By Q. Lars. Bridgewater State College. 2018.

The nature of the Lorentz factor differs from experimental setup to setup generic 1 mg decadron visa, that is generic 0.5 mg decadron fast delivery, with both the diffraction technique and the crystalline sample type. Within a certain diffraction technique and crystalline sample type, the Lorentz factor varies only quantitatively (3,4). For now, it may suffice that making L smaller than A3 and/or Q−1 by choice of certain parameters of a diffraction technique or by choice Structural Fingerprinting of Nanocrystals in the Transmission Electron Microscope 279 of the selection of a certain crystalline sample reduces the integrated coefficient of reflection so that structural fingerprinting may proceed within the frameworks of the kinematic or quasi-kinematic theories. Since a particular Q is proportional to a particular Fourier coefficient of the electrostatic potential, which is a parameter of a crystal structure, relations (5a) and (5b) will, for different reflections (hkl) of the same nanocrystal with a fixed size, be better or worse approximations to relations (4a) and (4b). The electron wavelength, size/thickness, and structure of the nanocrystal as well as the volume of its unit cell are fixed in a typical experiment, but they are also parameters that determine how well the two-beam dynamical diffraction theory will be approximated by the kinematic theory. It is, therefore, quite appropriate to introduce a “range of crystal sizes/ thicknesses, electrostatic potential values, electron wavelengths, and unit cell vol- umes” in which a nanocrystal diffracts quasi-kinematically. The mutual arrangement of the “electron scattering centers” also determines the electrostatic potential. While for face-centered cubic structures of elements such as aluminum, silver, and gold all atoms scatter in phase, that is, their individual contributions to the scattered waves add up, there will be constructive and destructive interferences in more complex structures. Also, there are typically more reflections for structures with large unit cell volumes than there are for struc- tures with small unit cell volumes. In addition, the reflections from large unit cells tend to be weaker than their counterparts from structures with small unit cells. The crystal orientation determines through Bragg’s law which reflections will be activated in a given experiment and, therefore, also affects the “range” in which a nanocrystal diffracts quasi-kinematically. As no definitive crystal size/thickness limit for the quasi-kinematic diffraction range can be given that would apply to all nanocrystals and all experiments, one may employ the relation Fhkl A ≈ 1 (8a) 3 where A has the meaning of Vainshtein’s “critical thickness range” (3–5), as an eval- 3 uation criterion for the gradual transition from the kinematic theory to the dynami- cal two-beam theory. The relation Fave A ≈ 1 (8b) 3 where Fave, the average over the structure factor of a certain structure, is also used as such as an evaluation criterion (5,14,32). A gradual transition from the kinematic theory to the dynamical two-beam theory will occur in the range Fhkl 0. Such corrections can be employed advan- tageously when integration over the excitation errors is achieved by the specifics of the employed diffraction technique (3,4) and are described in more detail in the following text. Note that Fhkl A3 ≈ (10) 2 implies that the two-beam dynamical diffraction theory becomes gradually valid (3,34) (with an A3 of approximately half of the extinction distance). The range Fhkl 1 < A3 ≈ (9c) 2 is, therefore, subject to gradually increasing primary extinction effects (4). From practical experience with mosaic nanocrystals and polycrystals with either random orientation or textures (3), it was recommended that a Blackman primary extinction correction should be employed within the whole range Fhkl 0. The reflections that possess small structure factor moduli may behave nearly kinetically and the ones with intermediate and large structure factor moduli may behave quasi-kinematically. Note that Blackman primary extinction corrections are in principle applica- ble to all of the ranges of relations (9a) to (9e) as long as the diffraction technique provides an effective integration over the excitation errors (3). They may, therefore, frequently not be justified when microphotometry of stacks of photographic films with vary- ing exposure times is employed in order to obtain the integrated coefficient of Structural Fingerprinting of Nanocrystals in the Transmission Electron Microscope 281 reflections. This illustrates a problem that structural electron crystallography (of unknowns) has learned to circumvent in an iterative manner: the approximate iden- tification of which reflection needs to be dealt with by what dynamical correction (4). The so-called “crystallographic reliability” values, R values for short, and model structures are used for this purpose. This representation is typically made on the basis of the Fourier coefficients of the electrostatic potential (i. Appropriate correction for dynam- ical scattering effects of the most important reflections can thus be identified by their effect on the R value. Note that structural fingerprinting at the structure fac- tor level works on the basis of a range of preidentified model structures that corre- spond within the experimental error bars to the projected reciprocal lattice geometry and 2D symmetry. Since these model structures are obtained from a comprehensive database, there is no shortage of model structures with which the experimentally obtained (and appropriately corrected) structure factor data can be compared. Over- all, in order to avoid structural misidentifications, one must try to minimize the total amount of corrections necessary to obtain a minimal R value. Note that these comparisons can be done without the benefit of a known model structure as a result of the averaging over certain sin / ranges. Such esti- mations work because the mean square value of the phase factors of relations (3a) to (3c) is unity when the atoms are uniformly distributed throughout the unit cell (36). Structure factor modulus information may, thus, be extracted for structural fingerprinting purposes very pragmatically either with or without the benefit of a structure model. The usage of relations (11a) and (11b) is especially recommended if there is some dispersion in the nanocrystallite size distribution in a polycrystalline sample, that is, in which some small crystals diffract kinematically (∼Q 2 or ∼Q2) and oth- ave ers diffract dynamically (∼Qave or ∼Q) because they are of a larger size (3). If the falloff of averaged integrated intensities at small values of sin / corresponds to the sum of the f-curves and at large values of sin / to the sum of the f2-curves, the crystal thickness will be in the quasi-kinematic range and a Blackman correc- tion may advantageously be employed to the small-angle Bragg reflections (3). A somewhat related pragmatic approach to extracting relative structure factor mod- uli from measured relative intensities that is also applicable in the quasi-kinematic range is to determine an exponent of Qave that is intermediate between 2 and unity by a fitting and averaging procedure (3). The phase grating approximation to dynamical multiple-beam scattering can also be used to extract quasi-kinematic structure factors from electron diffraction intensities on the basis of two experimental data sets that were recorded for the same kind of crystals at a highest voltage (e. This approach is highly advantageous, as the reflections that need to be corrected can be identified directly.

Pinocytosis is a non-specific process that goes on continually in all cell types purchase decadron 0.5 mg without prescription, in which the plasma membrane invaginates and forms an inward channel cheap decadron 0.5 mg on-line, into which extracellular fluid flows (Figure 1. Solutes dissolved in the extracellular fluid, including large (soluble) macromolecules, may flow with the extracellular fluid into the invaginations and become internalized. Alternatively, uptake may involve: • adsorptive pinocytosis, in which macromolecules bind to non-specific membrane receptors, prior to pinocytosis; • receptor-mediated pinocytosis, in which macromolecules bind to specific membrane receptors, prior to pinocytosis. The pinocytic vesicles (endosomes) migrate inwardly and fuse with lysosomes, which contain many lyosomal enzymes, to form secondary lyosomes. The ligand is degraded by the lysosomal enzymes, the degraded products are released and the membrane is recycled back to the plasma membrane. Alternatively, the secondary lysosomes can fuse with the cell membrane, leading to exocytosis of their contents, and the membranes are recycled back to the plasma membrane. Thus pinocytosis offers a pathway through which large macromolecules, which are otherwise incapable of passing through the membrane, may be taken up by cells. In some cases, following uptake of a drug via receptor-mediated pinocytosis, the endosomes carrying the drug actually bypass the lysosomes and migrate toward the basolateral membrane, resulting in the release of the undegraded drug into the extracellular space bounded by the basolateral membrane. This process, known as transcytosis, represents a potentially useful and important pathway for the absorption of high molecular weight drugs such as peptides and proteins. Indeed, some peptides and proteins are known to enter intestinal mucosal cells through pinocytosis; furthermore, a few peptides and proteins (including immunoglobulin G, nerve growth factor and epidermal growth factor) have been reported to reach blood vessels in the lamina propria and the portal venous circulation. This process may be facilitated by serum proteins knows as opsonins, which cover the particulate and promote adsorption and ingestion. The extent and pattern of opsonization depends highly on antigen surface characteristics such as charge and hydrophilicity. When digestion is complete, the lysosomal membrane may rupture, discharging its contents into the cytoplasm. Fixed macrophages are found lining certain blood and lymph-filled spaces, such as the sinusoids of the liver (these cells are commonly referred to as Kuppfer cells), bone marrow and spleen. For the purpose of completeness, the process of phagocytosis has been described briefly here. The process of phagocytosis is of particular relevance when particulate delivery systems, such as microspheres, liposomes and other advanced delivery systems (described in Chapter 5), are used. Phagocytic processes are also finding applications in oral drug delivery and targeting. Specialized epithelial cells known as M cells, which overly lymphoid sections of the gastrointestinal tract, may be involved in the phagocytic uptake of macromolecules and microparticles from the gut (see Section 6. Pore transport A further mechanism of transcellular transport is via the aqueous pores which exist in many lipid membranes. However, most drugs are generally much larger (≥1 nm in diameter) than the pore size, and this route is therefore of minor importance for drug delivery. These properties will influence the route and mechanism of drug absorption through the mucosa. For example, it is not unreasonable to assume that: • low molecular weight hydrophilic compounds would tend to be absorbed via the paracellular route, moving between the epithelial cells; • lipid-soluble drugs would usually absorbed via transcellular passive diffusion, diffusing through the lipidic membrane barrier; • macromolecules may be absorbed via endocytic processes; • drugs bearing structural similarities to endogenous nutrients may be absorbed via carrier-mediated mechanisms. However, this is a rather simplistic view and it is important to realize that these considerations are only broad generalizations. Thus although a drug molecule may be predominantly absorbed via one particular route/mechanism, it is also likely that suboptimal transport will occur via other routes and mechanisms. In particular, drugs that are absorbed via active mechanisms are often also absorbed, to a (much) lesser extent, via passive diffusion mechanisms. A brief description of the effect of the physicochemical properties of the drug on the absorption process is given below and is discussed in more detail in the relevant chapters. A measure of the lipid solubility of a drug is given by its oil/water equilibrium partition coefficient. This is determined by adding the drug to a mixture of equal volumes of a lipophilic liquid (often octanol, but other solvents also used) and water and shaking the mixture vigorously to promote partitioning of the drug into each phase. For a given drug: if log P=0, there is equal distribution of the drug in both phases if log P>0, the drug is lipid soluble if log P<0, the drug is water soluble 19 Table 1. Thus in general, the higher the log P, the higher is the affinity for lipid membranes and thus the more rapidly the drug passes through the membrane via passive diffusion. Values of log P that are too high (>6) or too low (<3) may be associated with poor transport characteristics. Drugs with very high log P values have poor aqueous solubility, which is partly the reason for their poor absorption properties, as some degree of aqueous solubility is required for drug absorption (see Section 1. Furthermore, if a drug is too lipophilic, it will remain in the lipidic membrane and never partition out again into the underlying aqueous environment.

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Less than 4% of the drug is excreted in the urine unchanged and ketamine use can be detected in urine for approxi- mately 3 days order 1 mg decadron. Pathological conditions affecting liver function result in decreased clearance of ketamine with prolonged and exaggerated effect Drug-Drug Interactions Prolonged recovery time may occur if barbiturates and/or narcotics are used concurrently with ketamine buy 1 mg decadron free shipping. Lorazepam may decrease ketamine-associated emotional distress but does not decrease cognitive or behavioral effects of ketamine. Haloperidol may decrease impairment by ketamine in executive control functions, but does not affect psychosis, perceptual changes, negative schizophrenic-like symp- toms, or euphoria. These effects resemble a direct stimulation and excitation of the central sympathetic nervous sys- tem. Increases in plasma epinephrine and norepinephrine levels occur as early as 2 minutes after I. This results in an increase in systemic and pulmonary arterial blood pressures, heart rate, cardiac output, cardiac work, and myocardial oxygen requirement, associated with appropriately increased coronary artery dilation and flow. In vitro ketamine produces a direct negative inotropic effect, myocardial depression, and vasodilatation, emphasizing the importance of 292 C. The use of inhaled anesthetic agents concomitantly with ketamine may block its cardiovascular effects as well. This reflects the depletion of their endogenous catecholamine stores and exhaustion of their sympathetic drive, leading to unmasking of ketamine’s direct myocardial depressant effect. Ketamine is also used in children undergoing painful procedures, such as dressing changes on burn wounds. Previous administration of thiopental, diazepam, or midazolam, along with hyperventilation, has been shown to blunt this ketamine-induced increase in cerebral blood flow. The cataleptic state induced is accompanied by nystagmus with papillary dilation, salivation, lacrimation, and spontaneous involuntary muscle movements and gaze into the distance without closing the eyes. These eye effects, along with increased intraocular pressure by ketamine, make its use controversial in open eye injury cases. Induction with ketamine produces a hypnotic state and a dose-related anterograde amnesia, during which the patients are unresponsive to painful stimuli. The added advantage over other parenteral anesthetics is the intense analgesia produced by ketamine. Emergence and recovery from ketamine anesthesia has been accompanied with both pleasant and unpleasant dreams. Illusions, visual disturbances and hallucinations, “weird trips,” floating sensations, alterations in mood and body image, and delirium have been reported. The psychedelic effects of dreams and hallucinations can occur up to 24 hours after the administration of ketamine. The incidence of these phenomena occurs less frequently in young children, and premedication with a benzodiazepine may decrease these effects. Emergence delirium probably occurs secondary to the ketamine-induced depression of the inferior colliculus and medial geniculate nucleus, leading to misinterpretation of auditory and visual stimuli. Sedative Hypnotic and Anesthetic Agents 293 Respiratory Ketamine does not produce significant depression of ventilation. Upper airway muscle tone and airway reflexes such as cough, gag, sneeze, and swallow are relatively intact and well maintained. The patients may be capable of main- taining an intact airway and swallowing during ketamine anesthesia. This effect is secondary to inhibition of extraneuronal uptake of catecholamines, by inhibition of calcium influx through calcium channels in the bronchial smooth muscle cells, and by inhibition of postsynaptic nicotinic or muscarinic receptors in the tracheobronchial tree. Under anesthesia with ketamine, salivary and tracheobronchial secretions are increased, the ventilatory response to carbon dioxide is maintained, and functional residual capacity in spontaneously breathing healthy young children is unaffected. Perhaps the most important property of ketamine is that, despite the induction of anesthesia and dissociation, the cough and gag reflexes usually are not affected. Hepatic and Renal Ketamine does not significantly alter hepatic and renal functions. Ketamine has been used safely in patients with myopathies and a history of malignant hyperthermia. Other Allergy (rarely because not followed by histamine release); cardiovascular stimulation; partial airway obstruction; and minor postanesthetic complica- tions (profuse salivation, lacrimation, sweating, involuntary purposeless move- ments, unpleasant dreams with restlessness, and a more prolonged recovery) have also been observed. Poisoning Information Drowsiness, perceptual distortions, and intoxication may be dose related in a concentration range of 50 to 200 ng/mL. Ketamine is considered a drug with abuse potential and is currently a Schedule C controlled substance in the United States. Ketamine crosses the placenta but studies in animals have not shown ketamine to cause any birth defects. Recreationally, ketamine is used as a psychedelic and for its dissoci- ative effects. Abrupt discontinuation in chronic users causes a physiological withdrawal syndrome.

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In Germany purchase 0.5mg decadron otc, by contrast cheap decadron 1 mg with mastercard, the medical profession exercised a near-monopoly over constructions of “the patient” and drug laws codifed existing power-sharing arrangements. Instead of the state claiming authority over pre-market testing, it acted as one member of a network overseeing pharmaceutical drugs. A fexible boundary between testing and market was predicated on informal trial protocols, a structured system for collecting reports of adverse reactions, and compromises among organized interests and government offcials. The drug approval process thus only rarely became a signifcant site for debates over national competitiveness or industry innovation. Nevertheless, Germany too has seen different waves of regulatory style, from physicians to a networked approach that incorporates the state, select disease-based organizations, and the medical profession. The comparative perspectives developed in this chapter suggest that despite recent convergences in government efforts to stimulate and steer innovation, for example through support for small biotech ventures, national regulatory differences infuence the competitive status of the pharmaceutical sector. In contrast to the argument that it is German and European healthcare cost containment that has undermined its domestic pharmaceutical industry, this chapter suggests instead that regulation also plays a role in the success and failure of industry. In fact, the emergence of a consumer/patient regulatory mode in the United States has driven increased use of prescription drugs. While this comes at high fnancial cost and stress on government regulators, it offers the benefts of avoiding painful cost vs. At the same time, the consumer mode that has emerged in the United States has proven easy to manipulate for industry, as in the cases of corporate-fnanced organizations claiming to be self-organized by patients. A combination of public attention to drug prices, health concerns from product withdrawals due to adverse reactions, and criticisms of the failure to deliver medicines to patients in developing countries pose signifcant challenges to industry and regulators. Research on the interplay of pharmaceutical innovation and regulation presented here suggests that signifcant change in the blockbuster model followed by most pharmaceutical companies may not happen as quickly as critics would like. An open question is whether the current “pharmacy to the world” of the United States may soon loose ground to competitors from developing countries. As Indian and Chinese frms that started in the generics business integrate upstream into the invention and testing of new molecules, they may become the next generation of competitors to the current top-ranking frms. Finally, the emergence of a consumer model of regulation poses a number of critical unresolved questions about the longer-term role of government, industry, the medical profession, and citizens. The era of paternalistic medicine has passed, but the notion that patients can act as consumers and make appropriate decisions concerning medical treatment poses countervailing risks of its own. A better accommodation among key players needs to be struck to foster safe use of pharmaceuticals. The precise form of this accommodation will necessarily vary from one country to the next, which holds out the possibility for additional policy learning from future cross-national comparisons. In the biomedical model, medication is defned as a substance that acts on the condition of a living organism. In many other models it is regarded as a mediator of symbolic relationships linking people to their environment. The complexity of these relationships indicates the extent to which – over the course of their interactions – social actors (industry representatives, physicians, pharmacists, patients, and the like) have become the builders of this representational universe. Moreover, by differentiating itself into a variety of social meanings depending on space and time, this plural universe gives rise to different types of social, economic and legal issues that engender ambiguity and make the analyst’s work diffcult. Consequently, in analyzing medications, the tendency is generally to break up the pathway they follow so that it is more accessible. Critics of biomedical models and supporters of the theory of complexity, such as Gatrell,2 Urry,3 Thrift,4 Byrne,5 and Cilliers,6 suggest instead that healthcare and, along with it, the medication pathway, be considered in their complexity and holistically. We would thus avoid the reductionism of the compartmentalization posited by certain academic disciplines in particular. In a way, paradigms are being changed so that we can examine the processes and interactions that occur all along the medication pathway from the biomolecular mechanisms to the socio-institutional ones, without which epidemiological and clinical fndings cannot be placed in context. The medication cycle To meet these paradigmatic demands, our studies in healthcare have led us to develop the notion of “la chaîne des medicaments,” which we have translated as the “medication cycle. Gatrell, Complexity theory and geographies of health: a critical assessment social. We are thus adopting a broader perspective inspired by the systemic visions of Le Moigne7 and Watzlawick8 and the theory of complexity of Byrne,9 Urry10 and Cilliers11. The notion of the cycle thus necessarily becomes a factor in both the different spheres of research and in care-providing settings. Indeed, it effects a radical conceptual transformation by putting medications back into the context of the total dynamic and steering clear of compartmentalization. In terms of interventions, it also allows us to surmount the gaps in multidisciplinarity by building bridges and providing a common language. The notion of the cycle may be said to take a variety of forms in a framework of variable geometry, in which different cycles ft into each other and mix together in a world of interactions. These dynamic interactions are defned by practices, implicit and explicit regulations derived from healthcare policies, and professional and public organizations that provide a framework for medication use. These dynamic interactions are also based on types of knowledge that simultaneously delimit the nature of medications, drug action and the transactions that take place around drugs.

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In the blood discount decadron 0.5 mg on line, the gradient allows fluid to be drawn from the intracellular Adverse into the intravascular spaces buy 0.5 mg decadron overnight delivery. Adverse reactions to os- Mannitol is used to promote diuresis in acute renal failure and to motic diuretics include: promote urinary excretion of toxic substances. They’re distributed in tissues with high carbonic anhydrase content, such as erythrocytes, plas- ma, kidneys, eyes, liver, and muscle. Pharmacodynamics In the kidneys, carbonic anhydrase inhibitors decrease the availability of hydrogen ions, which blocks the sodium- hydrogen exchange mechanisms. As a result, urinary excre- tion of sodium, potassium, bicarbonate, and water increases. Don’t lose your sense of humor In the eyes, carbonic anhydrase inhibition reduces aqueous humor production, which reduces intraocular pressure. Pharmacotherapeutics Carbonic anhydrase inhibitors are used for diuresis and to treat glaucoma. Drug interactions Adverse Carbonic anhydrase inhibitors produce a variety of drug interac- reactions to tions: carbonic • Salicylates may cause carbonic anhydrase inhibitor toxicity, in- anhydrase cluding central nervous system depression and metabolic acido- sis. They include darifenacin, flavoxate, oxybutynin, solife- How oxybutynin nacin, tolterodine, and trospium. These drugs are all widely dis- bladder, stimulating tributed, metabolized in the liver, and excreted in urine. Urinary tract antispasmodics relieve smooth muscle spasms by in- This anticholinergic ef- hibiting parasympathetic activity, which causes the detrusor and fect is what makes oxy- urinary muscles to relax. Flavoxate and oxybutynin also exhibit butynin useful in the many anticholinergic effects. Pharmacotherapeutics Urinary tract antispasmodics are used for patients with overactive bladders who have symptoms of urinary frequency, urgency, or in- continence. Urgent symptoms Trospium is also indicated for patients with overactive bladders who have symptoms of urge urinary incontinence, and oxybutynin acts as an antispasmodic for uninhibited or reflex neurogenic bladder. Adverse reactions to urinary tract antispasmodics Possible adverse reactions to urinary tract • constipation antispasmodics include: • nausea • blurred vision • vomiting • headache • weight gain • somnolence • pain • urinary retention • acute and secondary angle-closure • dry mouth glaucoma. This type of erectile dysfunction usually stems from vascular and neurologic conditions. Drugs used for erectile dys- function include alprostadil, sildenafil, tadalafil, and vardenafil. The majority of these drugs—including sildenafil, tadalafil, and vardenafil—are given orally, metabolized in the liver, and excreted in feces. An exceptional drug Alprostadil is the exception: it’s administered directly into the cor- pus cavernosum, metabolized in the lungs, and excreted in urine. Pharmacodynamics Sildenafil, tadalafil, and vardenafil selectively inhibit the phospho- diesterase type 5 receptors, which causes an increase in blood lev- els of nitric oxide. Alprostadil acts locally, promoting smooth muscle relaxation, which causes an increase in blood flow to the corpus cavernosum and produces an erection. Adverse reactions to erectile dysfunction drugs Adverse reactions to erectile dysfunction • headache drugs include: • dizziness • decreased supine blood pressure and car- • flushing diac output • dyspepsia • increased risk of cardiovascular events, in- • vision changes cluding myocardial infarction, sudden cardiac • prolonged erections (more than 4 hours), death, ventricular arrhythmias, cerebrovascu- which can result in irreversible damage to lar hemorrhage, transient ischemic attack, and erectile tissue Sometimes we just hypertension • penile pain (with alprostadil). Sildenafil is also indicated for potentially serious the treatment of pulmonary arterial hypertension. Drug interactions Erectile dysfunction drugs may interact with other drugs in the following ways: • Nitrates and alpha-adrenergic blockers used in combi- nation with erectile dysfunction drugs may cause severe hypotension and potentially serious cardiac events. For example, ethinyl estradiol may be combined with desogestrel, drospirenone, lev- onorgestrel, norethindrone, norgestimate, or norgestrel. Ethinyl estradiol or ethynodiol diacetate may also be used alone as a contraceptive. Patch power Some forms of hormonal contraceptives are available in a trans- dermal patch form. These contraceptives are absorbed through the skin but have the same distribution, metabolism, and excre- tion as orally administered contraceptives. The primary mechanism of action of combination hormonal con- traceptives (estrogen and progestin) is the suppression of go- nadotropins, which inhibits ovulation. Estrogen suppress- es secretion of follicle-stimulating hormone, which blocks follicular development and ovulation. Progestin suppress- es the secretion of luteinizing hormone, which prevents ovulation, even if the follicle develops. Progestin also thickens the cervical mucus; this interferes with sperm migration and causes endometrial changes that prevent implantation of a fertilized ovum. Pharmacotherapeutics The primary purpose for taking hormonal contraceptives is the prevention of pregnancy in women.

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