睿学教育Wisdome Education

Mr. John W. K. Harrison MSc FRCSEd (Tr & Orth)

• MFSEM (UK)
• Queen Elizabeth Hospital
• Gateshead, UK

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For example medicine hat lodge order isoniazid cheap, many drugs are metabolized D D by CYP2D6 25 medications to know for nclex cheap isoniazid 300 mg on line, CYP2C9 medicine versed order isoniazid 300 mg without prescription, or CYP3A4 enzymes. Tissue fluid around cells These enzymes, located within hepatocytes, are complex Figure 2–4 Plasma proteins, mainly albumin (A), act as carriers for proteins with binding sites for drug molecules (and endogenous drug molecules (D). Bound drug (A–D) stays in bloodstream and is pharmacologically inactive. They catalyze the chemical reactions of oxidation, and act on body cells. With chronic ad- Serum Drug Levels ministration, some drugs stimulate liver cells to produce larger amounts of drug-metabolizing enzymes (a process called A serum drug level is a laboratory measurement of the amount enzyme induction). Enzyme induction accelerates drug me- of a drug in the blood at a particular time. It reflects tabolism because larger amounts of the enzymes (and more dosage, absorption, bioavailability, half-life, and the rates of binding sites) allow larger amounts of a drug to be metabo- metabolism and excretion. As a result, larger doses of the tion (MEC) must be present before a drug exerts its pharma- rapidly metabolized drug may be required to produce or cologic action on body cells; this is largely determined by the maintain therapeutic effects. Rapid metabolism may also in- drug dose and how well it is absorbed into the bloodstream. Toxic concentrations may stem from a single large also may increase the rate of metabolism for endogenous dose, repeated small doses, or slow metabolism that allows steroidal hormones (eg, cortisol, estrogens, testosterone, the drug to accumulate in the body. However, enzyme induction does not occur high concentrations is the therapeutic range, which is the goal for 1 to 3 weeks after an inducing agent is started, because of drug therapy—that is, enough drug to be beneficial, but not new enzyme proteins must be synthesized. When a single dose of a drug is given, Metabolism also can be decreased or delayed in a process onset of action occurs when the drug level reaches the MEC. Then, drug levels decline as the drug is the slowly metabolized drug may be needed to avoid adverse eliminated (ie, metabolized and excreted) from the body. Enzyme inhi- Although there may still be numerous drug molecules in the bition occurs within hours or days of starting an inhibiting body, drug action stops when drug levels fall below the MEC. Cimetidine, a gastric acid suppressor, inhibits several the duration of action is the time during which serum drug CYP enzymes (eg, 1A2, 2C, and 3A) and can greatly decrease levels are at or above the MEC. The rate of drug metabolism also is reduced drug are given (eg, for chronic, long-lasting conditions), the in infants (their hepatic enzyme system is immature), in peo- goal is usually to give sufficient doses often enough to main- ple with impaired blood flow to the liver or severe hepatic or tain serum drug levels in the therapeutic range and avoid the cardiovascular disease, and in people who are malnourished or toxic range. In clinical practice, measuring serum drug levels is useful When drugs are given orally, they are absorbed from the in several circumstances: GI tract and carried to the liver through the portal circulation. These are drugs with a narrow margin of safety part of a drug dose reaching the systemic circulation for dis- because their therapeutic doses are close to their toxic tribution to sites of action. This is called the first-pass effect or doses (eg, digoxin, aminoglycoside antibiotics, lithium, presystemic metabolism. Ef- could be either a lack of therapeutic effect or increased fective excretion requires adequate functioning of the circu- adverse effects. Most drugs are excreted by the kidneys and eliminated unchanged or as metabolites in the urine. Some drugs or metabolites are excreted in bile, then eliminated in Serum Half-Life feces; others are excreted in bile, reabsorbed from the small intestine, returned to the liver (called enterohepatic recircu- Serum half-life, also called elimination half-life, is the time lation), metabolized, and eventually excreted in urine. Some required for the serum concentration of a drug to decrease by oral drugs are not absorbed and are excreted in the feces. Factors im- more frequent administration than one with a long half-life. Toxic concentration Steady-state serum drug level Regularly Waning scheduled doses serum Therapeutic Figure 2–5 Serum drug levels with single Drug action Last dose drug levels concentration and multiple oral drug doses. Drug action starts when enough drug is absorbed to starts reach the minimum effective concentration Minimum effective (MEC), continues as long as the serum level Duration of drug action concentration (MEC) is above the MEC, wanes as drug molecules Drug action are metabolized and excreted (if no more stops doses are given), and stops when the serum First dose of Time (days) Drug is eliminated level drops below the MEC. The goal of drug drug enters body from the body therapy is to maintain serum drug levels in the therapeutic range. Because maximal therapeutic effects do not occur until Receptor Theory of Drug Action equilibrium is established, some drugs are not fully effective for days or weeks. To maintain steady-state conditions, the amount Like the physiologic substances (eg, hormones and neuro- of drug given must equal the amount eliminated from the body. Receptors are mainly pro- continued, it is eliminated gradually over several half-lives. Specific receptors include enzymes involved in essen- tial metabolic or regulatory processes (eg, dihydrofolate re- PHARMACODYNAMICS ductase, acetylcholinesterase); proteins involved in transport (eg, sodium–potassium adenosine triphosphatase) or struc- Pharmacodynamics involves drug actions on target cells and tural processes (eg, tubulin); and nucleic acids (eg, DNA) in- the resulting alterations in cellular biochemical reactions and volved in cellular protein synthesis, reproduction, and other functions (ie, what the drug does to the body). When drug molecules bind with receptor molecules, the resulting drug–receptor complex initiates physiochemical re- actions that stimulate or inhibit normal cellular functions.

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Because this deficiency; a high-fat diet; the presence of oxalic acid (from beet equal ratio is present in milk medications hypertension buy 300 mg isoniazid visa, milk is probably the best source of greens symptoms you need glasses isoniazid 300 mg without prescription, chard) treatment walking pneumonia order 300 mg isoniazid visa, which combines with calcium to form insoluble cal- phosphorus. In general, factors that increase or decrease calcium cium oxalate in the intestine; alkalinity of intestinal secretions, absorption act the same way on phosphorus absorption. Vitamin D which leads to formation of insoluble calcium phosphate; diarrhea enhances, but is not essential for, phosphorus absorption. Large or other conditions of rapid intestinal motility, which do not allow amounts of calcium or aluminum in the GI tract may combine with sufficient time for absorption; and immobilization. In people daily through the intestines (in mucosal and biliary secretions and with acute or chronic renal failure, phosphorus intake is restricted sloughed intestinal cells). Functions Functions Phosphorus, most of which is located intracellularly as the phos- • Calcium participates in many metabolic processes, including phate ion, performs many metabolic functions: the regulation of: • It is an essential component of deoxyribonucleic acid, • Cell membrane permeability and function ribonucleic acid, and other nucleic acids in body cells. Thus, • Nerve cell excitability and transmission of impulses (eg, it is it is required for cell reproduction and body growth. This re- • Conduction of electrical impulses in the heart action also prevents buildup of excessive amounts of free • Blood coagulation and platelet adhesion processes fatty acids. When excess hydrogen ions are present • Catecholamine release from the adrenal medulla, Release of chemical mediators (eg, histamine from mast cells) in kidney tubules, phosphate combines with them and allows • Calcium is required for building and maintaining bones and their excretion in urine. Bone calcium is composed mainly of calcium phosphate tained by the kidneys and contributes to alkalinity of body and calcium carbonate. Although there are other buffering systems in the amount of calcium is available for exchange with serum. This body, failure of the phosphate system leads to metabolic aci- acts as a reserve supply of calcium. Calcium is constantly shift- dosis (retained hydrogen ions or acid and lost bicarbonate ing between bone and serum as bone is formed and broken ions or base). When serum calcium levels become low, calcium moves • It is necessary for cellular use of glucose and production of into serum. Increased daily amounts are needed by growing children (1200 mg), pregnant or lactating women (1200 mg), and Requirements and Sources postmenopausal women who do not take replacement estrogens Daily requirements for phosphorus are approximately 800 mg for (1500 mg to prevent osteoporosis). Good 8-oz glasses of milk daily contain approximately the amount sources are milk and other dairy products, meat, poultry, fish, eggs, needed by healthy adults. There is little risk of phosphorus deficiency with an ad- body because milk also contains lactose and vitamin D, both of equate intake of calcium and protein. It may be caused by inadequate intake of calcium poor memory, headache, and drowsiness. Severe hypercalcemia and vitamin D, numerous disorders (eg, diarrhea or malabsorption may produce lethargy, syncope, disorientation, hallucinations, syndromes that cause inadequate absorption of calcium and vitamin coma, and death. Other signs and symptoms include weakness and D, hypoparathyroidism, renal failure, severe hypomagnesemia, decreased tone in skeletal and smooth muscle, dysphagia, polyuria, hypermagnesemia, acute pancreatitis, rhabdomyolysis, tumor lysis polyphagia, and cardiac dysrhythmias. In addition, calcium may be syndrome, vitamin D deficiency), and several drugs (eg, cisplatin, deposited in various tissues, such as the conjunctiva, cornea, and cytosine arabinoside, foscarnet, ketoconazole, pentamidine, and kidneys. Calcium deposits in the kidneys (renal calculi) may lead to agents used to treat hypercalcemia). First, inability to Osteoporosis excrete phosphate in urine leads to accumulation of phosphate in Osteoporosis is characterized by decreased bone density (os- the blood (hyperphosphatemia). Because phosphate levels are in- teopenia) and weak, fragile bones that often lead to fractures, pain, versely related to calcium levels, hyperphosphatemia induces and disability. Second, when kidney function is impaired, vitamin ture sites are the vertebrae of the lower dorsal and lumbar spines, D conversion to its active metabolite is impaired. Risk factors include female sex, advanced age, small stature, Clinical manifestations are characterized by increased neuro- lean body mass, white or Asian race, positive family history, low muscular irritability, which may progress to tetany. Tetany is char- calcium intake, menopause, sedentary lifestyle, nulliparity, smok- acterized by numbness and tingling of the lips, fingers, and toes; ing, excessive ingestion of alcohol or caffeine, high protein in- twitching of facial muscles; spasms of skeletal muscle; carpope- take, high phosphate intake, hyperthyroidism, and chronic use dal spasm; laryngospasm; and convulsions. In young children, of certain medications (eg, corticosteroids, phenytoin). Post- hypocalcemia may be manifested by convulsions rather than menopausal women who do not take estrogen replacement ther- tetany and erroneously diagnosed as epilepsy. This may be a serious apy are at high risk because of estrogen deficiency, age-related error because anticonvulsant drugs used for epilepsy may further bone loss, and a low peak bone mass.

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Because he truly experiences the unity of all life medicine youkai watch generic isoniazid 300 mg on line, the sage perceives and understands all opposites as part of the same system symptoms by dpo order 300 mg isoniazid overnight delivery. As the sage does not oppose these opposites treatment hypercalcemia isoniazid 300 mg purchase on line, they can bring harmony and balance to all situations. These actions are natural, effortless, and spontaneous and are imbued with the power of the Tao. Taoist thought maintains that cultivating sage-like attributes is part of the pro- cess of human transformation. While we may think that to become sage-like hap- pens only at the final stage of this transformation, we also can recognize and foster those attributes already within us. The early Taoist writers, Lao Tzu and Chuang Tzu, themselves legendary sages, offer us numerous examples of behavior based on sage-like virtues. Whoever dares not to be first in the world can become leader of the world. It is through our caring that we connect with others and with all of life. By practicing frugality, we maintain a balanced existence with our environment and develop simplicity in action and thought. And by learning to follow, we determine the needs of the environment and provide the necessary service. The sage, in perceiving keenly, sees past the dualities of right and wrong, and harmonizes all opposites. The sage does not judge, but accepts everything as part of the intrinsic flow of life, and then acts accordingly. In this manner he (or she) provides the opportunity for all beings to become aware of their own self-worth and to express this as goodness. The sage lives her life not by conventional standards, but according to the prin- ciples that are a reflection of the Tao. She believes that the world is ruled by letting things take their course. Initially this process occurs because we consciously adopt and follow those principles that reflect the workings of the Tao—yin-yang and wu-wei, among others. In time we find that our sage-like behaviors occur reflexively and naturally. And this is the ultimate expression of the natural wisdom, the sageliness, that is the essence of our being. It also forms the traditional medicine of countries such as Korea and Japan and is widely practiced throughout the West- ern world in America, the United Kingdom, and parts of Europe and Australia. The underlying principle of TCM is that all living plants and animals contain a life force or energy that circulates continuously through them until they die. In humans, our life force (called Qi) circulates throughout channels or meridians, the main ones connecting with our internal organs. Basically, perfect health may be regarded as the smooth and unobstructed flow of Qi (and blood) throughout the body. Many factors con- tribute to this; hereditary, dietary, and environmental and lifestyle factors such as overworking and stress may all impede the flow of Qi and blood. One of the major differences between TCM and Western medicine is that the former views the body from a holistic viewpoint. Mind, body, and spirit are insepa- rable, interconnecting with and influencing one another. Western medicine in com- parison looks at the body from a scientific, microscopic point of view, isolating and treating each part as a separate entity with little recognition of its relationship to the whole. Treatment is specifically tailored to suit your particular condi- tion at that time. In contrast, the Western medicine doctor gives every patient with the same condition the same treatment without recognition of the fact that each patient is totally different from the next in virtually every regard.

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Esmolol has a rapid onset and short duration of bluish discoloration of skin and corneal deposits that may action medicine 93 3109 buy isoniazid 300 mg amex. It is given IV for supraventricular tachydysrhythmias symptoms stomach cancer buy isoniazid 300 mg without prescription, cause photosensitivity medications not to take after gastric bypass isoniazid 300 mg discount, appearance of colored halos around especially during anesthesia, surgery, or other emergency sit- lights, and reduced visual acuity. Most adverse effects are uations when the ventricular rate must be reduced rapidly. Propranolol may be given When oral amiodarone is used long-term, it also increases orally for chronic therapy to prevent ventricular dysrhythmias, the effects of numerous drugs, including anticoagulants, beta especially those precipitated by exercise. It may be given IV for blockers, calcium channel blockers, class I antidysrhythmics life-threatening dysrhythmias or those occurring during anes- (quinidine, flecainide, lidocaine, procainamide), cyclosporine, thesia. Sotalol is a noncardioselective beta blocker (class II) digoxin, methotrexate, phenytoin, and theophylline. Bretylium initially increases release of catecholamines Because its class III characteristics are considered more im- and therefore increases heart rate, blood pressure, and myo- portant in its antidysrhythmic effects, it is a class III drug (see cardial contractility. It is used primarily in critical care settings for acute con- trol of recurrent ventricular fibrillation, especially in clients Class III Potassium Channel Blockers with recent myocardial infarction. It is given by IV infusion, with a loading dose followed by a maintenance dose, or in re- These drugs act to prolong duration of the action potential, peated IV injections. Because it is excreted almost entirely by slow repolarization, and prolong the refractory period in both the kidney, drug half-life is prolonged with renal impairment 766 SECTION 9 DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM and dosage must be reduced. Thus, they reduce automaticity of the SA and AV nodes, tension and dysrhythmias. Diltiazem and verapamil are the only calcium channel the drug enhances the efficacy of cardioversion. Both structurally similar to sotalol but lacks clinically significant drugs may be given IV to terminate acute PSVT, usually within beta-blocking activity. Ibutilide is widely distributed and has 2 minutes, and in AF and flutter. When given IV, the drugs act metabolized, and the metabolites are excreted in urine and within 15 minutes and last up to 6 hours. Adverse effects include supraventricular and ventricu- be used in the chronic management of the aforementioned lar dysrhythmias (particularly torsades de pointes) and hypo- dysrhythmias. Ibutilide should be administered in a setting with the liver, and metabolites are primarily excreted by the kid- personnel and equipment available for emergency use. The drugs are contraindicated in digoxin toxicity be- Dofetilide is indicated for the maintenance of normal sinus cause they may worsen heart block. If used with propranolol rhythm in symptomatic clients who are in AF of more than or digoxin, caution must be exercised to avoid further im- one-week duration. Adverse effects increase with decreasing pairment of myocardial contractility. Do not use IV vera- creatinine clearance levels so renal function must be assessed pamil with IV propranolol; potentially fatal bradycardia and and initial dosage is dependent on creatinine clearance levels. High dosages in clients with renal dysfunction result in drug accumulation and prodysrhythmia (torsades de pointes). The drug has an elimination half-life of approximately 8 hours with Unclassified the kidneys being the major route of elimination. The drug should initially be administered in a setting with personnel and Adenosine, a naturally occurring component of all body equipment available for emergency use. Beta-blocking effects predominate duction at the AV node and is used to restore NSR in clients at lower doses and class III effects predominate at higher with PSVT; it is ineffective in other dysrhythmias. The drug is well absorbed after oral administration, has a very short duration of action (serum half-life is less than and peak serum level is reached in 2 to 4 hours. It must be ination half-life of approximately 12 hours, and 80% to 90% given by a rapid bolus injection, preferably through a central is excreted unchanged by the kidneys. If given slowly, it is eliminated before it can prevention or management of ventricular tachycardia and fib- reach cardiac tissues and exert its action. It has also been used, usually in smaller doses, to Magnesium sulfate is given IV in the management of sev- prevent or treat AF. However, it is less effective than amio- eral dysrhythmias, including prevention of recurrent episodes darone in the prophylaxis of AF. It is contraindicated in of torsades de pointes and management of digitalis-induced clients with asthma, sinus bradycardia, heart block, cardio- dysrhythmias.

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In discharge or the response to stretch of spindle end- parkinsonianrigidity medications questions buy isoniazid 300 mg free shipping,heightened s drivemightpro- ings in relaxed muscles greater than those in con- duce the more plastic increase in tone typical of trol subjects symptoms quitting weed buy isoniazid 300 mg without a prescription. Most of the patients suffered from dle activity for EMG (or effort) medications 8 rights buy isoniazid amex, and thereby to dis- tendonjerkhyperreflexia,withorwithoutanobvious turbed reflex support to the contraction. These Reflex disinhibition might lead to a fusimotor con- results argue against a contribution of overactiv- tribution to spasms and spasticity, particularly in ity to spasticity. However, it would be imprudent to spinal patients, in whom these manifestations are discard completely heightened fusimotor excitabil- more prominent. This conclusion is consistent with other data suggesting that merely Absence of α/γ co-activation in clonus increasing spindle discharge with, e. Spindleswereactivateddur- complications of paraplegia would result in a steady ing the stretching phase of the oscillating clonic afferent input to motoneurones in such patients, movement, and their activation appeared to drive producing widespread activity even in the absence the next clonic contraction, presumably through the of EMG activity. It remains to be proven whether same spinal pathways that underlie the tendon jerk heightened drive contributes to spinal spasticity reflex. The contraction itself was not accompanied and to flexor and extensor spasms. This led Hagbarth and colleagues to suggest In patients with spinal cord lesions, there is evi- thatproprioceptivespinalreflexesdonotinvolvesig- dence that increased group II excitation might be nificant activation of motoneurones in addition to an important spinal mechanism underlying spas- motoneurones, i. The absence of a correlation between projections of group Ia afferents onto motoneu- the increased electrically-induced group II excita- rones. Reflex little to the motor deficit activation of motoneurones because of disinhibi- A hypothesis of the study of Wilson et al. If this proved to be the case, In these recordings, fluctuations in rigidity were it is possible that the skin, joint, bladder and bowel associated with parallel fluctuations in muscle Conclusions 141 afferent activity and EMG, but with the latter leading of motoneurones should be viewed with an open the former. Voluntary efforts were associated with mind, scepticism being warranted when the data are the increase in muscle afferent discharge expected based on only an occasional recording from an affer- fromstudiesinnormalsubjects. However, as in the case of spasticity, There is considerable evidence suggesting that there itwouldbeimprudenttodiscardcompletelythepos- is little activity in static motoneurones innervating sibilitythatfusimotorneuronesplayaroleinparkin- resting muscles and, if there is any, it is insufficient sonian rigidity. Any enhanced motoneurone dis- to alter muscle spindle discharge materially. The charge need not result from enhanced descending tendon jerk does not require that spindle endings drive onto fusimotor neurones: it could also result be sensitised by d drive to be sufficiently respon- fromabnormalgatingofthetransmissionofgroupII sivethatpercussionevokesatendonjerk. Regardless excitation to motoneurones (see Chapter 12, of whether reinforcement manoeuvres can activate p. Clarification of this issue requires detailed some d motoneurones, the reflex potentiation pro- studies under identical conditions of the responses duced by the Jendrassik manoeuvre or in response of single spindle afferents in patients and control to some other alerting stimulus is not mediated by subjects. Parkinsonian resting tremor efferent activation by corticospinal drives In parkinsonian resting tremor, muscle spindles dis- charged during two phases: during the shortening Corticospinal drives, whether associated with vol- phase of the tremor cycle, with the EMG burst, and untary effort or produced by transcranial magnetic again in the opposite phase of the cycle as the end- or electrical stimulation of the motor cortex, can ingswerestretched(Hagbarthetal. Thispat- increase the discharge of spindle endings due, pri- tern is similar to that seen with voluntary alternating marily,toactivationof motoneurones(butalsodue movements(Hagbarth,Wallin&Lofstedt,¨ 1975b)but to activation of motoneurones), largely in paral- not clonus (Hagbarth et al. Theincrease in drive is translated into an enhanced spindle dis- charge when the contraction is near-isometric. The drive is even more effective when the contracting Conclusions muscleislengthening,andismuchlesssoifthemus- cleisshortening. Increasedspindlefeedbackaccom- the sensitivity of the muscle spindle panies shortening contractions only when the con- the muscle spindle is a more sensitive transducer tractions are relatively slow or the muscle is working of changes in muscle length and in the derivatives of against a load. There will probably be little increase lengththancouldbeconstructedbyhumansorfixed in spindle feedback from the contracting muscle in to the limbs of volunteers. This leads to the con- clusion that, if there is an abnormality of fusimo- Methodology tor function in patients, it is unlikely to represent a causal association. Discredited methods (i) There is now substantial evidence against the Resume´ ´ viewthatcomparisonsoftheHreflexandtendonjerk can be used to provide a reliable measure of fusimo- Background from animal experiments tor activity. While the tendon jerk and the H reflex are both dependent on the monosynaptic excitation the number of spindles in different muscles varies fromhomonymousIaafferents,theHreflexbypasses from <50 for intrinsic muscles of the hand to >1000 the muscle spindle while the tendon jerk does not. Muscle spindles contain modified respects that comparison of them as a measure of muscle fibres (intrafusal fibres).

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Acta Neurochir (Wien) terior cervical discectomy with and Carlson G treatment for 6mm kidney stone 300 mg isoniazid mastercard, Bohlman H (1998) Com- 135:105–121 without fusion: results treatment for pneumonia isoniazid 300 mg order without prescription, complications treatment for pneumonia discount isoniazid online american express, plications of anterior cervical corpec- 84. Weikel AM, Habal MB (1977) Meral- Thirteenth Annual Meeting, New Or- cal decompression and osteosynthesis. Shapiro S (1996) Banked fibula and Surg 60:572–574 (1999) Complications of buttress the locking anterior cervical plate in 100. Weiland AJ, Phillips TW, Randolph plate stabilization of cervical corpec- anterior cervical fusions following MA (1984) A radiologic, histologic tomy. Riley LH, Robinson RA, Johnson 84:161–165 autografts, allografts and free-vascu- KA, Walker AE (1969) the results of 86. Plast Reconstr anterior interbody fusion of the cervi- treatment of certain cervical spine dis- Surg 74:368–379 cal spine. Zdeblick TA, Cooke ME, Wilson D, RJ, Gainor JW, Hardy R (1973) Re- lopathy and myelopathy: when and Kunz DN, McCabe R (1993) Anterior lief of pain by anterior cervical spine what can surgery contribute to treat- cervical discectomy, fusion and plat- fusion for spondylosis: a report of ment? Yonenobu K, Fuji T, Ono K, Okada Spine 14:1974–1983 Am 5:525–534 K, Yamamoto T, Harada N (1985) 109. Williams JL, Allen MB, Harkess JW Choice of surgical treatment for mul- One-level cervical spine fusion. A (1968) Late results of cervical discec- tisegmental cervical spondylotic randomised study, with or without tomy and interbody fusion: some fac- myelopathy. Spine 10:710–716 plate fixation using radiostereometry tors influencing the results. Acta Orthop Scand Joint Surg Am 50:277–286 Cervical kyphosis and myelopathy. J Bone Joint Surg Am Plate fixation adds stability to two- 71:170–182 level anterior fusion in the cervical 107. Zdeblick TA, Ducker TB (1991) the spine: a randomised study using ra- use of freeze-dried allograft bone for diostereometry. Spine 16: 307 726–729 REVIEW Kazuo Yonenobu Posterior approach Takenori Oda to the degenerative cervical spine Abstract Laminoplasty has been expected outcomes and complica- gradually accepted as a treatment for tions of surgery. The historical perspec- Keywords Laminectomy · tive of laminoplasty is described. Laminoplasty · Cervical myelopathy · the aims of laminoplasty are to ex- History · Surgical technique K. Yonenobu (✉) pand the spinal canal, to secure spi- Department of Orthopaedic Surgery, Osaka-Minami National Hospital, nal stability, to preserve the protec- 2-1 Kidohigashi, Kawachinagano, tive function of the spine, and to pre- 586–8521 Osaka , Japan serve spinal mobility. Oda ment combined with a relatively nar- Department of Rheumatology row canal. Several laminoplasty and Orthopedics, Osaka-Minami National Hospital, techniques and supplementary tech- Osaka, Japan niques are described, together with Laminectomy was the sole procedure by which to access 2. In- the spinal canal until Robinson and Smith [24], and stability and malalignment are notorious as a reason for Cloward [2] devised the anterior procedures, and was a deterioration of neurological symptoms after laminec- choice of treatment for cervical spondylotic myelopathy tomy. The thick scar formation – so-called laminectomy (CSM) or ossification of the posterior longitudinal liga- membrane – occasionally seen subsequent to postlaminec- ment (OPLL). However, laminectomy for these condi- tomy hematoma may increase cord compression due to tions was not always rewarded. Spinal cord injury during and immediately after sur- not be expected if the laminectomy is limited [25]. The insertion of surgical instruments such as a Ker- rison rongeur or a curette into the spinal canal without Because of these shortcomings of laminectomy, many sur- awareness of canal narrowness, or uneven decompres- geons switched from posterior to anterior access to the spi- sion of the spinal cord during resection of the laminae, nal canal, and this led to the development of anterior tech- can impinge or distort the spinal cord and result in niques such as subtotal corpectomy and recent expansion of worsening of neurological function. At the same time, several surgeons pointed out the hazard of postoperative loss of neural continued to try to improve the shortcomings of laminec- function due to surgical intervention [1, 4, 18]. Kirita developed extensive simultaneous decom- toma in association with swelled nuchal muscles may pression laminectomy to avoid distorting the spinal cord compress spinal cord that has lost the protective shield by the edges of the resected laminae [20]. He attempted in this way to pre- tion of the lamina and facet, whereas in laminectomy vent the invasion of scar tissue, which was believed to be the site of the laminotomy is variable.

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Critical Thinking Scenario John Morgan symptoms indigestion order isoniazid 300 mg with amex, 79 years of age medicine of the prophet buy isoniazid online pills, is diagnosed with prostate cancer treatment x time interaction isoniazid 300 mg purchase online. After his third course of treatment, he becomes neutropenic and an infection develops that is treated with two broad-spectrum antibiotics. OVERVIEW Fungi that are pathogenic in humans exist in soil, decaying plants, and other environmental habitats or as part of the en- Fungi are molds and yeasts that are widely dispersed in the dogenous human flora. For example, Candida albicans organ- environment and are either saprophytic (ie, obtain food from isms are part of the normal microbial flora of the skin, mouth, dead organic matter) or parasitic (ie, obtain nourishment from gastrointestinal (GI) tract, and vagina. Molds are multicellular organisms com- ganisms is normally restrained by intact immune mechanisms prised of colonies of tangled strands. When these restrain- ing on various surfaces (eg, the mold that forms on spoiled ing forces are altered (eg, by suppression of the immune sys- food and the mildew that forms on clothing in damp environ- tem or antibacterial drug therapy), fungal overgrowth and ments). In addition, some fungi dermatophytes, can grow only at the cooler temperatures of have characteristics that enhance their ability to cause disease. Other fungi, called dimorphic, can grow as Cryptococcus neoformans organisms, for example, can be- molds outside the body and as yeasts in the warm tempera- come encapsulated, which allows them to evade the normal tures of the body. As molds, these fungi produce spores that immune defense mechanism of phagocytosis. Aspergillus can persist indefinitely in the environment and be carried by organisms produce protease, an enzyme that allows them to the wind to distant locations. When these mold spores enter the destroy structural proteins and penetrate body tissues. They have a thick, rigid cell wall, of which one of the com- human pathogens such as those that cause blastomycosis, ponents is a polysaccharide called glucan. Fungi also 595 596 SECTION 6 DRUGS USED TO TREAT INFECTIONS have a cell membrane composed of lipids, glycoproteins, and tochrome P450 enzyme (14-alpha demethylase) that is re- sterols. One of the sterols is ergosterol, a lipid that is similar to quired for synthesis of ergosterol from lanosterol, a precursor. Within This action causes production of a defective cell membrane, the cell membrane, structures are essentially the same as those which also allows leakage of intracellular contents and de- in human cells (eg, a nucleus, mitochondria, Golgi apparatus, struction of the cell. Both types of drugs also affect cholesterol ribosomes attached to endoplasmic reticulum, and a cyto- in human cell membranes, and this characteristic is considered skeleton with microtubules and filaments). Echinocandins or glucan synthesis inhibitors (eg, caspo- fungin) are a new class of antifungal drugs that disrupt fun- FUNGAL INFECTIONS gal cell walls rather than fungal cell membranes. They act by inhibiting beta-(1,3)-D-glucan synthetase, an enzyme re- Fungal infections (mycoses) may be mild and superficial or quired for synthesis of glucan. Dermatophytes cause superfi- saccharide in the fungal cell wall; its depletion leads to cial infections of the skin, hair, and nails. Drugs for superficial fungal infections of skin and mucous Most fungal infections occur in healthy people but are more membranes are usually applied topically. Patients with HIV infections (eg, oral, intestinal, or vaginal candidiasis) with anti- infection need aggressive treatment of primary fungal infec- bacterial drug therapy. In immunocompromised hosts, candi- tions and prolonged or lifelong secondary prophylaxis. Patients dal infections are more likely to be deep, widespread, and with prolonged or severe neutropenia secondary to treatment caused by non-albicans species. Instead, they of fungal infections, because they are at high risk for acute, grow in soil and decaying organic matter. Most invasive fungal life-threatening, systemic mycoses such as candidiasis and as- infections are acquired by inhalation of airborne spores from pergillosis. Selected antifungal drugs are further described in contaminated soil and severity of disease increases with inten- the following sections. Infections such as histoplasmosis, coccid- teristics of selected drugs are listed in Table 40–1; clinical in- ioidomycosis, and blastomycosis usually occur as pulmonary dications for use and dosage ranges are listed in Drugs at a disease but may be systemic. Serious, systemic fungal infections commonly occur and Polyenes are increasing in incidence, largely because of human immuno- deficiency virus (HIV) infections, the use of immunosup- Amphotericin B is active against most types of pathogenic pressant drugs to treat clients with cancer or organ transplants, fungi, including those that cause aspergillosis, blastomyco- the use of indwelling intravenous (IV) catheters for prolonged sis, candidiasis, coccidioidomycosis, cryptococcosis, histo- drug therapy or parenteral nutrition, implantation of pros- plasmosis, and sporotrichosis. The drug is fungicidal or thetic devices, and widespread use of broad-spectrum anti- fungistatic depending on the concentration in body fluids and bacterial drugs.

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Three superimposed sweeps medicine keeper discount isoniazid 300 mg visa, showing discharge of the ending (upper trace) during the rising phase of torque (lower trace) medicine prices purchase isoniazid 300 mg visa. This ending There is a bias in microneurographic recordings responded appropriately in a twitch test ) but was towards axons that are large and have a background sensitive to vibration at rest (as verified by the qui- discharge moroccanoil treatment cheap 300 mg isoniazid fast delivery. The former is because the action poten- escent EMG in panels (b ) and (c )), discharging at tial must be discriminated from noise, and action subharmonics of the vibration frequency (d ). The latter is because, if you can- not hear action potentials, you may not know that Uncertainties of the technique you have a suitable recording site. This might explain the sensitivity andlengthtransducersmustbeusedifonewishesto tovibrationofthethreetendonorgansinthestudyof have reasonable certainty that the receptor-bearing Burke et al. However, the very same These results do not necessarily imply that human recordings may not be appropriate if one wishes to tendon organs as a group are more stretch-sensitive know whether only the receptor-bearing muscle is than in the cat. More group Ib afferents might be active (in which case intramuscular needles or wires isolated if searching was undertaken during a back- should be used to record EMG). Thus, if a muscle is no force transducer will keep a limb absolutely iso- held in a stretched position and then abruptly short- metric. Hence, it is impossible to generate data with ened, intrafusal fibres will develop slack, and this the same degree of precision as in animal experi- will lead to a reduced spindle discharge. This disadvantage is offset by the ability to can be removed by activating fusimotor neurones study volitional processes in co-operative human to the spindle and, if the muscle is then slowly subjects, capable of generating or changing motor stretched back to the original length, spindle dis- drives on request. Nevertheless, the uncertainties charge and responsiveness will be greater than ori- must be kept in mind when assessing the validity of ginally even though the fusimotor activity may have evidence for, e. The type of fusimotor axon stimulated rones during different manoeuvres, a controversial will determine which intrafusal fibre is activated, topic discussed further below (pp. Studies that exploit the thixotropic properties Thixotropy in human investigations of intrafusal fibres In human subjects, the activity associated with Underlying principle avoluntary contraction can induce long-lasting Thixotropy refers to the change in passive stiffness enhancements in spindle discharge, changes that of muscle, analogous to the behaviour of certain gels persistlongafterthecontraction-MACROS-. The discharge of the spindle primary to set into a gel again when allowed to stand. The discharge of the secondary because intrafusal thixotropy can dramatically alter endinginFig. In both Edin & Vallbo, 1990a), (ii) the after-effects of fusimo- instances,theafter-dischargeisnotevidenceofcon- toractivationonspindledischarge(Brown,Goodwin tinuing drive but of a long-lasting change in stiff- &Matthews, 1969), and (iii) stretch sensitisation of nessofintrafusalfibresthatcontractedunder drive spindle endings (Edin & Vallbo, 1988;Edin, 1991). As actin–myosin bonds been studied extensively by Proske and colleagues break down and re-form at the prevailing muscle in the cat and in human subjects (Proske, Morgan length,thedischargeslowlydeclines. They depend upon the formation, the enhanced spindle discharge is a lasting mem- breakdownandre-formationofactin-myosinbonds ory of past efferent activity, not evidence of the in the intrafusal fibres, with consequent changes current level of fusimotor drive, and the enhanced in stiffness of the fibres and an alteration in the discharge can be abolished by stretch sufficient to stretch placed on spindle endings. Muscle spindle primary ending in tibialis anterior during and after a voluntary contraction illustrating the effects of thixotropy on spindle discharge. The traces are from top to bottom raw neurogram, force, and integrated EMG of tibialis anterior. The spindle was initially silent, maintained a discharge at ∼12 Hz throughout the 60-s contraction. There was a high-frequency burst of impulses on relaxation of the contraction, and the discharge continued at ∼8Hzinthe absence of EMG following the contraction. The lowest panel shows superimposed action potentials from the unit on a faster time base. A complicating factor is that some of the findings on / co-activation from that extrafusal muscle fibres also display thixotropic human studies can be attributed to incorrect iden- behaviour. This serves as a warning that careful tification of Ib afferents as Ia (Prochazka & Hulliger, controls are required even with this experimental 1983). A further lesson is that the thixotropic properties of intrafusal muscle can distort spin- Sensitivity to displacements dle discharge and must be considered when inter- preting unexpected changes in spindle discharge, Even small movements of the skin at the recording reflex behaviour or perception, especially when they site can disturb the microelectrode and disrupt the occurafteramusclecontraction. As a result the movement repertoire that the spindle was subjected to can influence how it can be studied with this technique is quite limited. This is possible in feline experiments but is rarely so in human sub- the technique is technically demanding jects, in whom spindle endings have been noted to It is not unusual to spend a couple of hours search- respond to mechanical stimuli that are not imme- ing in vain for a specific afferent type, having been diately obvious, such as respiration and the arterial unable to hold promising recordings for sufficiently pulse(Hagbarthetal. It is absolutely essen- tial that all possible perturbations to the highly sen- Thixotropy sitive spindle ending be controlled, whether they be Studies of intrafusal thixotropy can allow stronger external or internal. Organisation and pattern of connections 127 background spindle discharge or the response to Organisation and pattern stretch materially.

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Coman DR medicine journey cheap isoniazid 300 mg overnight delivery, DeLong RP (1951) the mary and metastatic tumors of the cer- Prabhu V medications during labor cheap isoniazid 300 mg buy on-line, Boland PJ (2002) Diagnosis role of the vertebral venous system in vical spine medicine 93 7338 buy 300 mg isoniazid overnight delivery. Spine 23:2767–2776 and management of a metastatic tumor the metastasis of cancer into the spinal 2. Spine 27: cord: experiments with tumor cell sus- strategies in the management of spinal 1062–1069 pensions in rats and rabbits. Batson OV (1940) the function of the Biagini R, Campanacci L, De Iure F, 12. DeLaney TF, Suit HD (2000) Treat- vertebral veins and their role in the Piccill P (1996) Chordoma of the spine ment of spine tumors: radiation ther- spread of metastases. Boriani S, Biagini R, De Iure F, C, Rodts MF (1985) Reconstructive Anderson K, Lipton A, Yee GC, Bier- Bertoni F, Malaguti MC, Di Fiore M, spinal surgery as palliation for metasta- mann JS, American Society of Clinical Zanoni A (1996) En bloc resections of tic malignancies of the spine. Spine 10: Oncology Bisphosphonates Expert bone tumors of the thoracolumbar 21–26 Panel (2002) American Society of spine. Doppman JL, Girton RT (1976) Angio- Clinical Oncology practice guidelines: tients. Spine 21:1927–1931 graphic study of the effect of laminec- the role of bisphosphonates in multiple 9. Boriani S, Weinstein JN, Biagini R tomy in the presence of acute anterior myeloma. J Clin Oncol 20:19–36 (1997) Primary bone tumors of the epidural masses. Terminology and surgical stag- 202 Healey JH (2000) Single-stage postero- ing. Dürr HR, Wegener B, Krödel A, Müller lateral transpedicle approach for 10. Bridwell KH, Jenny AB, Saul T, Rich PE, Jansson V, Refior HJ (2002) Mul- spondylectomy, epidural decompres- KM, Grubb RL (1988) Posterior seg- tiple myeloma: surgery of the spine. Spine 25:2240–2250 with posterolateral decompression and debulking for metastatic thoracic and lumbar spine disease. Schick U, Marquardt G, Lorenz R lier G, Mabesoone F, Aimard T, Sail- Metastatic disease of the cervical (2001) Intradural and extradural spinal lant G (1997) Vertebral metastases. Siegal T, Siegal T (1989) Current con- tive prognostic Tokuhashi Score in a Abumi K, Kaneda K, McAfee PC siderations in the management of neo- series of 71 cases. Spine 22:2293–2298 (1999) Biomechanical analysis of ante- plastic spinal cord compression. Enneking WF, Spanier SS, Goodman rior versus circumferential spinal re- 14:223–228 MA (1980) A system for surgical stag- construction for various anatomic 47. Spine 24: creases bone mineral density in men Orthop 153:106–120 445–450 receiving androgen deprivation therapy 18. Sundaresan N, Galicich JH, Lane JM, Psychiatry 47:761–768 surgical treatment for spinal metas- Bains MS, McCormack P (1985) 19. Int J Radiat Oncol Biol Phys 42: Treatment of neoplastic epidural cord bone disease. From the laboratory to 1127–1132 compression by vertebral body resec- the patient. Gerszten CP, Welch W (2000) Current Steinfeld AD (1999) Radiotherapy for 676–684 surgical management of metastatic spi- the treatment of giant cell tumor of the 49. Oncology 14:1013–1024 spine: a report of six cases and review K, Kelliher K (2002) Surgery for soli- 21. Rationale LF (2001) Spinal radiation before sur- 113 and results of treatment. Koehler PJ (1995) Use of corticoste- 1802–1806 outcomes of surgery for symptomatic roids in neuro-oncology. Landis SH et al (1999) Global cancer ing system for the preoperative evalua- 22. CA Cancer J Clin 49:33–64 tion of metastatic spine tumor progno- Preclinical pharmacology of CGP 37. J Neurosci Yoshida A, Murakami H, Akamaru T Res 9:745–751 Nurs 35:50–55 (2001) Surgical strategy for spinal 23. Spine 26:298–306 Wingo PA (2000) Cancer statistics, MK et al (2001) the initial outcome 52. Groot MT et al (2003) Costs of treatment of painful osteoporotic verte- A (1989) Initial bolus of conventional prostate cancer metastasis to the bone bral compression fractures.

Lares, 52 years: Journal of Phys- synaptic autogenetic inhibitory pathways activated by the iology (London), 445, 345–54. Nausea, vomiting, diarrhea Commonly occur with tetracyclines, sulfonamides, and urinary antiseptics, probably from local irritation of GI mucosa. Topically to skin lesions two to four times daily for 1–4 wk Oral suspension (100 mg/mL), 1 mL swish and swallow 4 times daily Amphotericin B lipid complex Systemic infections in clients who IV 5 mg/kg/d Same as adults (Abelcet) do not tolerate Fungizone Liposomal amphotericin B Systemic infections in clients who IV 3–5 mg/kg/d Same as adults (AmBisome) do not tolerate Fungizone Empiric treatment of presumed fungal infections in febrile, neu- tropenic clients Amphotericin B cholesteryl Systemic infections in clients who IV, 3–4 mg/kg/d Same as adults (Amphotec) do not tolerate Fungizone Butenafine (Mentax) Tinea infections Topically to skin lesions 1–2 times Safety and efficacy not established daily for 1–4 wk for children <12 y Butoconazole (Femstat, Vaginal candidiasis Intravaginally, once daily for 3 d Gynazole) Caspofungin (Cancidas) Invasive aspergillosis IV infusion over 1 h, 70 mg ini- Safety and efficacy not established tially, then 50 mg daily Hepatic impairment, 70 mg ini- tially, then 35 mg daily Ciclopirox (Loprox) Tinea infections, cutaneous Topically to skin lesions, twice candidiasis daily for 2–4 wk Clotrimazole (Lotrimin, Cutaneous dermatophytosis; Orally, 1 troche dissolved in Same as adults Mycelex, Gyne-Lotrimin) oral, cutaneous, and vaginal mouth five times daily candidiasis Topically to skin daily for 2–4 wk Intravaginally, once daily for 3–7 d Econazole (Spectazole) Tinea infections, cutaneous Topically to skin lesions, once or Dosage not established candidiasis twice daily for 2–4 wk Fluconazole (Diflucan) Oropharyngeal, esophageal, vagi- Oropharyngeal candidiasis, PO, IV Oropharyngeal candidiasis, PO, IV nal, and systemic candidiasis 200 mg first day, then 100 mg 6 mg/kg first day, then Prevention of candidiasis after daily for 2 wk 3 mg/kg/d for at least 2 wk bone marrow transplantation Esophageal candidiasis, PO, IV, Esophageal candidiasis, PO, IV, Cryptococcal meningitis 200 mg first day, then 100 mg 6 mg/kg first day, then 3 daily for at least 3 wk mg/kg/d for at least 3 wk CHAPTER 40 ANTIFUNGAL DRUGS 601 Drugs at a Glance: Selected Antifungal Drugs (continued) Routes and Dosage Ranges Generic/Trade Name Clinical Indications Adults Children Vaginal candidiasis, PO 150 mg Systemic candidiasis, PO, IV as a single dose 6–12 mg/kg/d Systemic candidiasis, PO, IV Cryptococcal meningitis, PO, IV 400 mg first day, then 200 mg 12 mg/kg first day, then daily for at least 4 wk 6 mg/kg/d for 10–12 wk Prophylaxis, PO, IV 400 mg once daily Cryptococcal meningitis, PO, IV, 400 mg first day, then 200–400 mg/d for 10–12 wk Flucytosine (Ancobon) Systemic mycoses due to Can- PO 50–150 mg/kg/d in divided Safety and efficacy not established dida species or Cryptococcus doses q6h neoformans Dosage must be decreased with impaired liver function. Load pects of locomotion relevant to motor rehabilitation and phase dependent modulation of motor pool out- of SCI.

Ugolf, 43 years: Parents may need infor- sis, human immunodeficiency virus infection, pancreatitis, mation about the potential hazards of acute and chronic adult respiratory distress syndrome, or other critical illnesses vitamin overdoses. Even in rats, significant interspecies and in- Laboratory rodents are kept in separate trastrain variablity may foil the results of stud- cages in most instances, so they do not injure ies carried out in different laboratories. For example, when a blood vessel is injured, platelets adhere to each other and Blood functions to nourish and oxygenate body cells, protect the edges of the injury to form a cluster of activated the body from invading microorganisms, and initiate hemo- platelets (ie, a platelet thrombus or plug) that sticks stasis when a blood vessel is injured. You update their immunizations and then talk with contacts should be examined carefully and treated if them about malaria prevention.

Roy, 29 years: In some cir- between taking no account of the multiplicity cumstances, one of these subgroup comparisons and retaining 0. The UCL and LCL are basically built around the standard statistical notion of establishing plus and minus 3 standard deviations around the mean. For example, applying the Denis classifica- tion for traumatic thoracolumbar fractures may not be ap- propriate as indication basis for surgical indications. First-generation drugs, mainly cefazolin, are used for procedures associated with gram-positive postoperative infections, such as pros- Use of Penicillins in Specific Situations thetic implant surgery.

Ramirez, 24 years: Course of treatment may be re- peated after 7 d off therapy if engraftment has not occurred. Numerous factors affect the rate and extent of drug Mitochondria absorption, including dosage form, route of administration, blood flow to the site of administration, GI function, the pres- Figure 2–1 Schematic diagram of cell highlighting cytoplasmic ence of food or other drugs, and other variables. These more sophisticated attempts at or on enhancing memory outside of the train- memory remediation cannot be isolated en- ing session. These con- patients in the community, including the lack of ditions include several varieties of eczematous any clinical assessment leading to long periods of dermatitis.

Daryl, 30 years: The drugs inhibit the ability Mechanisms of Action of these immune cells to increase in number and per- form their functions. It becomes much harder to make a piece of writing work when you have to balance the needs of distinct audiences, such as a panel of doctors and a group of patients. Cardiac stimulation is an adverse effect when the effects because the beta2-adrenergic receptors become un- drugs are given for bronchodilation. It is caused by drug-induced suppression of the HPA axis, which makes the client unable to respond to stress by increasing adrenocortical hormone secretion.

Grimboll, 27 years: Pavlow With 2 Figures Posterior approach to the degenerative cervical spine. Brain areas involved in inter- I, Tsunazawa Y, Suzuki T, Yanagida T, Kubota K. He gives you a verbal order for darone seems to be emerging as the drug of choice for lidocaine, IV push, to be followed by a continuous IV infusion. Desirable effects may include im- As with most other drugs, slowed metabolism and excretion provement in behavior, attention span, and quality and increase the risks of accumulation and toxicity.

Garik, 58 years: Analgesics Oxytocics Parenteral opioid analgesics are used to control discomfort Oxytocic drugs include oxytocin (Pitocin) and methyler- and pain during labor and delivery. These drugs also constrict urinary sphincters, crease myocardial oxygen requirement causing urinary retention and painful urination, especially in 4. They also may cause more adverse ef- but if given, the first dose should be approximately half that fects. ConvergenceinthereciprocalIa gle interneurones mediating reciprocal Ia inhibition of inhibitorypathwayofexcitationfromdescendingpathways motoneurones.

Kaelin, 56 years: Basic • Astringents (eg, dilute solutions of aluminum salts) are components of topical agents are one or more active ingredi- used for their drying effects on exudative lesions. There is abundant literature showing that the ratio Hmax/Mmax is, on average, increased in soleus in spastic patients (see Chapter 12,p. All of the shoulder tests are performed standing upright with your feet almost together. Movement- and task-related activations and assessment of forelimb sensorimotor outcome of motor cortical areas: A positron emission tomo- in unilateral rat models of stroke, cortical ablation, graphic study.

Brant, 35 years: If the opening is large, a platelet plug and tor XII interacts with biologic surfaces. Possible mechanisms and functional significance the different sensitivity to presynaptic inhibition of Weak sensitivity of stretch-evoked Ia electrically and mechanically evoked reflexes may volleys to presynaptic inhibition be explained by the repetitive discharge of Ia affer- ents in the stretch-induced volley and the differ- Evidence for differential sensitivity ences in dispersion of the afferent volleys. Thus, in the same subject with the same stimulation sites, one has: (d ) biceps (1. Just as you rise, brush your teeth, wash your face, and comb your hair, you should also exercise.

Armon, 46 years: Children under 12 years of age took 6- 10 grams of this powder, two times per day mixed in 80-100 milli- liters of hot water and taken warm. Once more, I reluctantly agreed to con- tinue to follow Veronica medically. But we do not know this (a total of 31 out of 280 eligible patients, or for certain. Clients with MDR-TB may require months hepatotoxicity, serum ALT and AST should be measured be- of treatment before sputum smears become negative, and fore starting and periodically during drug therapy.

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