in cerebrospinal fluid of psychiat- 5:137–152. Tapping time influences con- and pathological gambling. Functional magnetic tiates impulsive from non impulsive violent behavior. Life Sci resonance imaging of human brain activation during cue- 1983;33:2609–2614. Relationship patients with affective and personality disorders: correlates with between subjective effects of cocaine and dopamine transporter suicidal and impulsive aggressive behavior. Trends Pharmacol Sci 1992;13: changes in Pachinko players: beta-endorphin, catecholamines, 177–184. Psychiatry Res (mCPP) interactions with neurotransmitter receptors in the 1981;4:21–29.

An ultrasound beam is reflected back by the moving bloodstream at a different frequency than it was transmitted (Doppler shift) order rocaltrol 0.25mcg on-line, and from the Doppler equation discount rocaltrol 0.25mcg mastercard, the velocity of blood flow (FV) can be calculated buy generic rocaltrol 0.25mcg online. Changes in FV correlate well with changes in CBF rocaltrol 0.25 mcg without prescription, as long as the orientation of the transducer and the vessel diameter remain constant. It is used clinically to diagnose vasospasm, to test cerebral autoregulation, and to detect emboli during cardiac surgery and carotid endarterectomy (Moppett 2004). From the FV waveform systolic, diastolic, and mean velocities can be calculated. The mean FV in the middle cerebral artery (MCA) is usually 35-90 cm/s and correlates well with CBF. The FV can be influenced by age, being lowest at birth (24 cm/s), highest at age 4-6 years (100 cm/s), and then declining until the seventh decade of life (40 cm/s). FV is also 3-5% higher in females and increases in hemodilutional states. Technique for Insonating the Middle Cerebral Artery (MCA): The M1 branch of the MCA is the commonest vessel to be insonated, and is visualized through a transtemporal window with a 2 MHz pulsed Doppler signal. The anterior and posterior cerebral arteries can also be accessed through this window, whilst a transorbital approach allows access to the carotid siphon and the suboccipital route to the basilar and vertebral arteries. This reflects distal cerebrovascular resistance and correlates with CPP. Uses of TCD in Intensive Care Head Injury: Three distinct phases have been shown in severe head injury with regard to CBF and MCA FV. The use of TCD allows interpretation of the dynamic physiological changes seen in severe head injury, and in combination with other modalities allows perfusion and oxygenation to be optimized for the individual patient. The highest MCA FV recorded at any stage is an independent predictor of outcome from head injury, and the loss of autoregulation (calculated by regression of CPP on MCA FV) has also been shown to be a predictor of poor outcome from head injury. Subarachnoid Hemorrhage: Vasospasm occurs in approximately 50% of people with subarachnoid hemorrhage between 2-17 days post-event, and is associated with significant morbidity and mortality. TCD may be used to detect vasospasm by the increase in MCA FV associated with vessel narrowing. Spasm is also assumed to be occurring when blood velocity is Neurocritical Monitoring | 73 >120 cm/s. High MCA FV is associated with worse-grade SAH, larger blood loads on CT (assessed by Fisher Grade) and hence worse outcome (Steiger 1994). Near Infrared Spectroscopy While the criticism of jugular venous oximetry is that it is representative of global oxygen delivery, near infrared spectroscopy (NIRS) is a noninvasive technique that measures regional cerebral oxygenation. Light in the near infrared wavelength (700-1,000 nm) can pass through bone, skin, and other tissues with minimal absorption, but is partly scattered and partly absorbed by brain tissue. The amount of light absorbed is proportional to the concentration of chromophobes (iron in hemoglobin, and copper in cytochromes), and measurement of absorption at a number of wavelengths provides an estimate of oxygenation (Owen-Reece 1999). The probes illuminate a volume of about 8-10 ml of tissue and are ideally suited for use in neonates because of their thin skull, but have been used with success in adults. Advantages of this technique are that it is non-invasive, and provides a regional indicator of cerebral oxygenation. Its major limitation is its inability to distinguish between intra- and extra- cranial changes in blood flow. Electrophysiological Monitoring An electroencephalogram (EEG) is obtained using the standardized system of electrode placement. Practically, this is not often readily available and requires expert interpretation. The EEG is affected by anesthetic agents and physiological abnormalities such as hypoxia, hypoperfusion and hypercarbia. A number of methods have been developed to simplify and summarize the EEG data: – Cerebral Function Monitor (CFM): This is a modified device from a conventional EEG. It uses a single biparietal or 74 | Critical Care in Neurology bitemporal lead, and is processed to give an overall representation of average cortical activity. The bispectral index (BIS) is a dimensionless number statistically derived from these phased and power frequencies and ranges from 0 to 100 (100-awake, 60-unconscious, 0- isoelectric EEG). This technology was derived with normal subjects and is not readily transferable to the injured brain, but may have a use in guiding sedation and analgesia. Spectral Edge Frequency: Compressed Spectral Array: Raw EEG data is processed into a number of sine waves (Fourier analysis).

Point mutation analysis combined with appropriate phar- The availability of cDNAs encoding specific GPCRs and the macologic assays can be used to identify such divergent re- development of various cellular expression systems provide ceptor residues that are critical for drug binding cheap 0.25mcg rocaltrol visa, thus pro- powerful tools for examining the specificity of ligand bind- viding insight into the structural basis of ligand binding ing to receptors cheap rocaltrol 0.25 mcg without a prescription. In particular purchase rocaltrol 0.25 mcg amex, site-directed mutagenesis can specificity that is useful for drug design buy 0.25 mcg rocaltrol with visa. Many techniques have been For the very reason that nonconserved residues are often developed for introducing specific mutations into the recep- not essential for basic receptor function, these residues are tor cDNA, as discussed in detail elsewhere (27). Thus the pharmacology examples of the use of these techniques for understanding of many subtype-specific drugs can be highly dependent on the structural basis of ligand binding and receptor activation the species of animal studied. How- ever, the pharmacology with which subtype-selective drugs Point Mutagenesis bind to receptor subtypes encoded by mouse or rat receptor Point mutations refer to modifications of the cDNA that genes can differ substantially from the pharmacology char- result in the substitution of a single amino acid residue in acteristic of the corresponding human receptor (30). This 280 Neuropsychopharmacology: The Fifth Generation of Progress has led to considerable confusion in the correspondence mutagenesis, therefore, has the potential to reveal unantici- between pharmacologic and molecular biological defini- pated features of receptor structure and function. Random tions of specific receptor subtypes across species, and has mutagenesis typically requires functional assay of a much important implications for the use of animal models for the larger number of mutant receptors than analyzed using site- development of subtype-specific drugs for humans. The relatively low throughput inherent more, nonconserved residues involved in subtype-specific to traditional methods of receptor characterization have lim- drug binding can also differ within the human population, ited the practical utility of random mutagenesis of mamma- as a result of random mutation and genetic drift. This limitation has become less significant cept has not yet been extensively explored but may be an with the recent development of higher throughput func- important direction for the use of pharmacogenomics in tional assays and the successful expression of mammalian clinical medicine. For exam- ple, the budding yeast Saccharomyces cerevisiae has been used recently for studying the functional properties of a large Deletion Mutagenesis number of mutant chemokine receptors in which selected Another mutational approach useful for probing receptor regions of the receptor protein were mutagenized in a non- structure and function is removal of certain residues from biased manner. Analysis of these data identified residues in the receptor structure entirely. Deletions of multiple resi- the receptor protein essential for ligand binding and activa- dues in certain parts of the receptor protein (e. In addition, this nonbiased screening approach yielded brane helices) can be difficult to interpret because they often unanticipated information, including the identification of lead to massive disruption of receptor structure. However, mutations that constitutively activate receptors and the deletion of limited regions in extracellular or cytoplasmic identification of functional mutant receptors predicted to domains are often well tolerated and have been quite in- contain fewer than seven transmembrane domains (31). For example, deletion of residues located in the amino-terminal extracellular domain of polypeptide recep- Use of Biophysical Approaches tors [such as the follicle-stimulating hormone (FSH) recep- tor] and the calcium receptor implicate this domain in li- Biophysical techniques are essential for detailed examina- gand interaction. Deletion of residues located in the third tion of protein structure and conformational change. One cytoplasmic loop of various receptors, such as the musca- reason these methodologies have had limited application in rinic acetylcholine receptors, implicated this domain in the study of GPCRs is that they typically require milligram functional coupling to heterotrimeric G proteins (27). For many years rhodopsin, purified from retina, was the only GPCR that could be generated Substitution or Chimeric Mutagenesis in sufficient quantity for biophysical study. Indeed, much of A very powerful approach to site-directed mutagenesis is to what we know about GPCR structure and conformational substitute entire series of residues from one receptor with change has been elucidated from elegant biophysical studies the corresponding residues of another. Recently, the development of improved based on the idea that receptors are composed of modular expression and purification strategies have made it possible structural domains, and takes advantage of the fact that to obtain other GPCRs in sufficient quantity and purity receptor domains that mediate similar functions often have for biophysical study. Thus it is likely that biophysical ap- conserved amino acid sequence. Chimeric substitutions are proaches will play an increasingly important role in future often less disruptive than deletions to the overall structure studies of GPCR structure and activation. For example, chimeric mutagenesis has been useful for defining transmembrane residues that Structural Studies of Rhodopsin mediate subtype-specific and species-specific differences in ligand binding to adrenergic receptors. Receptor chimeras High-resolution structural information can be provided by between 2- and 2-adrenergic receptors defined multiple x-ray diffraction methodologies applied to ordered three- cytoplasmic domains that contribute to the specificity of dimensional crystals of pure protein. Rhodopsin, a GPCR receptor interaction with their cognate heterotrimeric G mediating phototransduction in the retina, has been a favor- proteins (4). Previous stud- ies using electron diffraction of two-dimensional crystals of Use of Random Mutagenesis rhodopsin obtained structural information to a resolution of In contrast to site-directed mutagenesis, random mutagene- approximately 7. Recently x-ray diffraction has 22: G-Protein–Coupled Receptors 281 been used to solve the structure of three dimensional crystals chemical probe. Approaches of this type have been applied of rhodopsin to a resolution of 2. This accomplishment˚ to several GPCRs, and have begun to yield interesting new is truly a major milestone in the field, revealing for the information about the dynamic effects of clinically relevant first time the atomic structure of any GPCR and providing drugs on GPCR structure (29).

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