Arthritis Australia

By Z. Gancka. University of Oklahoma. 2018.

There are no licence costs for the use of PCAM and the developers are committed to PCAM being freely available to use purchase warfarin 1 mg on line. In order to do this: l nurses were asked to provide anonymous case studies l evidence was presented for each of the LTCs under consideration l nurses were ask to share and reflect on the evidence and their case study patients 2mg warfarin fast delivery. Each case was discussed in terms of suitability and application of the PCAM tool l nurses were provided with some examples as to how the PCAM tool items may be introduced and discussed, and then invited to role play l each nurse was encouraged to practise the PCAM tool with around 10 patients. For the sake of the study, these did not always have to be LTC patients. In order to build experience and confidence, it was suggested that they begin with just a few domains. They should reflect on each experience and discuss with colleagues as required l a researcher was attached to the practice and provided support in one additional face-to-face session, online and by telephone. In addition, the nursing team were provided with: l hard copies of the presentation slides l a copy of Making it Easy, A Health Literacy Plan for Scotland64 l a copy of Good Mental Health For All. However, after the first session, it became apparent that nurses: l would be unlikely to be able to dedicate a full unbroken half-day l may benefit from focusing the evidence further upon their own experience. 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 95 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. APPENDIX 3 l may benefit from time to reflect on the evidence and the PCAM tool introduction, and some distance in time before trying to integrate it into their practice. In order to respond to this, the training was adapted over the course of the study: l advance creation and sending of three case studies each l 2. A list of local, regional or national groups/organisations/information sources for use by PNs as potential signposting/referral opportunities for patients with LTCs taking part in the PCAM study (intervention only). Design principles l Reference was to be made to ALISS, which is a search and collaboration resource tool for health and well-being resources in Scotland. It is used to collect, organise and share links to community support. ALISS is funded by the Scottish Government and is delivered by the ALLIANCE. Wherever possible, relevant leaflets were available. Design stages Preparation of the PCAM resource packs began following the randomisation of GP practices. Resource packs were prepared for only the three practices randomised to the intervention arm of the feasibility trial. Following randomisation, two researchers were allocated the relevant GP practice locations for initial preparation of the resource packs. Stage 1: internet search An internet search was structured and conducted using key search terms: l condition-specific descriptions (CHD, DM, COPD, LTCs) l PCAM domain headings (e. A range of search engines and directories were identified: l ALISS l NHS national and local search engines (e. Aberdeen City Council Community Contacts and Neighbourhoods directory) l third-sector community directories (e. Infobase, Glasgow Council for the Voluntary Sector) l other relevant websites. 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 97 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. Most frequently, researchers verified information by either contacting organisations by telephone/e-mail or speaking to staff with knowledge of local services in the relevant GP practice. These staff helped the researcher to check and supplement the resource pack contents for that area. Stage 3: draft preparation of resource pack Draft PCAM resource packs were prepared using the information gathered from the primary search results. Information was organised in discrete sections, structured using the six principal PCAM domains: 1. Within each section, information comprised national resources (e. Information about each resource comprised: l name of resource (e. Each section was printed on plain white paper and placed together in a clip file with a front index for ease of use. To make the pack usable for nurses, the lists of resources were not exhaustive, but were targeted. In addition, the low-technology approach was somewhat influenced by the feasibility nature of the research, but was appreciated by nurses. Stage 4: presentation of draft resource packs to practice nurses Each PN was given a copy of the draft resource pack at their PCAM training session.

Stratified by MAP: MAP 93 mmHg (58% remission) order warfarin 2 mg with mastercard, MAP 99 mmHg (33% remission) order warfarin 1mg without prescription, MAP 103 mmHg (25% remission), MAP 107 mmHg (20% remission), MAP 113 mmHg (17% remission). In a cohort of type 1 diabetic patients with nephropathy (N=301), more people with a lower follow-up MAP achieved regression. Stratified by MAP: MAP 93 mmHg (42% regression), MAP 99 mmHg (32% regression), MAP 103 mmHg (11% regression), MAP 107 mmHg (20% regression), MAP 113 mmHg (17% regression). The adjusted odds ratio for regression associated with a 10 mmHg decline in MAP was 2. SBP >120 mmHg (IDNT*) continued 106 9 Blood pressure control Table 9. Intense MAP control – – creatinine clearance usual MAP control (MDRD) (GFR decline 5. SBP <130 mmHg (RENAAL*) ESRD or death NS risk intense vs. SBP <130 mmHg (RENAAL*) Doubling serum NS risk SBP <110 to NS risk SBP 120–129 – – creatinine or ESRD >160 mmHg (Jafar vs. DBP <65 mmHg (US vet) Cardiovascular – – – DBP not predictive mortality (IDNT*) Congestive heart – – – DBP not predictive failure (IDNT*) Myocardial infarction – – – ↑ Risk DBP <70 mmHg vs. DBP <70 mmHg (RENAAL*) ESRD or death – – – NS risk DBP 70–-89 mmHg vs. DBP <70 mmHg (RENAAL*) ESRD – – – NS risk DBP 70–89 mmHg vs. DBP <70 mmHg (RENAAL*) Doubling serum DBP not predictive DBP not predictive – – creatinine or ESRD (Jafar meta-analysis) (Jafar meta-analysis) *Post-hoc analysis. Evidence relating to lifestyle advice (such as salt restriction) in blood pressure control can be found in the NICE clinical guideline 34 on hypertension. The evidence presented suggests that there are optimal ranges, with increased risk of adverse outcomes both above and below the optimal range, for both systolic and diastolic blood pressure. In practice, when treatment is given to maintain the systolic blood pressure in the optimal range, this results in the diastolic blood pressure falling below its optimal range. Recommendations were therefore made for a systolic range and a diastolic threshold. In people with CKD without diabetes, there is some evidence to suggest lower blood pressure targets in those with a threshold level of proteinuria equivalent to an ACR of ≥70 mg/mmol, or PCR ≥100 mg/mmol (approximately equivalent to urinary protein excretion of ≥1 g/day). In order to be consistent with the available evidence on ACEI/ARB therapy a threshold level of proteinuria at which ACEI/ARBs should also be recommended for blood pressure control in people without diabetes was set at an ACR of ≥30mg/mmol, or PCR ≥50 mg/mmol (approximately equivalent to a urinary protein excretion of 0. R40 In people with diabetes and CKD or when the ACR is ≥70 mg/mmol, or PCR ≥100 mg/mmol (approximately equivalent to PCR ≥100 mg/mmol, or urinary protein excretion ≥1. Danger zones: systolic blood pressure 120 130 140 150 160 Increased risk of: Increased risk of: Increased risk of: • mortality • 2 x SCr or ESRD* • 2 x SCr, ESRD or death • CV mortality • ESRD or death • stroke • ESRD • congestive heart failure *When proteinuria >1 g/24 h Danger zones: diastolic blood pressure 60 70 80 90 100 Increased risk of: Increased risk of: • mortality • 2 x SCr, ESRD or death • myocardial infarction • ESRD or death • decline in GFR • ESRD Figure 9. Hypertension is extremely common in people with CKD and the mean number of antihypertensive agents prescribed is associated with the stage of CKD, increasing as GFR falls. The UK CKD guidelines15 recommend that ACEI/ARBs should be used as first line therapy only for people with diabetic kidney disease and for those with proteinuria (urine PCR >100 mg/mmol) and this was endorsed by the UK consensus conference. Although the evidence is less clear in non- diabetic kidney disease with lesser degrees of proteinuria the Quality and Outcomes Framework requires the use of ACEI/ARBs in people with stage 3–5 CKD hypertension and proteinuria. The CARI guidelines36 recommend that regimens including ACEI/ARBs are more effective in slowing progression of non-diabetic CKD, and that combination of ACEIs and ARBs slow progression more effectively than either single agent. They also conclude that ACEI/ARBs are more effective than beta-blockers and dihydropyridine calcium channel blockers, and that beta- blockers may be more effective than dihydropyridine calcium channel blockers. Most trials used non-ACEI or non-ARB antihypertensive agents in both arms to achieve blood pressure control and to ascertain if ACEI or ARBs provided renoprotective effects beyond blood pressure control. The sample sizes in these studies ranged from N=180 to 39485 and the duration of the trials ranged from 6 months to 6 years. The mean age of study participants was under sixty years of age, with the exception of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study,118 in which the mean age was 67 or 70 in each treatment arm. The studies were also quite heterogeneous in terms of the population studied – diabetic nephropathy or nondiabetic CKD. A systematic review of ten RCTs241 comparing combination therapy ACEI + ARB versus monotherapy (ACEI or ARB) in adults with diabetic nephropathy was excluded because the quality of each included trial was not assessed; the primary outcome (proteinuria change) had significant heterogeneity and there was no heterogeneity analysis for sub-group analyses. Studies included in the meta-analysis were only 8–12 weeks long. There was wide variation in the dosage of ACEI and ARB, and few studies titrated to the maximum tolerated dose. Two more studies267,268 evaluated ACEI or ARB treatment based on meta-analysis of RCTs. Most papers evaluated the drugs in the context of diabetic nephropathy. Studies which are not UK-based may not be easily transferable to a UK setting.

What follows are examples of different molecular processes that contribute to different aspects and stages of substance use disorders warfarin 5 mg mastercard. These illustrations have been chosen based on the depth of available information order 2 mg warfarin fast delivery, and likely relevance to the clinical situation in humans. Adaptations That Produce Tolerance and Somatic Dependence to Opiates FIGURE 96. Mechanism of opiate tolerance and dependence Opiates and ethanol produce somatic dependence and with- in the locus ceruleus: Acute administration of opiates increases drawal because their targets are expressed on cells and cir- outward K current, thereby hyperpolarizing locus ceruleus cells cuits that regulate bodily functions such as autonomic activ- (top). With chronic opiate use the cAMP signaling system is up- regulated, leading to PKA-dependent phosphorylation of the ity. Tolerance and dependence are generally thought to Na channel. In this state, the channel is more active, allowing represent homeostatic adaptations that compensate for Na ions to flow into the cell, increasingly the intrinsic excitability overstimulation by a drug or neurotransmitter. Up-regulation of the cAMP system also increases CREB Ser133 phosphorylation and CRE-dependent gene transcription. The molecular adaptations probably responsible for some aspects of tolerance and somatic dependence are best understood signaling mechanisms in opiate receptor-bearing cells (Fig. With repeat administration of mu agonist opiates such The locus ceruleus (LC), located in the dorsal pons, is as morphine or heroin, both tolerance and dependence the major noradrenergic nucleus of the brain and regulates emerge. There is a significant somatic component to heroin arousal, attention, and vigilance. It is involved in responses dependence as manifest by the classic heroin somatic with- to stress, and together with other noradrenergic cell groups drawal syndrome. It had initially been hypothesized that plays a role in regulation of the autonomic nervous system. Thus, despite continued op- turned out to be the case; rather opiate tolerance and depen- iate exposure, LC firing rates gradually return to their basal dence appear to be caused by adaptation in postreceptor levels. At this point, administration of an opioid receptor Chapter 96: Molecular and Cellular Biology of Addiction 1373 antagonist, such as naloxone or naltrexone, causes a dra- mice exhibited markedly reduced signs of withdrawal in- matic increase in LC firing rates. In animals, the period cluding complete absence of sniffing and ptosis (44,45). Opiate-induced syndrome, and drugs, such as the 2-adrenergic receptor up-regulation of PKA does not involve CREB and may be agonist clonidine, which inhibit LC firing, attenuate with- mediated posttranslationally. When the regulatory subunits are bound erance and dependence depend on the cyclic AMP (cAMP) by cAMP, the catalytic subunits are free to phosphor late pathway. In the LC, as in most other cell types, -opioid substrate proteins. However, free catalytic subunits of PKA receptor activation inhibits the cAMP pathway via Gi acti- are highly vulnerable to proteolysis, whereas inactive sub- vation and stimulates an inwardly rectifying K current by units bound to regulatory subunits are proteolysis-resistant. As the number of enzyme the actions of agonist opiates on these K and Na molecules increases, the kinase activity can be more readily channels expressed by LC neurons decrease the excitability activated by the low levels of cAMP. With long-term opiate administration, however, a homeostatic compensatory re- Adaptations That May Produce Tolerance sponse occurs: key components of the cAMP pathway be- and Somatic Dependence on Ethanol come up-regulated in LC neurons; thus, for example there Like opiates, ethanol produces somatic dependence and are increased concentrations of adenylyl cyclase and protein withdrawal, although the clinical syndrome is quite distinct, kinase A. This up-regulation increases the intrinsic excitabil- and potentially more dangerous. The molecular mecha- ity of LC neurons, by activating the cAMP-dependent Na nisms are less well understood than those underlying opiate current. The activation of this current may explain why LC tolerance and dependence, but the comparison is instruc- firing rates return to normal despite the continued presence tive. There is some evidence that homeostatic adaptations of an opiate (an example of tolerance). These observations occur in response to ethanol that decrease GABAA receptor may also explain the dramatic increase in LC firing that expression and increase NMDA receptor expression on occurs if an opiate antagonist such as naloxone is adminis- some neurons. The decrease in receptors for the major in- tered to precipitate withdrawal (illustrating dependence). The de- to glutamatergic projections to the LC from the nucleus crease in GABAA receptor function is possibly due in part paragigantocellularis of the medulla. Lesions of the paragi- to decreased GABAA-1 subunit expression in the striatum, gantocellularis, or glutamate receptor antagonists admin- cortex, and hippocampus (46). Conversely, chronic ethanol istered locally in the LC, attenuate withdrawal-induced appears to increase the number and function of NMDA increases in LC firing rates by approximately 50%. During withdrawal, glutamate release is in- regulated cAMP pathway also may mediate this effect, as creased for up to 36 hours in the NAc, hippocampus, and long-term use of opiates causes up-regulation of the cAMP striatum (48). Overall, there is increasing evidence to sug- pathway in the paragigantocellularis and its major afferents. In these animals two of the major CREB iso- Motivational Aspects of Dependence forms, and , were disrupted.

Parallel efforts will continue in targets or other biological measures in this disorder warfarin 5mg line. For example cheap warfarin 5mg with mastercard, of opportunity, including informative chromosomal trans- it may not be appropriate to generalize to all forms of TS the locations. Ultimately, genes conferring a risk of TS will be biology that is described by neurochemical brain imaging identified and cloned. Experience from similar efforts that studies, which, because of ethical concerns, exclusively in- are already completed with the Huntington disease gene volve adults with TS. At another level, current TS studies suggest that identification of the TS genes will be followed that include children will likely involve both 'types' of TS, by a substantial amount of work designed to understand without any clear way to stratify this heterogeneous sample. These markers could greatly enhance and the Harvard Brain Tissue Resource Center, approxi- the power of linkage analyses, by allowing a 'physiologic' mately three new, optimal TS brains are collected each year, parsing of the phenotype of affected and at-risk individuals. A common 'library' of antisaccade measures (74), eyeblink measures of prepulse 1694 Neuropsychopharmacology: The Fifth Generation of Progress inhibition of startle (73) or condition-test paired pulse para- Although several new therapeutic approaches to TS are digms (76), and measures of cortical silent periods after being developed, as discussed earlier, there is clearly a signifi- rTMS (80). The neural bases of these various measures are cant need to understand the proposed role of streptococcal infec- consistent with our present conceptualization of CSPT sub- tions in the pathogenesis of TS and to assess the potential strates of TS, but the effect sizes of existing measures are role of antistreptococcal or immunosuppressive therapies. This area of work in TS, however, has been rela- with childhood tic disorders and OCD, without any con- tively understudied. Mutant rodent models may proven, experimental treatments for autism (146). Cer- prove useful (142), particularly in understanding the behav- tainly, repeated injections or even oral treatment with anti- ioral and physiologic consequences of the selective loss of biotics can have detrimental consequences in children. Even a specific neural element, such as the dopamine transporter more concerning is the increasing use of plasmapheresis or (143). Essentially, such models provide a nonpharmaco- intravenous immunoglobulin therapies in affected children, logic, nonsurgical means of studying the effects of a chronic with only preliminary data from controlled studies demon- perturbation in basal ganglia circuitry. Animal models can strating efficacy for these costly and invasive interventions also be used, however, in guiding the development of candi- (147). Given the expanding clinical boundaries of strepto- date endophenotypes; particularly valuable would be mea- coccal-associated conditions, controlled, large sample stud- sures that can be assessed across species and that can be ies of penicillin prophylaxis in TS, and perhaps of other shown in preclinical studies to have predictive or construct related therapies as well, should be a major priority from a validity for TS. One animal model that promises to be particularly in- formative regarding the neurobiology of TS involves the manipulation of the relative activity of medium spiny pro- SCIENTIFIC HURDLES jection neurons within the striosomal and matrix compart- ments of the striatum (144). These two compartments differ Major obstacles impede the search for the pathophysiology with respect to their cortical inputs: striosomal neurons re- of TS. Serious ethical issues complicate invasive studies ceive limbic and prelimbic inputs, and neurons in the matrix in children and affect TS research tools ranging from the receive inputs from ipsilateral primary motor and sensory use of radioisotopes in neuroimaging studies to the acquisi- motor cortices. Dopamine projection neurons from the pars tion of meaningful age-matched control samples. The lon- compacta of the substantia nigra serve to 'tune' this system gevity of patients with TS is certainly a blessing, but it also as it determines responsivity to certain cues (interoceptive precludes the availability of neuropathologic material for or exteroceptive). As noted by Leckman and Riddle (145), systematic studies. The lifelong interval between diagnosis this model may provide a meaningful integration of knowl- and study increases the likelihood that the 'lesion' will melt edge drawn from different perspectives that may be directly into the compensatory milieu of nervous tissue or will be relevant to certain important clinical issues, including (a) camouflaged by the many other insults that befall an aging the stress responsiveness of tics, (b) the presence of premoni- brain. The medical care of patients with TS is rarely focused tory sensory urges and 'just-right' perceptions, (c) the need on 'end-of- the-life-spectrum' issues, and thus pediatricians to 'even-up' sensory and motor stimuli in a bilaterally sym- and families rarely consider procedures for brain donation. Such a model may also guide hypothesis-driven thrive with TS. Neuropathologic material is thus most read- studies in other areas of TS research. For example, based ily available from persons whose TS has remained severe on the distinct input-output characteristics of neurons in throughout adulthood and who are identified by family and the striatal matrix versus striosomes, it may be useful to physicians as being particularly impaired by this disorder. Even more subtle clinical distinctions within the illness, and thus neuropathologic studies with tissue ac- 'TS spectrum' may be predicted to reflect a differential quired from elderly patients with TS may not be generally involvement of these striatal components, with more affec- informative about TS and potentially could be scientifically tively laden symptoms common to 'tic-related OCD' re- misleading. Symptoms in obses- ing TS research are not unique to this disorder, but are sive compulsive disorder and Tourette syndrome: a spectrum? In this manner, the quest comorbidity in primary school children. A prospective longitudinal study of tic, obsessive-compulsive and attention deficit-hyperac- tivity disorders in an epidemiological sample. J Am Acad Child ACKNOWLEDGMENTS Adolesc Psychiatry 2001;40:685–695. J Am Acad Child were supported by grants to JFL from the National Insti- Adolesc Psychiatry 1994;33:377–385. Adolescent out- come of boys with attention-deficit/hyperactivity disorder and NS16648, and RR00125, as well as by the concerted and social disability: results from a 4-year longitudinal follow-up visionary leadership of the Tourette Syndrome Association. Adult psychiatric status of hyperactive boys grown up.