By F. Chris. Art Institute of Ft Lauderdale. 2018.
A B FIGURE 9-3 (See Color Plate) H istologic features of hyperacute rejection order propecia 1mg fast delivery. H yperacute rejection is of neutrophils in the glomeruli and peritubular capillaries in the kidney very rare and is caused by antibody-m ediated dam age to the graft buy propecia 5mg on line. A, H em atoxylin and eosin stain of The clinical m anifestation of hyperacute rejection is a failure of the biopsy showing interstitial hem orrhage and extensive coagulative kidney to perfuse properly on release of the vascular clam ps just necrosis of tubules and glomeruli, with scattered interstitial inflam- after vascular anastomosis is completed. The kidney initially becomes matory cells and neutrophils. B, Immunofluorescence stain of kidney firm and then rapidly turns blue, spotted, and flabby. The presence with hyperacute rejection showing positive staining of fibrins. A and B, Photo- whom preform ed anti-H LA antibodies are present. This type of micrographs showing histologic features of acute accelerated vascular rejection occurs in patients who have had a previous graft and presents rejection. Glomerular and vascular endothelial infiltrates and swelling with a decrease in renal function; the clinical picture is sim ilar to are visible. An accelerated rejection, which m ay start on the second that for hyperacute rejection. Acute rejection episodes may occur entities m ay be extrem ely difficult. The classic acute rejection episode of and cyclosporine nephrotoxicity m ay be difficult, especially in the the earlier era (ie, azathioprine-prednisolone) was accom panied by early posttransplant period when more than one cause of dysfunction swelling and tenderness of the kidney and the onset of oliguria can occur together. Knowledge of the natural history of several with an associated rise in serum creatinine; these sym ptom s were clinical entities is extrem ely helpful in lim iting the differential diag- usually accom panied by a significant fever. Reversible m edical and m echanical causes should be excluded who have been treated with cyclosporine, the clinical features of an first. Percutaneous biopsy of the renal allograft using real-time ultra- acute rejection are really quite m inim al in that there is perhaps sound guide is a safe procedure. It provides histologic confirmation som e swelling of the kidney, usually no tenderness, and there m ay of the diagnosis of rejection, aids in the differential diagnosis of be a m inim al to m oderate degree of fever. Because such an acute graft dysfunction, and allows for assessm ent of the likelihood of a rejection may occur at a time when there is a distinct possibility of response to antirejection treatm ent. CHRONIC ALLOGRAFT chronic rejection REJECTION fibrosis and intimal thickening. Interstitial Acute rejection fibrosis and tubular atrophy. C, Typical Antibody deposition presentation and pathologic features. Chronic Oxidized LDL rejection occurs during a span of m onths Typical clinical presentation Infection Gradual increase in creatinine (months) to years. It appears to be unresponsive to Non-nephrotic–range proteinuria current treatm ent and has em erged as the T cells m ajor problem facing transplantation. No recent nephrotoxic events M acrophages Because chronic rejection is thought to be the Key pathologic features Platelet aggregates end result of uncontrolled repetitive acute Interstitial fibrosis rejection episodes or a slowly progressive Arterial fibrosis and intimal thickening inflam m atory process, its onset m ay be as Cytokines/ early as the first few weeks after transplan- growth factors tation or any tim e thereafter. D, The likely sequence of events in chronic Cell proliferation rejection and potential m ediating factors for Fibrosis key steps. Progressive azotem ia, proteinuria, and hypertension are the clinical hallmarks Tubulointerstitial of chronic rejection. Im m unologic and Vascular injury injury nonimmunologic mechanisms are thought Arteriosclerosis Glomerular sclerosis to play a role in the pathogenesis of this entity. Im m unologic m echanism s include antibody-m ediated tissue destruction that Reduced nephron occurs possibly secondary to antibody- mass dependent cellular cytotoxicity leading to obliterative arteritis, growth factors derived from m acrophages and platelets leading to Graft loss D fibrotic degeneration, and glomerular hyper- tension with hyperfiltration injury due to reduced nephron mass leading to progressive glomerular sclerosis. Nonimmunologic causes can also contribute to the decline in renal function. Atheromatous renovascular disease of the transplant kidney m ay also be responsible for a significant num ber of cases of progressive graft failure. ATG— antithym ocyte globulin; ATN — acute tubular necrosis; BP— Slowly rising creatinine blood pressure; CsA— cyclosporine; LDL— low-density lipoprotein. Check CsA level High Low Lower CsA dose and repeat creatinine Improved No improvement Ultrasound Obstruction No obstruction Biopsy Rejection ATN Glomerulonephritis Recurrent GN de novo GN Acute Acute Chronic on chronic Adjust immunosuppressant Temporizing measures Steroid bolus Control BP OKT3 or ATG Avoid nephrotoxins E FIGURE 9-7 BANFF CLASSIFICATION OF RENAL The Banff classification of renal allograft rejection. This schem a is ALLOGRAFT REJECTION an internationally agreed on standardized classification of renal allograft pathology that regards intim al arteritis and tubulitis as the m ain lesions indicative of acute rejection. Normal Patchy mononuclear cell infiltrates without tubulitis is not uncommon Borderline changes No intimal arteritis; mild tubulitis and endocapillary glomerulitis Acute rejection Grade I: tubulitis ++ Grade II: tubulitis with glomerulitis Grade III: intimal arteritis, interstitial hemorrhage, fibrinoid, thrombosis Transplant Rejection and its Treatment 9. A 23- or 25-gauge spinal needle is used under aseptic conditions. A 20-mL syringe containing 5 mL of RPM I-1640 tissue culture medium is connected to the needle. Ultrasound guidance m ay be used on the rare occasions when the graft is not easily palpable. M onitoring of other products of inflam m ation such as neopterin Constant (but not excessive) suction and lym phokines continues to be explored. It has been shown that acute rejection is associated with elevated plasm a interleukin (IL)-1 in azathioprine-treated patients and IL-2 in cyclosporine-treated patients. IL-6 is also increased in the serum and urine im m ediately after transplantation and during acute rejection episodes. The m ajor 25-G needle problem, however, is that infection, particularly viral, can also elevate cytokine levels.
W ith the onset of cardiac failure propecia 1 mg cheap, there appeared to be an inverse rela- tionship between arterial pressure and m ortality quality 5 mg propecia. From the outset, the strongest predictor of congestive heart failure was elevated blood pressure. Blood pressure values Loss of diurnal blood pressure patterns 200 Heart rate have been im plicated in increased rates of target organ injury in patients with hyper- 150 tension. In norm al persons with essential 140 hypertension, nocturnal pressures decreased by at least 10% and were associated with a 100 decrease in heart rate. Several conditions have 90 been associated with a loss of the nocturnal decrease in pressure, particularly chronic 50 steroid adm inistration and chronic renal MMMM RxFd Fd ZZZZZ Rx RxZZZ ZZZZZZZZZZZZZZZZZZ MMMM failure. Such a loss in norm al circadian MMMM rhythm , in particular loss of the nocturnal 0 decrease in blood pressure is more commonly 0. Data from a single subject with end-stage renal disease studied with are depicted here. The biopsy patients with parenchym al renal disease. A, Photom icrograph of specimen shows the following features of malignant nephrosclerosis: malignant phase hypertension. Regardless of the cause of renal disease, these patients develop vascular and glomerular injury, which can untreated hypertension leads to more rapid loss of remaining nephrons progress to irreversible renal failure. Before the introduction of antihy- and decline in glom erular filtration rates. A striking exam ple of pertensive drug therapy, patients with malignant phase hypertension pressure-related injury may be observed in patients with malignant routinely proceeded to uremia. Effective antihypertensive therapy can phase hypertension. This image is an open biopsy specimen obtained slow or reverse this trend in some but not all patients. B, Progressive from a patient with papilledema, an expanding aortic aneurysm, and renal failure in malignant hypertension over 8 years. Similarly, follow-up studies after 16 years of Line graph showing Kaplan-M eier estimates of ESRD rates; 15-year more than 300,000 men in M RFIT demonstrated a progressive increase follow-up. B, Age-adjusted 16-year incidence of all-cause ESRD in in the risk for ESRD, m ost pronounced in blacks. These data men in the M ultiple Risk Factor Intervention Trial (M RFIT). Large- suggest that blood pressure levels predict future renal disease. However, scale epidemiologic studies indicate a progressive increase in the risk it rem ains uncertain whether benign essential hypertension itself for developing ESRD as a function of systolic blood pressure levels. SBP— systolic blood visit was predictive of progressively higher risk of ESRD over a 15-year pressure. Shown are rates of decrease of glom erular filtration rate lar filtration rate is illustrated. The rates of decline decreased con- (GFR) for patients enrolled in the M DRD trial, depending on level siderably with adm inistration of antihypertensive drug therapy. A component Among other mechanisms, the decrease in arterial pressure lowers of this trial included strict versus conventional blood pressure control. The term strict was defined as target m ean arterial pressure (M AP) This effect is correlated with a reduction in proteinuria and slower of under 92 m m H g. The term conventional was defined as M AP developm ent of both glom erulosclerosis and interstitial fibrosis. The rate of decline in GFR increased at higher distinctive feature of m any glom erular diseases is the m assive pro- levels of achieved M AP in patients with significant proteinuria teinuria and nephron loss associated with high single-nephron (>3. N o such relationship was evident over the duration of glomerular filtration, partially attributable to afferent arteriolar this trial (m ean, 2. The appearance of worsening proteinuria (>3 g/d) is These data em phasize the im portance of blood pressure in deter- related to progressive renal injury and development of renal failure. N o distinction was m ade in this study regarding the tion and slow the progression of renal injury. Ccr— creatinine clear- relative benefits of specific antihypertensive agents. Rates of disease progression (defined as the slope of 1/creatinine) were determ ined in –0. The rates of progression were defined between mean creatinine levels –0. Brazy and coworkers dem onstrated that the slope of disease progression appeared to be related to the range of –0. H ence, these authors argue that m ore intensive antihypertensive therapy m ay –0. As noted in the M odification of Diet in Renal Disease 0 trial, such benefits are m ost apparent in patients with proteinuria 70–85 85–90 90–96 96–113 over a shorter follow-up period. Attention m ust be given to drug accu- Diuretics: m ulation and lim itations of individual drug efficacy as glom erular Thiazide class filtration rates decrease in chronic renal disease. Potassium levels m ay increase during adm inistration of potassium -sparing agents Loop diuretics and m edications that inhibit the renin-angiotensin system , especial- Potassium-sparing agents ly in patients with im paired renal function. Adrenergic inhibitors Peripheral agents, eg, guanethidine Central -agonists, eg, clonidine, methyldopa, and guanfacine -Blocking agents, eg, doxazosin -Blocking agents Combined - blocking agents, eg, labetalol Vasodilators Hydralazine Minoxidil Classes of calcium-channel blocking agents Verapamil Diltiazem Dihydropyridine Angiotensin-converting enzyme inhibitors Angiotensin receptor blockers 4 60 Conventional M ean Strict ±SEM n=87 patients 3 55 Bars=95% confidence intervals for GFR estimates 2 50 45 1 40 0 35 –1 30 –2 25 –3 –6 0 6 12 18 24 30 36 42 48 Strict Conventional A Time, mo B Blood pressure control group FIGURE 2-26 Strict blood pressure control and progression of hypertensive these patients were low. It should be emphasized that entry criteria nephrosclerosis. W hether vigorous blood pressure reduction reduces excluded patients with diabetes and m assive proteinuria.
Lower concentrations of have demonstrated elevated numbers and densities of 5HT homovanillic acid (HVA) propecia 5mg free shipping, a DA metabolite buy propecia 5mg free shipping, have been ob- neurons in the dorsal raphe of suicide victims, most of served in CSF of patients with depression, and depression- whom had major depression. In addition, Becker and col- inducing effects of DA-depleting agents or DA antagonists leagues (18) have demonstrated significantly low echogeni- have been reported (143,144,189). In contrast, agents that city of the dorsal raphe nucleus in patients with major enhance DA transmission, at least in part, such as buprop- depression using a novel transcranial ultrasound technique. Given that DA is intimately involved in pathologic involvement of brainstem serotonergic nuclei in motivational process and affect (73,167), these findings sug- depression, but the study by Underwood and associates gest that a deficiency of mesolimbic and/or mesocortical ruled out a loss of serotonergic neurons in depressed sui- DA is a leading candidate for the etiology of core symptoms cides, suggesting that the postulated hypofunction of the of depression, such as difficulty in the experience of pleasure serotonergic system is not owing to fewer serotonergic neu- (anhedonia), social isolation, loss of motivation (lack of in- rons, but dysfunction of serotonergic neurons. As is the case terest), and psychomotor retardation (190). In fact, repeated treatment of rats dysfunction or activation of mesolimbic and/or mesocorti- with antidepressant drugs results in a net enhancement of cal DA systems are implicated in psychiatric disorders, in- serotonergic transmission (24). This effect is regardless of cluding depression, schizophrenia, and psychostimulant the primary pharmacologic site of action of the drug and drug abuse disorders. However, some overlap in the pathol- includes selective 5HT transporter inhibitors, MAOIs, tri- ogy of PD and psychiatric disorders apparently occurs be- cyclic antidepressants, and electroconvulsive shock. Selec- cause cell loss in the VTA (in addition to substantia nigra) tive 5HT transporter inhibitors and MAOIs enhance sero- has been observed in patients with PD who have complica- tonergic transmission by desensitizing the somatodendritic tions of co-morbid mood and cognitive disorders (171). Chronic administra- have delineated reciprocal pathways linking various limbic Chapter 73: Neurocircuitry of Mood Disorders 1055 and cortical regions with dopaminergic brainstem nuclei. A lower density of D1 receptors induced behavioral responses (75). This circuit includes the nucleus by chronic antidepressant medication might contribute to accumbens, amygdala, prefrontal cortex, mediodorsal thala- enhancement of D2 receptor functions as a result of a reduc- mus, ventral pallidum, and midbrain neurons located in the tion in the inhibitory interactions between these two recep- VTA. Of brain limbic structures, the nucleus accumbens tors at the level of the subunit of G proteins (182). Following expo- lished role in motivation and affect (167,75). Neurons in sure to uncontrollable foot shock, an animal model of the nucleus accumbens receive a highly compressed input depression, rats display a pronounced reduction of respond- from the amygdala, hippocampus, cingulate gyrus, and pre- ing for electrical brain stimulation of the nucleus accum- frontal cortex (68,194). This response is attenuated by repeated treatment with neurons in the nucleus accumbens are DA-containing fibers the antidepressant drug desipramine (193). Rats exposed to from the VTA (68), suggesting that the nucleus accumbens chronic mild stress, another animal model of depression, may integrate information coming from the prefrontal cor- experience decreased responsiveness to rewards (anhedonia), tex and limbic regions with those originating from the VTA. These behavioral Besides projecting to the nucleus accumbens, DA neurons changes are accompanied by lower D2/3 receptor binding ascending from the VTA project to other limbic structures, in the limbic forebrain that is reversed by 5 weeks of imipra- including discrete regions of amygdala, to cortical areas, and mine treatment (127). Overall, preclinical findings imply to the septum (116). Prefrontal, orbitofrontal, and cingulate that a putatively important pharmacologic effect of antide- cortices receive robust innervation from the VTA. Interest- pressant treatment is the augmentation of mesolimbic DA ingly, most of the areas receiving DA projections from the activity. A few recent studies have measured the DA receptors in If DA neurotransmission were disrupted in depression, depressed patients in vivo using brain imaging techniques. Numer- in the striatum in depression, possibly reflecting reduced ous studies demonstrate that antidepressant drugs enhance DA function and a consequential up-regulation of these mesolimbic DA activity. On the other hand, Ebert and associates, antidepressant drugs (tricyclics, mianserin, or citalopram) 1996 (43) found striatal D2 receptor binding unchanged in enhances DA agonist-induced locomotor hyperactivity, an major depression. It is noteworthy that stereotypy (a behavioral ef- INTERACTIONS BETWEEN THE fect reflecting the activity of nigrostriatal system) induced MONOAMINE NUCLEI AND MONOAMINES by D-amphetamine or apomorphine, is not increased by AND OTHER NEUROTRANSMITTERS repeated treatment with antidepressant drugs (156); there- fore, it has been assumed that the mesolimbic DA system Abnormalities of the biochemistry of one or more mono- mediates the increased behavioral responses to DA agonists amine systems may cause depressive disorders. Consistent with this disrupted monoamine biochemistry may be secondary to effect, antidepressant drug treatment increases the affinity other root biological, environmental, and/or psychological of D2 receptors for their agonist in the limbic forebrain, causes. A multitude of experimental approaches will be re- but not in the striatum (78) and chronic treatment with quired to determine the core cause(s) of depressive disorders, antidepressant drugs results in postsynaptic DA receptor even as considerable evidence of monoamine dysfunction supersensitivity in the nucleus accumbens (40). Nevertheless, it is interesting to toradiography studies confirm these findings by showing consider the relationship of the monoamines with other that when [3H]raclopride, an antagonist at D receptors, neurotransmitters that modulate monoaminergic chemistry. Several neurotransmitter inputs [3H]quinpirole, an agonist at D receptors is used as a to monoamine nuclei are of particular relevance to major 2/3 radioligand, a significant increase in its binding is observed depression because of the accumulation of evidence that in the caudate and NAC of antidepressant-treated rats these systems are also disrupted in depression. Most of the noradrenergic innervation of the VTA arises from LC neurons and noradrenergic input to the VTA is excitatory, mediated by excitatory 1-adreno- ceptors (59). In rats, chemical denervation of noradrenergic projections by DSP4 treatment suppresses mesolimbic DA release (83) and reduces the effectiveness of positive reinfor- cers (109). Hence, if noradrenergic transmission is reduced, as has been hypothesized to occur in major depression, then reduced noradrenergic input to the raphe nuclei and VTA would be expected to contribute to reductions in serotoner- gic and dopaminergic transmission (109). The LC and the VTA receive serotonergic terminals orig- inating in the raphe nuclei. Serotonergic innervation to the LC originates from several sources including the dorsal and median raphe nuclei (93,108,181). Neurotransmitter interactions at the level of monoaminergic cell bodies. Solid lines represent excitatory inputs the activity of the LC are complex, and depend on whether to theraphe nuclei,LC, and VTA;dashed linesrepresent inhibitory drugs used to manipulate the serotonergic system are admin- inputs. In some cases, neurotransmitter inputs may be both direct istered directly into the LC or whether they are administered and indirect via synapses with other neurons projecting to the nuclei. Neurotransmitters inputs shown are only those that are systemically. Systemic administration of 5HT1 and 5HT2 discussed in this chapter. These effects appear to be mediated indirectly, at least in part, rather than by actions at these receptors within the LC (30,57,64).
Because Medicaid formularies allow unrestricted and colleagues (74) and Foster and Goa (75) would not be access to any of these medications independent of location expected among treatment-refractory patients discount propecia 1 mg overnight delivery, even though in the country and the same financial incentives apply cheap propecia 1 mg online, one these patients are heavy users of inpatient services. Under would expect to see similar rates of prescribing these medica- other scenarios, these patients are the very ones for whom tions. Indeed, the distributions do appear quite similar to new interventions are associated with cost savings because each other and to the national data (Fig. That these they have higher initial rates of utilization on which to show distributions do not reflect what we know about the relative an impact (25,40). An independent study of risperidone effectiveness of these agents suggests that other factors are compared to conventional antipsychotics among outpa- strong influences on medication choice and that these influ- tients with schizophrenia using a matched comparison ences combine to create similar patterns of antipsychotic group found no difference in total treatment costs or effec- prescribing under Medicaid nationwide. These figures serve as CONCLUSION AND ADDITIONAL reminders that medications are started and discontinued for RESOURCES reasons other than effectiveness. The emphasis has been on illustrating the than dollars and does not label the cost units. Many of these studies have any findings reported as point estimates. It is important to methodologic shortcomings similar to those of the earlier tell patients, prescribers, and payers not just the best esti- cost studies of clozapine described above. Another concern mate of costs and effectiveness, but the likelihood that their is that industry sponsorship of many of these studies means costs and outcomes will fall within their acceptable ranges that they do not meet the criteria for lack of an incentive for what they are willing to pay and/or risk to gain a given for bias set forth by the New England Journal of Medicine outcome. Although their work cannot be quite arbitrary as they are prices (not costs) set by the be summarized here, useful source books include those by manufacturer. Although such studies form good starting points ics and thoughtful analyses of the economic influences on for further investigation, they need follow-up by indepen- the treatment of individuals with schizophrenia. An example of an important follow-up study is that of Conley and col- This research is the product of the collaboration of many leagues (73), who found that, among 84 treatment-refrac- individuals, both within and outside the Connecticut De- tory patients randomly assigned to a double-blind 8-week partment of Mental Health and Addiction Services fixed-dose trial of either olanzapine or chlorpromazine, (DMHAS). In particular, we would like to thank Carlos olanzapine appeared to have limited efficacy, showing only Jackson, Ph. Hence, the reduction in treatment costs assistance with the data extraction and statistical analyses associated with olanzapine noted in the reviews of Palmer of the Medicaid prescription data. The research was funded Chapter 57: The Economics of the Treatment of Schizophrenia 817 in part by U. Economic burden of mental disorders in the United MH-48830 and R01 MH-52872 from the National Insti- States. The economic burden tute of Mental Health (NIMH) to Susan Essock, Ph. Br J Psychiatry 1997;171: tion does not express the views of the Department of Mental 509–518. Health and Addiction Services or the State of Connecticut. Costs of services for schizophrenic patients The views and opinions expressed are those of the authors. Expenditures for treating schizophrenia: a population-based study of Georgia Medicaid recipients. Growth of a field in policy research: the economics tive community treatment teams. Financing psychotherapy: costs, effects, and public offset as an incidental effect of psychotherapy. Inpatient and outpatient psychiatric Health J 1983;19:42–53. Cost sharing and the treatment on psychiatric and medical-surgical hospital days. Public health care for the chronically study of supported employment for people with severe mental mentally ill: financing operating costs. Family costs associated with severe mental illness and 7. Capital costs in economic Administration 1991;18:264–271. New direction Wood Johnson Foundation program on chronic mental illness. San Francisco: Jossey-Bass, 1985: Millbank Q 1994;72:37–47. Estimating the capital mental health costs: the case of New Hampshire. Administration component of mental health care costs in the public sector. Legal system involvement health services reform on clinical practice in the United Kingdom. How transfer payments are treated in the state hospital in the care and treatment of older adults: state cost-effectiveness and cost-benefit analyses. Balancing the interests of the state and the local commu- for mental health. Administration and Policy in Mental Health 1995;23: 36. Managed behavioral health care: Current realities analysis approach. Int J Psychiatry Clinical Pract 1998;2: and future potential.
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