By T. Kerth. University of Wisconsin-Oshkosh. 2019.

Their pump went out two years ago because lightning hit the house which was grounded to the pump purchase synthroid 75mcg online. For the next year she had arm numbness buy 50 mcg synthroid otc, dizziness purchase 125 mcg synthroid with amex, could not go up and down stairs buy discount synthroid 100 mcg online. They agree to not use well water for any pur- pose and bring sample for testing next time. They all prom- ised to rid themselves of parasites and stick to some new health rules. At her first visit, I told her about the pro- panol/cancer connection and she took herself off cosmetics. So when the solvent test was done later on, no isopropyl alcohol was found in her. Then she went to Ellis Fischel Clinic in Columbia, Missouri, they found a blood clot; they used heparin in hospital (plus chemo) for eight days. Eight days later They coated her glasses frames instead of getting plastic frames. Her daughter recalled that the yard was “treated” last fall, this could be her source of arsenic. But the son had taken her to her medical doctor for a last follow up before a happy leave-taking. The doctor, seeing her improvement, felt she could tolerate more radiation and chemo. How sad it was to see her miss her chance to finish out her life in her own home in a normal way. Two weeks later She brought in the blood test along with her allergy test and house air samples. Phosphates is slightly low Vitamin D [A and D 1000] take 1 a day for 3 months only 7. Triglycerides is high (225) kidney (Blood tests and abbreviations are described more fully in The Tests. Summary: This is another one of those cases where it is impossible for the client to discuss cancer. Her friend (who was extremely concerned about her) played this pretend game with her, probably to get her compliance. Fortunately, she did comply with all instructions, and she regained her health in a short time. Summary: It was heartbreaking to see such a young person so dis- abled due to no fault of her own. She appreciated the encouragement we could give her that she would be completely well in a few months. Probably her family or friends were angry, in a well-intentioned way, that she was “wasting” her money on alternative therapies. If she had acted quickly, she would most certainly have survived and gotten reasonably well again. Perhaps she missed her appointment because of embarrassment over not being able to stop smoking. The thymus is a small gland and the fluke is a large parasite; it is like having an elephant in the kitchen. Now she has these problems: 1) Chronic respiratory problems (a bout of bronchitis every year). She was put on the parasite killing recipe immediately while the kidney cleansing waited and dental work was to be scheduled. She did not bring a blood test but she will bring a copy since she had a recent one done. So I hope she abides by the meat-avoidance rule and the cosmetics and beverage avoidance rules. Note that only the pancreatic fluke was multiplying in her, although she must be picking up the others at the same time - from rare meat. Only the pancreatic fluke survived and is multiplying - because of the solvents in the pancreas! Her clinical doctor said that present che- motherapy will not cure, but only “hold it back” for a while. Summary: This woman was given a minimal test at our office, just to remove her cancer. Hopefully, she has removed the propanol from her lifestyle and carried out the parasite program. Lenora Wilson Colon Cancer Lenora Wilson is a 55 year old woman whose main problem, she said, was ovarian cancer. Instead she went to Ann Wigmore Foundation for 2 weeks and changed diet to vegetarian. But it came back recently; her doctor used the cancer marker Ca 125 to monitor it. Two years later a different doctor found it quite abnormal, and she got cold knife conization. Calcium slightly low Drink 2% milk, 3 glasses/day; magne- sium (300 mg) 1/day; Vit D (by pre- scription from dentist 50,000) 1- 2/week forever. Summary: Mary came from several states away and had only 16 days to accomplish her goal: to avoid a hysterectomy. We hope she will eventually do a liver cleanse to lose the weight she suddenly gained. I was out of wormwood so I started her on quassia (see Recipes), rather than have her merely wait until it arrived. She will switch to wormwood and the usual parasite killing program now that it has arrived. Summary: This woman did not come in for health problems but only because she was worried about cancer, since her husband had died of it. Indeed, her intuition was right, but very quickly she removed all of the cancer, even though she substituted quassia for our regular parasite recipe. She has probably not returned for financial reasons (she lives on Social Security). Her good attitude will probably bring her back quickly if she has a health problem. The intestinal fluke was in the liver as usual, with a stage present in the breast. The first priority was to eliminate the cancer, although her purpose in coming to the office was her high blood pressure and ringing in the head. Hopefully, she will return free of her cancer, so we can pursue her other health prob- lems. Three weeks later He has had top right wisdom tooth pulled (#1), it had an abscess. His blood test sug- gested parasites (high platelet count) and Fasciolopsis was found. He acted quickly to clear up his Staph aureus infection by having a wisdom tooth pulled. Later we noticed a common lung infection, Pneumocystis, but he still could not stop smoking. At the last visit he had picked up the intestinal fluke again, probably from eating rare meat but he had no solvents in his body. This explains why the parasite stayed in the intestine and did not move to his liver or lungs. This bout with lung cancer was missed by his medical doctor whom he continues to see regularly. Perhaps if his medical doctor had also seen the cancer, he would have quit smoking. He and his wife have been neglectful of the parasite program and other restrictions. Richard England Lymphoma In Bone Richard England has 2 preschool children and a wife who brought him here. Due to his resentment at being “dragged” in by his wife, I tested only for Fasciolopsis and Sheep liver fluke. His young children sat quietly in their chairs during the appointment, sensing the grave danger their father was in. But he made jokes about my technical com- petence and devices instead of listening. A friend who had gone through our cancer program successfully tried to encourage him at home. He was always talking about his exceptional oncologist and the great rapport and team work in the hospital. His wife would have gladly moved from their fossil fuel contaminated home or turned the furnace off and put in an electric space heater till they could sell the home. So I began with a conversation with her husband in the office instead of with her. The chronology of her illness was: 6 months ago she had arthritis; 3 months ago it became more serious; 1½ months ago walking was very painful; 1¼ months ago she needed a walker; 4 weeks ago she could not walk. Her clinical doctor diagnosed rheumatoid arthritis and treated her with a steroid. They put steel reinforcement in one leg and cut out the cancerous part in the other leg.

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There are some significant distinctions between thin-filament based regulation of Ca2+ sensitivity in cardiac and skeletal muscle generic 100 mcg synthroid amex. Cardiac TnC has one less functional Ca2+ binding site than skeletal TnC discount 100 mcg synthroid overnight delivery, making the Ca2+ regulation more graded synthroid 75 mcg. In the case of cardiac muscle buy 75 mcg synthroid with visa, the input output relation of log [free Ca2+] vs tension rises steeply above 0. The Ca2+ sensitivity in heart can be regulated by TnI phosphorylation, which decreases the affinity of TnC for Ca2+, thereby increasing the rate of cardiac muscle relaxation. This relative newcomer to the field is proving interesting as a likely contributor to the elasticity of the muscle. The importance of elasticity will become clearer later in the course, when we discuss the mechanical properties of muscle. Titin is an enormous (3 mega-daltons), filamentous protein that spans half the length sarcomere and interacts with both the actin thin filament and myosin thick filament. It is thought to uncoil when the muscle is stretched, eventually acting to resist over-stretching of the sarcomere, keeping the muscle in its useful working range. On the other hand, when sarcomere length becomes very short, titin may help resist over compression and provide an elastic restoring force to quickly restore the sarcomere to resting length. Force Development Thick Filament Thick Filament Force S1 Thin Filament Thin Filament B. Shortening Thick Filament Thick Filament Thin Filament Thin Filament Displacement A. Huxley & Simmons 1971 model was very influential in thinking about the nature of the conformational change in myosin. It was a specific proposal for coupling chemical energy to molecular motion, involving a local conformational change, amplified by a lever arm, whereby metabolic reactions drove energy storage in the form of an extension of some kind of molecular spring (series elasticity). The existence of two myosin heads is thought to confer a 2-fold increase in Vmax for actin motion in motility assays. It is known that light chain phosphorylation occurs in a frequency-dependent manner, which might increase Ca2+ sensitivity. This is the rising and falling ability to support tension as muscle length progressively increases. The L-T relationship is a property of all striated muscle, and the key to the Frank-Starling Law of the Heart, as you will learn in Dr. In skeletal muscle, where it has been best studied, the various phases of the L-T relationship have been traced to variations in the ability of the crossbridges to exert productive force. However, there are some major differences between skeletal and cardiac muscle in the position of the rising phase of the L-T curve, the important phase for the Frank-Starling Law. The cardiac L-T curve is steeper, and operates over a very narrow range of lengths (dashed curve in diagram). This phase is supported by cardiac TnC but not skeletal TnC and has been found to depend in large part on changes in Ca2+ sensitivity of Ca2+ binding to cTnC V. Such alterations are important in tuning the heart’s performance in response to changing contractile demands. As you will see, these changes are highly relevant to clinical situations, including hypertension-induced heart failure and hypertrophic cardiomyopathy. The human heart contains two myosin heavy chain isoforms, called  and , both cloned and sequenced. Clearly, the myosin heavy chain composition of a muscle fiber is important for its physiological performance. These three myosin types can be distinguished on electrophoresis of human ventricular myosins and are often designated as V1 (/ homodimer), V2 (/ heterodimer), and V3 (/ homodimer). Cardiac isoform expression can be altered by work overload, diabetes, removal of the gonads, and thyroid hormone levels. Thus, extreme changes in cardiac myosin expression are seen in diseases of the thyroid. Replacement or correction of T3 levels restores the normal amounts of these two isoforms within the ventricle. Cardiac Hypertrophy from Work Overload produces quantitative and qualitative changes. There are two components to cardiac hypertrophy, a quantitative increase in cardiac mass (increase in muscle protein, fiber diameter and number of sarcomeres) and a qualitative change in the proteins expressed. Therefore, cardiac hypertrophy appears to mimic the fetal and the hypothyroid state. Secretion of this peptide alters solute and fluid balance in the body in response to intravascular volume. The composition of human heart myosin also changes drastically in heart failure, as examined by comparison of donor and recipient hearts in cardiac transplantation procedures. To what extent these changes are purely adaptive and beneficial or partly maladaptive is not clear. They are probably not thyroid-hormone based because these hormone levels remain unchanged in work overload states. It can arise from a mutation in one of several genes encoding protein components of the sarcomere. Besides genetics, additional factors or importance are environmental factors, including exercise, lifestyle. Besides heart muscle, slow skeletal muscles may also behave in a detectably abnormal manner. The initiating factors are defects in one of a wide variety of sarcomeric proteins (one can think of this inadequate supply of pumping in the face of continuing demand) In heart failure, hypertrophy of the ventricular free wall causes to a massively enlarged heart. The initiating factor is generally extrinsic, often a hemodynamic overload (one can think of this as excessive demand for mechanical output). Thus, hypertrophy may be a homeostatic mechanism that has simply been pushed too far. The heart has a limited number of mechanisms by which it can alter its force of contraction. As we discussed in the last lecture, one way is by increasing the end-diastolic length of its sarcomeres, which increases the effectiveness of the tension-developing crossbridges formed by myosin interactions with actin. This structurally based mechanism contributes to the augmentation of force during the next contraction, the classic "Frank-Starling Law of the Heart". This principle will have great importance for the overall performance of the heart as a pump, as discussed later in this course. Contraction is of course a mechanical event, produced by biochemical changes in the muscle. This contraction, as you know, must be triggered by an electrical event - the cardiac action potential. For now, let us simply consider the fact that the electrical changes occur only at the plasmalemma: a protein deep inside of the cell cannot tell if the membrane potential is -70 mV or +20 mV. Activation of contraction is due to a rise in the intracellular Ca2+ concentration. The temporal relation between a cardiac action potential, the rise in cytoplasmic Ca2+, and force development is shown in Fig. The level of membrane depolarization which must be reached for activation of the contractile process to occur (mechanical threshold) is approximately -35 to -30 mV but this is reached within a millisecond or so. The mechanical threshold potential coincides with the level at which Ca2+ channels begin to open. Judging by measured Ca2+ transients, only a few more milliseconds are required for Ca to diffuse from its entry or storage site(s), to reach threshold concentration at the troponin complex in the sarcomeres. The major portion of the latency period is attributable to the time required for crossbridges to attach, change conformation, and develop externally measurable force. Why is it always Ca2+ that seems to couple electrical changes to biochemical changes? In almost every case that you might think of, Ca2+ is the active messenger that does the signaling: it couples the action potential to neurotransmitter release, it couples changes in electrical activity to changes in gene expression, it couples electrical activity to enzymatic changes in the cell, and of course it activates the cardiac muscle that we are now discussing. There are several reasons why Ca2+ emerged as the preeminent ionic messenger through the course of evolution: Excitation-contraction Coupling - Richard Tsien, Ph. Because it is doubly charged, a Ca2+ ion can engage in very strong and specific interactions with protein sites comprised of amino acids with negatively charged side chains (aspartates or glutamates). Ca2+ is large enough that multiple asp or glu side chains can coordinate a single ion, causing a conformational change in the parent protein. This in principle is how Ca2+-receptive molecules like troponin C or calmodulin work. Because Ca2+ forms an insoluble precipitate with phosphate, one of the major internal anions derived from metabolism, cells probably evolved in such a way as to work with relatively low Ca2+ concentrations in their cytoplasm. Transport systems pump Ca2+ from the cytoplasm into the extracellular space, holding the resting Ca2+ level in the cytosol to approximately 0. The large chemical gradient sets up a greatly favorable situation for Ca2+ as a signaling entity. Because the basal Ca2+ concentration is so low, only a small number of ions need to flow in order to cause a large percentage change in the local internal concentration, making the signal stand out against its background. Indeed, when a voltage-gated Ca2+ channel opens or when Ca2+ is released from an intracellular pool, the movement of hundreds or thousands of Ca2+ ions can cause the local Ca2+ concentration near the mouth of the channel can soar up to 1 mM within a fraction of a millisecond. In contrast, a cell with 5 mM intracellular Na+ would need to flux 5 times as much Na+ in order to accomplish a mere doubling of the intracellular Na+ concentration. No wonder then that the cell has evolved so many processes that are triggered by Ca2+ concentration, rather than Na+ (or any other ion). Returning to excitation-contraction coupling in heart, regulation of the Ca2+ signal and its downstream effects is a fair amount more complicated than you may suspect. Moreover, such regulation is critical to the performance of the heart and a clear comprehension of it is key to understanding a great deal of cardiac pharmacology and pathology. The next section reviews the sources and sinks for Ca2+ and the proteins that regulate the movements of this ion across the sarcolemma and within the cell. Before proceeding to a deeper discussion of the basis of E-C coupling, it is necessary to review the fine structure of heart cells.

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Papular dermatitis is characterized by small buy 100 mcg synthroid free shipping, ery- thematous papules that usually involve all of the skin discount 75 mcg synthroid overnight delivery. High-dose systemic steroids buy synthroid 200 mcg with visa, such as prednisone buy generic synthroid 25mcg line, are used to treat this dermatitis. The rash usually starts on the abdomen and spreads to the extremities, with facial spar- ing (Alcalay et al. Treatment consists primarily of topical steroids, although oral prednisone may be required for severe cases. Herpes gestationis Another rare dermatologic disease of unknown etiology is herpes gestationis. Contrary to what might be implied from the name, herpes gestationis is not a viral infection but an autoimmune disease. Erythematous papules and large, tense bullae, usually on the abdomen and extremities characterize this disease. Some investigators have reported that an increased frequency of pregnancy loss is associated with this condition in some studies (Lawley et al. Minor malformations characteristic of the retinoic acid embryopathy and other birth outcomes in children of women exposed to topical tretinoin during early pregnancy. Quinine overdoses are associated with an attempt to induce abortion over 90 percent of the time, but most other over- doses of the drug are also attempted suicide. Successful suicide during pregnancy occurs among one in every 88 000–400 000 live births (Table 14. Among 162 pregnant women who presented with an indication of poisoning, 86 percent were overdoses (78 percent suicide attempts and 8 percent induced abortion attempts (Czeizel et al. Maternal death associated with suicide gestures occurs in approx- imately 1 percent of gravid women and more than 95 percent of suicide gestures involve ingestion of a combination of drugs (Rayburn et al. In New York city, suicide was identified as the cause of 13 percent of maternal deaths (Dannenberg et al. Use of drug megadoses that are potentially lethal in pregnant women involves two patients: mother and fetus. Assessment of the pregnant woman who has potentially toxic (megadoses) amounts of drugs must begin with laboratory evaluation of the sub- stance(s) ingested (i. In Finland in the late 1990s, the pattern was similar with the top three substances used in suicide attempts being benzodiazepines, analgesics, and psychotropics (antipsychotics/antidepressants) (Table 14. The patient will usually recall approximately how much she took of which substances. If family members or signifi- cant others are present, they may be able to provide corroborative information, such as presence of medicine bottles, known prescriptions, etc. Toxicology screens with samples every hour or two (for serial evaluation) should be ordered as soon as possible to deter- mine exactly what substances are involved and whether or not levels are rising or falling, or toxic or approaching toxic. However, a generalized treatment plan may be under- taken before toxicology results are available. If the patient still has a gag reflex, orogastric lavage with normal saline should be begun. Following lavage, administer an activated charcoal slurry regimen (the nonspecific anti- dote regimen). Whole-bowel irrigation has been used successfully in some cases of drug overdose and has a clinically significant effect on lowering serum drug levels. Evaluation of the fetal heart rate should begin as soon as possible, especially in cases in which the fetus is viable. When toxico- logical screens are available to document what drugs and/or chemicals have been ingested and may be in potentially toxic doses, information on antidote regimens for given substances may be obtained from several sources. A general plan for the management of the drug-overdosed gravida includes sta- bilization, monitoring, supportive care, and toxicology screens (Box 14. Specific management plans should be formulated in consultation with the regional certi- fied poison control center, which is available 24 h per day, and handles international calls. Maternal and fetal sequelae for specific antidote regimens are provided below for the 14 drug classes most frequently taken in suicide gestures by pregnant women (Table 14. Sixty-nine cases of acetaminophen overdose in suicide gestures during pregnancy have been reported (Table 14. The salient clini- cal features of these cases are that early administration of the specific antidote (N-acetyl- cysteine) can prevent maternal hepatotoxicity if the antidote is tolerated and fetal hepa- totoxicity is uncommon. In a case series of 60 acetaminophen overdoses during pregnancy from a multicenter study in which 24 mothers had serum acetaminophen levels in the toxic range (Riggs et al. The distribution of these cases across trimesters of pregnancy is given in Table 14. No evidence of teratogenicity of acetylcysteine (or paracetan) was found in one study (Janes and Routledge, 1992). However, the investiga- tors concluded that delays in the administration of the antidotal treatment might increase the risk of spontaneous abortions, fetal death, and serious maternal liver damage. Of the available antidote regimens, N-acetylcysteine is the most effective (Table 14. Acetaminophen overdose during pregnancy should be treated with either oral or intra- venous N-acetylcysteine without delay according to the protocols provided in the man- ufacturer’s insert. Delay in administering the antidote increases the risk of maternal and fetal toxicity, hepatorenal failure, and death (Kozer and Koren, 2001). Measured levels of acetaminophen at time postingestion can broadly predict whether or not hepatotoxicity should be expected (Fig. Acetaminophen’s metabolic pathways (sulfation and glucuronidation) become saturated, causing an increased metabolic load to cytochrome P-450 oxidases. The P-450 system oxidizes the drug and produces a highly reactive intracellular metabolite that complexes with hepatic glutathione. The P-450-produced metabolite binds to hepatocellular macromolecules when glutathione is depleted and hepatotoxicity ensues (Andrews et al. Fetal P-450 has 10 per- cent or less of adult activity and produces negligible amounts of the toxic metabolite. Some authorities speculate that the increased risk of maternal hepatotoxicity compared to fetal hepatotoxicity may be related to the largely inactive fetal enzyme complement, i. It was also speculated that fetuses of more advanced gestational age may be at greater risk 260 Drug overdoses during pregnancy 300 Toxic 200 100 Possible 45 45 30 Unlikely 30 0 4 8 12 16 Hours after intake Figure 14. However, in the largest series studied, this relationship was not readily apparent (Table 14. The critical determinant of maternal–fetal outcome following acetaminophen overdose is the expediency in administering the antidote. The most critical aspect of treating acetaminophen overdoses is administering the antidote as early as possible. Those gravidas given N-acetylcysteine within 10 h of ingesting large doses of acetaminophen have the best pregnancy outcomes (Table 14. Aspirin Aspirin is the second most frequently used drug in attempted suicide or gestures among pregnant women (Rayburn et al. Clinical details have been reported of several cases of aspirin overdose during pregnancy as part of a suicide gesture (Table 14. The mean salicylate half-life has been shown to be approximately 20 h, and disappearance of salicylate from the circulation in the post-absorptive period (approximately 6 h after ingestion) is a first-order reaction (Done, 1968). Unfortunately, there is no specific anti- dote to aspirin, and nonspecific antidote treatment (i. Alkalinization of the urine by intra- venous administration of bicarbonate greatly increases the renal excretion of salicylic acid, as well as enhancing ionization of salicylate in plasma, which facilitates movement of the drug out of the central nervous system (Done, 1968). The risk of congenital anomalies does not seem to be higher among children of women who used aspirin during pregnancy. Among 41 infants born to women who had taken significant amounts of aspirin at various times during pregnancy, one infant was born with congenital anomalies (McElhatton et al. Notably, aspirin overdose during pregnancy poses a greater risk for fetal death than acetaminophen. Aspirin is the toxic agent, and not a metabolite; it is transferred across the placenta and reaches concentrations in the fetus that are higher than those in the mother (Garrettson et al. The cases of salicylate poisoning in pregnancy that have been reported support the same basic Table 14. Consider charcoal even for late-presenting patients; peak absorption may be delayed up to 12 h postingestion especially with enteric coated tablets. Consider gastric lavage followed by 50 g activated charcoal, if patient presents within 1 h. If history is reliable for an ingestion >120 mg/kg and tablets are enteric coated, consider measuring levels for minimum 12 h postingestion even if no salicylate is detected initially. Monitor and correct urine and electrolytes, arterial blood gases and pH, blood sugar, prothrombin time. Urinary alkalinisation For salicylate level 500–700 mg/L in adults or salicylate level 350–600 mg/L in children/elderly where patients have moderate clinical effects. An estimated 8 h after maternal ingestion of 5 g of naproxen at 35 weeks of gestation, nonspecific and supportive antidote therapy was initiated because no specific antidote is available. The mother recovered with no evidence of hepatotoxicity or other adverse effects (Alon-Jones and Williams, 1986). In contrast to the pharmacokinetics of salicylate elimination, high doses of naproxen (1–4 g) result in a disproportionate increase in renal excretion of the drug without apparent saturation of the excretory mechanism or metabolic pathway (Erling and Strand, 1977; Runkel et al. Increase in renal elimination may contribute to a lower incidence of acute toxicity compared with salicylate overdose. Ibuprofen Ibuprofen overdose during pregnancy has not been described in case studies and no spe- cific antidote exists. Symptoms of ibuprofen toxicity include nausea, epigastric pain, diarrhea, vomit- ing, dizziness, blurred vision, and edema. Fifty reports of ibuprofen overdose during pregnancy have been reported, with mothers and infants suffering no untoward effects (i. Since there is no specific antidote to prenatal vitamins, nonspecific and supportive antidote therapy should be given.

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