The cells are separated based phocytes by fusion with continuously replicating tumor cells 75 mcg thyroxine free shipping treatment lung cancer. The other technique is to span clones of normal immune most often on T and B cells but found also on nonlym- T lymphocytes stimulated with appropriate antigens and phoid tissues such as brain purchase thyroxine us medications list, kidney safe thyroxine 75 mcg medicine checker, and heart. On about virus, Epstein–Barr virus infection, and measles, as well 75% of the cells, the FcR are specifc for IgM; the remain- as in graft-vs. Con A interacts with carbohydrate residues rich in immortal and releases interleukin-2 when activated by anti- mannose. Macrophages must be present for T lymphocytes gen provided by an antigen-presenting cell. There is A T lymphocyte subpopulation is a subset of T cells that one binding site for saccharide, one for Ca2+, and one for a have a specifc function and express a specifc cluster of dif- metallic ion such as Mn2+ in each con A subunit. This could be induced by cross-linking Calcineurin is a protein phosphatase that is serine/threonine of the effector and target cells by con A, which is capable specifc. Activation of T cells apparently requires deletion of of linking to high-mannose oligosaccharides on target cell phosphates from serine or threonine residues. Its action is surfaces as well as to high-mannose sugars on the T cell inhibited by the immunosuppressive drugs, cyclosporin-A receptor. It links to and of the immune response to exogenous antigen, which is pre- stimulates protein kinase C, leading to threonine and serine sented to them by antigen-presenting cells. They react to endogenous antigen and often express their effector function by a cytotoxic mecha- nism, e. Calcineurin A T lymphocyte clone is a daughter cell of one T lympho- cyte derived from the blood or spleen that is added to cul- ture medium and activated by antigen. Those T cells that are stimulated by the antigen form blasts which can be separated from the remaining T cells by density gradient centrifuga- Transcription events tion. The T cells that have responded to antigen are diluted, and aliquots are dispensed into tissue culture plates to which figure 9. Mast cells, polymorphonu- clear leukocytes, and platelets may all degranulate in the By light microscopy, resting lymphotytes (Figure 9. It par- a narrow rim of basophilic cytoplasm with occasional vacu- ticipates in T and B cell activation and is a receptor for phor- oles. The nucleus usually has a poorly visible single indenta- bol ester that acts by signal transduction, leading to hormone tion and contains densely packed chromatin. Occasionally, secretion, enzyme secretion, neurotransmitter release, and nucleoli can be distinguished. It is also involved in lipogenesis ant, which is the predominant morphologic form, is slightly larger than an erythrocyte. Larger lymphocytes, ranging between 10 to 20 μm in diameter, are diffcult to differ- entiate from monocytes. It associates with membrane lipid rafts and coordinates downstream signaling events in T lym- for visualization of the cellular organelles which are not phocyte activation. Activated lymphocytes are cells with surface receptors that interact with specifc antigens or mitogens such as phyto- H7 is a pharmacological agent used to study T cell activa- hemmagglutinin, concanavalin A, or staphylococcal protein tion. The morphologic appearance of activated (or stimulated) lymphocytes is characteristic, and in this form the cells are Herbimycin A is an inhibitor of T cell activation. These cells increase in size from 15 to is the src family of protein tyrosine kinases. Transferrin receptor (T9) is the receptor on the membranes Pinocytotic vesicles are present on the cell membrane. The of cells for the 76-kDa protein transferrin in serum that serves nucleus contains very little chromatin, which is limited to as a conveyer for ferric (Fe3+) iron. Monoclonal antibody can a thin marginal layer, and the nucleolus becomes conspicu- detect the transferrin receptor on activated T lymphocytes, ous. The array of changes that follows stimulation is called even though resting T cells are essentially bereft of this transformation. Transferrin activated B lymphocyte may synthesize antibody molecules, receptor is comprised of two 100-kDa polypeptide chains whereas an activated T cell may mediate a cellular immune that are alike and fastened together by disulfde bonds. Licos, Resting lymphocyte Activated lymphocyte the ligand to which it binds, is distinct from B7 molecules. A sensitized lymphocyte is a primed lymphocyte that has been previously exposed to a specifc antigen. Thus far, only thymulin is characterized as a hormone that fts the accepted classical endocrine and physiological criteria, i. It may also cell is a relatively large cell that is greater than 8 μm in diam- alter thymocyte TdT concentrations. Thymic hormones are soluble substances synthesized by thy- Thymopoietin functions biologically to normalize immune mic epithelial cells that promote thymocyte differentiation. These could be related to thymic involution with age, help to regulate differentiation of T lymphocytes. It offers protection against nity is of critical importance in the defense against mycobac- intracellular bacteria, viruses, and neoplasms, and mediates terial and fungal infections, resistance to tumors, and for the graft rejection. It may be transferred passively with primed signifcance of its role in allograft rejection. Thymin is a hormone extracted from the thymus that has an Thymic involution occurs following puberty. T lymphocytes are absent; there- fore, no manifestations of T cell immunity are present, i. These nude or nu/nu mice the indirect effect mediated by antibodies of the humoral limb are homozygous for a mutation, v on chromosome 11, which is inherited as an autosomal recessive trait. These features make the strain useful in studies evaluating thymic-indepen- Tymopentin dent immune responses. An autosomal recessive mutation that inhibits hair follicle devel- opment and prevents or greatly diminishes thymus develop- ment. These mice serve as Tymopentin highly effective animal models to investigate immunologic 32 36 consequences of not having a thymus. They fail to develop Arg Lys Asp ValTyr cell-mediated (T lymphocyte-mediated) immunity, are unable to reject allografts, and are unable to synthesize anti- figure 9. Their B lymphocytes 340 Atlas of Immunology, Third Edition and natural killer cells are normal even though T lympho- Runting syndrome is characterized by wasting, ruffed fur, cytes are missing. The immune system employs apoptosis for clonal to a chronic and eventually fatal disease called runt disease or deletion of cortical thymocytes by antigen in immunologic wasting disease, or runting syndrome, which is characterized tolerance. Animals may develop occurs to regulate steady-state levels of hematopoietic cells ruffed fur, diarrhea, and a hunched appearance. No local (germ-free) animals fail to develop wasting disease following infammatory response is induced with apoptosis because neonatal thymectomy. Thus, thymectomy of animals that are cellular contents, which stimulate infammation, are not not germ free may lead to fatal infection as a consequence released. Regulatory genes that control apoptosis have been of greatly decreased cell-mediated immunity. It is accompanied by weight loss, failure to circulation so that unnecessarily activated lymphocytes are thrive, diarrhea, splenomegaly, and even death.

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The most common thera- rectum because of the complexity of the resultant fistula peutic mistake is the creation of bilateral counter incisions (Fig thyroxine 50mcg mastercard symptoms mercury poisoning. This treatment usually results in a relatively challenging fistula Inappropriate treatment may result from an overly cautious (Fig discount 25mcg thyroxine fast delivery symptoms nausea headache fatigue. A penrose drain was passed from one ischioanal fossa to the other via bilateral counter incisions days earlier purchase 25mcg thyroxine otc medicine bg. The sur- rounding cellulitis remains and an external opening is beginning to appear over the post-anal space in the posterior midline the preferred approach in the management of the horseshoe abscess is exploration of the post-anal space. The primary cryptoglandular trajectory appeared to be subcutaneous in this case through this midline incision. If pus is encountered in either fossa, a radial counter incision is made either unilaterally or bilaterally (Fig. Once the superficial post-anal space is opened, it is often possible to delineate an intersphincteric trajectory of the cryptoglandular process. In this setting, some surgeons will elect to divide the internal sphincter unroofing the inter- sphincteric abscess into the superficial post-anal space. A reasonable alternative is the placement of a seton in this trajectory for management in a staged fashion (Fig. A normal exploration of the superficial post-anal spaced suggests a deeper infection in the deep post-anal space. Transanal division of the internal and the subcutaneous portion of the external sphincters. Vertical sectioning of the anococcygeal ligament in its crypt to the tip of the coccyx in continuity with sectioning of the inter- midline. It is highly definitive in that it drains the postoperative incontinence is the rule and not the exception. The disadvantage is that immediate However, it is particularly disturbing to the patient as well as 24 A. The anococcygeal ligament is functionally required for access to the deep post-anal space. This approach also detached from the sphincter complex provides access to the supralevator space posteriorly as the pubococ- cygeus and ileococcygeus muscles insert onto to the sides of the tip of the coccyx. In essence, the primary infection has already accom- rior crypt to the tip of the coccyx. This maneuver theoretically maintains the stability of long-term keyhole deformity (Fig. The primary Transverse sectioning of the anococcygeal ligament also cryptoglandular complex may be encircled with a seton for provides access to the deep post-anal space. The long-term effect It is important to note that horseshoe abscesses may not upon the sphincter is not precisely known. Moreover, the authors prefer entering the deep post-anal space by the classic bilateral rubor over the ischioanal fossa may a vertical division of the anococcygeal ligament along its represent underlying frank suppuration or merely cellulitis 4 Classification and Treatment of Anorectal Infections 25 emanating from the primary abscess. Ueber die analen Divertikel der Rectumsschleim-haut assessment is made from the posterior midline incision. Perianal fistula tract with an indwelling draining seton may then be abscesses and fistulas. Clinical Assessment of Anal Fistulas 5 Herand Abcarian bowel disease are often much less painful, contain very thin Introduction pus and the patient may present with some pain and drainage for weeks without a significant acute illness. Patients with A successful outcome from any type of fistula operation is hematologic disorders such as acute myelogenous leuke- dependent on accurate clinical assessment and classification. This is more likely to the patient gives a history of a prior episode of perianal be seen in hematology–oncology units of major medical cen- swelling and pain (low abscess) or deep rectal pain with ters than in physician/surgeon’s offices. The abscess are encountered, the surgeon must not rush into attempting to either ruptures spontaneously and drainage of pus and blood drain the abscess especially when in the majority of cases is followed by resolution of acute pain or alternately the severe thrombocytopenia is part and parcel of pancytopenia. Intermittent the patient must be told that the infectious process begins swelling and pain followed by drainage and relief of pain are in the anal canal and spreads outward and drainage of the typical symptoms of anal fistulas. It should be noted that abscess alone may not be adequate to eradicate the infection. This typical history can be found in the overwhelming majority of patients with fistula in ano. The patient may be examined on a tilt table in the knee external penetrating injury is much clearer and the clinical chest position, but the same can be carried out in the Sims course easier to follow. The first landmark is often readily visible to the secondary opening of the fistula, is often open and draining or has a telltale granu- H. Abcarian in chronic fistulas with fibrosis and retraction of the external and obscure its ease of identification. Palpation of the be able to find the internal opening at a second or third try soft tissue between the secondary opening and the anal canal and the surgeon should avoid getting frustrated and persist to often feels like a firm cord (much like the extensor tendons the point of causing a false passage. In deeper (higher) fistulas, ing is found after some additional maneuvers, it is best to this cord-like structure can be palpated only to the margin if insert a loose marking seton to allow easy identification of the external sphincter as the tracts dips under the muscle to the fistula tract during a subsequent definitive surgical proce- connect with the anal canal. Other helpful maneuvers in identification of the bilaterally in cases of horseshoe fistulas. Rectal examination with bi-digital palpation may elicit Ordinarily, a fistula being treated for the first time requires induration in the perianal or ischiorectal fossa at the same very little if any additional imaging. This signifies presence of an acute or operations resulting in scarring and distortion of the fistula chronic abscess cavity associated with the fistula. The pri- tract, and in cases where there is more than one fistula mary opening may feel like small grain of rice or lentil. Fistulography, which was popularized in the 1970s and as an indentation above the dentate line in the anorectal ring 1980s but has fallen out of favor with advent of other or lower rectal wall. There were publications pro and con often at the dentate line corresponding to Goodsall’s rule, of fistulography but currently this procedure is rarely uti- unless the patient has had previous surgery or the fistula is lized [4 ]. Endoanal ultrasonography without or with injection of sharp foreign body as mentioned above. Computerized tomography of pelvis and perineum with from the primary opening, which confirms the diagnosis. Magnetic resonance imaging is quite helpful in diagnos- however may judiciously proceed to use a draining seton ing fistula and assessing the closure of the fistula after instead of definite surgical procedure if the fistula is consid- seemingly successful procedures, especially in Crohn’s ered to be too complex or undrained pus is encountered dur- disease. Identification of primary and secondary openings and the lateral traction using a Kocher clamp is often helpful to fistula tract itself which is described above. If the fistula tract is very thin, lacrimal probes may be classification and the thickness of sphincter muscle used instead of the regular fistula probes. This is much harder than simple identification of very narrow, one may have difficulty delineating it even with the tract because it takes experience and judgment to decide lacrimal probes. In such cases slow injection of hydrogen which fistula is easily amenable to fistulotomy and which peroxide alone or with the addition of 1–2 drops of methy- requires sphincter-sparing procedure. As Phillip suggests, lene blue might result in bubbling of the injected material it is more important to know how much sphincter will be through the primary opening. A larger amount of methylene left behind rather how much will be divided during fistu- blue tends to stain the granulation tissue in dark blue color lotomy (see Chap. Reducing this to its simple form, it is 5 Clinical Assessment of Anal Fistulas 29 important for the surgeon to be sure whether the fistula is It is for this reason and medical/legal implications of high or low and if the surgeon is inexperienced, unsure, or treatment-related fecal incontinence that the involve- does not treat anal fistulas on regular basis, it is better to ment of a colon and rectal surgical specialist in the treat- insert a loose marking seton (braided suture or vessel loop) ment of anal fistula is not only desirable, but most often in the tract and refer the patient to a specialist [3]. Role of seton in fistulot- Although fistula in ano is not a life-threatening disease, it is omy of the anus.

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Histamine is converted to methylhistamine by hista- receptors mediate inflammation and allergy cheap thyroxine 125 mcg fast delivery medications kidney infection. All are found in inhibit release of histamine and other neurotransmitters brain and peripheral tissues 100mcg thyroxine otc medications during pregnancy. These histaminergic fibers are involved in the control of blood pressure generic thyroxine 75mcg on line symptoms internal bleeding, sexual and Histamine acts mainly on the cardiovascular system, ingestive behaviors, arousal and alertness, pain and secre­ smooth muscles, and exocrine secretions. It also decreases the cardiac Antihistaminics are used frequently in clinical practice for output. On Smooth Muscles H1 receptor antagonists: H1 antagonists like mep- yramine and promethazine are used to prevent histamine Histamine increases tone of most of the smooth muscles. Due to its higher concentration in the intestine, it Role in Allergy is also known as enteramine. It is also present in platelets Allergic reactions are mostly mediated via histamine: and basophils. In acute systemic allergy (anaphylaxis), hypotension occurs due to release of histamine from mast cell that Synthesis and Metabolism produces acute vasodilation. Bronchial asthma is precipitated or induced by hista­ action of enzyme tryptophan hydroxylase. Histamine is released from mast cells in response to (serotonin) catalyzed by the enzyme 5­hydroxytryptophan the antibody IgE (the reagin antibody). Serotonin Receptors Experimentally, when histamine is injected into the skin, it produces sever itch. Itching associated with skin allergy Till date, seven types of serotonin receptors have been (urticaria) is cured by antihistaminics. Inhibits transmission of pain impulses in dorsal horn of spinal cord, and thus, it is an important component of endogenous analgesia system. Regulates circadian rhythm (suprachiasmatic nucleus receives heavy serotonergic innervation). Anti­ depressant drugs such as fluoxetine act by inhibiting serotonin reuptake in the brain. It inhibits feed­ ing by acting on hypothalamic and other feeding areas in the brain. Physiological Actions Clinical Correlation Serotonin mainly acts on cardiovascular system, respira­ tory system, kidney, smooth muscle, and nervous system. It produces vasodilation and increases local blood and temporarily stops urination. Central Nervous System It is released as a neurotransmitter in different parts of Clinical Importance the brain. The most important serotonergic pathway in the brain is the raphespinal system that on stimulation Bradykinin is secreted from abnormal endocrine tumors produces analgesia. It was named prostaglandin for its enumeration in the secre­ tion from prostate gland. Afterwards, prostaglandins were found to be synthesized in various tissues of the body. Scientist contributed Ulf Svante von Euler (1905-1983) was a Swedish physiologist and pharmacologist. He shared the Nobel Prize in Physiology or Medicine in 1970 for his work on neurotransmitters. His short stay as a postdoctoral student in Dale’s laboratory was very fruitful, where in 1931 he worked with John H Gaddum and discovered substance P. After return ing to Stockholm, he pursued his research, and discovered Ulf S von Euler (1905–1983) four other important endogenous active substances, prostaglandins, vesiglandin (1935), piperidine (1942) and noradre­ naline (1946). Prostaglandins increase in uterine fluid and cause enzyme phospholipase A2: necrosis of blood vessels of the uterus just before the 1. Arachidonic acid is then converted to cyclic endoper­ bleeding starts during menstrual cycle. The balance between the prostacyclin and thrombox­ Physiological Actions ane A2 determines the degree of platelet plug forma­ Prostaglandins are present in almost all the tissues of the tion (refer to Fig. Thus, prostaglandins greatly influence temporary of various organ systems, hemostasis, and metabolisms hemostasis. The con­ Prostaglandins E and F inhibit absorption of sodium and 2α centration of this chemical increases in the maternal water: Chapter 64: Local Hormones 573 1. The watery diarrhea produced in cholera is mediated in the peritubular capillary bed of kidney. Steroidal anti-inflammatory drugs such as cortisol kidney tubule to inhibit sodium reabsorption. It causes vasodilation, leading to decrease in blood as ibuprofen inhibit prostaglandin synthesis by inhibit­ pressure. It also increases capillary permeability that causes extravasation of fluid into interstitial tissue space. These episodic attacks occur due to secretion of vari­ is more in children and less in adults. Therefore, the disease is diagnosed by the excretion of Thymosin is the hormone secreted from thymus. At birth it weighs about 10 g, which increases in size to about Other Local Hormones 30 g during adolescence. It converts by the reticular epithelial cells of thymus (for details, angiotensinogen to angiotensin I, which is further con­ refer Chapter 18). Hence, thymus has the central position in the deve­ Erythropoietin is the glycoprotein hormone containing lopment of cellular immunity. For details of T cell 165 amino acids secreted mainly from interstitial cells development, refer ‘Immunity’. Though local hormones act locally in the tissue where they are produced, some of them have systemic effects. Female Reproductive System: Functional Anatomy, Oogenesis and Follicular Development 69. Ovarian Hormones and Control of Ovarian Functions Part D: Physiology of Conception, Pregnancy, Lactation and Contraception 71. Physiology of Contraception “To live, to love are signs of infinite things, Love is glory from eternity’s spheres. Abased, disfigured, mocked by baser mights That steal his name and shape and ecstasy, He is still the Godhead by which all can change. Describe the mechanism of sex differentiation and development in males and females. List the abnormalities of sex differentiation and understand the physiological basis of their causation. Apply the knowledge of sex determination and differentiation in understanding the physiology of reproductive system. Reproduction serves a primary goal of the nature in preservation and perpetuation of the species. The crea- tion of two sexually complete and different individuals in same species, known as sexual dimorphism is the cen- tral scheme of the nature to achieve its principal inten- tion of continuation of species through reproduction. Therefore, to appre- ciate the physiology of reproduction one should study the process of sex differentiation, development of gonads, gonadal functions, physiology of puberty and sexual mat- uration, the principles of functioning of the female and Fig.

How this might translate experiments do not demonstrate whether polymer-based adeno- to man is not yet clear but it is obviously of concern buy 25mcg thyroxine mastercard symptoms heart attack. In addition buy thyroxine 50 mcg with visa medicine klonopin, as sine release inhibits seizures in fully kindled subjects cheap thyroxine 125mcg mastercard symptoms nasal polyps, nonetheless, at best this approach seems to reduce seizure severity rather than the results are promising and should be investigated in models reducing seizure frequency, it is dubious whether the benefts in with a more chronic epileptogenic region. Proof of principle of a all but a few individuals with severe frequent falls and convulsion focal drug delivery approach has also been described in human would outweigh the risks involved. Tere broventricular delivery [19,20] (which might carry less risk of dam- are a number of established animal models of refex epilepsies. Terefore, a cortical stimulation mapping [35] and to abolish interictal spiking further step on from chronic focal drug delivery might be to link [36]. The fnal goal is the development of an implantable thermoe- seizure onset with acute focal drug delivery, which is an area under lectric device built into a closed-loop system and capable of cooling investigation. Eforts subdural hybrid neuroprosthesis (reviewed in [24]) and validated it in this direction are already under way; simple thermoelectric Pel- in rat and primate models of epilepsy [25]. This is the most advanced tier devices combined with recording electrodes have been shown implantable prosthetic drug delivery system to date and consists to be successful in terminating epileptiform discharges in neocor- of silicon subdural strips or grids, much like the ones implanted tical and hippocampal seizure models, without causing neuronal for electrocorticographic recording. In addition to recording elec- damage in both rodents and cats (reviewed in [37,38]). As a proof trodes, the strips contain single or multiple drug delivery ports that of principle, focal cooling was applied to the epileptogenic zone of are regularly fushed with saline and flled via a transcutaneously human patients before surgical resection, and a reduction in epilep- accessible minipump. Drugs such as muscimol are delivered local- tiform discharges was demonstrated when the cortical temperature ly and absorbed transmeningeally, without signifcant leak into the was reduced to less than 25°C [38]. Patient-activated drug delivery temperature gradient in the surrounding parenchyma. Focal cool- systems might also be devised for some patients who have a reliable ing of the perilesional cortical tissue not only prevented the emer- clinical aura of sufcient duration. A number of challenges remain gence of post-traumatic seizures, the treatment efect persisted for to be overcome, however, before any of these systems can be tested up to 10 weeks afer cessation of cooling, with only rare mild sei- in human patients: guaranteeing accuracy of the seizure prediction zures emerging [39]. Tese results are very promising and point in algorithm and protecting against potential confounding factors, an important direction – the prevention of epileptogenesis. Future such as movement artefacts and unnecessary release of drugs, es- studies will be required to address optimal timing and duration of tablishing whether long-term application of drugs leads to toler- cooling for the prevention of post-traumatic seizures, and should be ance [29] and if cessation of treatment leads to withdrawal seizures explored in other models of acute symptomatic seizures. Genetic approaches to treatment As discussed, many of these studies have limitations but, none- theless, they demonstrate a proof of principle that may open new Viral vectors therapeutic avenues for patients with identifed but non-resectable Molecular biology advances mean that now we can not only change epileptic foci, and potentially also for others with poorly localized the genetic make-up of cells in vitro before grafing into the brain onset by targeting known propagation or trigger pathways. Howev- (as will be reviewed in Section Neuronal grafing), but also achieve er, even with the best of slow-release mechanisms or drug delivery modifcations in vivo using recombinant viral vectors to insert systems, in the lifetime of an epilepsy patient, repeated implantation genes into host cells in living brain. This is proving to be a very im- or refll procedures would be needed, with the attendant increasing portant research tool, enabling long-term expression of the inserted risks of complications. In this context, focal treatment approaches gene/relevant protein in a way that is not limited by either poor providing longer-term solutions may be advantageous and are dis- survival of grafed donor cells or the inevitable need to replenish cussed in Sections Focal cooling, Genetic approaches to treatment drug delivery devices during the life of the individual. How- injury to the nervous system: they suppress metabolic activity, de- ever, other vectors, such as herpes simplex virus have also been used crease tissue adenosine triphosphate and oxygen consumption, and both in animal models and in human trials [40]. In addition, the blood–brain barrier becomes less perme- cell-type-specifc promoters and even achieve conditional expres- able, thereby limiting oedema, and infammation is mitigated [31]. The degree of hypothermia used is usually between to suppress gene expression of excitatory neurotransmitters or to 30 and 35°C and is accompanied by potentially life-threatening overexpress genes involved in neuronal inhibition. Shivering has to be controlled with delivered to the piriform cortex or hippocampus alone or in com- neuromuscular blockade. Herpes-based vectors were used ways easy to interpret, given the variation in models, experimental to overexpress the neurotrophic factors fbroblast growth factor-2 detail and variable graf–host integration. In addition, as long as grafs are undertaken before any seizures genic epileptic milieu infuences the transduction efcacy and viral have been provoked, then the seizure threshold is similarly returned tropism for neurons is currently the subject of investigations [53]. Tese studies thus support the poten- Unfortunately, most studies to date involve transfection before the tial of neuronal grafs in terms of neurochemical restoration in epi- epilepsy/seizure-inducing insult in kindling or acute seizure prov- lepsy, but the real question is whether this approach can be utilized ocation models, so are of largely mechanistic rather than clinical in models with spontaneous seizures in the absence of specifc prior interest, although anticonvulsant efects are demonstrable. In addition to this initial acutely provoked (electrical stimulation or chemical, e. The as a treatment for epilepsy, and have been authoritatively reviewed grafs also appear to reverse or prevent other secondary patholog- elsewhere [40,56]. This includes aberrant sprouting of host mossy perimental paradigms in which specifc neurotransmitter inputs to fbres into the dentate supragranular layer, thereby restoring the the hippocampus (noradrenergic, cholinergic or serotonergic) are damaged cytoarchitecture, possibly by providing appropriate target specifcally lesioned using physical or chemical means, increasing neurons. The grafs themselves survive well, diferentiate into ma- susceptibility to subsequent seizure provocations. For good connectivity both the and restoring seizure susceptibility to control (predepletion) levels. In animals receiving untreated fetal hippocampal neurons that established robust projections to the contralateral hip- grafs, in which approximately 30% of grafed cells survived, no pocampus, resembling the projection pattern seen in intact animals. Improvements of similar magnitude were described, when, specifc lesion types and, as the authors point out, in contrast to the using similar experimental paradigms, rats were grafed with stri- kainic acid model, human hippocampal sclerosis involves damage atal precursor cells [71]. When cells were jority of patients with temporal lobe epilepsy do not have a clear grafed 45 days postlesion, and examined 1 month later, cell sur- initial insult and, conversely, many with the commonest insults vival had fallen to 31% [62] in comparison with 69% at 4 days pos- (febrile seizures) do not ever develop epilepsy. It is not known when hippocampal cell loss in epilep- methodological questions (for example relating to cell type, strat- tic patients occurs but it is likely that any grafing would only be egies for enhancing graf survival, timing of grafing, etc. However, survival 1 month afer grafing appeared grafing as a treatment for epilepsy, and in our view it is unlikely this to be a good predictor of long-term (1 year) cell survival [64], and will translate into clinical practice within the next decade. The biggest limitation of these Transplantation of genetically engineered cells studies, however, is that the model did not exhibit spontaneous be- Arguably, a more promising approach is to efectively combine what havioural seizures (personal communication, A. Shetty, 2002), so we know from focal drug studies and epilepsy therapeutics gener- no information on the potential therapeutic benefts of these grafs ally with advances in genetic and stem cell biology, by engineering in terms of seizure outcome is available. It is also recognized that cells for grafing that can efectively serve as a potentially perma- hippocampal cell death is neither necessary nor sufcient for epi- nent drug delivery reservoir. Although grafing had no interneurons are ablated by injections of the neurotoxin saporin efect on subsequent kindling-induced seizures, there was a slight conjugated with substance P. This study is relevant for a number of reasons: frst, the authors Optogenetics is a technique that combines optics and genetics, use a mouse model harbouring a mutation found in a form of hu- and relies on a family of proteins called opsins. Opsins are found in all animal kingdoms, from fag- tical inhibition by increasing inhibitory transmission and reduce ellate algae to higher mammals, where they are crucial to support a seizure severity and duration. An inherent problem of all techniques involving fetal cells is relied on expressing opsin genes from the fy Drosophila in neu- the relative scarcity of fetal tissue. Over the last decade, an array of molecularly Adenosine engineered opsin variants has emerged and continues to expand; Adenosine is an endogenous neuromodulator with established an- it now includes channelrhodopsins with activation wavelengths tiepileptic and neuroprotective actions and, as such, is an attrac- in the infrared spectrum, diferent channel kinetics and from the tive target in epilepsy. However, therapeutic use of adenosine or its species Volvox carteri (reviewed in [83,84]). Initial work in this area used polymer-based Newer inhibitory opsins include an opsin from the fungus Lepto- drug delivery systems but has since moved on, as reviewed in [3], sphaeria maculans (Mac), archaerhodopsin-3 (Arch) [86] and the to bring together technology from drug delivery systems, genetic chloride-conducting channelrhodopsin ChloC [87]. Due to their versatility and their electrophysiological characteristics, the use of New therapeutic approaches for optogenetic tools has revolutionized neuroscience in recent years: focal epilepsy opsins have been used to investigate basic physiological functions The techniques mentioned so far sufer from several limitations. Second, tions to the epileptic network and as potential therapeutic tools the changes efected are likely to be long term and are difcult to (reviewed in [98]). This may increase the risk of unwanted employed cultured hippocampal slices from mice that had been side-efects. Epileptiform discharges were elicited by electrical stimula- neocortex would be an important advance.