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By Y. Brenton. Mississippi Valley State University.

As mentioned previously order female cialis 20 mg otc, an axon generally makes either an axo-dendritic or axo- somatic synapse with another neuron buy female cialis 20 mg low cost. Gray (1959) has described subcellular features that distinguish these two main types of synapse buy generic female cialis 10 mg online. Under the electron microscope order 10mg female cialis visa, his designated type I synaptic contact is like a disk (1±2 mm long) formed by specialised areas of opposed pre- and postsynaptic membranes around a cleft (300 A) but showing an asymmetric thickening through an accumulation of dense material adjacent to only the postsynaptic membrane. Vesicles of varying shape can sometimes be found at both synapses, and while some differences are due to fixation problems, the two types of synapse described above are widely seen and generally accepted. They appear to be associated with fast synaptic events so that type I synapses are predominantly axo-dendritic, i. Anatomical evidence can also be presented to support the concept of presynaptic inhibition and examples of one axon terminal in contact with another are well documented. The electromyograph from the anterior nuclear complex of the adult rat thalamus shows two terminals 1 and 2 establishing synaptic contact on the same dendrite. Asymmetric synapses are 1±2 mm long with a 30 nm (300 A) wide cleft and very pronounced postsynaptic density. Symmetric synapses are shorter (1 mm) with a narrower cleft (10±20 nm, 200 A) and although the postsynaptic density is less marked it is matched by a similar presynaptic one. The presynaptic vesicles are more disk-like (10±30 nm diameter) the shape of the presynaptic vesicle is of particular interest because even if the net result of activating this synapse is inhibition, the initial event is depolarisation (excitation) of the axonal membrane. In the lateral superior olive, antibody studies have shown four types of axon terminal with characteristic vesicles (Helfert et al. In smooth muscle the noradrenergic fibres ramify among and along the muscle fibres apparently releasing noradrenaline from swellings (varicosities) along their length rather than just at distinct terminals. In the brain many aminergic terminals also originate from en passant fibres but it seems that not all of them form classical synaptic junctions. The fact that vesicular and neuronal uptake transporters for the monoamines can be detected outside a synapse along with appropriate postsynaptic receptors does suggest, however, that some monoamine effects can occur distant from the synaptic junction (see Pickel, Nirenberg and Milner 1996, and Chapter 6). For further details on the concept of synaptic transmission and the morphology of synapses see Shepherd and Erulkar (1997) and Peters and Palay (1996) respectively. The system is fitted for the induction of the rapid short postsynaptic event of skeletal muscle fibre contraction and while the study of this synapse has been of immense value in elucidating some basic concepts of neurochemical transmission it would be unwise to use it as a universal template of synaptic transmission since it is atypical in many respects. There are also positive and negative feedback circuits as well as presynaptic influences all designed to effect changes in excitability and frequency of neuronal firing, i. Such axons have a restricted influence often only synapsing on one or a few distal neurons. The axons, especially the very long ones, show little divergence and have a relatively precise localisation, i. Distinct axo-dendritic type I asymmetric synapses utilising glutamate acting on receptors (ionotropic) directly linked to the opening of N‡ channels are common and a these systems form the basic framework for the precise control of movement and monitoring of sensation. Such pathways are well researched and understood by neuro- anatomists and physiologists, but their localised organisation makes them, perhaps fortunately, somewhat resistant to drug action. Since these interneurons exert a background control of the level of excitability in a given area or system their manipulation by drugs is of great interest (e. Although intrinsic neurons can only have a localised action they may be influenced by long-axon inputs to them and so incorporated into long pathway effects (Fig. The tonic background influence of these systems and their role in behaviour have instigated the development and study of many drugs to manipulate their function. It also seems that the cholinergic input into the cortex from subcortical nuclei can also be included in this category (see Chapter 5). Of course, while the identification of these distinct systems may be useful there are many neural pathways that would not fit easily into one of them. The dopamine pathway from the substantia nigra to striatum may start from a small nucleus but unlike other monoamine pathways it shows little ramification beyond its influence on the striatum. The object of the above classification is not to fit all neural pathways and mechanisms into a restricted number of functional categories but again to demonstrate that there are different forms of neurotransmission. It could unfold a whole new requirement and dimension to our understanding of synaptic physiology and pharmacology and the use of drugs. On the other hand, it may be of little significance in some cases for although cholinergic-mediated nicotinic and muscarinic responses as well as dopamine and peptide effects are observed in sym- pathetic ganglia, it is only nicotinic antagonists that actually reduce transmission, acutely anyway. All are required for a perfect picture but some are obviously more important than others. While the mechanism of their release may be similar (Chapter 4) their turnover varies. Such processes are ideally suited to the fast transmission effected by the amino acids and acetylcholine in some cases (nicotinic), and complements the anatomical features of their neurons and the recepter mechanisms they activate. By contrast, the peptides are not even synthesised in the terminal but are split from a larger precurser protein in the cell body or during transit down the axon. They are consequently only found in low concentrations (100 pmol/g) and after acting are broken down by peptidases into fragments that cannot be re-used. It is perhaps not surprising that they have a supporting rather than a primary role. In between the above two extremes are the monoamines (1±10 nmol/g) which are preformed and stored in terminals but at much lower concentrations than the amino acids and when released are removed primarily by reuptake for re-use, or intraneuronal metabolism to inactive metabolites. Those like the amino acids while having high affinity for their receptors have low potency while the peptides found at much lower concentration have high potency but low affinity. As guidelines they provide a reasonable scientific framework of the type of investigations that must be undertaken to establish the synaptic role of a substance. As rigid rules they could preclude the discovery of more than one type of neurotransmitter or one form of neurotransmission. Nevertheless, the criteria have been widely employed and often expanded to include other features which will be considered as subdivisions of the main criteria. This does not mean it cannot have an important function in other areas such as the mesolimbic system and parts of the cerebral cortex where it is present in much lower concentrations. Glycine is concentrated more in the cord than cortex and in ventral rather than dorsal grey or white matter. Section of dorsal roots and degeneration of afferent fibres produces a reduction in glutamate and substance P which can then be associated with sensory inputs. Intrinsic neurons can also be destroyed through overactivity caused by kainic acid injections. Excessive firing of a neuron may be controlled by activating a feedback inhibitory system or evoking presynaptic inhibition. Indeed the distinct patterns of distribution of ascending monoamine pathways from brainstem nuclei could probably be considered as adequate evidence alone for their neurotransmitter role. Unfortunately, although it may be possible to show the presence of a substance and some effect when it is applied directly to neurons its release may not be measurable for technical reasons.

Among these drugs discount 20 mg female cialis with visa, the most widely used primarily for autoimmune diseases are vincristine order 10mg female cialis otc, methotrexate cheap female cialis 10 mg with visa, and cytarabine buy female cialis 10mg with mastercard. Only methotrexate is seriously and sufficiently recog- nized as an initial drug for treating rheumatoid arthritis. In addition, one of the sulfur analogs of mercaptopurine, azathioprine, has been pro- posed as a cytotoxic drug, and it turned out to be more effective as an immunosuppressant. This is a possibly reason why it is advantageous over mercaptopurine as an immunosup- pressant. The mechanism of action of azathioprine as a cytotoxic drug is not different from the mechanism of action of other antimetabolites. Azathioprine is the primary drug used for transplants, especially for kidney transplants. However, azathioprine is useful in combination with cyclosporine, and it is even preferred in certain cases. Cyclophosphamide: Synthesis and properties of this drug are described in Chapter 30. Second, it kills proliferating cells, and evidently alkylates a certain region of 31. Finally, its action on T-cells is such that despite its overall suppressive effect, it can, in certain environments, suppress the response of these cells to antigens. Cyclosporine A: Cyclosporine A, [R-[R*,R*-(E)]]-cyclo-(L-alanyl-D-alanyl-N-methyl-L- leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6- octenoyl-L-α-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucine) (31. A new era in the development of immunopharmacology began with the discovery of cyclosporines. Cyclosporines are produced by mycelial mushrooms Tolypocladium inflatum, Tricoderma polysporum, and Cylindrocarpon lucidum, which are found in the ground. Cyclosporine A is the first drug to affect a specific line of protecting cells of the body. Unlike usual cytotoxics, it suppresses T-cells and acts on all cell lines simultaneously. Cyclosporine A significantly eases the ‘reception’ of transplants, and increases the possi- bility of treating autoimmune system diseases. All cyclosporines (A,B,C, … U,V,W), are oligopeptides containing 11 amino acids closed in a cyclic form. All of these are known amino acids except the first, which some- times has not been isolated from natural sources. Because of all of the hydrogen bonds, the structure of cyclosporine is quite rigid. Cyclosporine A itself and a number of other cyclosporines have been completely synthe- sized. Many structural analogs have also been synthesized, and a few patterns have been discovered in terms of their structure and activity. It is known that the activity of the drug is determined by the entire cyclic structure, and not by its separate fragments. Likewise, it is also clear, that the structure of amino acids at position 1 is an important factor of 424 31. Despite the fact that the molecule is relatively large, cyclosporine eas- ily diffuses through the cellular membrane. It is possible that there are no corresponding ‘recognizing’ receptors for cyclosporine. However, there is a cytosol cyclosporine-binding protein known as cyclophilin, which has a molecular weight of about 15,000. Cyclophilins are observed mainly in T-cells; however, they are found in other tissues, in particular, in the brain and kidneys. Since the mechanism of action of cyclosporine is still being intensively studied, it must be noted that it is not cytotoxic in the general sense of the word, because it suppresses bone marrow function. Despite the fact that cyclosporine has not been used for a long time, it is the number one drug used for transplants. Cyclosporine is also being studied as a substance for treating a number of autoimmune diseases, including diabetes, multiple sclerosis, myasthenia, rheumatoid arthritis, and psoriasis. It also has had a great effect in treating schistosomia- sis, malaria, and filariasis. Despite the fact that all of these terms are basically interchangeable, the first three—antibiotics, anti-infectious agents, and anti- microbial drugs—are generally used to describe drugs used for treating infectious dis- eases, while the term chemotherapeutic drugs is more associated with drugs used for treating cancer. Antibiotics are essentially natural compounds produced by microorganisms that are capable of inhibiting growth of pathogenic microbes, bacteria, and a few of the more sim- ple microorganisms. Semisynthetic antibiotics generally are products that are a partially chemically altered versions of antibiotics that are isolated from natural sources. Thus, antibiotics are compounds produced by microorganisms and that are able to kill or inhibit growth of bacteria and other microorganisms. This definition makes a specific distinction between antimicrobial drugs produced by microorganisms and completely syn- thetic compounds. The difference is of a completely academic nature, and today the word antibiotic is used quite often for specifying antimicrobial drugs in general. It should be noted that there are compounds produced by microorganisms with antifungal and antitu- mor action, which also are classified as antibiotics. The general concept of antimicrobial action is called selective toxicity, which entails that the growth of the infected organism is inhibited or destroyed by certain drugs without harming host cells. All of the antimicrobial drugs used in clinical practice are selectively toxic with respect to microorgansisms. High selective toxicity of antibiotics to microor- ganisms is explained by the unique qualities of the organization of microbial cells, which are principally different from mammalian cells. The nature and degree of this selectivity determines whether the given antimicrobial drug is generally non-toxic in its relationship with mammalian cells or if it just exhibits certain toxicity on certain mammalian tissues. Antimicrobial drugs exhibit antibacterial effect using one or all of the following mecha- nisms: 1. Inhibition of cell membranes synthesis in microorganisms (beta-lactam antibiotics, vancomycin, cycloserine). Inhibition of protein synthesis in microorganisms (aminoglycosides, erythromycin, clindamycin, chloramphenicol, and tetracyclines). Inhibition of nucleic acid synthesis or their function in microorganisms (sulfonamides, trimethoprim, metronidazole, quinolones, and rifampicin). Inhibition or alteration of function of external or cytoplasmic membranes of microor- ganisms (polymixin). An effective approach of antimicrobial therapy of an infection is based on the isolation and identification of the infected organism and determining its sensitivity to antimicrobial drugs. In vitro tests, such as diffusion in agar and determining the minimally inhibitory concentration in a liquid medium are the most widely used tests.

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It weakens intracellular uptake of biogenic amines and reduces the ability if storing them in vesicles female cialis 20mg lowest price. Breakdown of catecholamines is expressed by a decreased number of intraneuronal serotonin and dopamine generic female cialis 20 mg amex. Reserpine is used for treating hypertension; however discount 10 mg female cialis free shipping, it is not the drug of choice because of a number of side effects buy female cialis 20mg low price. A number of drugs combined with other hypertensive agents— diuretics in particular—are based on reserpine. Reserpine is prescribed under a number of names, including serpasil, brinerdin, diupres, and others. Azocine is alkylated by chloracetonitrile, which forms 1-azocinylacetonitrile (12. It acts on branched ends of sympathetic peripheral nerve fibers and permeates into the neuron by the same mechanism of reverse uptake that returns norepinephrine from the synaptic cleft to neu- ron endings. Inside the neuron, guanethidine accumulates and competes with norepi- nephrine for storage space as granules. With an increase in guanethidine concentration, norepinephrine is replaced and thus the quantity of neurotransmitters capable of being released is reduced. In response to stimulation, the nerve may release guanethidine, which, however, is not an adrenergic receptor stimulant. In addition to this disturbance and the presence of stores of catecholamines in adrenergic nerve endings, guanethidine also acts on the stores of catecholamines in organs such as the heart, spleen, and aorta. Adrenoblocking Drugs Since it does not pass through the blood–brain barrier, it does not act on the central sym- pathetic neurons. Guanethidine is used for severe hypertension, where use of more universally accepted drugs is not successful. It is a very powerful and long-lasting drug, and its effects last for 2–3 days after using it. It is used for treating hypertension in patients who do not respond to thiazide diuretics. It can be used as an adjuvant drug in thiazide treatment for reaching an optimal level of blood pressure. Treating this with hydrogen iodide removes the methyl-protecting group on the phenyl hydroxyl group and the product (12. It competitively inhibits tyrosine hydroxylase action, thus reducing the formation of epinephrine and norepinephrine. It is used for treating patients with pheochromocytoma, in cases where a rise in the level of catecholamines is observed. It is known that the effect of acetylcholine in certain organs can be reproduced by the alka- loid muscarine, and in other organs by the alkaloid nicotine. The division of cholinore- ceptors into so-called mucarinic (M-cholinoreceptors) and nicotinic (N-cholinoreceptors) is based on this observation. Cholinoreceptors in certain locations have different sensitiv- ities to different drugs. There are more than 10 billion neurons that make up the human nervous system, and they interact with one another through neurotransmitters. Acetylcholine, a number of bio- genic amines (norepinephrine, dopamine, serotonin, and in all likelihood, histamine and norepinephrine), certain amino acids and peptides, and adenosine are neurotransmitters in the central nervous system. Acetylcholine is the primary neurotransmitter in the parasympathetic division of the autonomic nervous system, which mainly innervates the gastrointestinal tract, eyes, heart, respiratory tract, and secretory glands. Although its receptors are crucial for maintaining all normal functions of the body, an extremely small number of illnesses can be explained by the dysfunction of cholinergic regions of the peripheral autonomic system. Although acetylcholine itself is a substance without which normal body function would not be possible, two properties make it extremely undesirable for use as medicinal agents. First, its action is very brief because of the rapid breakdown by cholinesterases, and sec- ond—and more importantly—the diversity of action, which makes it practically impossi- ble to make its action specific in accomplishing certain tasks. However, a number of acetylcholine derivatives are more resistant to cholinesterase action and can have more selective action. Thus, cholinomimetics are those drugs that imitate action of endoge- nously released acetylcholine. Cholinergic receptors are coupled to G proteins (intramem- brane transducers that regulate second messengers). Classifications of these drugs are based on the mechanism of their action, which is exhibited either by direct stimulation of 179 180 13. Cholinomimetics cholinergic receptors by choline esters or cholinomimetic alkaloids, or in an indirect man- ner of inhibiting acetylcholinesterases, which are enzymes responsible for the chemical decomposition of acetylcholine. These, in turn, are subdivided into reversible cholinesterase inhibitors and irreversible cholinesterase inhibitors. So, parasympathetic nerves use acetylcholine as a neurotransmitter and cholinomimetic drugs mimic the action of acetylcholine at its receptors. Indirect-acting (cholinesterase inhibitors), which, in turn, can be reversible or irreversible. At the same time they selectively stimulate uri- nary and gastrointestinal tracts, facilitating emptying of neurogenic bladder in patients after surgery or parturition or with spinal cord injury. Nicotinic receptor agonists mimic the effects of acetylcholine at nicotinic receptors on autonomic ganglionic synapses and skeletal neuromuscular junctions. The single case of medical usefulness is their use as a transdermal patch or as chewing gum for cessation of smoking. These drugs are divided into drugs that stimulate muscarinic (M-cholinoreceptors) or nicotinic (N-cholinoreceptors) receptors. Drugs whose efficacy is primarily connected to stimulation of muscarinic receptors, including choline esters, i. Drugs whose action is based on stimulation of nicotinic receptors include the alkaloids nicotine and lobeline. Despite the fact that these drugs are able to directly stimu- late all cholinergic receptors, their therapeutic efficacy is mediated by reaction with mus- carinic receptors (subtypes M1 and M2). The only difference between these drugs is their duration of action, and to some extent selectivity for receptors. For example, 2-chloroethanol is reacted with trimethylamine, and the resulting N,N,N-trimethylethyl-2-ethanolamine hydrochloride (13. A second method consists of reacting trimethylamine with ethylene oxide, giving N,N,N-trimethylethyl-2-ethanolamine hydrox- ide (13. Finally, acetylcholine is also formed by reacting 2-chloroethanol acetate with trimethylamine [1–7]. Because of the presence of a highly polar, charged ammonium group, acetylcholine does not pene- trate lipid membranes. Because of this, when the drug is introduced externally, it remains in the extracellular space and does not pass through the blood–brain barrier.

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In fact purchase female cialis 20mg without a prescription, the presenceofatrial 26 Chapter 1 tachycardia with block should always make one consider the possi- bility of digitalis toxicity female cialis 10 mg. Atrial flutter and atrial fibrillationcanusually be distinguished by simple inspection buy 20 mg female cialis. Automatic ventricular tachyarrhythmias Abnormal automaticity accounts for a relatively small proportion of ventricular tachyarrhythmias female cialis 20 mg with amex. As is the case with automatic atrial arrhythmias, automatic ventricular arrhythmias are usually associ- atedwith acute medical conditions, suchasmyocardial ischemia, acid–base disturbances, electrolyte abnormalities, and highadren- ergic tone. Automatic ventricular arrhythmias are most often seen in patients with acute myocardial ischemiaorinfarction,orsome other acute medical illness. Most arrhythmias occurring within the first few hours of an acute myocardial infarction are thought to be automatic. Once the ischemic tissue dies or stabilizes, however, the substrate for automaticity is nolonger present. Ingeneral, the treatmentofautomatic ventricular arrhythmias consists of treating the underlying illness. Reentrant ventricular tachyarrhythmias Most ventricular arrhythmias are reentrant in mechanism. While the conditions producing automatic ventricular arrhythmias are usually temporary in nature (e. Because the intra- atrial reentrant circuit can be located anywhere within the atria, the P-wave morphology can have any configuration. Reentrant circuits within the ventricular myocardium usually arise after scar tissue develops, a conditionmost commonly seenin patients who have myocardial infarctionsorcardiomyopathy. Once the scar tissue gives rise to a reentrant circuit, the circuit persists, and the potential for a ventricular arrhythmiaalways exists. Reentrantventricular arrhythmias are seen only rarely in individuals who have normal ventricles. Most antiarrhythmic drugs affect the ventricular myocardium and,accordingly, most are used to treat ventricular tachyarrhyth- mias. Channelopathic ventricular tachyarrhythmias Channelopathies probably account for several distinctive types of ventricular tachyarrhythmias, at least twoofwhich have now been Mechanismsofcardiac tachyarrhythmias 29 well characterized. These are the ventricular arrhythmias dueto triggered activity and Brugadasyndrome. Triggered activity in the ventricles Because ventricular tachyarrhythmias duetotriggered activity are reasonably common,and because the managementoftriggered ven- tricular arrhythmias is very different from the managementofmore typical ventricular arrhythmias, it is importanttorecognize their characteristics. Twofairly distinct clinical syndromes are caused by ventricular triggered activity:catechol-dependent arrhythmias and pause-dependent arrhythmias. They are the classically polymor- phic ventricular tachyarrhythmias generally referred to as torsades de pointes. Patients with catechol-dependenttriggered activity therefore expe- rience arrhythmias (oftenmanifested by syncopeorcardiac arrest) in times of severe emotional stress or during exercise. Pause-dependenttriggered arrhythmias are caused by afterdepolarizations that occur during 30 Chapter 1 Delayed afterdepolarization (a) Early afterdepolarization (b) Figure 1. These patients, from available evidence, have one of several channelopathies that become clinically manifest only when theiractionpotential durations are increased by drugs or electrolyte abnormalities. The T-U abnormalities tend to be dynamic; that is, they wax and wane from beat to beat, mainly depending on beat- to-beat variations in heart rate. The slower the heart rate, the more exaggerated the T-U abnormality; hence, this conditionissaid to be pause dependent. In thisfigure, eachburst of polymorphic ventricular tachycardia causes a compensatory pause, and the pause causes the ensuing normal beat to be associatedwith pronounced U-wave abnormalities (i. The acute treatmentofpause-dependenttriggered activity con- sists of attempting to reduce the duration of the actionpotential, to eliminate the pauses, or both. Intravenous magnesium often ameliorates the arrhythmias evenwhen serum magnesium levels are in the normal range. The mainstay of emergent treatmentof the arrhythmias, however, istoeliminate the pauses that trigger the arrhythmias—that is, to increase the heart rate. This is most often ac- complished by pacing the atrium or the ventricles (usually, at rates of 100–120 beats/min)or,occasionally, by using anisoproterenol infusion. The top two strips show the typical pattern—eachburst of polymorphic ventricular tachycardia is followed by a compensatory pause; the pause, in turn, causes the ensuing sinus beat to be followed by another burst of ventricular tachycardia. The bottom strip shows the sustainedpolymorphic ventricular tachycardia that followed after sev- eral minutes of ventricular tachycardiabigeminy. Brugadasyndrome is usually seeninmales and is probably the same disorder as the suddenunexpectednocturnal death syndrome seeninAsianmales. Patients with Brugadasyndrome have genetic abnormalities in the rapid sodium channel. Several varieties of sodium channelopathies have beenidentified, probably accounting for the several clinical varieties seenwith Brugadasyndrome. The implantable defibrillator is the mainstay of therapy for patients with Brugadasyndrome. Mechanismsofcardiac tachyarrhythmias 35 Miscellaneous ventricular arrhythmias Several clinical syndromes have beendescribedinvolving unusual ventricular arrhythmias that do not fit clearly into any of these cate- gories. Nomenclature for these arrhythmias is unsettledinthe litera- ture, reflecting the lackofunderstanding of their mechanisms. It islikely that at least some of these will eventually prove to be duetochannelopathies. Thus, it should not be surprising that drugs that alter the actionpotential might have important effects oncardiac arrhythmias. How antiarrhythmic drugs work Thinking of an antiarrhythmic drug as a soothing balm that sup- presses an“irritation of the heart”is more thanmerely naive;it is dangerous. If this ishow one imagines antiarrhythmic drugsto work, thenwhen an arrhythmiafails to respond to a chosendrug, the natural response istoeither increase the dosage of the drug or, worse, add additional drugs(in afutile attempttosufficiently soothe the irritation). Effect on cardiac action potential What antiarrhythmic drugsactually do—the characteristic that makes them“antiarrhythmic”—istochange the shapeofthecar- diac actionpotential. Antiarrhythmic drugs dothis, in general, by altering the channels that control the flow of ionsacross the cardiac cell membrane. When an appro- priate stimulusoccurs, the mgate opens, which allows positively charged sodium ionstopour into the cell very rapidly, thus causing the cell to depolarize(phase 0 of the actionpotential). Panels (a) through(c) display the function of the two controlling gates in the baseline(drug-free) state. Panels (d)and (e) display the effectofadding a Class I antiarrhythmic drug (opencircles). Consequently, reaching the end of phase 0 takes longer; the slopeofphase 0 and the conduction velocity are decreased. Class I antiarrhythmic drugs work by binding to the h gate, mak- ing it behave as if it is partially closed.

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