Professor Robert Unwin

• St Peter? Professor of Nephrology
• Centre for Nephrology
• Royal Free and University College Medical School
• London

Most patients are treated with a combination of pred typically undergo fibrosis bipolar depression in children and teens discount wellbutrin sr 150mg on line, thus creating nodules along the nisone and cyclophosphamide depression test scale buy 150 mg wellbutrin sr fast delivery. Within the central nervous system depression test long buy generic wellbutrin sr 150 mg line, involvement of small perforating arteries leads to Polyarteritis nodosa depression symptoms questions generic 150mg wellbutrin sr with amex, also known as periarteritis nodosa borderline depression definition buy wellbutrin sr 150mg cheap, is lacunar infarctions; in those uncommon cases involving a rare systemic vasculitis characterized pathologically by a larger arteries river depression definition wellbutrin sr 150 mg generic, territorial infarctions may occur and, with segmental necrotizing panarteritis. Most patients present rupture of an aneurysm, an intracerebral hemorrhage may with constitutional symptoms and involvement of the kid be seen. Within the central nervous system, several different patholo gies may be found (Drachman 1963, Nishino et al. Small, or rarely large, vessels may undergo a vasculitis and, with occlusion, Treatment with corticosteroids and cyclophosphamide is infarction occurs. Granulomas may be found, and these recommended; consideration may also be given to may appear by extension from an extracranial source. Granulomatous involvement of the meninges, primarily the pachymeninges, may also occur, and cranial nerves may be 10. In some terized pathologically by a systemic necrotizing granuloma cases granulomas may appear in the hypothalamus. The nervous system is involved in a not known, an autoimmune response, perhaps to an minority of cases: peripheral neuropathy is the most com inhaled substance, is suspected. Sarcoidosis may Over 90 percent of patients have symptoms referable to gran be considered, but this disease has features not seen in ulomas within the respiratory tract. Polyarteritis nodosa may norrhea; involvement of the nasal septum may lead to its col also be considered, although in polyarteritis nodosa one lapse, and extension of granulomatous disease to the orbit does not find the respiratory tract involvement typical of may cause proptosis. Some three-quarters of patients will have renal involvement, which may manifest initially with proteinuria and microscopic hematuria. Treatment Nervous system involvement generally occurs in the con text of respiratory or renal symptomatology (Hoffman et al. Clinical evidence of a mononeuritis multiplex or and cyclophosphamide is required. The symptomatic polyneuropathy is seen in about one-third of patients (de treatment of delirium and dementia is discussed in Groot et al. The cere matologist Hulusi Behcet, is characterized pathologically by brospinal fluid may be normal or may show a lymphocytic a systemic, primarily venular, vasculitis, and clinically by pleocytosis and an elevated total protein. Definitive diagnosis is made by uncommon in Japan and the Eastern Mediterranean region, biopsy of the lung or kidney. Meningeal inflammation may also occur, which may phlebotomy, a large pustule forms at the site of the trauma. Other symptoms include furuncles, erythema nodosum, Although the etiology is not known, an autoimmune migratory thrombophlebitis, and a non-deforming poly process is suspected; the vast majority of cases are sporadic. Within the context of these symptoms evidence of central nervous system involvement may appear. When the central nervous system is involved, a wide Differential diagnosis variety of symptoms may appear (Akman-Demir et al. These include delirium, dementia, pseudobulbar palsy with emotional inconti nence (Pallis and Fudge 1956; Motomura et al. Magnetic resonance Before proceeding, some words are in order regarding venography may be required to demonstrate dural sinus the syndrome known as reversible posterior leukoen thrombosis. Some authors use this as anumbrellaterm, total protein and/or a pleocytosis, which is generally subsuming not only hypertensive encephalopathy but also lymphocytic (Akman-Demir et al. These remissions, however, are generally not com nausea and vomiting, and a majority will experience bilat plete, and most patients are left with residual symptoms. Acute cardiac and renal failure may with apthous and genital ulcers (Borson 1982). Acute treat Diffusion-weighted imaging is generally normal unless ment may be accomplished with intravenous sodium nitro infarction has occurred. Seizures may be treated with intravenous lorazepam and fosphenytoin, as described in Section 7. With a blindness, and seizures, occurring secondary to treatment sufficient number of strategically placed infarctions, with various chemotherapeutic agents. Etiology Clinical features As blood pressure rises above a critical level, autoregulation of small and medium-sized cerebral arteries fails and there is the syndrome (Hinchey et al. As noted earlier, renal failure is not uncommon, and ure mic encephalopathy must also be considered. Intracerebral With prompt and adequate treatment, clinical findings hemorrhage may also be considered in the differential, but resolve within days to weeks. Reversible posterior leukoencephalopathy should be considered in cases that are clinically identical to hypertensive encephalopathy in all respects except for the fact Pathology and etiology that hypertension is either lacking or only mild. Vasogenic edema is seen within the white matter, as indi cated by both brain biopsy (Lavigne et al. Hypertensive encephalopathy is a medical emergency and this syndrome has been noted secondary to treatment the pressure must be lowered within an hour. Normotensive with a variety of chemotherapeutic and immunomodula levels, however, are not the goal because, with a loss of tory agents, including tacrolimus, cyclosporine, vincristine, p10. Importantly, these areas gen Differential diagnosis erally do not fall within the area of distribution of any major vessels and are most commonly seen in the occipital the differential with hypertensive encephalopathy rests on and parietal lobes. Course Treatment Although the overall course is characterized by progres sion, the rate of progression, and the sequence with which Potentially offending medications should be discontinued. Seizure may be treated with lorazepam and fosphenytoin, as described in Section 7. Infarcts, which, as noted earlier, do encephalomyopathy, lactic acidosis, and stroke-like not conform to vascular territories, are found to affect episodes) is a rare inherited disorder characterized by vary both gray and white matter, primarily in the parietal and ing combinations of encephalopathy, stroke-like episodes, occipital lobes. Although almost all cases present before the age of 40 years, with most occurring before the age of 20 Differential diagnosis years, later onsets have been reported. Some white matter changes in the anterior portion of the tempo may present with stroke-like episodes, with hemiparesis, ral lobes. Delirium may accompany these episodes and may persist, only to resolve into a dementia, which, in turn, may Treatment be gradually progressive (Sharfstein et al. Symptomatic treatment of delirium and dementia is Seizures may occur, and may be simple partial (Canafoglia described in Sections 5. It is marked by the subacute through the lungs, leaving the patient in respiratory dis onset of delirium and thrombocytopenia (Druschky et al. Clinical features Clinical features Anywhere from 1 to 3 days after relevant trauma or sur gery, patients develop dyspnea and confusion; there may the delirium is marked by a pronounced fluctuation in the also be seizures and strokes and in severe cases coma may severity of symptoms throughout the day. In some matology includes focal signs, such as hemiparesis or apha cases a petechial rash may appear on the trunk. Course Course the mortality rate is as high as 10 percent; those who sur the disorder may persist for days to months; untreated, it vive experience a variable degree of recovery over the fol is typically fatal. Etiology Etiology Procoagulants are released from vessel endothelial cells With fractures or surgery of the long bones, neutral fat is with the subsequent appearance of widespread platelet released into the venous circulation and travels to the lungs microthrombi in arterioles, capillaries, and venules. A similar scenario may occur with Presumably, the ongoing aggregation and disaggregation trauma to fatty tissues. Within the brain, multiple microin of platelet thrombi account for the classic waxing and farctions occur (von Hochstetter and Friede 1977; waning nature of the symptomatology of this disorder. Differential diagnosis In cases secondary to trauma, head trauma may also have Differential diagnosis occurred; in post-operative cases, other causes of post operative delirium, as discussed in Section 5. When pulmonary involvement is severe, respi a decreased fibrinogen level, an increase in fibrin split ratory failure may occur and global cerebral hypoxia must products, and a prolonged partial thromboplastin time. With timely treat In addition to any necessary respiratory support, seizures ment most patients recover, with only a minority being left may be treated with anti-epileptic drugs and symptomatic with persistent deficits. Anti-epileptic drugs may be treatment of delirium may be provided, as outlined in required pending the effect of plasma exchange. In patients with severe atheromatous disease of the ascend Furthermore, extra caution should be exercised regarding ing aorta or cerebral vessels, multiple crystals of cholesterol instrumentation affecting the ascending aorta or cerebral may break off from plaques, either spontaneously or with vasculature in any patient with severe atherosclerosis. Adams 1958), is an uncommon disorder characterized by Cases occurring secondary to instrumentation. Although the etiology of this coronary artery bypass grafting, cardiac catheterization, or disorder is not known, it is included in this section on vas carotid angiography [Hagiwara et al. By contrast, spontaneously occurring cases or venous congestion of medial temporal structures. Acute cases occurring after instrumentation present Clinical features with delirium (Ezzeddine et al. Evidence of multiple emboli to other organs ber of papers (Bolwig 1968; Fisher and Adams 1958, 1964; (Colt et al. The first episode of transient global amnesia generally Subacute cases occurring spontaneously may present occurs in the sixth or seventh decade. Whether or not a Course precipitating event is present, patients suddenly experience an amnesia that has both retrograde and anterograde com In cases of acute onset, fatalities, often secondary to multi ponents. Patients with subacute cases vious few hours and in many cases may stretch much further typically develop severe renal failure. The anterograde component is fairly dense, and Acute cases must be differentiated from other causes of patients are unable to keep track of any ongoing events dur post-operative delirium, as discussed in Section 5. Most patients, although not confused, are Subacute cases must be distinguished from the lacunar more or less alarmed at their state, and many will anxiously state: here the accompanying renal failure provides a clue. Formal mental status testing reveals that patients are coherent, alert, and, as noted, not confused. Etiology Although digit span is intact, patients are unable to recall any of three words after 5 minutes; furthermore, they will be Showers of microemboli composed of cholesterol crystals unable to recall events of the recent past leading up to the eventually lodge in small arterioles where they provoke an onset of the episode. The final proposed mechanism, namely venous reflux, After the episode has cleared, patients are once again able is quite interesting. To understand the theory of venous to keep track of ongoing events, and their ability to recall reflux one must recall some anatomy. When they try and temporal structures are drained by the deep veins of recall what happened, however, they often find anislandof Rosenthal. These veins, in turn, drain to the great vein of amnesia that covers not only the duration of the event itself Galen, which drains to the straight sinus. The straight but also any events that occurred anywhere from a few min sinus, in turn, courses posteriorly to join the superior sagit utes to an hour or so just before the onset of the episode. The sinus confluens gives Although clinically patients are thus fully restored, detailed rise to the left and right transverse sinuses, which in turn testing may reveal some subtle decrements in memory drain to the sigmoid sinuses and eventually into the inter (Guillery-Girard et al. Of note, and of particular importance to the venous reflux theory, in the majority of individuals, the straight sinus drains not into both transverse sinuses but Course only into the left transverse sinus. The reflux itself could be related to a Valsalva-type maneuver, consistent It appears that the amnesia seen in transient global amnesia with some of the precipitating events mentioned earlier, represents the effects of a similarly transient dysfunction of or, as indicated in one study, to intrathoracic compression medial temporal lobe structures. Several mechanisms have been distribution of the posterior cerebral arteries, in addition proposed to account for these changes, including epileptic to amnesia one typically also sees evidence of ischemia of activity, transient ischemia, migraine, and, recently, venous the occipital lobes, such as hemianopia or cortical blind reflux. Transient ischemia has long been an attrac an epileptic amnestic episode generally do not engage in tive hypothesis, but patients with transient global amnesia the anxious questioning typical of transient global amne generally have few risk factors for stroke (Hodges and sia. Other distinguishing features include the occurrence of Warlow 1990; Lauria et al. Migraine may play a role: there is a definite association Concussion is immediately suggested by a history of between transient global amnesia and migraine (Crowell head injury, which, of course, must often be gained from et al. Furthermore, during concussion, patients may dis Schmidtke and Ehmsen 1998; Zorzon et al. Epileptic seizures in ication with benzodiazepines, are suggested by other evi Behcet disease. Cholesterol embolism as a cause of transient ischemic attacks and cerebral Apart from supervision during the episode itself, and reas infarction. Efficacy and tolerability of donepezil in vascular dementia; positive results of a 24 Abu-Shakara M, Khraishi M, Grossman H et al. Musical performance during transient global angiitis of the central nervous system. Noninfectious granulomatous angiitis involving spectrum of cerebral amyloid angiopathy: presentations the central nervous system. Standardized neurologic involvement in hypertensive encephalopathy: clinical and evaluation of 128 patients with Wegener granulomatosis.

Guideline 5: Guideline for standard electroencephalographic abnormalities provoked by electrode position nomenclature economic depression definition wikipedia order 150mg wellbutrin sr visa. Electroencephalogr Clin Neurophysiol 1959; apractagnosia due to lesions of the minor cerebral 11:615 depression and pregnancy discount wellbutrin sr line. Significance of alpha variants and their relationship electroencephalogram in migraine: a study of 560 patients depression test for child buy wellbutrin sr with visa, to epileptiform syndrome depression symptoms help guide buy discount wellbutrin sr 150mg online. Anterior temporal electrodes in and electroencephalographic study of intravenous diazepam depression condition definition cheap wellbutrin sr 150 mg online, complex partial seizures bipolar depression vs depression buy discount wellbutrin sr 150 mg on line. The ten-twenty electrode system of the International tomographic, nuclear magnetic resonance, and clinical Federation. Diagnosis and management of pituitary with autism monitored in a tertiary care center. Supplementary motor youths: Controlled study of 14 and 6-per second positive seizures: clinical and electroencephalographic findings. Artifacts in computed tomography of long-term follow-up study by brain scan and the posterior fossa: a comparative phantom study. Photomyoclonic response of magnetic resonance imaging identifies theclinically relevantepileptic and nonepileptic subjects during wakefulness, sleep, small-penetrator infarcts. Electroencephalogr Clin Neurophysiol 1968; electroencephalogram: a review of controlled clinical studies. Nature of dendritic potentials and disease: a clinical and neuropathological study. Multiple electrodes for detecting spikes in of diagnostic methods and guidelines for management. Accuracy and reliability Hyperekplexia: a syndrome of pathological startle responses. Computed tomography as a computed tomography of the brain on the accuracy of possible aid to histological grading of supratentorial tumors. J Neurol Neurosurg Psychiatry of sleep: clarification of the small sharp spike controversy. Normal pressure transients of sleep: relationships to nocturnal sleep cycle in hydrocephalus: diagnosis and patient selection for shunt man. For example, during the neu Aphasia is a fascinating clinical phenomenon, as it repre rologic examination it may appear that the patient has sents a disruption of that most human of all characteristics, trouble understanding certain commands as, for example, namely language. The classification of the various types of when one instructs the patient to take the index finger and aphasia has a long and contentious history: although the touch the nose. If one suspects a perhaps more subtle approach offered here is currently dominant, further deficit in comprehension, it is appropriate to present a research may require a more or less substantial revision. Coherence, or, again, its lack, becomes apparent during Clinical features conversation with the patient. Paraphasias represent a specific distortion in word usage, Fluency, or its absence, is immediately apparent. Fluent and come in one of two forms: phonemic (also known as speech occurs at a normal, or perhaps even increased rate: literal) paraphasia, and semantic (also known as verbal) phrases and sentences are present, and there is a normal paraphasia. In phonemic paraphasia, a letter or syllable is complement of prepositions, conjunctions, adjectives, and replaced or added thus producing an incorrect word: for adverbs. Repetition may have a remarkable effect in some cases Consequently, telegraphs often lacked prepositions, con of aphasia. Non-fluent aphasias tion, tell the aphasic patient that you are going to ask him share this characteristic and, as this was first described in the to repeat something and then provide the patient with a age of telegraphs, the termtelegraphicwas applied. Repetition does not improve speech; complex phrase, for exampleto get out of the hospital, naming, although effortful, is generally preserved. Motor aphasia can be a very frustrating experience and Finally, the ability to name things may be tested by patients tend to become irritable or depressed (Benson pointing to an object in the room, such as a lamp, or per 1973). In most cases, the responsible lesion is seen to involve Importantly, however, it must be borne in mind that this the posterior portion of the inferior frontal gyrus (Mohr classificatory scheme is but an approximation: clinical real et al. Given that most lesions extend beyond atypical cases are not at all uncommon (Brown and the inferior frontal gyrus, it is very common to find associ Simonson 1957). Among left-handers, Transcortical motor aphasia is essentially identical to the majority also exhibit language dominance in the left motor aphasia, with the exception that repetition is pre hemisphere (Goodglass and Quadfasel 1954; Humphrey served. Transcortical motor aphasia is most often seen with and Zangwill 1952), and among the remainder some form of lesions of the medial aspect of the left frontal lobe, as may mixed dominance is generally present. Consequently, and occur with infarctions in the area of distribution of the especially in right-handers, the presence of aphasia lateral anterior cerebral artery (Alexander and Schmitt 1980; izes the lesion to the left hemisphere. A syndrome similar to transcorti are referred to ascrossed aphasia(Bakar et al. Crossed apha or thalamus (Alexander and LoVerme 1980; Ghika-Schmid sia has been noted for motor aphasia (Hindson et al. In some cases, patients may appear relatively uncon Comprehension is preserved and although one may miss cerned, despite a severe deficit. In other cases, patients may hearing the expected prepositions, conjunctions, and the become agitated and suspicious, and some may develop like, coherence is generally preserved and, paraphasias, if delusions of persecution (Benson 1973, Singer et al. Spontaneous speech is both fluent and the left thalamus, principally the dorsomedial nucleus coherent, and there are no paraphasias. Another Global aphasia is characterized by a combination of speech patient, although able to recognize non-speech sounds such that is effortful and sparse with an inability to follow as telephone rings or automobile horns, could not under complex commands. Pure word deafness has been noted with bilateral dam Repetition does not improve their speech. Global aphasia has also been noted with a Anomic aphasia is characterized by a more or less isolated lesion of the thalamus (Kumar et al. Speech, although over men and adjacent anterior and posterior limbs of the inter all fluent and coherent, is marked by circumlocutions and nal capsule (Naeser et al. Although cueing is not effective, if the examiner pro this aphasia, which could also just as well be calledtrans vides the correct name, the patient generally recognizes it. Aphasia may also appear in the context of a pre-existing dementia, and this may occur in each of the disorders, noted above, that may also cause the syndrome of primary Etiology progressive aphasia. In passing, it may be noted that, with the exception of frontotemporal dementia, it is rare that As noted above, the various different types of aphasia, these neurodegenerative disorders present with an isolated although generally lateralizing to the left hemisphere, aphasia. Aphasia is also common in the midst of a delir localize, according to the type present, to multiple different ium, and here one typically finds elements of either a areas of the cortex and, less commonly, subcortical struc sensory or an anomic aphasia. Rarely, a similar onset may be seen secondary to an emerging plaque in multiple sclerosis Motor aphasia must be distinguished from dysarthria. Aphasia of paroxysmal onset may effortful, but there are no word finding pauses or circum occur on an ictal basis, representing either a simple partial or locutions and, if one listens carefully one finds a normal a complex partial seizure. This differential is relatively easy if one pays also finds other typical symptoms, such as confusion or attention to the clinical context and associated symptoms. Post-ictal states may also be characterized by Loosening of associations, in contrast with sensory aphasia, and this strongly suggests that the seizure focus is in aphasia (Faber et al. In my experience it is far more use focal onset of various neurodegenerative disorders (Josephs ful to attend to the presence of associated symptoms, such et al. Clinically, most patients present might argue that the difference between this and sensory with a motor or anomic aphasia or, less commonly, a sen aphasia is moot and go on to simply say that this finding, in sory aphasia (Clark et al. From a clinical point of Over a long period of time, and as the aphasia gradually view, however, the important point is not to resolve this p02. If these are present, then one pursues the speak fluently and coherently, are yet unable to compre differential as noted in Section 5. Deaf patients, in contrast, fail to respond to with alexia without agraphia (Cohen et al. Remarkably, in alexia without agraphia, some patients, although unable to read words, are still able to read indi vidual letters, and this preserved ability enables patients Treatment with pure alexia to circumvent their deficit by utilizing aletter-by-letterreading strategy. Here, patients read each In addition to treatment, if possible, of the underlying con letter out loud, and in hearing the letters, they reconstruct dition, speech therapy and, controversially, drug treatment the word, which is then understood (Stommel et al. Speech therapy is generally reserved for cases of aphasia In cases of alexia without agraphia, one often, but not secondary to stroke or other more or less static lesions; its always, finds a right hemianopia. Drug therapy has been attempted with bromocriptine, donepezil, and amphetamine, with inconclusive results. Bromocriptine has been studied in the treatment of motor Etiology aphasia secondary to stroke in four double-blind studies, with one positive result (Bragoni et al. In one double-blind study of patients with chronic begin, recall that fibers of the optic tract terminate in the aphasia of various different types, donepezil was superior lateral geniculate body of the thalamus. Fibers from the left calcarine group of patients with various aphasia types secondary to cortex proceed directly anteriorly toward the left angular stroke but this benefit was not maintained to a statistically gyrus, whereas fibers from the right calcarine cortex must significant degree over the long haul. Given these incon first pass forward, and then cross in the splenium of the cor clusive results, prudence may dictate abstaining from drug pus callosum, after which they proceed laterally to an even treatment pending further studies. These conjoined fibers then proceed ante riorly, to terminate finally in the left angular gyrus. Hence, lesions of the gyrus itself cause As noted in the immediately preceding chapter, alexia (the the syndrome of alexia with agraphia. Lesions, however, inability to read) may be seen in conjunction with aphasia; which spare the angular gyrus but which deprive it of visual p02. In cases characterized by an inability, despite ade from both hemispheres may occur via a number of differ quate intelligence and educational opportunity, to acquireent mechanisms. First, and most commonly, one finds a this skill, one speaks ofdevelopmental dyslexia(discussed lesion in the splenium of the corpus callosum (which sev in Section 9. This first mechanism occurs most commonly secondary to Speech therapy may also be considered in addition to treat an infarction in the area of distribution of the left posterior ment, where possible, of the underlying lesion. As noted earlier, cases of alexia without agraphia may be accompanied by a right hemianopia, and this occurs with either the first or second mechanisms just described.

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X800008200 Stanley Cohen From the Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146 rowing up on the streets of Brooklyn, I remember being interested in how things worked: taking apart an old telephone and the gears of my new 4-speed bicycle was most enjoyable. My only insight into the problem was the thought that it was necessary to understand the chemical reac tions inside the egg and embryo and not simply observe biological structures. I, therefore, became a double major in chemistry and biology (also with the hope of earning a living as a laboratory technician). My first job after graduating was working nights as a bacteriologist in a milk process ing plant. One of my professors at Brooklyn College wrote asking whether I was interested in going to graduate school. Because Oberlin offered to pay my tuition plus some $300 a semester for living expenses, I jumped at the chance. My research involved studying the Krebs urea cycle in the common earthworms that I collected from the university campus. I had been told at Oberlin that the yellow cells surrounding the gut in the worm corresponded to the mam malian liver. I decided to check whether the enzymatic reactions in worms were similar to those in mammals. My first real job was in the Pediatrics Department at the University of Colorado studying creatine metabolism in premature infants under Harry Gordon. I think he hired me because he was impressed by my ability to stomach tube earthworms. After several years, I decided I needed to learn the then new technique of using radioisotopes in metabolic studies, and I obtained an American Cancer Society fellowship to work in the Radiology Department of Washington Uni versity under Martin Kamen where I combined this new knowledge with my interest in embryol ogy. Although fertilized frog eggs and early embryos are impermeable to small molecules 14 (amino acids, phosphates, etc. Kamen recommended me for a position in the Zoology Department of Washington University in the laboratory of Viktor Hamburger and Rita Levi Montalcini. Nerve Growth Factor the original neuroembryological experiments started more than half a century ago in the laboratories of Drs. If a chick limb bud is extirpated, the was Kornberg who suggested I was dealing with a virus and nerve cells that would have enervated the limb die. If an that I should add some phosphodiesterase to destroy all extra limb bud is transplanted to another embryo, new known nucleic acids. Their terase from one of his faculty members (Osamu Hayaishi) research focused on how the periphery affected nerve fiber who was purifying it from snake venom. The next day I saw the most incred Buecker, reported that if he grafted a fragment of a mouse ible culture I had ever seen. The ganglion in culture had tumor (Sarcoma 180) onto the body wall of a 3-day chick produced a massive number of nerve fibers in a single day. He con I first thought that the phosphodiesterase had removed an cluded that the sarcoma was a favorable field for growth of inhibitor that might have been present in the tumor sensory fibers. In a control experiment it was the phos Louis from her laboratory in Italy, decided to repeat this phodiesterase preparation itself that induced nerve fiber experiment. Further tests showed that it was not the dies fibers penetrated the tumor and also reached tissues they terase but an impurity; a second protein was present in the were not supposed to enter. We purified other experiments; instead of placing the tumor in the this new biologically active protein from snake venom (4); embryo, she put it where there were no nerve fibers (on the it was thousands of times more potent than our best chorioallantoic membrane) and obtained the same results. Its activity in cultures was She concluded that a soluble, diffusible agent was released inhibited by commercially available anti-snake venom from the tumor and stimulated the growth of the nerve serum, and amazingly, when Dr. Levi-Montalcini injected the purified venom protein into the yolk sac of chick cells. She then devised a hanging drop tissue culture sys embryos, it produced nerve fiber outgrowth identical to tem on glass slides in which a sensory ganglion from a that produced by the transplanted tumor (5). I then pon chick embryo was placed in a plasma clot near a fragment dered, What could be the connection between nerve of tumor. After 1 day of culture, she observed a cluster of growth, tumors, and snake venom Three effects were noted; not It was a good combination; I knew very little about neu only did the sympathetic ganglia become greatly enlarged, roembryology, and they knew very little about biochemis but unexpectedly the mice opened their eyes earlier than try so we interacted but never argued. As a biochemist, I normal (as early as 7 days after birth rather than the nor ground up the tumor and made an extract. Further crude extract prepared from the tumor made nerve fibers more, a rabbit antiserum prepared against the purified sal grow out from chick sensory ganglia when placed in cul ivary gland nerve growth factor, when injected into ture (3). In those days, it was crude extracts of the male mouse salivary gland induced thought that protein hormones did not enter cells but early eyelid opening in the mouse. Based on the eye small membrane vesicles that eventually were degraded in lid-opening assay, we were able to isolate the protein lysosomes. Fortunately, I had a friend at the National Institutes of Our laboratory then spent a number of years examining Health (Dr. Mem of liters of urine they isolated urogastrone and found that branes from A-431 cells were solubilized in detergent and it was a small protein that unexpectedly was identical to passed through the column. In the reference list of the publications Originally we thought that threonine was the amino from this laboratory, I have provided the titles of each acid phosphorylated, because our analytical method did paper to indicate the research area to which each investi not distinguish it from tyrosine. I also wish to acknowledge with grati reported a new method that could separate phospho tude the support of the National Institutes of Health and threonine from phosphotyrosine and that the transform the American Cancer Society. Originally it had been thought that the transforming Address correspondence to: stancohen@earthlink. Thestimulation cific transmembrane, ligand-activated tyrosine kinases of protein and ribonucleic acid synthesis in chick embryo epidermis. Increased ac loci are found in insects and round worms; the amino acid tivityofribosomesfromchickembryoepidermisforcell-freeproteinsynthesis. Thestimulation tosis virus is closely related to the amino acid sequence of ofpolysomeformationinchickembryoepidermis. X800009200 Alexander Varshavsky From the Division of Biology, California Institute of Technology, Pasadena, California 91125 was born and educated in Russia and was 30 at the time of emigration to the United States, in 1977. Although the title of this article is about our main contribution to date, I describe other I significant advances as well, in addition to new biochemical and genetic methods introduced by the lab. A condensed summary, below, is followed by an account of specific discoveries and inventions in their historical contexts. Studies of these dynamic structures have become a large field, as the exposed regions are critical signposts of chromosome organization, being a part of transcriptional promoters, replication origins, and other functionally important segments of chromatin. In the 1990s, several groups identified a com plementary pathway of chromosome segregation in which proteins called cohesins form circles around replicated chromosomes. Acquired or inherited perturbations of these pathways lead to a decreased fidelity of chromosome segregation and other genomic instabilities. The third major advance, a set of interconnected studies between 1984 and 1990, revealed the manifold biological significance of ubiquitin (Ub) conjugation and Ub-mediated proteolysis. During that time, we also discovered the first degradation signals in short-lived proteins (9); the first complete pathway of the Ub system (termed the N-end rule pathway). The supercoiled state stemmed from the presence of nucleosomes diated proteolysis, a fundamental capability of the Ub in the minichromosomes, prior to removal of histones for analyses of system that makes possible protein remodeling (19, 21). Upon release from the decatenation block, the highly intertwined C-type multicatenanes were decatenated to supercoiled We also cloned the first Ub genes, discovering their monomers (vertical dashed arrows; recovery pathway). This advance opened up a particularly large field, as individual mammalian genomes are now known chains (15); the first physiological substrate of the Ub to encode at least a thousand (! N-terminal residues are indicated by single-letter abbrevia damental and applied tions for amino acids. Type 1 and 2 primary destabilizing N-terminal residues are recognized bomb project. Through their other substrate-binding sites, these E3 1950s, he became inter enzymes also recognize internal (non-N-terminal) degrons in other substrates of the N-end rule pathway, denoted by the larger oval. Ramifications of this advance became the beginnings admitted as an undergraduate to the Chemistry Depart of several biomedical fields. It kept me working and hoping ing the inventions of new biochemical and genetic that things might improve, despite evidence to the con methods. The time was the mid-1970s, a couple of years away descriptions of the early history of the Ub field (31, 32). Istvan escape, which involved help from friends and a lot of luck, Hargittai, a distinguished Hungarian chemist. The narrative below bor exactly grants were (and before the colleagues who hired rows from these sources and mentions our more recent me became aware of that fact) (33). To reduce potential nucleosome sliding (noth minichromosomes and saw what appeared to be a similar ing was known about it at the time), I cross-linked the set of bands. Our first results were published two relatively small (5 kb pairs) circular chromatids in 1978 (1), and a more detailed account in 1979 (2). Two (daughter circles) are intertwined around each more than other groups, Carl Wu and Sarah Elgin at Harvard, and 30 times! These and other findings showed that the a linear sequence of steps but a matrix of transitions that multicatenane segregation pathway. As one would expect, the multicatenane path disposition with linear chromosomes is fundamentally way and its aberrations are relevant to human diseases and the same, except that the number of replication forks is their therapies. These findings expected to be essential for decatenation of the multiply included the identification of multisubunit cohesins, intertwined chromosomal fibers that formed during chro which were later shown to form circles around replicating mosome replication and functioned as segregation inter chromosomes (Refs. This brief description of cohesin tion, first observed with the yeast Saccharomyces cerevi mechanisms does not do justice to their intricate design siae (58), is relevant to multicellular eukaryotes as well (J. The latter is a component of the N-end rule path two pathways provides mechanisms for the adhesion and way that arginylates the N-terminal Asp, Glu, or (oxi release of sister chromatids, yet both pathways are essen dized) Cys residues of N-end rule substrates, thereby tial. It remains to be determined, in functional and mech making them recognizable by Ub ligases of this pathway anistic detail, how the two segregation pathways interact. This result is which grew from our elucidation of the multicatenane seg in agreement with the inference, from findings by the lab regation pathway. Varshavsky, unpublished data), a determine whether the separase-produced fragment of phenotype similar to that of an S. Remarkably, be required for the proper functioning of cohesin machin however, in all eukaryotes examined, this residue is a ery and the high fidelity of chromosome segregation, thus destabilizing one in the N-end rule. Debananda Pati (University physiological example of protein remodeling by the of Texas, Houston), has shown that the function of the N-end rule pathway.

These T cells would have been eliminated by negative selection in a nonmutant mouse (see depression definition and meaning quality 150mg wellbutrin sr. In normal mice mood disorder youth buy wellbutrin sr online, the T cells bearing these receptors would be deleted by negative selection (middle and bottom left panels) mood disorder journal pdf trusted wellbutrin sr 150 mg. The influence of peptide diversity on positive selection is seen even more clearly in experiments using H2-M deficient mice that have been bred to carry a rearranged T-cell receptor chain transgene anxiety helpline buy wellbutrin sr 150 mg line. Endogenous gene rearrangements are suppressed in such mice and this limits the range of antigen receptor specificities on which positive selection can act anxiety 2 months postpartum generic wellbutrin sr 150mg with visa. T cells that react strongly with ubiquitous self antigens are deleted in the thymus severe depression quotes discount 150 mg wellbutrin sr amex. In contrast, when the T-cell receptor of a developing thymocyte is similarly ligated by antigen on stromal or bone marrow-derived cells in the thymus, it dies by apoptosis. The response of immature T cells to stimulation by antigen is the basis of negative selection. Elimination of these T cells in the thymus prevents their potentially harmful activation later on, if they should encounter the same peptides as mature T cells. As explained in Section 7-15, all the T cells developing in such a mouse will express the transgenic receptor. Similar results can be obtained in thymic organ culture with T cells from both normal and transgenic mice, showing that secondary effects caused by the induction of cytokines or corticosteroids due to simultaneous activation of peripheral T cells in vivo cannot account for this cell death of immature thymocytes. If the mice are injected with the peptide that is recognized by the transgenic T-cell receptor, then massive cell death occurs in the thymus, as shown by the increased numbers of apoptotic cells in the right-hand bottom panel. The deletion of developing T cells that recognize self peptides synthesized naturally in the thymus has also been demonstrated experimentally. The negative selection of such thymocytes was observed in mice made transgenic for rearranged genes encoding T-cell receptors specific for self peptides expressed only in male mice. By contrast, in female mice, which lack the male-specific peptide, the transgenic T cells mature normally. This initial observation has been confirmed using T-cell receptor transgenes that recognize other antigens, with similar results. Not all self proteins are expressed in the thymus, however, and those that appear in other tissues, or are expressed at different stages in development, such as after puberty, will encounter mature T cells with the potential to respond to them. However, there are mechanisms that prevent mature T cells from responding to such antigens, and these will be discussed in Chapter 13, when we consider the problem of autoimmune responses and their avoidance. Negative selection is driven most efficiently by bone marrow-derived antigen-presenting cells. These are professional antigen-presenting cell types that also activate mature T cells in peripheral lymphoid tissues. The self antigens presented by these cells are therefore the most important source of potential autoimmune responses, and T cells responding to such self peptides must be eliminated in the thymus. Experiments using bone marrow chimeric mice have shown clearly the role of thymic macrophages and dendritic a b cells in negative selection. The dendritic cells and macrophages are therefore assumed to have a crucial role in negative selection. In addition, both the thymocytes themselves and thymic epithelial cells also have the ability to cause the deletion of self-reactive cells. Such reactions may normally be of secondary significance compared to the dominant role of bone marrow-derived cells in negative selection. Endogenous superantigens mediate negative selection of T-cell receptors derived from particular Vgene segments. It is virtually impossible to demonstrate directly the negative selection of T cells specific for any particular self antigen in the normal thymus because such T cells will be too rare to detect. There is, however, one case in which negative selection can be seen on a large scale in normal mice and the point at which it occurs in T-cell development can be identified. In the most striking examples, T cells expressing receptors encoded by particular Vgene segments are virtually eliminated in the affected mouse strains. This occurs as the consequence of the interaction of immature thymocytes with endogenous superantigens present in those strains. Mice that carry these endogenous superantigens are said to be Mls, a b and a series of Mls antigens (Mls-1, Mls-1. Thus, the expression of endogenous superantigens in mice has a profound impact on the T-cell receptor repertoire. This sort of deletion has not yet been seen in any other species, including humans, despite the presence of endogenous retroviral sequences in many mammals. In mice that express the superantigen and thus are tolerant to it, cells expressing receptors responsive to superantigens are found among the double-positive thymocytes and are abundant in thymic cortex. This suggests that superantigens might delete relatively mature T cells as they migrate out of the cortex into the medulla, where a particularly dense network of dendritic cells marks the cortico-medullary junction. T cells with Mls-1 b responsive receptors encoded by V 6 are seen in both the cortex and medulla of Mls-1 mice (top panel, cells stained brown with anti-V 6 antibody). Note that the mature cells in the medulla express higher levels of the receptor and a thus stain more darkly than the immature cells in the cortex. In Mls-1 mice (lower panel) there is no obvious reduction in the number of immature cortical T cells expressing the V 6 receptor, but the mature cells are not found. The specificity and strength of signals for negative and positive selection must differ. The answers to these questions are still not known for certain, but two possible mechanisms have been suggested. We will briefly describe each, before going on to discuss some recent experiments that bear on the mechanism of positive selection. First, the interactions that lead to positive selection must include more receptor specificities than those that lead to negative selection. Otherwise, all the cells that were positively selected in the thymic cortex would be eliminated by negative selection, and no T cells would ever leave the thymus. The specificity or affinity of positive selection must differ from that of negative selection. If the specificity and/or avidity of positive and negative selection were the same (left panels), all the T cells that survive positive selection would be deleted during negative selection. Only if the specificity and/or avidity of negative selection is different from that of positive selection (right panels) can thymocytes mature into T cells. Two main hypotheses have been proposed to account for these differences between positive and negative selection. Thymocytes that are signaled weakly are rescued from apoptosis and are thus positively selected, whereas thymocytes that are signaled strongly are driven to apoptosis and are thus negatively selected. Because more complexes are likely to bind weakly rather than strongly, this will result in the positive selection of a larger repertoire of cells than are negatively selected. Alternatively, the delivery of incomplete activating signals by self peptides could account for positive selection: we will call this the differential signaling hypothesis. Under this hypothesis, it is the nature of the signal delivered by the receptor, not just the number of receptors engaged, that distinguishes positive from negative selection. This could not occur under the differential signaling hypothesis, because it proposes that the signals leading to positive and negative selection are qualitatively different. A new approach to testing these hypotheses has opened up with the recent description of antagonist peptides. These are known as antagonist peptides because they inhibit the response of mature T cells to their normal stimulatory, or agonist, peptide. Recognition of antagonist peptides by thymocytes has been shown to induce positive selection, whereas recognition of agonist peptides induces negative selection. Thus the differences between the ways agonist and antagonist peptides interact with the receptor and signal to the cell are likely to be relevant to the issue of how positive selection works. Initially, affinity measurements were carried out at room temperature and revealed very slight differences in affinity for the agonist versus antagonist peptides. However, the affinities were still broadly similar and this parameter failed to capture a more radical difference in the binding of the T-cell receptor that was observed under these conditions. This suggests that in vivo the agonist peptides induce the receptor clustering required for generating the signals that lead to activation (see Section 6-2) and, during thymocyte development, to deletion. The antagonist peptides, in contrast, bind but fail to induce receptor clustering, and therefore deliver a qualitatively different signal; during thymocyte development, recognition of the antagonist peptide delivers a survival signal to the cell. As the agonist and antagonist peptides bind the T-cell receptor with similar affinity, but only the antagonist induces positive selection, the implication is that the signals delivered by the agonist peptides that cause deletion and by the antagonist peptides that mediate positive selection are fundamentally different. This suggests that the differential signaling hypothesis of T-cell selection is correct. These experiments have, however, only been carried out in a single laboratory, so one should keep an open mind until other laboratories produce similar results in other systems. The differences between negative and positive selection may be due to differences in the aggregation of T-cell receptors upon ligand binding. Agonist, antagonist, and null peptides can be identified for a particular T-cell receptor by assaying the responses of mature T-cell clones. Their effects on mature T cells in vivo can be tested in mice made transgenic for this T-cell receptor (left-hand panels). Binding to an agonist peptide (top panels) induces organized aggregation of T-cell receptors on the cell surface and effective signaling through the T-cell receptor. Agonist peptides trigger the full activation of mature T cells, however if they are encountered as self peptides by developing thymocytes they induce apoptosis and hence negative selection. Antagonist peptides (center panels) bind the T-cell receptor but fail to induce organized receptor aggregation. These peptides inhibit mature T cells but can drive the positive selection of developing thymocytes. Irrelevant peptides fail to engage the T-cell receptor at all and are ignored by mature T cells and developing thymocytes. If only irrelevant peptides are presented, the thymocyte is not positively selected and it dies by neglect. The B-1 subset of B cells has a distinct developmental history and expresses a distinctive repertoire of receptors. A minority subset of B cells (comprising about 5%) in mice and humans, and the major population in rabbits, arises during fetal development and has a restricted receptor repertoire. They are termed B-1 cells, because their development precedes that of the conventional B cells whose development has been discussed up to now and which are sometimes termed B-2 cells. There is great debate about the origin of B-1 cells, and it is not yet clear whether they arise as a distinct lineage from a unique precursor cell, or instead differentiate to the B-1 phenotype from a precursor cell that could also give rise to B-2 cells. In the mouse, fetal liver mainly produces B-1 cells, whereas adult bone marrow generates predominantly B-2 cells, and this has been interpreted as support for the unique precursor hypothesis. However, the weight of evidence favors the idea that the antigen specificity of the B-cell receptor determines whether the precursor becomes a B-1 or a B-2 cell. Under this hypothesis, commitment to the B-1 or B-2 subset would be due to a selection step, rather than being a distinct lineage difference like that between:and:T cells. It is, however, difficult to rule out the idea that cells are committed before this but only survive if their receptor specificity matches the predetermined fate. B-1 cells can develop in unusual sites in the fetus, such as the omentum, in addition to the liver. B-1 cells predominate in the young animal although they probably can be produced throughout life. Being mainly produced during fetal and neonatal life, their rearranged variable-region sequences contain few N-nucleotides. B-1 cells are best thought of as a partially activated self-renewing pool of lymphocytes that are selected by ubiquitous self and foreign antigens. Because of this selection, and possibly because the cells are produced early in life, the B-1 cells have a restricted repertoire of variable regions and antigen-binding specificities. B-1 cells seem to be the major population of B cells in certain body cavities, most probably because of exposure at these sites to antigens that drive B-1 cell proliferation. Partial activation also leads to secretion of mainly IgM antibody; B-1 cells contribute much of the IgM that circulates in the blood. The limited diversity of the B-1 cell repertoire and the propensity of B-1 cells to react with common bacterial carbohydrate antigens suggest that they carry out a more primitive, less adaptive, immune response than conventional B cells (B-2 cells). The two hypotheses of B-cell commitment might be reconciled by proposing that fetal cells tend to generate B-1 cells because of the particular antigen specificities their immunoglobulin gene rearrangements tend to generate. The V gene segments that are commonly used to encode the receptors of B-1 cells seem to have evolved to recognize common bacterial and self antigens. These specificities may then be positively selected so that the cell matures with the phenotype of a B-1 cell. Regardless of how B-1 cells originate, they are certainly expanded and maintained by interaction with self antigens or nonself antigens normally present in the body, such as those of the bacterial gut flora. Expansion by a relatively small number of ubiquitous antigens is a form of positive selection that would also tend to restrict the receptor repertoire of the B-1 cell population. Some of the antigens that drive B-1 cell expansion, such as the phospholipid phosphatidylcholine, are encountered on the surface of bacteria that colonize the gut. Interestingly, a self antigen that can drive the expansion of B-1 cells has recently been identified on the surface of thymocytes. Their location suggests a role in defending the body cavities, while their restricted repertoire of receptors appears to equip them for a function in the early, nonadaptive phase of an immune response (see Section 2-28). Indeed, the V gene segments that are used to encode the receptors of B-1 cells might have evolved by natural selection to recognize common bacterial antigens, thus allowing them to contribute to the very early phases of the adaptive immune response. In practice, it is found that B-1 cells make little contribution to adaptive immune responses to most protein antigens but contribute strongly to some antibody responses against carbohydrate antigens. Moreover, a large proportion of the IgM that normally circulates in the blood of nonimmunized mice derives from B-1 cells. Initially, random receptor rearrangements and junctional diversity create a broad repertoire of antigen receptors.

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