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By F. Yussuf. Smith College. 2018.

It’s like a library where no one checks out any books cheap cardizem online amex blood pressure up and down quickly, but the librarian keeps buying more buy cardizem 120 mg amex peripheral neuropathy. The excess estrogen keeps recirculating in the body, and the result is dysestrogenism, which means you’ve got a problem regulating your estrogen levels. When your diet is based on a food plan with too much fat, such as the Standard American Diet, you may raise your estrogen levels excessively. Here’s why: dietary fat encourages your gut to reabsorb estrogens by slowing down the conjugation process that causes you to excrete excess estrogens. On the other hand, more dietary fiber increases conjugation—that is, more fiber lowers estrogen levels in the body—and you poop and pee more estrogen out of your system. Estrogen metabolism occurs primarily via four pathways, starting either with estradiol or estriol. Sara’s Top 7 Root Causes Several factors can interfere with normal estrogen metabolism, causing you to produce or accumulate too much of the “less good” estrogens, or too much estrogen relative to progesterone. These factors include the aging ovaries, wayward cortisol levels, exposure to xenoestrogens, and nutritional factors such as fat, fiber, and alcohol consumption. Perimenopause Revisited and Diminished Ovarian Reserve We can blame perimenopause for so many things! In the two to ten years before your final period, your estrogen levels fluctuate madly. Overall, women experiencing perimenopause show higher estrogen relative to progesterone, compared with women in their twenties and thirties. I know this becomes confusing: initially, estrogen levels drop slightly starting in your late twenties, and then estrogen levels increase when your ovaries are running out of ripe eggs, usually after age thirty-five. Women are born with one to two million eggs in their ovaries, but by the time you reach perimenopause, you are down to one to three thousand. As your ovaries age based on the decreasing number of ripe eggs, the production of estradiol climbs. These are examples of basic feedback loops in your body, and they mean that your control hormones keep rising in order to try to get the ovaries to do what they did when you were twenty-four. Why does estradiol production rise as women age, until one to two years prior to the final period? We don’t completely understand the process, but it’s a bit like sprinters who jump the gun at the start of a race. Instead of waiting for the gun—which is what your follicles do superbly in your twenties if you are normal—your follicle at around age forty-something will “jump the gun” and start growing and producing estradiol. Ultimately, estrogen plummets at the end of perimenopause—when you are closer to your final menstrual period. Cortisol-Linked Estrogen Dominance Premenopausal women treated with hormone therapy —specifically, estrogen plus progesterone—have been shown to develop a high level of cortisol at night. Over time, that will lead to lower levels of progesterone, and the result is estrogen dominance. They come from artificial chemicals that you get exposed to in your daily life, such as plastics in the environment. They act like all the other guests, drinking and chatting convivially, but they are really party crashers who will disrupt the whole affair when they take off their masks. Xenoestrogens are stored in fat tissue for decades, and your greatest concentration of fat is usually in your breasts. When xenoestrogens bind to your estrogen receptors, they can activate some of them, such as those in the breast, and block others, such as those in the bone. When estrogen passes from the blood into the cells, it attaches to one of two types of estrogen receptors to trigger a particular task, such as stimulating breast-cell growth or slowing bone loss. Lengthened exposure to estrogen creates a significant risk factor for breast cancer. Recently, flame retardants such as polybrominated biphenyls have been linked to estrogen disruption and a higher rate of abnormal Pap smears. They interrupt the action of natural, endogenous hormones, with reproductive and developmental consequences. Just living our normal lives, we are exposed to more than seven hundred of these dangerous chemicals; they can be found in toothpaste, deodorant, sunscreen, food preservatives, the lining of cans that hold food, and many kinds of plastic. Be wary of your cosmetics: one report describes a woman who developed both breast and endometrial cancer after using the same estrogen- containing cosmetic cream for seventy-five years. Your quest for youthful looks may have the opposite effect, causing excess estrogen to enter your body through your moisturizer. Since the 1990s, menarche (onset of menstruation) has been occurring in the United States at younger and younger ages. You guessed it: xenoestrogens have been clearly implicated in the early onset of menstruation and puberty. They are a sign of estrogen dominance in men —estrogen out of balance with testosterone—which leads to less muscularity and more fat deposits, including at the breasts and love handles. Estrogen pollution doesn’t affect only humans; animals exposed to estrogens also suffer the consequences.

The method of Korotkoff is utilized safe cardizem 60mg blood pressure medication young adults, which takes advantage of the fact that laminar flow through an artery is silent while intermittent forward flow produces a sound discount cardizem 120mg visa arteria lumbalis. By implanting a cuff around an extremity to a pressure in excess of systolic pressure, flow distal to the cuff ceases. When pressure in the cuff is reduced to just below systolic pressure, flow proceeds across the artery beneath the cuff for that portion of the cardiac cycle during which arterial pressure exceeds cuff pressure. This transient "spurt" gives rise to a sound which can be heard with a stethoscope placed over the artery just distal to the cuff. The flow will be intermittent as long as the falling pressure continues to exceed diastolic arterial pressure. When cuff pressure falls below diastolic arterial pressure, there will be no cessation of flow. Thus the pressure at which sounds appear and disappear signal systolic and diastolic pressure, respectively. It shows a rise to a peak, then a fall, interrupted by a notch, followed by a slight secondary rise and then further fall until the cycle starts again. The specific anatomy of the curving aortic arch with its proximal major branches and its distal bifurcation creates numerous loci from which the advancing wave front is partially reflected backward. This, as well as the tapering diameter of the normal aorta is responsible for the changing shape of the wave front as it travels from the aortic root to the distal arterioles. The rising arterial pressure in the proximal aorta with early systole reflects the fact that blood is being expelled into the aorta faster than it is escaping into distal vessels and tissues. Thus, as the pressure rises, the rate at which net volume is increasing in the aorta falls. With the downslope of aortic pressure, the volume of blood in the segment of aorta in which pressure is being monitored falls. This closure of the aortic valves and transient interruption of flow gives rise to the dicrotic notch which punctuates the declining arterial pressure. The found produced by this closure (5-2) separates systole (ejection) from diastole during cardiac auscultation. Pressure falls throughout diastole as blood leaves the proximal aorta and the tension in the aortic wall falls. Obviously, the more rapidly ejection volume is delivered, the more rapid will be the rate of rise and the higher will be systolic peak pressure. Also, as aortic root compliance is reduced by atherosclerosis, age, and calcification, higher pressures are needed to distend the aorta by the same volume. Following the completion of ejection, blood is leaving the arteries via the major resistance vessels, the arterioles. If the arterioles are dilated and resistance is low, blood will be delivered to tissues more rapidly and the slope of arterial pressure will decline more quickly. A high peripheral resistance will do the opposite, leading to a higher diastolic arterial pressure at the time of the next systolic interruption of the declining diastolic pressure. Although "drainage" of the aorta is normally only through the arteries, certain pathological conditions allow blood to leave the aorta through a low-resistance shunt. This similarly speeds the descent of diastolic pressure to a lower nadir than normal. The enhanced stroke volume and more rapid aortic decompression produce the characteristic high systolic and low diastolic pressure of aortic insufficiency G. Regardless of the rate of decline of arterial pressure during diastole, the longer the cardiac cycle, the longer the diastolic period and thus the lower trough pressure will be. Although viscosity is potentially important, it is relatively constant with normal hematocrit and protein concentration in plasma, neither of which will increase appreciably over hours or days (in the event of hemorrhage, hematocrit will fall in hours, but the viscosity vs. Viscosity, when it rises to abnormally high levels, is usually due to marked increase in hematocrit (the percentage of whole blood composed of erythrocytes). Although this occurs rarely in Polycythemia Vera among adults, in children it is more commonly caused by cyanotic congenital heart disease with right-to-left intracardiac shunts leading to arterial hypoxemia and secondary bone marrow overproduction of red blood cells in an attempt to maintain whole blood O2 content. With hematocrits of this magnitude, viscosity is elevated enough to interfere with tissue perfusion. Elevation of plasma globulins occurs with certain malignancies of lymphocytes or plasma cells. Nevertheless, hyperviscosity is a relatively rare contributor to arterial hypertension. Therefore, excessive blood volume could be expected to cause arterial hypertension and in fact this can be seen with inadvertent hypertransfusion or in the disease Polycythemia Vera, in which red cells are overproduced by the bone marrow in an unregulated fashion raising total blood volume as well as hematocrit. Small changes in venous tone could alter venous compliance and venous volume, although normal, might raise peripheral venous pressure and augment venous return, leading in turn to increased cardiac output. Conversely, inadequate venous tone, such as might occur with disease of the peripheral autonomic nerves (as in long-standing Diabetes Mellitus), after the use of drugs which block sympathetic ganglia or even severe chronic distention of peripheral veins (as in severe varicose veins) may all lead to transient failure of venous return upon assuming an upright posture. Loss of extracellular volume in the form of excess perspiration, diarrhea or diuresis (urine loss) may be due to environmental factors (heat), intestinal disease, or inadequate renal concentrating mechanisms due to intrinsic renal disease, endocrine (adrenal, pituitary) insufficiency, or drugs (diuretics) to name several causes of dehydration and hypotension. Abrupt loss of cardiac contractility affecting a large segment of the left ventricle (40% or more) can precipitate a drastic fall in stroke volume and a fall in cardiac output severe enough to cause hypotension and shock. On the other hand, a few cases have been described of persistent hypercontractility of the heart leading to sustained supranormal cardiac output and mild (predominantly systolic) hypertension.

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Various iron preparations may also con- tribute to constipation in the pregnant patient purchase cardizem 180 mg amex arrhythmia joint pain. The majority of such agents are absorbed very little order 120mg cardizem with mastercard blood pressure 5040, if at all, from the gas- trointestinal tract. Overall, they should have no systemic effects or pose any serious threat to the fetus. Simethicone is log- ically not expected to cause systemic effects or have access to the fetal–placental unit, because simethicone is not absorbed from the gastrointestinal tract. From a practical standpoint, it has no clear indications for use during pregnancy, nei- ther does this agent offer any advantage over simethicone. However, it should be used without hesitation when it is needed in the treatment of acute poisoning. This combination can be used safely in pregnancy, avoid- ing chronic high doses which pose a risk (hypercalcemia, etc). Laxatives and purgatives Laxatives/purgatives can generally be divided into several classes depending on the mode of action: (1) emollients and softeners; (2) bulk-forming agents; (3) stimulants; and (4) saline, hyperusmetic, or lubricant agents (Box 12. Chronic use of the agents should be avoided because diarrhea and electrolyte imbalances may occur. Congenital anomalies were not increased in frequency among the offspring of over 800 women who utilized this agent in early pregnancy (Aselton et al. Congenital anomalies were not increased in frequency among offspring of mothers who utilized either casanthranol (21 patients) or cascara sagrada (53 patients) in early pregnancy (Heinonen et al. It is very unlikely that it poses any risk to the fetus because this agent is mini- mally absorbed from the gastrointestinal tract. In one mouse study, decreased lit- ter size and fertility were observed, but no somatic effects (Anonymous, 1997). Although there are no human reproduction studies, this agent is not absorbed from the gastrointestinal tract for the most part, and thus is unlikely to be associated with adverse fetal effects. There are no published human epidemiological or animal teratology studies with this agent. However, chronic use of mineral oil as a lax- ative might interfere with the absorption of fat-soluble vitamins such as vitamin K and D, and thus theoretically could have adverse fetal effects. There are also no reports of an association of adverse fetal effects with the use of castor oil during pregnancy. It has been a commonly held belief that this agent would stimulate labor and it is often utilized for this purpose in women close to term. However, little scientific data support the use of this agent as a potent stimulant of labor. Antidiarrheal agents Unlike constipation, diarrhea is an uncommon complaint of pregnancy and is usually secondary to medications (especially antibiotics), infections (bacterial, viral, and para- 234 Nutritional and dietary supplementation during pregnancy Box 12. Fortunately, most cases of acute diar- rhea are self-limited and require no specific therapy. Antidiarrheals can generally be divided into three major categories – bulk- forming agents, absorbents, and opiates (Box 12. There are no epidemiological studies regarding the use of this agent in pregnant women. However, since very little, if any, of it is absorbed from the gastrointestinal tract, it seems very unlikely that this antidiarrheal poses a significant risk to either mother or fetus. The addition of belladonna and opioid agents results in decreased gastrointestinal mobility. There is little available information regarding the use of opium-containing agents in pregnant women. There were only 36 women with early pregnancy exposure included in the Collaborative Perinatal Project database, but there was no evidence of a significant increase in the frequency of congenital anomalies (Heinonen et al. Almost 100 women were exposed to paregoric in early preg- nancy with no significant increase in frequency of congenital anomalies (Aselton et al. There is, however, the possibility of addiction and withdrawal syndrome in neonates whose mothers use this agent on a chronic basis. Another commonly used antidiarrheal is the combination of diphenoxylate and atropine (Lomotil and others). Diphenoxylate is a compound similar to meperidine and acts primarily to reduce intestinal motility. Of interest is the fact that atropine is included in this preparation in an effort to prevent abuse. Although there is a case report of an infant born with congenital heart disease whose mother used this agent during pregnancy (Ho et al. Moreover, there were less than 10 patients who utilized this agent in early pregnancy included in the Collaborative Perinatal Project (Heinonen et al. According to its manufacturer, loperamide was not ter- atogenic in rats and rabbits. Nausea and vomiting All pregnant women probably experience nausea to some degree in early pregnancy.

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Cells are then drawn from the cell banks and used in biophar- maceutical production generic cardizem 180mg free shipping blood pressure and caffeine. Broadly speaking discount cardizem 120 mg visa blood pressure healthy, the production pro- cess is divided into the following steps: Cultivation: The cells are transferred from the cryogenic cell bank to a liquid nutrient medium, where they are allowed to reproduce. The cells secrete the desired product, ent solution is inoculated with cells from a cell bank. These which is then isolated from the solution, purified and trans- are allowed to reproduce in stages up to a scale of several ferred to containers. During the growth phase the cell culture is transferred to progressively larger culture vessels. Fermentation: The actual production of the biopharmaceutical occurs during this phase. The culture medium contains sub- stances needed for the synthesis of the desired therapeutic protein. In total, the medium contains around 80 different constituents at this stage, although manufacturers never dis- close the exact composition. The industrial-scale steel vessels in which fermentation takes place have capacities of 10,000 liters or more. There are not only technological but also bio- logical constraints on the size of the reactor vessel: The big- ger a fermenter is, the more difficult it becomes to create uni- form conditions around all the cells within it. Purification: In technical terms, the production of biopharma- ceuticals in cells is a one-step process and the product can be purified immediately after fermentation. In the simplest case the cultured cells will have secreted the product into the am- bient solution. If, on the other hand, the product remains in the cells follow- ing biosynthesis, the cells are first isolated and digested (i. Theyield frombioproduction processes isusually much lower than from chemical synthesis. For example, a 10,000-liter fermenter yields only a few kilograms of a therapeutic anti- body such as MabThera/Rituxan (rituximab) or Herceptin (trastuzumab). Several more weeks are then needed to test the product: Each product batch is tested for purity to avoid quality fluctuations, and a 99. Formulation: The final steps in the production of biopharma- ceuticals are also demanding. The sensitive proteins are con- verted to a stable pharmaceutical form and must be safely packaged, stored, transported and finally administered. Throughout all these steps the structural integrity of the molecule has to be safeguarded to maintain efficacy. At pres- 34 ent this is only possible in special solutions in which the product can be cryogenically frozen and preserved, though the need for low temperatures does not exactly facilitate transport and delivery. Biopharmaceuticals are therefore produced strictly on the basis of demand – even more so than traditional drugs. Because of the sensitive nature of most biopharmaceuticals, their dosage forms are limited to injectable solutions. Thera- peutic proteins cannot pass the acidic milieu of the stomach undamaged, nor are they absorbed intact through the in- testinal wall. Though work on alternatives such as inhalers is in progress (especially for the relatively stable insulin mol- ecule), injection remains the only option for introducing biopharmaceuticals into the body. Nowadays all the steps in the production of biopharmaceuticals are fully automated. Because cell cultures react so sensitively to fluctuations in ambient conditions, the window for high-yield production is quite narrow: If the physical and chemical properties of the nu- trient medium deviate ever so slightly from the norm, the pro- duction staff must take action to restore optimum conditions. Even trace amounts of impurities can spell considerable economic loss, as the entire production batch then has to be dis- carded and the production process has to be restarted from scratch with the cultivation of new cells. Advantages in terms of Despite their elaborate production process, bio- efficacy and safety pharmaceuticals offer a number of advantages, two of which are uppermost in patients’ minds: efficacy and safety. Thanks to their structure, proteins have a strong affinity for a specific target molecule. Unlike traditional, low-molecular- weight drugs, biopharmaceuticals therefore rarely enter into nonspecific reactions. The result is that interference and danger- ous interactions with other drugs as well as side effects are rare. Nor do therapeutic proteins bind nonspecifically to receptors that stimulate cell growth and cause cancer. Biopharmaceuticals are unable to penetrate into the interior of cells, let alone into the cell nucleus, where many carcinogenic substances exert their dangerous (side) effects. Ultimately, only substances that occur in an unbound state between cells or on the outer cell surface come into ques- tion. Another ambivalent property is the fact that therapeutic pro- teins strongly resemble endogenous proteins.

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