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By Y. Dudley. Wilkes University.

A recent study showed that the onset of multimorbidity occurred 10–15 years earlier in people living in the most deprived areas than in those living in the most affluent areas levitra professional 20 mg amex, with socioeconomic deprivation particularly associated with multimorbidity that included mental health disorders (coexistence of physical and mental health disorders) generic levitra professional 20 mg online. The presence of a mental health disorder increased as the number of physical morbidities increased buy generic levitra professional 20mg line, and was much greater in more deprived people than in less deprived people. Engaging in health-promoting behaviour and self-care practices can be limited or even impossible when adverse social circumstances intervene. The Department of Health has long anticipated that, with increased self-care practices, there would be a corresponding reduction in the use of health-care resources, better quality of life and reduced mortality. This often includes reduced health literacy, which will require a different type of input if self-care behaviours are to be understood and accommodated within difficult lives. Again, attention to recognising and addressing these broader needs and organising responses (which other sectors are better positioned to meet) will ensure the more efficient use of NHS resources. 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 1 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. INTRODUCTION, BACKGROUND AND AIMS in which one of the first recommendations is about strengthening links between general practice and communities. Supporting People with Long Term Conditions4 based its improvement programme on models from the USA (Kaiser Permanente, Pfizer and Evercare). These models are based on nurses acting as case managers who have a key role in co-ordinating services from other health and social care providers. The RCGP promotes care planning,15 but acknowledges that coexisting mental and social circumstances may prevent such approaches. There are few validated tools for such assessment, especially for use by nurses. The development of interventions for primary care that encourage holistic assessment and action to address complex health and social needs is urgently required. Depression screening in LTCs has now been removed from the QOF, but patient and carer groups have argued that this will serve only to remove the imperative to include assessing mental health needs in LTCs. The National Institute for Health and Care Excellence (NICE) now recommends that a biopsychosocial assessment is carried out, but only for patients newly diagnosed with depression, and it provides little guidance on how this should be addressed and no imperative to act on this assessment. The tool encourages linking with other sectors to more appropriately address these problems for patients and to access alternative types of resources. The PCAM tool also encourages new ways of working that enhance opportunities for health promotion, even in those with few current health or social problems, to maintain healthy behaviour. It is anticipated that this will lead to improved quality of life for patients and better patient–professional interactions and relationships. The PCAM tool is an adapted version of the Minnesota Complexity Assessment Method (MCAM), which 17–19 was derived from the INTERMED (a method to assess health service needs). The PCAM has previously been evaluated in anticipatory (Keep Well) health check clinics, which were initiated by the Scottish Government for early identification of LTCs, or risk of LTCs, in those aged 40–64 years and living in deprived communities in Scotland. The PCAM tool may also provide a more systematic approach for primary care in responding to the NICE and RCGP recommendations for biopsychosocial assessment of patients with LTCs and/or depression. There is strong potential for the PCAM tool to make a real difference to the quality of care delivered in primary care to patients living with LTCs. The PCAM tool aims to encourage nurses to address more than just the physical care needs of their patients, or at least to determine these needs for others to address. By addressing these needs, patients could be better positioned to engage with health promotion and self-care advice and should also see improvements in their physical and mental well-being. There is also a strong potential for the PCAM tool to result in a greater range of services and support being enlisted in the care and support of those with LTCs, and especially for those patients from disadvantaged communities. This has the potential to reduce the burden on the NHS as the main or sole provider of care and support for many of these patients, who often end up with repeat hospitalisations and high levels of primary care use. It is also hoped that it will result in greater integration of health and social care needs and the co-ordination of meeting these needs, and that use of the PCAM tool can result in greater use of community and voluntary sector resources, as was demonstrated in the Keep Well evaluation in Scotland. This research also aimed to determine whether or not a future full-scale randomised controlled trial (RCT) is feasible and whether or not the methods proposed for such a trial are acceptable, with the aim of developing a research protocol and application for funding for such a trial. Aims l To assess the acceptability and implementation requirements of the PCAM tool for use in UK primary care, particularly in the context of PN-led annual reviews for people with LTCs. Research questions Overall, this study sought to answer the following two main questions: 1. Is it feasible and acceptable to use the PCAM tool in primary care nurse-led annual reviews for those with LTCs? Is it feasible and acceptable to run a cluster randomised trial of the PCAM intervention in primary care? The pilot trial aimed to answer the following questions: 1. Can we recruit practices and nurses to take part in the study and retain them? Can the practices and nurses implement study procedures correctly? Are patients willing to complete questionnaires/outcome measures? How many missing data are there, and does this relate to nurse- or patient-level follow-up? What estimates of effect size, variance and likely intracluster correlation coefficient (ICC) should be used to inform the sample size of the full study? Should the unit of analysis be at the nurse or patient level, or is it feasible or necessary to include both? 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 3 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. INTRODUCTION, BACKGROUND AND AIMS Objectives l To conduct focus groups with primary care staff and patients with LTCs to assess acceptability and implementation requirements. Structure of the report The research is reported as five related research studies (studies A to E). Chapter 2 provides an overview of the overarching study design and conceptual framework for the research, and the general methodological approach to each of the individual studies. Chapter 2 also reports on the general management and conduct of the research, including ethics approval and patient and public involvement (PPI). Chapters 3–7 report on each of the separate studies (A–E), including their methods, findings/results and a discussion of the findings and conclusions. Chapter 8 presents on overall discussion, including the strengths and limitations of our work, a reflection on our PPI and summary conclusions and recommendations.

Finally discount levitra professional 20 mg line, the NMDA channel provides ready pas- tribution at the cellular and synaptic level in a matter of sage of Ca2 order generic levitra professional canada, a cation involved in a number of intracellular days (70 buy levitra professional discount,71). In addition, although NMDA receptors have signaling processes. The most comprise a family of polypeptides that form the various dramatic example of this is in CA3 of the hippocampus, subtypes of the NMDA receptor (1). NR1 was the first where NMDA receptors are present postsynaptically in the component cloned and, when expressed in Xenopus oo- distal dendrites (i. Seven splice variants of NR1 have been de- gests that there are intracellular trafficking mechanisms or scribed, which reflect the exclusion or inclusion of three local synthesis that can position NMDA receptors in a sub- exons, two in the C terminal and one in the N terminal set of synapses receiving a particular input to a given cell portion (1). These splice variants significantly impact the while not mediating other inputs. The NR2 sub- The data on the distribution of other subunits are less units, NR2A-D and the recently identified NMDARL or well developed, and this is partly owing to the fact that it has NR3A, do not form channels (67); however, when coex- been very difficult to develop antibodies that differentiate pressed with NR1, the heteromeric channels exhibit a mark- NR2A from NR2B, the two dominant subunits in the NR2 edly increased current as compared to the homomeric NR1 group in the hippocampus and neocortex. Each of the NR2 subunits, when complexed with appears that NR2A and NR2B overlap in their distribution the NR1 subunit, exhibits different biophysical and phar- with NR1 to a large degree (73–75); however, there are macologic properties. The NR2A and NR2B subunits, regions such as CA3 where they differ in their distribution more highly expressed in adult cortex in contrast to NR2C/ with NR1 (75,76), but this has yet to be worked out at D receptors, appear to be less sensitive to NMDA receptor the synaptic level. The detailed delineation of the synaptic antagonists, not as vulnerable to Mg2 blockade, and have distribution of NR2A and NR2B is an important task for lower Ca2 conductance (1). The NR2A subunit is highly or down-regulation of one of these subunits can profoundly expressed in the neocortex, hippocampus, cerebellum, and impact their function. For example, NR2B overexpression several thalamic nuclei. The NR2B subunit is found in the in mouse enhances learning and memory (77). Thus, as is neocortex, hippocampus, striatum, septum, and thalamic the case for AMPA and kainate receptors, delineating the nuclei of the adult rat brain. The expression of the NR2C subunit representation and potential stoichiometry at spe- subunit is much more restricted in the adult brain, being cific circuits and synapses for the NMDA receptor is of enriched in the olfactory bulb, thalamic nuclei, and cerebel- paramount importance if this receptor is to be definitively lum. Finally, the NR2D subunit is enriched in brainstem linked to circuits that mediate specific behaviors and suffer nuclei, midline thalamic nuclei, and bipolar cells of the ret- under certain pathologic conditions. The NR2B and NR2D subunits appear early in brain Several endogenous amino acids, aside from glutamate, development, followed by a decline in NR2D expression in are selective agonists at the NMDA receptor, including L- the third week after birth of the rat, whereas the acquisition homocysteic acid, L-aspartic acid, L-cysteine sulfate, L-ser- of NR2A and NR2C subunits appears primarily postnatally ine-O-sulfate, L-cysteic acid, and quinolinic acid in order in the rat (1). Given the multiple modulatory With respect to NMDA receptor localization, as in the sites and agonist binding sites for the NMDA receptor, it case of AMPA/kainate receptors, the early in situ hybridiza- is not surprising that the antagonist pharmacology for this tion studies discussed in the preceding offered important receptor is complex. Several phosphonate analogues of glu- information as to the regional distribution of NMDA recep- tamate, including D-aminophosphonovaleric acid (APV), Chapter 6: L-Glutamic Acid in Brain Signal Transduction 75 D-aminophosphonoheptanoic (APH) acid, D-aminoadipic and heteroreceptors that negatively regulate neurotransmis- acid, and the cyclic analogue of AHP, (2-carboxypiperazin- sion (82). As described, the NMDA receptor chan- the cerebellum, the thalamus, and the lateral septum (87). The gly- tion with high levels expressed in the neocortex, the pyrami- cine modulatory site, which must be occupied for glutamate dal cells in CA1 sector of the hippocampus, lateral septum, gating of the ion channel, is subject to inhibition by the striatum, and nucleus accumbens (88). Although studies in endogenous metabolite of tryptophan, kynurenic acid as vivo suggest a low level of expression of mGluR 5 in glia, well as synthetic analogues such as 7-chlorokynurenate (79). The expres- For greater selectivity, attention is now directed at develop- sion of group II receptors is more restricted than group I, ing subtype specific antagonists such as ifenprodil, which with mGluR 2 found in the cerebellum, pyramidal cells in inhibits NMDA receptors bearing the NR2B subunit (80). The majority of the cerebellar Golgi cells have mGluR 2 but a minor subset express mGluR 5 in a complementary fashion (91). With of glutamate were mediated exclusively by iGluR, until Sla- regard to group III, mGluR 4 is found in the thalamus, deczek and colleagues (81) reported that glutamate catalyzed lateral septum, dentate gyrus, and cerebellar granule cells phosphoinositide hydrolysis through a receptor coupled to (92). Since then, research has disclosed the existence nent representation in sensory afferent systems including the of a family of glutamate receptors whose effects are largely dorsal root ganglia and the trigeminal nucleus in addition to mediated by G-proteins, the so-called metabotropic gluta- the cerebral cortex, hippocampus, striatum, thalamus, and mate receptors (mGluRs). Finally, mGluR8 is apses where iGluRs are also engaged (82). On the basis of pharmacology, physiologic NMDA receptors are localized predominantly in the post- effects, and sequence homology, the eight mGluRs have synaptic density, mGluRs are principally localized presynap- been subdivided into three groups (85). Group I includes tically and perisynaptically (97–99). In addition, the mGluR 1 and mGluR 5, which act via phospholipase C; mGluRs exhibit a high degree of specificity in this regard group II includes mGluR 2 and mGluR 3, which are nega- with mGluR7 (100,101) and mGluR4 (102) (which are tively coupled to adenylyl cyclase; and group III, which primarily present presynaptically) and mGluRs 1 and 5 includes mGluR 4, 6, 7, and 8, and are also negatively (which are primarily present perisynaptically) (103–105). Adding to this complexity, These patterns suggest that synaptic localization is partially mGluR 1 has four splice variants, whereas mGluR 4 and 5 segregated by mGluR group (99), with group I primarily each have two. The mGluRs within a group exhibit greater perisynaptic, surrounding the postsynaptic density, group than 70% sequence homology, whereas the homology falls II primarily presynaptic or extrasynaptic, and group III opti- to approximately 45% between groups (82). These synaptic distribution patterns position mGluRs transmembrane domains separated by short intracellular to play a critical role in modulating excitatory neurotrans- and extracellular loops and an unusually large extracellular mission. Group I mGluRs stimulate phospholipase C and the hy- In further contradistinction to other GPCRs, the agonist drolysis of phosphoinositide. These two receptors have been binding sites for the mGluRs are located in the extracellular reported to stimulate cAMPformation in different model domain. As a family, mGluRs are broadly expressed in the systems (106). They also increase the excitability of neurons nervous system, with group I having primarily a postsynap- currents, through a mechanism that by reducing the K tic localization, whereas groups II and III primarily have a appears to be independent of G-protein action (107). Al- presynaptic localization where they serve as autoreceptors though the AMPA receptor agonist, quisqualic acid, is the 76 Neuropsychopharmacology: The Fifth Generation of Progress most potent agonist at the group I mGluRs, 3,5-dihydroxy- traordinary gradients with the extracellular concentration phenylglycine (3,5-DHPG) is the most specific agonist. Energy deprivation not only collapses the so- pharmacology. The group porter, thereby inhibiting glutamate uptake, but also results III mGluRs inhibit adenylyl cyclase via GI-protein, al- in reverse transport with massive efflux of glutamate stores though they may utilize other transduction mechanisms. Pharmacologic inhibition of glutamate transport in The most specific agonist at group I mGluRs appears to tissue culture models has been shown to promote excitotoxic be 2R, 4R-4-aminio pyrrolidine-2, 4 dicarboxylate neurodegeneration (118). LY354740 is an exceptionally potent and selective Early pharmacologic studies pointed to the existence of agonist at group II mGluRs and is effective with systemic subtypes of sodium-dependent glutamate transporters in administration (108). Notably, N-acetylaspartyl glutamate brain with cerebellum exhibiting a form that is much more (NAAG), an endogenous neuropeptide, is a relatively potent sensitive to inhibition by L- -aminoadipate and forebrain agonist at mGluR 3, although it also serves as an antagonist sensitive to dihydrokainate (119). L-aminophosphonobutyric heterogeneity as well as the diverse cellular distribution of acid (L-AP4) is the most potent and selective agonist at the the sodium-dependent glutamate transporters have been il- group III mGluRs with the exception of mGluR 7, where luminated recently by their cloning and molecular charac- L-serine-O-phosphate has greater potency. EAAT 1 or GLAST has its highest expression in macology of these receptors remains less well developed than brain but is also found in peripheral tissue and placenta. The cerebellum appears to have the highest level within The heterogeneity of the mGluRs and their role in mod- brain, depending on the species. EAAT 2 (GLT 1) is primar- ulating glutamatergic neurotransmission make them attrac- ily expressed in brain, although low levels have been re- tive potential therapeutic targets for drug development. Its associated with protection against excitotoxicity, whereas expression is predominantly if not exclusively astroglial in activation of group I mGluRs may actually enhance NMDA localization. The predominant neuronal transporter is receptor-mediated neuronal degeneration (110,111). Re- EAAT 3, which is also expressed in kidney and to a lesser cently it has been shown that inhibition of GCPII, the extent in other peripheral tissues. Consistent with the broad enzyme that degrades the selective mGluR 3 agonist NAAG, distribution of glutamatergic neuronal systems in brain, the provides potent protection against neuronal degeneration levels of EAAT 3 are fairly uniform. EAAT 3 is not consis- caused by transient occlusion of the middle cerebral artery tently expressed in all glutamatergic systems, and some non- (112).

Behavioral inhibition to tates the acoustic startle in humans levitra professional 20 mg low price. Fear-potentiated startle history of drug dependence order levitra professional 20 mg free shipping. Drug Alcohol Depend 1998;50: in adolescent offspring of parents with anxiety disorders purchase 20mg levitra professional overnight delivery. Effect of darkness on acoustic components in air puff startle. Physiol Behav 1991;49: acoustic startle in Vietnam veterans with PTSD. Startle potentia- variability in posttraumatic stress disorder patients in response to tion by threat of aversive stimuli and darkness in adolescents: a trauma-related reminder. Fear-potentiated startle conditioning York: Basic Books, 1994:261–262. Hemodynamic responses to laboratory traumatic stress disorder. Long-term potentiation in the amygdala: a mechanism stressors in children and adolescents: the influences of age, race, for emotional learning and memory. Types of panic attacks and their associa- Nature Neurosci 1999;2:833–839. Comorbidity of migraine and learning in mGluR1mutant mice. Heart rate variability in depressive and Genet 1997;17:335–337. Regional brain polygenes influencing susceptibility to anxiety. Hum Psycho- function, emotion and disorders of emotion. Curr Opin Neuro- pharmacol Clin Exposure 1999;14:S3–S10. Emotional arousal and formation through regulated expression of a caMKII transgene. Autonomic nervous sys- and anxiety: Brain mechanisms and psychophysiology. Biol Psy- tem activity distinguishes among emotions. Baseline and fear-poten- 882 Neuropsychopharmacology: The Fifth Generation of Progress tiated startle in panic disorder patients. Biol Psychiatry 1994; miology of anxiety disorders in Florence. Biologic findings in and their relation to anxiety and depressive disorders. J Abnorm panic disorder: neuroendocrine and sleep-related abnormalities. Reactivity to a 35% CO2 challenge in of stressful life events. Life events and panic disorder/ Psychiatry 2000;47:830–835. Arch Gen Psychiatry 1995;47: antecedent stressful life events to childhood and family history 21–26. Smoking and panic attacks: an epidemio- Gen Psychiatry 2000;51:960–962. Parental representa- in children with anxiety disorders. Am J Psychiatry 2000;157: tions of patients with panic disorder and generalised anxiety 1236–1242. Vulnerability factors in the anxiety disor- adolescent depression: a review of the past 10 years, part II. Lactate infusions: The ogy, parenting styles and the risk of social phobia in offspring: a role of baseline anxiety. Philos Trans R Soc on brain systems involved in the pathophysiology of anxiety Lond [B] 1997;352:1755–1759. Fear and the brain: where have we been, and where 169. The emotional Stroop section with anxiety disorders. Biol Psychiatry 1999;1999: task and psychopathology. The adolescent brain and age-related behavioral mani- and its amelioration by effective treatment with SSRis. KALIN ANIMAL MODELS OF PSYCHIATRIC fore, it is difficult to come up with an animal model for an ILLNESS illness that meets the aforementioned criteria and also models the pathologic syndrome in its entirety. An alterna- Animal Models: Types Of Validity tive approach that has been used involves the modeling of An important criterion for developing animal models to discrete symptom clusters and physiologic alterations rather study psychopathology involves establishing the validity of than the whole syndrome, with the assumption that what the model as a true representation of the process being stud- causes the symptoms contributes mechanistically to the ill- ied. Generally, three types of validity are applied to animal ness. This general approach has involved the use of endo- models: face validity, construct validity, and predictive va- phenotypes that may be related to a particular psychiatric lidity (1–3). Face validity refers to the outward similarity disorder. The term endophenotype refers to a set of behavioral in appearance between the model and the illness. Construct and/or physiologic characteristics that accompany a basic validity, on the other hand, does not exclusively involve process that is altered in relation to the illness that is being outward tangible signs of the modeled illness. It is important to note that this more narrowly refers to the internal mechanism or state that underlies the defined endophenotype approach does not necessarily have illness. Finally, predictive validity refers to the ability of to capture specific symptoms that are a part of the clinical the animal model to identify therapeutic treatments for the diagnosis, but rather may focus on a core process or function illness. It should be noted that the different types of validity that is abnormal in the clinical population under study and can be independent of each other; an animal model can that is thought to be related to the manifestation of the possess predictive and construct validity without possessing illness. For example, in the case of anxiety-related disorders, face validity. Ideally, an animal model should possess both investigators have focused on studying the genetic, physio- construct and predictive validity so that it may be used to logic, and neurochemical correlates of fearful or anxious understand the mechanisms and etiology of the disorder endophenotypes because a core aspect of anxiety-related dis- and also to identify promising treatments for the disorder. Thus, by identify- Endophenotype Approach ing animals that display fearful endophenotypes, it is possi- ble to study the neural substrates that contribute to this Species differences in the manifestation of a particular inter- basic process that may underlie the development and expres- nal state can cloud the usefulness of face validity in animal sion of anxiety-related psychopathology. In addition, when considering a complex psychiat- Using endophenotypes that are based on core and basic ric illness, it is likely that several different symptom clusters processes rather than the entire illness offers certain advan- contribute to the final pathologic condition; these different tages.

Close monitoring of patients ful in follow-up of the course of the disease and patient response is essential during tapering and after discontinuation of steroid to treatment generic 20 mg levitra professional free shipping. In symptomatic cases cheap 20 mg levitra professional fast delivery, steroids are highly effective in sup- Other drugs that have been used in cases unresponsive to pressing the cellular inflammatory reaction of sarcoidosis and steroids are m ethotrexate buy generic levitra professional 20mg on-line, chloroquine, azathioprine, and in reversing most forms of organ dysfunction caused by granu- cyclophosphamide. Of these, methotrexate seems to be more lomatous infiltration. Persistent patients who fail to respond to steroids or have extensive multi- dysfunction can result from residual fibrosis after reversal of organ involvement. Pathophysiology and Diagnosis A B C D FIGURE 8-1 (see Color Plate) Pathology of granulomatous lesions in lungs affected by sarcoidosis. The fibrotic response organs are the lungs and liver. M ononuclear cell infiltra- lesions tion is the initial step in the sequence of events that leads to granu- lom a form ation. Recruited m acrophages then differentiate into M ononuclear cell infiltration epithelioid and m ultinucleated giant cells. Activated lym phocytes are interspersed in the evolving lesion and com e to form a rim around the granulom as. In tim e, fibroblasts, m ast cells, and colla- M acrophage aggregation ↑ Synthesis of 1,25-dihydroxy-vitamin D gen fibers begin to encapsulate the m ature sarcoid granulom a. This capacity resides in Epithelioid and multinucleated ↑ Synthesis of angiotensin-converting giant cells the infiltrating m acrophages and is not unique to sarcoidosis but a enzyme feature of m ost other granulom atous disorders. Although lacking in specificity to be of diagnostic m erit, radioactive gallium scans Encapsulating rim can be used as noninvasive m ethods of assessing the activity of sar- CD4>CD8 (except in rare cases) coid granulom as. The uptake of radioactive gallium by the B cells, few m acrophages and lym phocytes reflects the activity of the infiltrat- Fibroblasts ing cells in affected organs. M ast cells FIGURE 8-4 CYTOKINES IM PLICATED IN SARCOIDOSIS FREQUENCY OF ORGAN INVOLVEMENT Frequency of organ PERPETUATING GRANULOM AS involvem ent. Interferon- Parenchym al Thoracic 90–100 involvem ent by Interleukin-2, 6, and 1 Stage I: hilar adenopathy granulom atous Chemoattractants Stage II: hilar adenopathy plus lesions is m ost Adhesion molecules pulmonary infiltration com m on in the Tumor necrosis factor- Stage III: pulmonary infiltration lungs, whereas that Dermatologic 25 of renal involvement Erythema nodosum, lupus pernio, papules, macules, plaques is relatively rare. Ophthalmic 25 FIGURE 8-3 Uveitis, iritis, conjunctivitis Cytokines im plicated in perpetuating granu- Nervous system 10 lom as. It is the loss of the otherwise Cardiac 5–10 balanced ability of cytokines to m odulate Renal 1–20 the inflam m atory response that accounts for Musculoskeletal 10–15 the progression of the initial inflam m atory Polyarthritis, lower > upper reaction to granulom atous form ation, and ultim ately to the m ore detrim ental process of fibrosis. M acrophages are critical in inducing fibroblasts to proliferate and deposit fibronectin and collagen in the extracellular m atrix. The lungs are the principal organs involved PULM ONARY SARCOIDOSIS in sarcoidosis. Pulm onary involvem ent m ay or m ay not be associated with hilar lym - phadenopathy. In contrast to the pulm onary diseases listed, pulm onary sym ptom s m ay be absent in sarcoidosis even in the presence of extensive pulm onary lesions seen on chest radi- Sarcoidosis ographs. Pulm onary sym ptom s develop when the disease is in its late fibrotic phase and are Beryllium exposure associated with airway obstruction. The diagnosis of sarcoidosis depends on the dem on- IN SARCOIDOSIS stration of the characteristic pathologic lesion of noncaseating granulom as within the affected organs. Several laboratory abnorm alities characterize sarcoidosis and are useful in supporting but not establishing the diagnosis. H yperglobulinem ia is a principal feature, Hyperglobulinemia being present in two thirds of cases. About half of patients have liver involvem ent, with Abnormal liver function tests som e abnorm ality of liver function tests; anergy is present in about half of patients; Anergy leukopenia is present in 25% to 30%. H ypercalciuria is com m on because of increased lev- Leukopenia els of calcitriol. In 50% to 60% of patients levels of angiotensin-converting enzym es are Hyperuricemia elevated. Hypercalciuria Hypercalcemia Elevated calcitriol (1,25-dihydroxy-vitamin D3) Elevated angiotensin-converting enzyme Cryoglobulinemia FIGURE 8-7 RENAL INVOLVEM ENT IN SARCOIDOSIS Renal involvem ent in sarcoidosis. The principal m anifestations of renal involvem ent in sarcoidosis are the functional abnorm alities resulting from the altered m etabolism of calcium as a result of the Patients, % increased synthesis of 1,25-dihydroxy-vitam in D3 by the m acrophages of the granulom atous lesions. The consequent Calcium metabolism increased calcium absorption from the gastrointestinal tract results Hypercalciuria 50–60 in the hypercalciuria that can be detected in m ore than half of Hypercalcemia 10–20 patients. The frequency of hypercalciuria depends on the extent of Nephrolithiasis ≈10 granulom atous lesions and on the tim e of the year, being m ore Nephrocalcinosis 5–10 com m on in spring and sum m er when exposure to the sun is great- Tubulointerstitial nephritis est. H ypercalcem ia is less com m on and usually depends on coexis- Granulomatous 15–40 tent deterioration of renal function when the capacity of the kidney Fibrotic 10–20 to excrete calcium is com prom ised. In m ost patients, hypercalciuria Glomerulopathy Rare is asym ptom atic. Its principal m anifestations are inability to con- Membranous centrate the urine and polyuria. N ephrolithiasis occurs in about Proliferative 10% of patients; another 10% develop nephrocalcinosis. Focal segmental glomerulosclerosis Arteritis Rare Granulomatous angiitis Obstructive nephropathy Rare Retroperitoneal lymphadenopathy Retroperitoneal fibrosis Renal Involvement in Sarcoidosis 8. Abnormal calcium metabolism and pathophysiology of renal involvement in sarcoidosis Polyuria and a reduced capacity to concen- trate the urine are its main manifestations. Sarcoid Either of these two features may be the result granulomas of tubulointerstitial nephritis caused by sar- coidosis, and can be present in the absence of any altered calcium metabolism. Hypercalcemia develops only when the load of calcium to be excreted ↑ Intestinal calcium absorption exceeds the ability of the kidneys to excrete and ↑ bone resorption the calcium load, either because of reduced renal function or, less commonly, when the ↓ Tubular calcium ↑ Calcium load for amount of calcium absorbed is excessive. The absorption renal excretion magnitude of hypercalcemia determines its symptomatology. The circulating level of parathyroid hormone should be determined Renal calcium ↓Renal in patients with hypercalcemia. An increase deposition Function in the prevalence of parathyroid adenomas seems to occur in sarcoidosis. In hypercal- ↓ Total calcium cemia caused by elevated levels of calcitriol Outflow tract parenchymal excretion and by reduced renal excretion of calcium, parathyroid hormone levels should be negligi- ble. Detection of elevated levels of parathy- Hypercalciuria Nephrolithiasis Nephrocalcinosis Hypercalcemia roid hormone should lead to the search for an adenoma. Patient management is directed at reducing calcitriol synthesis by treating the FIGURE 8-8 granulomatous lesions with steroids. Equally Abnorm al calcium m etabolism and pathophysiology of renal involvem ent in sarcoidosis. Patients with hypercalciuria, which by far is the m ost com m on, m ay rem ain asym p- sunlight, and increased fluid intake.

Cells injured sublethal- ly undergo repair and adaptation (eg cheap levitra professional 20 mg mastercard, stress response) in response Compensatory Cellular Cellular Cellular to the nephrotoxicant purchase levitra professional american express. Cells not injured and adjacent to the injured hypertrophy adaptation proliferation repair area m ay undergo dedifferentiation 20mg levitra professional with visa, proliferation, m igration or spreading, and differentiation. Cells that were not injured m ay also undergo com pensatory hypertrophy in response to the cell loss and Re-epithelialization Cellular adaptation injury. Finally the uninjured cells m ay also undergo adaptation in response to nephrotoxicant exposure. Differentiation Structural and functional recovery of the nephron Pathophysiology of Nephrotoxic Acute Renal Failure 15. Adhesion of sloughed the norm al distribution of m em brane proteins such as N a+, K+- cells to other sloughed cells and to cells rem aining adherent to ATPase and 1 integrins in sublethally injured renal tubular the basem ent m em brane m ay result in cast form ation, tubular cells. These changes result in loss of cell polarity, tight junction obstruction, and further com prom ise the glom erular filtration integrity, and cell-substrate adhesion. Basement membrane Toxicant inhibition Toxicant inhibition Toxicant inhibition of cell repair of cell migration/spreading of cell proliferation 15. Approxim ately 25% cell loss and m arked inhibition of m itochon- drial function active (N a+) transport and N a+-coupled glucose transport occurred 24 hours after oxidant exposure. The activity Phagocytosis Phagocytosis of the brush border m em brane enzym e -glutam yl transferase inflammation by macrophages (GGT) was not affected by oxidant exposure. Cell proliferation or nearby cells and m igration or spreading was com plete by day 4, whereas active N a+ transport and N a+-coupled glucose transport did not return to control levels until day 6. These data suggest that selective physio- FIGURE 15-12 logic functions are dim inished after oxidant injury and that a hier- Apoptosis and oncosis are the two generally recognized form s of archy exists in the repair process: m igration or spreading followed cell death. Apoptosis, also known as program m ed cell death and by cell proliferation form s a m onolayer and antedates the repair of cell suicide, is characterized m orphologically by cell shrinkage, cell physiologic functions. In contrast, oncosis, also known as necrosis, necrotic cell death, and cell m urder, is characterized m or- phologically by cell and organelle swelling, plasm a m em brane bleb- bing, cell lysis, and inflam m ation. It has been suggested that cell death characterized by cell swelling and lysis not be called necrosis or necrotic cell death because these term s describe events that occur well after the cell has died and include cell and tissue break- down and cell debris. For m any toxicants, low concentrations cause prim arily apoptosis and oncosis occurs principally at higher concentrations. W hen the prim ary m echanism of action of the Oncosis Oncosis nephrotoxicant is ATP depletion, oncosis m ay be the predom inant cause of cell death with lim ited apoptosis occurring. Apoptosis Apoptosis Toxicant concentration Toxicant concentration Pathophysiology of Nephrotoxic Acute Renal Failure 15. GSH-Hg-GSH Proxim al tubular uptake of inorganic m ercury is thought to be the CYS-Hg-CYS GSH-Hg-GSH result of the transport of m ercuric conjugates (eg, diglutathione γ-GT Urine GLY-CYS-Hg-CYS-GLY? At the lum inal m em brane, GSH -H g-GSH appears Lumen Dipeptidase to be m etabolized by (-glutam yl transferase ((-GT) and a dipepti- CYS-Hg-CYS Na+ dase to form CYS-H g-CYS. The CYS-H g-CYS m ay be taken up by Neutral amino an am ino acid transporter. At the basolateral m em brane, m ercuric –R-Hg-R– + acid transporter conjugates appear to be transported by the organic anion trans- Proximal Na CYS-Hg-CYS tubular cell CYS-Hg-CYS porter. Uptake of m ercuric-protein conjugates by endocytosis Dicarboxylate Organic anion transporter transporter m ay play a m inor role in the uptake of inorganic m ercury trans- port. N ephrotoxicants are generally thought to pro- duce cell injury and death through one of two m echanism s, either Biotransformation alone or in com bination. In som e cases the toxicant m ay have a high affinity for a specific m acrom olecule or class of m acrom ole- High-affinity binding Reactive intermediate Redox cycling cules that results in altered activity (increase or decrease) of these to macromolecules m olecules, resulting in cell injury. Alternatively, the parent nephro- toxicant m ay not be toxic until it is biotransform ed into a reactive Covalent binding Increased reactive interm ediate that binds covalently to m acrom olecules and in turn Altered activity of to macromolecules oxygen species alters their activity, resulting in cell injury. Finally, the toxicant m ay critical macromolecules increase reactive oxygen species in the cells directly, after being bio- transform ed into a reactive interm ediate or through redox cycling. Damage to critical Oxidative damage to The resulting increase in reactive oxygen species results in oxida- macromolecules critical macromolecules tive dam age and cell injury. Cell injury Cell repair Cell death FIGURE 15-16 Plasma RSG Plasma RSG This figure illustrates the renal proximal tubular uptake, biotransfor- Glomerular filtration mation, and toxicity of glutathione and cysteine conjugates and mer- R + SG 1. R-SG R-SG R-SG glutathione conjugate within the renal cell (R-SG). NH +H CCOCO H Basolateral membrane uptake of R-SG (6), R-Cys (7), and a mercap- Na+ 3 3 2 R-SH turic acid (N -acetyl cysteine conjugate; R-NAC)(8). Covalent binding 11) Deacetylation of R-NAC to form R-Cys. Cell injury Plasma of the penultimate nephrotoxic species (R-Cys) by cysteine conjugate R-NAC R-NAC R-NAC R-NAC + 9. Na Basolateral Brush border 13) Binding of the reactive thiol to cellular macromolecules (eg, lipids, membrane membrane proteins) and initiation of cell injury. A, Binding of tetrafluo- roethyl-L-cysteine (TFEC) metabolites in vivo to rat kidney tissue detected immunohisto- chemically. Staining was localized to the S3 segments of the proximal tubule, the segment that undergoes necrosis. C, Isolation and A B fractionation of renal cortical mitochondria from untreated and TFEC treated rats and Representative immunoblot analysis revealed numerous pro- starting Submitochondrial fractions teins that bind to the nephrotoxicant (inner- material A. TFEC (30 mg/kg) inner membrane, matrix-soluble matrix, M (kDa) outer-outer membrane, inter-intermembrane r space). The identity of three of the proteins 228 that bound to the nephrotoxicant: P84, P99 109 mortalin (HSP70-like); P66, HSP 60; and P84 P42, aspartate aminotransferase. The first step, hydrogen HO• Lipid abstraction from the lipid by a radical (eg, hydroxyl), results in the H2O form ation of a lipid radical. Rearrangem ent of the lipid radical Hydrogen abstraction results in conjugated diene form ation. The addition of oxygen •H R results in a lipid peroxyl radical. Additional hydrogen abstraction Lipid radical results in the form ation of a lipid hydroperoxide. The Fenton reac- Diene conjugation tion produces a lipid alkoxyl radical and lipid fragm entation, R resulting in lipid aldehydes and ethane. Alternatively, the lipid per- • oxyl radical can undergo a series of reactions that result in the for- H Lipid radical, conjugated diene m ation of m alondialdehyde. O2 Oxygen addition R R •O–OH Lipid peroxyl radical O O LH Hydrogen abstraction L• R O O Lipid hydroperoxide HOO H Fe(II) Fenton reaction M alondialdehyde • Fe(III) HO R •O H Lipid alkoxyl radical Fragmentation H R • H H H O Lipid aldehyde LH H L• H H Ethane H Pathophysiology of Nephrotoxic Acute Renal Failure 15. In contrast, halocarbon-cysteine conjugate–induced renal proxim al tubular while DEF and DPPD com pletely blocked the lipid peroxidation lipid peroxidation and cell death. The m odel oxidant t-butylhy- caused by DCVC, cell death was only delayed. These results droperoxide (TBH P) and the halocarbon-cysteine conjugate suggest that the iron-m ediated oxidative stress caused by TBH P dichlorovinyl-L-cysteine (DCVC) caused extensive lipid peroxi- is responsible for the observed toxicity, whereas the iron-m ediat- dation after 1 hour of exposure and cell death (lactate dehydro- ed oxidative stress caused by DCVC accelerates cell death. Decreased oxygen delivery secondary to vasoconstriction Inhibition of mitochondrial respiration Increased tubular cell oxygen consumption 15. Citrinin 3 H+ Ochratoxin A Hg2+ CN– 4 Oligomycin 5 + H Pi Pi 6 7 + H M atrix O2 H2O Ochratoxin A 10 Pentachlorobutadienyl–L–cysteine H+ Inner membrane Citrinin FCCP Outer membrane Disruption of ion homeostasis Na+ 100 H2O Na+ 90 80 Na+ + Na+ Na+ ATPase Na ATPase 70 ATP 60 – – Cl– ATP – Cl– 50 QO M embrane – 2 potential Cl– – 40 Cl – K+ – 30 K+ – H2O K+ – 20 10 ATP A K+ B Antimycin A K+ 0 0 5 10 15 20 25 30 Antimycin A Time, min FIGURE 15-22 Early ion m ovem ents after m itochondrial dysfunction.

Although early work supported (55) have reported that it does not increase cocaine use and its use discount levitra professional 20mg on-line, even in an early double-blind clinical trial 20mg levitra professional mastercard, bromo- retains patients better than placebo safe levitra professional 20mg, but have not shown a criptine at 5 to 7. In another small double-blind, placebo- Mazindol is a DA reuptake inhibitor that is without controlled trial Moscovitz et al. A report on the patients presenting to an emergency room for minor medi- effects of cocaine alone and in combination with mazindol cal complaints. They found no difference in retention (bro- at 1 or 2 mg orally in cocaine abusing volunteers found mocriptine group 43%, placebo group 31%), but those ran- that the combination significantly increased heart rate and domized to bromocriptine had more urine toxicology blood pressure (56). Mazindol did not alter the subjective screens negative for cocaine (67%) than those randomized effects of cocaine. One 12-week, double-blind, placebo-con- to placebo (31%). Cocaine administration studies have trolled clinical trial of mazindol 2 mg daily in cocaine- found a lack of effects with pergolide (49). A placebo-con- dependent subjects reported no difference from placebo trolled outpatient study of pergolide found no difference in (57). Mazindol was also not well tolerated, with 16 of 33 patients dropping out, and the average length of treatment cocaine use and significant side effects, in spite of early pilot was 5 weeks. A similar trial in methadone maintained pa- work in 21 patients suggesting good responses in 16 of 21 tients found limited efficacy for those patients who had patients (50). Most recently, the D1 agonist ABT431 has been cocaine abstinent for at least 2 weeks before starting been examined in human cocaine administration studies mazindol (58). This compound is only available intravenously, but this offers promise for related compounds such as the D3 partial ago- Nonspecific Anticraving Agents nist recently reported in the animal laboratory (19). A number of other agents have been tested to reduce the Amantadine increases dopaminergic transmission, but desire or craving for cocaine. The rationales have broadly whether the mechanism is DA release, direct effects on DA involved mechanisms such as sensitization and kindling as receptors, or DA reuptake blockade is unclear. One study well as neurotransmitter systems that are indirectly affected examined the effects of acute amantadine (200 or 400 mg) by cocaine such as the opioid, excitatory amino acid/gluta- and chronic amantadine (100 mg twice daily for 4 days) mate, and GABAergic systems. For most of these ap- followed by insufflation of cocaine 0. Al- proaches, outpatient clinical trials have been quite limited. Finally, stress responses and the associ- The effectiveness of amantadine was evaluated in a double- ated elevation of cortisol have been considered as potentially blind, placebo-controlled trial in which 42 patients in a day important in cocaine craving induction and as a therapeutic treatment program were randomized to amantadine 100 mg agent. However, a cocaine administration study showed no twice daily (n 21) to be taken over 10 days or placebo reduction in cocaine effects or self-administration with the (n 21). Urine toxicology screens showed that those who cortisol synthesis inhibitor ketoconazole in spite of signifi- had received amantadine were significantly more likely to cant reductions in cortisol levels (59). A double-blind, placebo- human volunteers examined the effects of 10 mg L-deprenyl controlled, crossover study of the interaction of 400 mg of alone and in combination with cocaine, but found no atten- CBZ daily for 5 days with cocaine found no effects on uation of cocaine effects (54). More recently, it was found subjective response to cocaine (60). A double-blind, pla- to attenuate some subjective effects of cocaine, and an out- cebo-controlled study in outpatients included a 20-day, patient trial showed reduced cocaine use reported in com- controlled, fixed-dose (CBZ 200 mg or 400 mg or placebo) Chapter 102: Pathophysiology and Treatment of Cocaine Dependence 1467 trial in 30 volunteers and found that cocaine use was un- caine 'high,' it decreased craving for cocaine. Another study in 183 cocaine abusers ran- cocaine concentration following cocaine administration was domized to CBZ 400 or 800 mg daily or placebo showed significantly greater while on disulfiram, and this may have that CBZ at 400 mg was associated with a significant de- contributed to the decreased craving and increased dys- crease in cocaine-positive urines and a reduction in cocaine phoria observed in some subjects. However, three other double-blind, placebo- that cocaine use was significantly reduced in the disulfiram controlled studies with CBZ treatment in over 150 subjects group compared to psychotherapy alone, with patients who found no significant difference in cocaine use, cocaine-posi- abused both alcohol and cocaine. The patients reported a tive urine samples, or depressive symptoms measured by the significantly lower percentage of cocaine use days and fewer Beck Depression Inventory (63–65). Plasma CBZ levels of days of cocaine use, and fewer positive urine screens for 5. In surveys of cocaine abusers, 65% have reported signifi- Naltrexone is an opioid antagonist that has been exam- cant problems in concentration and 57% reported memory ined as a treatment agent for cocaine abuse. One study ex- problems, and formal testing suggests some sustained abnor- amined the effects of cocaine after 10 days of treatment with malities in memory and concentration among abusers (3, naltrexone 50 mg or placebo in a double-blind, randomized, 16). Initial studies of recovering cocaine-dependent patients within-subjects design (66). Some cocaine-induced subjec- have revealed impairments of short-term memory, atten- tive effects were less during naltrexone than placebo admin- tion, and complex psychomotor and simple motor abilities, istration. A placebo-controlled outpatient study of naltrex- but the data are limited (16,77). The calcium channel antago- functional brain damage caused by cocaine including strokes nist nifedipine has been studied and shows some promise (16). Structural imaging using computed tomographic scan- (68). Nimodipine showed a reduction in the effects of intra- ning and magnetic resonance imaging (MRI) have shown venous cocaine as well as reductions in acute cocaine-related enlarged ventricles and sulci in cocaine abusers (79). Func- cardiovascular toxicity, but lamotrigine did not reduce co- tional neuroimaging studies have shown focal reductions in caine effects in a similar placebo-controlled crossover study regional cerebral blood flow(rCBF) among chronic cocaine (69,70). Memantine, a glutamate inhibitor, showed no effi- abusers (15–17). These defects also appear to be persistent cacy in reducing cocaine effects acutely (71). Outpatient for several weeks of abstinence at least, and can be associated placebo-controlled studies have not been done with these with neuropsychological deficits (15–17,80). Unfortu- normally high levels of phosphomonoesters and lowlevels nately, this agent is not available in the United States, and of nucleotide triphosphates compared to normals (81). However, baclofen, which is a involve vasoconstriction (82) and platelet abnormalities. Abnormal platelets may produce thrombosis No other controlled trials have been published with this or in cerebral vessels and produce blood flowalterations (18). One study in six cocaine-dependent nary test of 4 weeks of aspirin therapy led to a 50% improve- volunteers examined the effect of disulfiram 250 mg on ment in cerebral perfusion (16). In a placebo-controlled responses to intranasal cocaine (2 mg/kg) using a random- study that has just been completed, aspirin significantly re- ized double-blind, placebo-controlled design (75). Al- duced perfusion defects on single photon emission com- though disulfiram induced no significant differences in co- puted tomography (SPECT) imaging (84,85). It was a large, multisite psychother- apy clinical trial for outpatients who met the DSM-IV crite- Although the simplest peripheral blocking approach of pas- ria for cocaine dependence. For 480 randomized patients, sively injecting polyclonal antibodies to cocaine into a four treatments were compared over an 18-month period. One treat- ies would not last very long and might be of limited use as ment also added cognitive therapy, one added supportive- a sustained treatment. For any type of relapse prevention, expressive psychodynamic therapy, and one added individ- the immune response elements must remain at relatively ual drug counseling. The final group had drug counseling high levels for periods of several weeks or months, which alone. Two specific interaction hypotheses, one involving is best done by active immunization (86).

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