By C. Reto. University of Texas at Austin. 2018.

CD4— T-helper cells; CD8— cytotoxic cells; -IN F— -interferon; IL— interleukin purchase citalopram 40 mg mastercard. Initial events Late events Renal Involvement in Tropical Diseases 6 generic citalopram 40 mg visa. Am astigotes downregu- late the host cells that show no attem pt at eradicating the parasite. A, H ere Trichinella spiralis is encysted in the m uscle tissue of a patient. This lesion usually is subclinical but m ay be m anifested as an acute nephritic syndrom e that can be resolved with anti- parasitic treatm ent. A, The parasite O nchocerca volvulus deposits lesions in tissues. Some patients, however, develop an autoimmune reaction that leads to progressive glomeru- lonephritis. A, Prolifer- ative glom erulonephritis with capillary wall thickening. This lesion also is associated with autoim m unity or concom itant viral infection. A B A B FIGURE 6-31 FIGURE 6-32 Intestinal schistosom iasis. A, Pair of adult Schistosom a m ansoni worm s in colonic m ucosa. Patient with hepatosplenic schistosom iasis, (H em atoxylin-eosin stain 75. O f these patients, 15% develop clinically overt glom erular lesions. H alf of the 15% becom e hypertensive, m ost becom e nephrotic at som e stage, and alm ost all progress to end-stage disease. O ther im m unofluorescent deposits at this stage include im m unoglobu- lins M and G and com plem ent C. This lesion m ay be encountered in infection by Schistosom a m ansoni, S. The lesion does not necessari- ly progress any further. A, M esangial proliferative glom eru- The two lesions in panels C and D are associated with advanced lonephritis. N ote the crucial role of the portal vein hepatic fibrosis, which 1) induces glom eru- lar hem odynam ic changes; 2) perm its schis- Egg granulomata Egg granulomata tosom al antigens to escape into the system ic in the portal tracts in the colonic mucosa circulation, subsequently depositing in the glom erular m esangium ; and 3) im pairs clearance of im m unoglobulin A (IgA), M ucosal Switching which apparently is responsible for progres- Autoimmunity Antigens breach sion of the glom erular lesions. IgA synthesis seem s to be augm ented through B-lym pho- cyte switching under the influence of inter- IgG,M ,E Immune complexes IgA leukin-10, a m ajor factor in late schistoso- m al lesions. Impaired macrophage function Periportal fibrosis Portosystemic collaterals Glomerular deposits B A C FIGURE 6-36 (see Color Plate) Renal am yloidosis in schistosom iasis. A, Schistosom al granulom a (top), three glom eruli with extensive am yloid deposits (bottom ), and dense interstitial infiltration and fibrosis in a patient with m assive Schistosom a haem atobi- um infection. The m onocyte Interleukin-1,6 Hepatocyte continues to release interleukin-1 and interleukin-6 under the influ- + Antigen ence of schistosom al antigens. These antigens stim ulate the hepato- cytes to release AA protein, which has a distinct chem oattractant function. The m onocyte is the norm al scavenger of serum AA pro- Uptake tein, a function that is im paired in hepatosplenic schistosom iasis. AA protein Serum AA protein accum ulates and tends to deposit in tissue. M atrix adhesion Tissue deposition Chemoattraction Toxic Tropical Nephropathies Toxins of Animal Origin FIGURE 6-38 NEPHROPATHIES ASSOCIATED W ITH EXPOSURE TO ANIM AL TOXINS N ephropathies associated with exposure to toxins of anim al origin. N ote that acute renal failure is the m ost com m on and Acute renal failure Vasculitis Subnephrotic proteinuria Nephrotic syndrome im portant renal com plication. Vascular and glom erular lesions are occasionally encoun- Snake bite +++ + + (MPGN) tered with specific exposures [56–62]. Scorpion sting + Insect stings + ++ (MCD, MPGN, MN) Jelly fish sting + Spider bite + Centipede bite + Raw carp bile ++ MCD— minimal change disease; MN— membranous glomerulonephritis; MPGN— mesangial proliferative glomeru- lonephritis; +— <10%; ++— 10%–24%; +++— 25%–50%. The im m ediate effect of Snake venom exposure is attributed to direct hem atologic toxicity involving the coagulation system Direct toxicity Immunologic reaction and red cell m em branes. The m assive release of cytokines and rhabdom yolysis also contribute. Late effects m ay be encoun- Disseminated Hemolysis Cytokines tered as a consequence of the im m une intravascular Rhabdomyolysis M ediators M esangiolysis response to the injected antigens. N ote that with the exception of Djenkol bean nephrotoxicity, Acute renal failure Hypertension Proteinuria Hematuria m ost plant toxins lead to acute renal failure due to hem odynam ic effects [63–66]. Djenkol bean +++ ++ +++ ++++ Mushroom poisoning + + Callilepis laureola +++ Semecarpus anacardium + +— <10%; ++— 10%–24%; +++— 25%–49%; ++++— 50%–80%.

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But buy citalopram 10 mg without prescription, when the electricity is provided from outside citalopram 10 mg cheap, via skin electrodes, there are difficulties in focusing it on particular brain sites. The skull (like wood) is very poor conductor of electricity. Thus, high levels of electrical energy are needed at the skin electrodes and the current spreads out. For example, during ECT, some electricity enters the skull via the eye sockets, nasal passages and auditory canals. In delivering sufficient electrical energy to particular brain regions for an antidepressant effect, energy is widely dispersed throughout the brain, making convulsion and temporary memory difficulties unavoidable. The convulsion means that a general anaesthic is necessary, ushering in further potential complications. In the mid 1980s it became possible to stimulate cortical regions with single pulses of transcranial magnetic stimulation (TMS). Immediately, TMS became an important tool in clinical neurophysiology. Subsequently, machines were developed which the capacity to provide repeated (r) stimulation – from 1–50 Hz. It may be found useful in other psychiatric disorders in the future. In 1831 Michael Faraday found that when two coils are close together (but not touching) and a current is passed through one, as the current is turned on and off, a brief pulse of electricity passes through the second coil. The magnetic field created by the electrical current in the first coil extends into the second coil, and when this magnetic field starts and stops, it creates a current in the second coil. These are termed the primary and secondary currents. The principle is used in transformers to alter voltage. A second coil is not necessary; a secondary current will be induced in any conductor (water-melon, brain) which is close to a coil through which a primary current is pulsed. We have all moved a paper-clip around on a wooden tabletop with a magnet held underneath. This demonstrates that magnetic fields, unlike electricity, pass relatively unimpeded, through non-conductors of electricity. This allows the TMS operator (unlike the ECT operator) to place a (secondary) current in a precise location in the cerebral cortex. Physiology When TMS is applied, the induced electric field causes a flow of current and electric charge accumulates on neural membranes, causing depolarization. With the flat, figure-of-eight coil, depolarization occurs at about the junction of the grey and white matter. At this point, axons with cell bodies in the grey matter bend (altering physical Pridmore S. Thus, for purists, this is not “magnetic” stimulation. The magnetic aspect is important in getting the electricity to the other side of the skull, painlessly and with precision. Chervyakov et al (2015) offer possible mechanisms underpinning clinical effects: 1. Low-frequency TMS (defined as stimulation below 1 Hz) reduces neuronal excitability, whereas high-frequency TMS (defined as greater than 5 Hz) increases neuronal excitability. Long-term potentiation (LTP) and long-term depression (LTD) refer to changes in synaptic strength (efficiency) associated with TMS. LTP is caused by high-frequency stimulation, LTD is caused by low-frequency stimulation LTP and LTD are probably the key mechanisms supporting long-term effects of TMS. TMS stimulation induces gene expression and enhances the production of a number of enzymes, including NO synthase. TMS affects the expression of various receptors, including NMDA receptors. The response of patients to TMS is influenced by polymorphisms within the genes that encode for serotonin (5-HT) carriers, 5-HT1a receptors, and brain derived neurotrophic factor (BDNF). May et al (2007) found that 1 Hz stimulation to the left superior temporal gyrus on 5 days led to increased grey matter volume at this site. These macroscopic changes were likely dependent on synaptogenesis, angiogenesis, gliogenesis, neurogenesis, increased cell size, and increased blood flow. Imaging, MDD and TMS Imaging is a rapidly developing field, and the physiology of MDD and the effects of TMS are not yet fully understood. Nevertheless, important observations are being made and we need to try to make sense of them. TMS was effective in correcting this pathological state (Speer et al, 2000).

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The contribution of a presy­ Within 2 weeks of carbamazepine treatment at doses rang­ naptic cholinergic deficit to memory and other cognitive ing from 100 to 300 mg/d purchase 10mg citalopram mastercard, behavioral improvement was impairments in AD (69 purchase citalopram 20 mg amex,70) has been a cornerstone of AD noted in all subjects. In a larger open study of AD patients drug development. Interest in a potential contribution of who had failed to respond to antipsychotic drugs (93), re­ this cholinergic deficit to noncognitive behavioral problems duction in hostility, agitation, and uncooperativeness was in AD increased after Cummings (101) observed that the noted in five of nine patients. In this study, two patients agitation and psychotic symptoms characteristic of delirium whose agitated behaviors decreased manifested ataxia and induced by anticholinergic drug toxicity resemble some confusion, which resolved with reduction of the carbamaze­ noncognitive behavioral symptoms occurring sponta­ pine dose. The mean dose of carbamazepine in this study neously in AD (e. In contrast to enthusiastic authors of these reasoned that enhancing brain cholinergic neurotransmis­ small reports, Chambers et al. Empiric from carbamazepine in 19 elderly patients with dementia support for this hypothesis came from a carefully performed who were prescribed carbamazepine at doses of 100 to 300 single-case study in which the cholinesterase inhibitor phy­ mg/d. Target symptoms in this study were wandering, over- sostigmine reduced psychotic symptoms in a patient with activity, and restlessness. Further support has come in long-term care facilities with disruptive agitated behav­ from post hoc and secondary outcome analyses of large, mul­ iors. The modal carbamazepine dose at 6 weeks was 300 ticenter cholinesterase inhibitor outcome trials in AD. Statistical addition to demonstrating modest effects on cognitive func- 1262 Neuropsychopharmacology: The Fifth Generation of Progress tion, the cholinesterase inhibitors tacrine (104), galantam­ AD remains limited despite the prevalence of these prob­ ine (105), donepezil (106), metrifonate (107), and (in DLB lems and their impact on patient management. Extrapolat­ subjects) rivastigmine (108) significantly improved such ing from psychopharmacologic outcome studies in younger, noncognitive behaviors as delusions, hallucinations, pacing, nondemented patients with such diseases as depression and and uncooperativeness more than did placebo. However, schizophrenia has not been a satisfactory approach to devel­ these large, multicenter cholinesterase inhibitor studies ex­ oping effective pharmacologic treatments for noncognitive cluded AD patients with substantial noncognitive behav­ behavioral disturbances in elderly patients with AD and ioral problems. It is just such severely disturbed patients other dementing disorders. The clear placebo responses who must be studied prospectively to establish the clinical noted in several carefully performed pharmacologic trials in importance of cholinesterase inhibitors in the management AD patients with noncognitive behavioral problems empha­ of noncognitive behavioral problems in AD. More must be learned about fects of cholinergic enhancement on noncognitive symp­ the neurobiological substrates of psychotic and disruptive toms in AD come from a multicenter trial of the selective agitated behaviors in AD. Such knowledge is essential to M1 muscarinic cholinergic agonist xanomeline (109). Al­ the rational development of more effective pharmacothera­ though the effects of xanomeline on cognitive function dis­ peutics for these disturbing and costly problems. Raskind receives research support and/or consultant observed over the three doses of xanomeline administered. About a peculiar disease of the cerebral cortex �-Adrenergic Antagonists [1907 article translated by L. Despite substantial loss of noradrenergic locus ceruleus neu­ 2. Neuropsychiatric as­ rons in AD, studies measuring the concentrations of norepi­ pects of multi-infarct dementia and dementia of the Alzheimer type. Pharmacotherapy of agitation tissue or cerebrospinal fluid (110–112) suggest that nora­ in dementia. Behavioral symptomatology AD manifest an enhanced behavioral agitation response to in dementia of the Alzheimer type. In a recently reported placebo-controlled pilot 153:1438–1443. Mental and be­ havioral disturbances in dementia: findings from the Cache placebo in reducing disruptive agitated behaviors in elderly County study on memory in aging. Am J Psychiatry 2000;157: nursing home residents with AD. Propranolol was well tolerated nursing home admission because of disruptive behavior. J Clin placebo-controlled trials of propranolol in AD patients with Psychiatry 1987;48[Suppl 5]:9–15. Identifying patterns of disruptive behavior in long-term care residents. J Am Geriatr The database supporting guidelines for the pharmacologic Soc 1999;47:830–836. A new rating scale for medication and the quality of care in rest homes. Psychoactive medication sertraline and nortriptyline in the treatment of major depressive use in intermediate-care facility residents. JAm depression in dementia patients: a controlled clinical trial. Imipramine in the treatment in nursing home residents.

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FIGURE 12-3 O ver 95% of the filtered am ino acid load is norm ally reabsorbed in Cystine actually is a neutral am ino acid that shares a com m on the proxim al tubule buy 40 mg citalopram free shipping. The term am inoaciduria is applied when m ore carrier with the dibasic am ino acids lysine 40mg citalopram otc, arginine, and ornithine. Am inoaciduria The transport of all four am ino acids is disrupted in cystinuria. The can occur in the context of m etabolic defects, which elevate plasm a rarer disorder, lysinuric protein intolerance, results from defects in am ino acid concentrations and thus increase the glom erular filtered the basolateral transport of dibasic am ino acids but not cystine. In addition, am inoaciduria can arise from genetic defects in consequent hyperam m onem ia. Three distinct groups of inherited am inoacidurias are distin- H artnup disease, blue diaper syndrom e, m ethioninuria, im inogly- guished based on the net charge of the target am ino acids at neutral cinuria, and glycinuria. Several neutral am ino acid transporters pH : acidic (negative charge), basic (positive charge), and neutral have been cloned and characterized. H artnup disease involves a neutral am ino acid transport system Acidic am inoaciduria involves the transport of glutam ate and in both the kidney and intestine, whereas blue diaper syndrom e aspartate and results from a defect in the high-affinity sodium - involves a kidney-specific tryptophan transporter. M ethioninuria potassium –dependent glutam ate transporter. It is a clinically appears to involve a separate m ethionine transport system in the benign disorder. Case reports describe seizures, m ental retardation, Four syndrom es caused by defects in the transport of basic and episodic hyperventilation in affected patients. The patho- am ino acids or cystine have been described: cystinuria, lysinuric physiologic basis for this phenotype is unclear. Im inoglycinuria protein intolerance, isolated cystinuria, and isolated lysinuria. Differences in the urinary Category Phenotype Intestinal transport defect excretion of cystine in obligate heterozygotes and intestinal amino acid transport studies in I hom ozygotes have provided the basis for Heterozygote No abnormality defining three distinct phenotypes of cystin- Homozygote Cystinuria, basic aminoaciduria, cystine stones Cystinine, basic amino acids uria. Genetic studies have identified II m utations in the gene (SCL3A1) encoding a Heterozygote Excess excretion of cystine and basic amino acids Homozygote Cystinuria, basic aminoaciduria, cystine stones Basic amino acids only high-affinity transporter for cystine and the III dibasic am ino acids in patients with type I Heterozygote Excess excretion of cystine and basic amino acids cystinuria [10,11]. In patients with type III Homozygote Cystinuria, basic aminoaciduria, cystine stones None cystinuria, SCL3A1 was excluded as the disease-causing gene. A second cystin- uria-susceptibility gene recently has been From Morris and Ives; with permission. Excessive urinary excretion of cystine (250 to 1000 mg/d of cystine/g of creatinine) coupled with its poor solubility in urine causes cystine precipitation with the formation of characteris- tic urinary crystals and urinary tract calculi. Stone formation often causes urinary tract obstruction and the associated problems of renal colic, infection, and even renal failure. The treatment objective is to reduce urinary cystine concentration or to increase its solubility. High fluid intake (to keep the urinary cystine concentration below the solubility threshold of 250 mg/L) and urinary alkalization are the mainstays of therapy. For those patients refractory to conservative management, treatment with sulfhydryl-containing drugs, such as D-penicillamine, mercaptopropionylglycine, and even captopril can be efficacious [14,15]. These disorders include X-linked hypo- osteomalacia in adults. These disorders can be distinguished on phosphatemic rickets (HYP), hereditary hypophosphatemic rickets the basis of the renal hormonal response to hypophosphatemia, the with hypercalciuria (HHRH), hypophosphatemic bone disease (HBD), biochemical profile, and responsiveness to therapy. In addition, the autosomal dominant hypophosphatemic rickets (ADHR), autosomal rare disorder XLRH is associated with nephrolithiasis. The clinical recessive hypophosphatemic rickets (ARHR), and X-linked recessive features of the two most common disorders HYP and HHRH are hypophosphatemic rickets (XLRH). W hereas both disorders have defects in renal Pi two com m on features: persistent hypophosphatem ia caused by reabsorption, the renal hormonal response to hypophosphatemia is decreased renal tubular phosphate (Pi) reabsorption (expressed as im paired in H YP but not in H H RH. Indeed, in children with decreased ratio of plasma concentration at which maximal phosphate HHRH, phosphate supplementation alone can improve growth rates, reabsorption occurs [Tm P] to glom erular filtration rate [GFR], resolve the radiologic evidence of rickets, and correct all biochemical [TmP/GFR], a normogram derivative of the fractional excretion of abnormalities except the reduced TmP GFR. Cell culture, parabiosis, and transplantation experiments have demonstrated that Phosphatonin Degradation the defect in HYP is not intrinsic to the kidney but involves a circulat- ing humoral factor other than parathyroid hormone [16,17]. Phosphate is transported across the lum inal m em brane of the proximal tubule by a sodium-phosphate cotransporter (NaPi). This ATP transporter is regulated by multiple hormones. Among these is a puta- + 3Na+ tive phosphaturic factor that has been designated phosphatonin. Na It is postulated that phosphatonin inhibits Pi reabsorption by way of Pi 2K+ the sodium-coupled phosphate cotransporter, and it depresses serum 1α-hydroxylase ADP 1,25-dihydroxy-vitamin D3 production by inhibiting 1- -hydroxlase activity and stimulating 24-hydroxylase activity. Positional cloning studies in families with HYP have identified a gene, designated PEX 25-Vitamin D 1,25-Vitamin D (phosphate-regulating gene with homologies to endopeptidases on the X chromosome), that is mutated in patients with X-linked hypophos- phatemia.

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