By Y. Akrabor. William Woods University. 2019.
Since the substrate saturation curve is defined by the Km of the enzyme buy antabuse 500mg with visa treatment 2 degree burns, regioselectivity cannot be a function of substrate or inhibitor concentration [I] order 250mg antabuse fast delivery medicine cards. This equation shows that the presence of the inhibitor modifies the observed Km but not the observed Vm cheap 500 mg antabuse fast delivery xerostomia medications side effects. Experimental Design and Analysis of Inhibition Data By far the best method for characterizing inhibition data is to vary both substrate and inhibitor concentration order antabuse 500 mg on line medicine you can give cats. Initial estimates for the parameters can be obtained from the control (no inhibitor) data and by a double reciprocal plot. If a minimum of effort is required, the Km of the reaction is known, and competitive inhibition is assumed. Equations (6) to (9) can be used to determine the Ki by varying [I] at a single substrate concentration. Only an observation of partial inhibition or nonhyperbolic kinetics indicates that simple competitive inhibition is not involved. If both substrate and inhibitor concentration are varied, the data can also be fit to 40 Korzekwa equations for other types of inhibition, e. For the P450 enzymes, the second most prevalent type of inhibition is the partial mixed type of inhibition, which will be discussed later. Autoactivation occurs when the activator is the substrate itself, resulting in sigmoidal saturation kinetics. For partial inhibition, saturation of the inhibitor does not completely inhibit substrate metabolism. Substrate inhibition occurs when increasing the substrate beyond a certain concentration results in a decrease in metabolism. Although most of the observed kinetics are consistent with allosteric binding at two distinct sites (23), previous studies suggest that the activation of metabolism involves the simultaneous binding of both the activator and the substrate in the same active site (24,25). The possibility of binding two substrate molecules to a P450 active site could almost be expected, given the relatively nonspecific nature of the P450-substrate interactions. If an active site can accommodate very large substrates, it can be expected that more than one naphthalene mole- cule can be bound. Thus, even a P450 with rigid structural requirements can simultaneously bind two small substrates. If enzyme activation and the other unusual kinetic characteristics result from multiple substrates in the active site, kinetic parameters will be difficult to characterize and drug interactions will be more difficult to predict, since they are a function of the enzyme and of both the substrates. In addition, there are some indications that non-Michaelis-Menten kinetics can be seen in vivo (27–29). Non-Michaelis-Menten Kinetics for a Single Substrate If non-Michaelis-Menten kinetics for all P450 enzymes are a result of multiple substrates binding to the enzyme, then the reaction kinetics for the binding of two substrates to an active site can be complicated. A number of analyses of In Vitro Enzyme Kinetics Applied to Drug-Metabolizing Enzymes 41 Figure 3 Proposed kinetic scheme for an enzyme with two binding sites within an active site and a single substrate. Differences in analyses are due to different numbers of distinct binding sites and distinct binding constants. For this section and the next, we make the assumption that two compounds can bind to the active site with different affinities, but the binding sites are not defined regions of the active site. These assumptions can describe all observed kinetic characteristics and are still simple enough to allow for the determination of kinetic constants. If product release is fast relative to the oxidation rates, the velocity equation is simplified to Eq. Km2 would be the standard Michaelis constant for the binding of the second substrate, if [E] ¼ 0 (i. In the complete equation, these constants are not true Km values, but their form (i. Likewise, k25 and k35 are Vm1/Et and Vm2/ Et terms when the enzyme is saturated with one and two substrate molecules, respectively. Autoactivation (sigmoidal saturation curve) occurs when k35 > k24 or Km2 < Km1, substrate inhibition occurs when k24 > k35,andabiphasicsaturation 42 Korzekwa curve results when k35 > k24 and Km2 ) Km1. This equation was used to fit experimental data for the metabolism of several other substrates, as described next. Sigmoidal Saturation Kinetics Although sigmoidal binding kinetics can be discussed in terms of binding cooperativity, this is not always the case for enzymes. This figure also shows that quinine converts the sigmoidal curve into a hyperbolic curve. This conversion will be discussed in section V, on interactions between different substrates. This fit becomes apparent when the influence of the second substrate is considered. For this discussion, Km1, Km2, Vm1,andVm2 are Figure 4 Effect of quinine on the carbamazepine saturation curve. In Vitro Enzyme Kinetics Applied to Drug-Metabolizing Enzymes 43 defined as described for Eq. If the second substrate binds with a lower Km than the first substrate and has the same rate of product formation, the slope will equal (V/K)1 at low substrate concentrations, since only one substrate will be bound. Therefore, the enzyme becomes saturated faster, resulting in a concave-upward region in the saturation curve. Likewise, if the second substrate binds with a Km identical to that of the first substrate but has a higher Vm, the linear portion of the curve will again have a slope of (V/K)1. From a sigmoidal saturation curve, one can determine (V/K)1 from the slope at low substrate concentrations, and Vm2 at saturating substrate con- centrations. However, Vm1, Km1,andKm2 remain undetermined, since (V/K)1 can have either a Km1 higher than Km2 or a Vm1 lower than Vm2. Therefore, multiple solutions are possible when sigmoidal saturation data are fit to Eq. If a sigmoidal saturation curve is obtained, information relevant to in vitro– in vivo correlations can be obtained from appropriately designed experimental data. The values of (V/K)1, Vm2, and the concave-upward region should be defined if they occur within the therapeutic concentration range. The (V/K)1 region will define the rate of metabolism at low substrate concentrations. If the concave-upward region occurs in the therapeutic range, a dose-dependent increase in drug clearance can be expected. On the other hand, if enzyme sat- uration occurs, a dose-dependent decrease in clearance can be expected. This is probably due to Vm1 ¼ 0, since an enzyme with a very high Km will not be very active at moderate substrate concentrations. Biphasic Saturation Kinetics A second type of nonhyperbolic saturation kinetics became apparent during studies on the metabolism of naproxen to desmethylnaproxen (32). Studies with human liver microsomes showed that naproxen metabolism has biphasic kinetics and is activated by dapsone (T.
Before you go the übermedical route discount antabuse 500mg online medications for depression, you may be able to improve your fertility with a few small lifestyle and food changes specifically targeted to women who want to get pregnant cheap antabuse 500 mg line medicine 8 soundcloud. The folks at the University of Arizona Center for Integrative Medicine have several excellent resources on fertility generic antabuse 250 mg free shipping symptoms of diabetes. I especially recommend their chapter on cortisol and fertility in the book Integrative Women’s Health discount antabuse 500 mg symptoms zoloft dosage too high. Dramatic hair loss is often an early-warning sign of low thyroid, especially if your hair gets thinner, coarse, and brittle. Another cause of hair loss in women is high testosterone; this is usually the case when the symptom is male-pattern hair loss. The good news is that you can often stop and even reverse the symptoms of hair loss once you balance your hormones. Treatment strategies include 1,000 mg per day of evening primrose oil, which inhibits the conversion of testosterone to dihydrotestosterone. It’s also a good source of essential fatty acids—and the symptoms of hypothyroidism are quite similar to those for insufficient essential fatty acids. You can also help hair loss with your fork: one study showed that 90 percent of women with thinning hair were deficient in iron and the amino acid lysine, which helps transport the iron that is essential for many 11 metabolic processes. You can add lysine to your diet with foods rich in protein, such as meat and poultry, soy, eggs, cheese (especially Parmesan), and some fish (cod, sardines). Grains contain small quantities of lysine, but legumes contain lots; therefore, meals that combine the two—Indian dal with rice, beans with rice and tortilla, falafel and hummus with pita bread—are a good way to get complete protein in your diet and keep hair on your head. Sleepless nights, a wonky circadian rhythm, and trouble falling asleep are classic signs of hormonal imbalance, and 80 percent of my patients suffer from a lack of quality sleep. I’ve got two recommendations: find a natural strategy that works for you (see more below) and don’t resort to sleeping pills. Not only do they add an average of only 20 minutes of additional sleep per night, but they’re also associated with so many additional health issues that I think they should be taken off pharmacy shelves for good. High cortisol and low progesterone commonly affect sleep patterns, so following The Gottfried Protocol for those issues could be the solution to your bedtime woes. If you need a little additional help, here are my favorite recommendations for getting a restorative night’s sleep, seven days a week: • Set a technology curfew: the blue lights of television, phone, computer, and tablet screens confuse your brain and keep it in “daytime” mode. Alcohol may help you fall asleep faster, but it hijacks the quality of your sleep later in the night. One trial in menopausal women showed that 12 530 mg of valerian extract improved sleep in 30 percent of treated insomniacs. It took me years to learn her truth, which I now translate as Get help and build your network before you need it. First, I need to acknowledge the true superstars of this book: my beloved patients and clients, whom I care for in my Berkeley integrative medicine office and also virtually in my online Mission Ignition e- courses and mentoring programs. Thank you for sharing with me your narratives, many of which landed in this book (with changed names and no identifying data, of course). I am grateful for your partnership and trust, and for allowing me to be of service. You provide an incredible gift: you activate my inner healer, a wellspring of vitality and creativity. It’s paradoxical that when I am of service, cortisol is better behaved, and I feel more energized, balanced, and ready to rock my mission. Deep appreciation to my parents, Albert and Mary Lil Szal, for your unconditional love and support throughout my life, and especially over the past eighteen months of my writing this book, my labor of love. Thank you both for your enduring love, calming words, honest advice when I need to take a chill pill, dance, share a cocktail— and especially for taking my daughters to the mall when I needed to write. Next, thanks to my growth friends, change agents, and revolutionaries: Ana Forrest of ForrestYoga. Thank you to the many bighearted people who wrote about The Hormone Cure, interviewed me, shared the love on social media, hosted me for a blog tour, joined the revolution, became a Hormone Cure Evangelista, and moved the conversation forward. Let’s keep talking and offering up more solutions to women who need help and are too young to feel old. Big thanks also to our revolutionary group of Hormone Cure Practitioners —to learn more if you’re a doctor, coach, nutritionist, or other allopathic or alternative health provider, go to http://www. I’m grateful to my early mentors, who taught me to relish evidence and to keep women safe, using the crucial yet underutilized tools of epidemiology and critical thinking. We are in magnificent agreement that connection to inner divinity is the most powerful epigenomic influence. Seely, Kilpatrick, Brizendine, and Northrup were my greatest influences when it comes to how I think of the matrix of the female body. You all taught me an exquisitely original form of synthesis and showed by your example how to craft an original conceptual model. Thank you for spending your time and considerable intellect reading the text as it unfolded, and for your valuable contributions. As always, it was my darling husband who burned the midnight oil to clarify each chapter. This book would not be possible without the enduring support of my agent, Katherine (“Kitty”) Cowles. Through Kitty, I met Whitney Frick at Scribner, my brilliant editor with whom collaboration has been pure joy, every step of the way. Thanks also to my editorial team here in the Bay Area—Elaine Hooker, Nora Isaacs, Deborah Burstyn, and Pam Feinsilber: you propelled me forward and set me straight. Special thanks to Nancy Siller Wilson for excellent illustrations, designs, and reflections. Thanks especially to Leslie Murphy for helping to keep the house running and picking up the girls from school, Jennifer Seligman for nourishing lunches and organizing principles, and my terrific assistants, including Cary Masin, Rachel Jurkowicz, and Liora Shachar. To my awesome girlfriends who provide therapy, laughs, and endless oxytocin—thank you. You heard the blow-by-blow details for The Hormone Cure on a weekly basis yet doggedly hung in there with me, offering wise advice, laughter, and desperately needed coaching. Not only that, you stepped up graciously every time I asked, even when you had plenty on your own plate with three children and a thriving professional coaching practice. Leslye Robbins, you keep me laughing and happily married, and always floor me with your insights. Ariella Chezar, I crazypants miss you since you moved back to the Berkshires, but please know you were as potent an influence on my ideas of natural ways to heal the female body, and healthier alternatives for neurohormonal balancing, as any doctor or book. You were there, Sister, in those insane years, nudging me to walk with you and think differently about conventional paradigms of health. To my Saturday-morning walking group—especially Leslye Robbins, Rachel Engel, Sue Proctor, Jennifer Panish, and Hana Rotman—thank you for your unwavering support, fantastic parenting and husband-management advice, and for the warmest welcome to the school community. I’m honored to grow old with all of you (in a neurohormonally optimized way), walking and dishing our lives every Saturday! Gratitude also to my uncle, Chuck Teubner, for your perpetual support and enthusiasm throughout my career.
There are no published studies regarding the teratogenic effects of this adenosine buy antabuse 250 mg without prescription medications medicaid covers. Cardiac glycosides are effective because of their inotropic effects on the heart and antiarrhythmic effects buy antabuse 500 mg visa medications during breastfeeding. Various digitalis preparations cross the placenta readily generic antabuse 500mg visa keratin intensive treatment, resulting in significant fetal levels with cord levels that are 50–80 percent of maternal levels (Chan et al buy antabuse 250mg lowest price medications like xanax. No scientific studies regarding the safety of cardiac glycosides in pregnant women have been published. Fetal digitalis toxicity has occurred, but this was secondary to maternal overdose (Sherman and Locke, 1960). Available information supports the view that car- diac glycosides are probably safe for use during pregnancy. Low-molecular-weight heparin is also used to treat thromboembolism in pregnancy, and does not cross the pla- centa (Feijgin and Lourwood, 1994; Macklon et al. Warfarin derivatives are contraindicated for use during pregnancy Coumarin derivatives, including warfarin, are contraindicated for use during pregnancy. Use after the first trimester includes brain and eye defects, and other anomalies associated with vascular disruption. However, in a review of 172 pregnant women from published reports, Turrentine and associates (1995) found no increase in congenital anomalies and a pregnancy loss rate of 5. Among more than 140 infants exposed to heparin during the first trimester, the frequency of congenital anomalies was not increased (Chan et al. Similarly, in a literature review among more than 440 infants exposed to low molecular weight heparins during pregnancy, including nearly 200 infants whose mothers were treated during the first trimester, no congenital anom- alies were noted (Sanson et al. Seven to 10 infant defects would have been expected to occur in the absence of any drug exposure. Therefore, ascertainment bias may confound the detection of birth defects in their study. Protamine sulfate is used to reverse the anticoagulant effects of heparin prior to sur- gery (e. One infant with neonatal depression following maternal protamine sul- fate injection was reported Wittmaack et al. Organic nitrites are the most commonly used agents in this group, and nitroglycerin is the prototype organic nitrite agent. No human studies of organic nitrites in pregnant women have been pub- lished, although these agents were not teratogenic in animal studies. Antihypertensives 59 Intravenous nitroglycerin has also been utilized to blunt the hypertensive effect of endotracheal intubation in women with severe preeclampsia undergoing Caesarean sec- tion (Cheek and Samuels, 1996; Longmire et al. Other calcium antagonists, such as diltiazem, nicardipine, and nifedipine, may also be useful as antianginal agents and have not been reported to be associated with an increase in mal- formation rates in animal studies (Ariyuki, 1975). No studies of the use of other calcium channel antagonists use during pregnancy have been published. No information has been published on the use of dipyramidole, a selective coronary vasodilator, in pregnant women. The beta-blockers are discussed above, as well as in the Antihypertensives section below. Nonetheless, the available data suggest that methyldopa does not pose a significant risk of birth defects, and postnatal growth and development seems unaffected by prenatal exposure. In summary, it would appear that methyldopa is not a human teratogen and is prob- ably one of the safest antihypertensives for use during pregnancy. Hydralazine One of the commonly used antihypertensive drugs is hydralazine, especially for acutely lowering of blood pressure in women with severe preeclampsia. No epidemiological studies of congenital anomalies in children born to women who took hydralazine dur- ing pregnancy have been published. Although there are no large human reproduction studies for labetolol, metaprolol, or atenolol use in pregnant women, there are reports of their use without apparent adverse fetal effects. There are no reports of human teratogenicity for any of the beta-adrenergic blockers. Comparing oral labetolol to intravenous diazoxide for hypertensive crisis during pregnancy, no significant maternal or fetal side effects were observed (Michael, 1986). Among 104 labetolol- versus methyldopa-treated women with pregnancy-induced hypertension, labetolol caused fewer side effects than methyldopa (el-Qarmalawi et al. Labetolol is the agent of choice to blunt the hypertensive response to endotracheal intubation, with few maternal, fetal or neonatal side effects (Cheek and Samuels, 1996). No studies on the use of these agents during the first trimester of pregnancy are published. No increase in adverse maternal or fetal effects, includ- ing no significant differences in birth weight, were reported in 120 women treated with atenolol or placebo during pregnancy (Rubin et al. Similarly, no adverse fetal effects or pregnancy outcomes associated with metoprolol or metprolol/hydralazine treat- ment in second and third trimesters of pregnancy were noted (Sundstrom, 1978). Breastfeeding is allowed during maternal therapy with either metoprolol or atenolol (American Academy of Pediatrics, 1994), despite a case report of toxicity in a neonate whose mother was receiving atenolol while breastfeeding (Schmimmel et al. Neonatal hemodynamic adaptation failure occurred in five of 11 infants whose mothers were treated with aceb- utolol during pregnancy (Yassen et al. It seems unlikely that this drug is associ- ated with an increased risk of congenital anomalies. Among 51 women with pregnancy-induced hypertension randomized to Antihypertensives 61 hydralazine, hydralazine and propranolol, or hydralazine and pindolol, pindolol was associated with fewer maternal and fetal side effects (Paran et al. However, infants born to mothers who received propranolol had smaller birth weights. In a com- parative study of atenolol or pindolol on uterine/fetal hemodynamics and fetal cardiac function, investigators found that pindolol was preferable to atenolol for the treatment of pregnancy-induced hypertension based upon maternal and fetal cardiovascular func- tion (Rasanen and Jouppila, 1995). No increase in congenital malformations was noted in the offspring of pregnant mice who received up to 150 mg/kg. Also, no increase in the frequency of malformations was found among the offspring of rats, rabbits, and hamsters that had received nadolol in doses several times higher than the usual human dose (Sibley et al. No increased frequency of adverse fetal effects was found in the offspring of mice treated with penbutolol (Sugisaki et al. No epidemiologic studies of the frequency of congenital anomalies and cloni- dine use during early pregnancy have been published. Anecdotal case reports of clonidine use during pregnancy suggest no adverse fetal effects (Horvath et al. Head size and neurologic examination of 22 children whose mothers received clonidine during pregnancy were normal (Huisjes et al. One rat teratology study found no increased frequency of birth defects (Angelova et al. Clonidine is probably not associated with an increased risk of congenital anomalies when used therapeutically. An oral form of this drug (Proglycem) is also used to treat hypoglycemia secondary to hyperinsulin- ism. An anecdotal case report of abnormalities of body and scalp hair, including alopecia, in four neonates of women who received oral diazoxide during the last trimester of pregnancy has been published (Milner and Chonskey, 1972). Maternal diazoxide therapy was also reportedly associated with hyperglycemia in the neonate (Milsap and Auld, 1980).
Sometimes thyroidectomy is the only feasible meansofcontrolling amiodarone-induced hyperthyroidism cheap antabuse 250mg without a prescription medicine and technology. Signiﬁcant photosensitivity occurs in about 20% of patients taking the drug buy antabuse 500mg otc treatment laryngomalacia infant,and some patients eventually develop ablue-gray discol- oration of sun-exposed skin 500 mg antabuse free shipping treatment definition statistics, which can be quite disﬁguring buy discount antabuse 250 mg online medications 123. Neurologic side effects are rare but can include ataxia, tremor, sleepdisturbances, and peripheral neuropathy. Ocular symptoms(most often, poor night vision or halo vision) occasionally accompany the corneal microdeposits seeninvirtually all patients taking amiodarone. Amiodarone canpotentiate the effect of beta blockers and calcium blockers and lead to negative inotropic effects and bradyarrhythmias. Sotalol Sotalol, a noncardioselective beta blocker, was initially developed as an antihypertensive agent. Clinical pharmacology Sotalol is well absorbed from the gastrointestinal tract, and peak plasma concentrationsoccur within 2–3 hours after an oral dose. The drug is not metabolized; it isexcreted unchanged by the kidneys, and the dosage should be reducedinpatients with renal insufﬁciency. Dosage The usual starting dosage of sotalol is80mg twice daily, and the dosage is increasedgradually, as needed,to240–320 mg/day in di- videddoses. Indications Sotalol isapproved for the treatmentofsigniﬁcantventricular ar- rhythmias but can be useful for treating all types of tachyarrhyth- mias. Adverse effects and drug interactions The major side effects of sotalol are related to its noncardioselective beta-blocking effects (e. Exacerbation of congestive heart failure is most commonly seeninpatients whose left ventricular ejection fractions are less than 0. So, for in- stance, if sotalol isbeing used to treat atrial ﬁbrillation, the relative safety of using the drug (i. Thus, suchapatient shouldnever be senthome taking sotalol untilheor she has been observedinsinus rhythm. Therefore, the drug should be usedwith trepidationinpatients taking potassium- wasting diuretics—another good reason to avoid the drug in patients with congestive heart failure. A multicenter randomized trial using D-sotalol in patients with ventricular arrhythmias was stopped be- cause of an excess of suddendeath in the D-sotalol arm. Clinical pharmacology After intravenous infusion, ibutilide is extensively metabolized to eight metabolites. More than 80% of the drug isexcretedinthe urine, only 7% as unmetabolizedibutilide. The drug issubjectto pronounced ﬁrst-pass metabolismwhengiven orally, which is why only the intravenous formis available. Dosage Ibutilide is infused as a 1-mg intravenous bolus during a period of 10 minutes. If the arrhythmiabeing treated (atrial ﬁbrillation or atrial ﬂutter) persists for 10 minutes after the infusion has been completed,asecond 1-mg bolus can be administered. Indications Ibutilide is indicated for the elective conversion of atrial ﬁbrillation or atrial ﬂutter. Inclinical studies, the efﬁcacyof ibutilideadministrationinterminating these arrhythmias (after two 1-mg doses) was 44%. The incidence of sustained ventricular arrhythmias was muchhigher in patients with a history of congestive heart failure (5. Most ventricular arrhythmias were seenwithin 1hourofthedrug infusion,butsome were seennearly 3 hours after the infusion. Itis thought that the arrhythmogenic potential of ibutilide is increasedwhenit is used with other drugs that prolong the duration of the actionpotential. Ibutilide should also be avoided in patients receiving phenothiazines, tricyclic antidepressants, tetra- cyclic antidepressants, or antihistamineagents that block the H1 re- ceptor. Clinical utility of ibutilide The overall clinical utility of ibutilide probably ought to be con- sideredmarginal, mainly because of the disadvantages of the drug. The incidence of torsades de pointes with ibutilide is also troubling,and the relatively prolonged monitoring required after its use (regardless of whether it is effec- tive) can be quite inconvenient. Its major side effect, typical for drugs with these elec- trophysiologic properties, is torsades de pointes. While it iselim- inated by both the kidneys and the liver, the renal route of elimina- tionis particularly important clinically. The dosage of the drug needs to be carefully adjustedinpatients with reducedcreatinine clear- ances. The drug is available only to hospitals and physicians that have beencertiﬁed to administer itand is dispensed only by a limited number of pharmacies. Certiﬁcationisachieved by completing an educational programprovided by Pﬁzer, the manufacturer. If the creatinine clearance is greater than 60 mL/min, 500 µg of dofetilide is given twiceaday. If the creati- nine clearance is between40and 60 mL/min, 250 µg twiceaday is given. Indications Dofetilide is indicated for conversion to normal sinus rhythm,and especially for the maintenanceofsinus rhythm, in patients with atrial ﬁbrillation or atrial ﬂutter. Because of the drug’s narrow ther- apeutic to toxic ratio, and the extraordinary precautions that must be takeninusing it, dofetilide is generally reserved for patients whose arrhythmias are highly symptomatic. Dofetilide is moderately effective in converting atrial ﬁbrillation and atrial ﬂutter to sinus rhythm. W ith doses of 500 µg, conver- sionwithin 24–36 hours has been reported to occur in 30–70% of patients. Dofetilideappears to be more useful in maintaining sinus rhythm after successful conversion. Ifdosages of 500 µg twice per day can be maintained, 60–65% of patients treatedwith dofetilide have been reported to remain in sinus rhythm for up to 12months after con- version from atrial ﬁbrillation. Only very limitedinformationis available on the efﬁcacyof dofetilide for ventricular arrhythmias. Torsades de pointes was seeninas few as 1% butasmanyas>3% of patients givendofetilide in clinical trials. Reducing the oddsofexperiencing this arrhythmia requires carefultitration of the drug,and reduc- ing death from torsades de pointes requires prolongedin-hospital monitoring. The need to take such precautions has led to an ex- traordinarily restrictive approval status for dofetilide in the United States. Dofetilide has minimal hemodynamic effects and can be usedin patients with heart failure. Dofetilide has been reported to cause occasional noncardiac symp- toms, including headache, gastrointestinal disturbances, sleepdisor- ders, and ﬂulike symptoms.
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