By N. Kippler. Capitol College.

Microvilli from the trophoblast cells in- phoblast cells have differentiated into large polyhedral cy- terdigitate with and form junctional complexes with the totrophoblasts trusted furosemide 100 mg, surrounded by peripheral syncytiotro- uterine endometrial cells buy furosemide 40 mg free shipping. Maternal blood In the presence of progesterone emanating from the cor- vessels in the endometrium dilate and spaces appear and pus luteum buy discount furosemide 100 mg on line, the endometrium undergoes decidualization discount furosemide 40mg amex, fuse safe furosemide 100 mg, forming blood-filled lacunae. Between weeks 2 and 3, which involves the hypertrophy of endometrial cells that villi, originating from the embryo, are formed that protrude contain large amounts of glycogen and lipid. In some cases, into the lacunae, establishing a functional communication the cells are multinucleated. This group of decidualized between the developing embryonic vascular system and the cells is called the decidua, which is the site of implantation maternal blood (see Fig. In the ab- oblast has differentiated into three layers: sence of progesterone, decidualization does not occur and • Ectoderm, destined to form the epidermis, its ap- implantation would fail. As the blastocyst implants into the pendages (nails and hair), and the entire nervous system decidualizing uterus, a decidual reaction occurs involving • Endoderm, which will give rise to the epithelial lining of the dilation of blood vessels, increased capillary permeabil- the digestive tract and associated structures ity, edema formation, and increased proliferation of en- • Mesoderm, which will form the bulk of the body, in- CHAPTER 39 Fertilization, Pregnancy, and Fetal Development 689 cluding connective tissue, muscle, bone, blood, and and maternal circulations do not mix. The chorionic villi aggregate into groups known as cotyle- PREGNANCY dons and are surrounded by blood from the maternal spiral arteries that course through the decidua. Pregnancy is maintained by protein and steroid hormones Major functions of the placenta are the delivery of nu- from the mother’s ovary and the placenta. The maternal en- trients to the fetus and the removal of its waste products. Oxygen diffuses from maternal blood to the fetal blood down an initial gradient of 60 to 70 mm Hg. The oxygen- transporting capacity of fetal blood is enhanced by fetal The Mother and Fetus Contribute to the Placenta hemoglobin, which has a high affinity for oxygen. The In the human placenta, the maternal and fetal components PCO2 of fetal arterial blood is 2 to 3 mm Hg higher than are interdigitated. The functional units of the placenta, the that of maternal blood, allowing the diffusion of carbon chorionic villi (see Fig. Other com- tend tissue projections into the maternal lacunae that form pounds, such as glucose, amino acids, free fatty acids, elec- from endometrial blood vessels immediately after implan- trolytes, vitamins, and some hormones, are transported by tation. By week 4, the villi are spread over the entire surface diffusion, facilitated diffusion, or pinocytosis. As the placenta matures, it becomes ucts, such as urea and creatinine, diffuse away from the fe- discoid in shape. During the third month, the chorionic tus down their concentration gradients. Large proteins, in- villi are confined to the area of the decidua basalis. The de- cluding most polypeptide hormones, do not readily cross cidua basalis and chorionic plate together form the pla- the placenta, whereas the lipid-soluble steroids pass centa proper (Fig. The blood-placental barrier allows The decidua capsularis around the conceptus and the the transfer of some immunoglobulins, viruses, and drugs decidua parietalis on the uterine wall fuse and occlude the from the mother to the fetus (Fig. The yolk sac becomes vestigial and the am- niotic sac expands, pushing the chorion against the uterine The Recognition and Maintenance of Pregnancy wall. From the fourth month onward, the fetus is enclosed Depend on Maternal and Fetal Hormones within the amnion and chorion and is connected to the pla- centa by the umbilical cord. Fetal blood flows through two The placenta is an endocrine organ that produces proges- umbilical arteries to capillaries in the villi, is brought into terone and estrogens, hormones essential for the continu- juxtaposition with maternal blood in the sinuses, and re- ance of pregnancy. The placenta also produces protein hor- turns to the fetus through a single umbilical vein. The fetal mones unique to pregnancy, such as human placental Trophoblast Cytotrophoblast Blastocoele Embryoblast Uterine epithelium Multinucleated giant cells Fibrin plug (syncytium) Cytotrophoblast Amniotic cavity Yolk sac Uterine stroma Decidua Syncytiotrophoblast Endometrial vessel Lacuna (Maternal) FIGURE 39. Several peptides and polypeptides, including corti- of two dissimilar subunits, and. It belongs to the same cotropin-releasing hormone (CRH), GnRH, and insulin- hormone family as luteinizing hormone (LH), follicle-stim- like growth factors, are also synthesized by the placenta ulating hormone (FSH), and thyroid-stimulating hormone and function as paracrine factors. The subunit is made of the same 92 amino acids During the menstrual cycle, the corpus luteum forms as the other glycoprotein hormones. The subunit is made shortly after ovulation and produces significant amounts of of 145 amino acids, with six N- and O-linked oligosaccha- progesterone and estrogen to prepare the uterus for receiv- ride units. If the egg is not fertilized, the corpus acid extension at the C-terminal end. Because of extensive luteum regresses at the end of the luteal phase, as indicated glycosylation, the half-life of hCG in the circulation is by declining levels of progesterone and estrogen in the cir- longer than that of LH.

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Somatostatin 2 binding to its receptor also lowers intracellular Ca generic 100 mg furosemide mastercard, re- ducing GH secretion proven furosemide 40 mg. When the somatroph is exposed to both somatostatin and GHRH buy discount furosemide 40mg on line, the effects of somatostatin IGF-I 2 are dominant and intracellular cAMP and Ca are re- duced cheap furosemide 100 mg online. GH is not consid- shown in red discount furosemide 40 mg overnight delivery, inhibit GHRH secretion and action on the soma- ered a traditional trophic hormone; however, it does stim- totroph, causing a decrease in GH secretion. The feedback loops ulate the production of a trophic hormone called insulin- ( ), shown in gray, stimulate somatostatin secretion, causing a like growth factor I (IGF-I). IGF-I was originally called somatomedin C or soma- totropin-mediating hormone because of its role in promot- fect of these actions is the inhibition of GH secretion. Somatomedin C was renamed IGF-I because of stimulating IGF-I production, GH inhibits its own secre- its structural similarity to proinsulin. This mechanism is analogous to the way ACTH and Insulin-like growth factor II (IGF-II), an additional TSH regulate their own secretion through the respective growth factor induced by GH, is structurally similar to IGF- negative-feedback effects of the glucocorticoid and thyroid I and has many of the same metabolic and mitogenic ac- hormones. However, IGF-I appears to be the more important somatostatin, GH, and IGF-I comprises the hypothalamic- mediator of GH action. Because of its structural similarity to Feedback Effects of GH on Its Own Secretion. An in- proinsulin, IGF-I can produce some of the effects of in- crease in the blood concentration of GH has direct feed- sulin. IGF-I is produced by many cells of the body; how- back effects on its own secretion, independent of the pro- ever, the liver is the main source of IGF-I in the blood. These effects of GH are due to the Most IGF-I in the blood is bound to specific IGF-I-bind- inhibition of GHRH secretion and the stimulation of so- ing proteins; only a small amount circulates in the free matostatin secretion by hypothalamic neurons (see Fig. GH circulating in the blood can enter the intersti- sulin-like activity, so it does not play a physiological role tial spaces of the median eminence of the hypothalamus in the regulation of blood glucose level. GH increases the expression of the genes for IGF-I in various tissues and organs, such as the liver, and stimulates Pulsatile Secretion of GH. Excessive secretion of periodic bursts, which produce large but short-lived peaks GH results in a greater than normal amount of IGF-I in the in GH concentration in the blood. Individuals with GH deficiency have lower than of high GH secretion, somatotrophs release little GH; as a normal levels of IGF-I, but there is still some present, since result, the blood concentration of GH falls to very low lev- the production of IGF-I by cells is regulated by a variety of els. It is believed that these periodic bursts of GH secretion hormones and factors in addition to GH. It acts directly on somatotrophs to inhibit between bursts, when GH secretion is suppressed, are the stimulatory action of GHRH on GH secretion. The net ef- from neural activity generated in higher levels of the CNS, 592 PART IX ENDOCRINE PHYSIOLOGY which affects the secretory activity of GHRH and somato- increase in the blood concentration of the amino acids argi- statin producing neurons in the hypothalamus. Bursts of GH secretion occur during both awake and sleep periods of the day; however, GH secretion is maximal The Actions of GH. The bursts of GH secretion during sleep usually of the body have receptors for GH in their plasma mem- occur within the first hour after the onset of deep sleep branes. The interaction of GH with these receptors pro- (stages 3 and 4 of slow-wave sleep). Mean GH levels in the duces its growth-promoting and other metabolic effects, blood are highest during adolescence (peaking in late pu- but the mechanisms that produce these effects are not fully berty) and decline in adults. The binding of GH to its receptor activates a with aging is mainly due to decrease in the size of the GH tyrosine kinase (JAK2), which initiates changes in the secretory burst but not the number of pulses (Fig 32. These factors are thought to work by changing the the transcription of specific genes, such as that for IGF-I. For example, emotional or physical stress IGF-I; however, evidence indicates that GH has direct causes a great increase in the rate of GH secretion. Vigor- growth-promoting actions on progenitor cells or stem cells, ous exercise also stimulates GH secretion. Obesity results such as prechondrocytes in the growth plates of bone and in reduced GH secretion. GH stimulates such pro- Changes in the circulating levels of metabolites also af- genitor cells to differentiate into cells with the capacity to fect GH secretion. An important action of GH on the tion stimulates GH secretion, whereas hyperglycemia in- differentiation of progenitor cells is stimulation of the ex- hibits it. Growth hormone secretion is also stimulated by an pression of the IGF-I gene; IGF-I is produced and released by these cells. IGF-I exerts an autocrine mitogenic action on the cells that produced it or a paracrine action on neighbor- ing cells.

For example discount furosemide 100mg overnight delivery, a pendent calcium pumps in mitochondria and other or- newborn infant cannot concentrate urine as well as an adult ganelles (e order furosemide 100mg with mastercard. For example generic 40 mg furosemide fast delivery, older adults are less able to tol- minished ATP production can lead to an abnormally ele- 2 2 erate stresses trusted furosemide 40 mg, such as exercise or changing weather purchase furosemide 40 mg, than vated cytosolic [Ca ]. Intracellular Homeostasis Is Essential for Normal Cell Function Negative Feedback Promotes Stability; Feedforward Control Anticipates Change The term homeostasis has traditionally been applied to the in- ternal environment—the extracellular fluid that bathes our Engineers have long recognized that stable conditions can be tissues—but it can also be applied to conditions within achieved by negative-feedback control systems (Fig. In fact, the ultimate goal of maintaining a constant in- Feedback is a flow of information along a closed loop. The ternal environment is to promote intracellular homeostasis, components of a simple negative-feedback control system and toward this end, conditions in the cytosol are closely include a regulated variable, sensor (or detector), controller regulated. Each component controls the The many biochemical reactions within a cell must be next component. Various disturbances may arise within or tightly regulated to provide metabolic energy and proper rates of synthesis and breakdown of cellular constituents. Metabolic reactions within cells are catalyzed by enzymes and are therefore subject to several factors that regulate or Feedforward Feedforward path controller influence enzyme activity. End-product inhibition is an example of negative-feed- Feedback back control (see below). Cells reg- The regulated variable is sensed, and information about its level is fed back to a feedback controller, which compares it to a desired ulate their pH via mechanisms for buffering intracellular value (set point). If there is a difference, an error signal is gener- hydrogen ions and by extruding H into the extracellular ated, which drives the effector to bring the regulated variable fluid (see Chapter 25). A feedforward controller generates The structure and activity of cellular proteins are also af- commands without directly sensing the regulated variable, al- fected by ionic strength. Feedforward controllers often on the total number and charge of ions per unit volume of operate through feedback controllers. One explanation for this remarkable behavior is that is sensed, information is fed back to the controller, and the exercise simultaneously produces a centrally generated feed- effector acts to oppose change (hence, the term negative). Room tem- feedback information generated as a consequence of in- perature (regulated variable) is subjected to disturbances. For creased movement and muscle activity, adjusts the heart, example, on a cold day, room temperature falls. In addition, control mometer (sensor) in the thermostat (controller) detects the system function can adapt over a period of time. The thermostat is set for a certain tem- ence and learning can change the control system’s output so perature (set point). The controller compares the actual tem- that it behaves more efficiently or appropriately. The resulting change in room temperature is diabetes, and hypertension, develop because of a defective monitored, and when the temperature rises sufficiently, the control mechanism. Such a negative-feedback system allows sult in inappropriate actions, such as autoimmune diseases, some fluctuation in room temperature, but the components in which the immune system attacks the body’s own tissue. Effective com- Scar formation is one of the most effective homeostatic munication between the sensor and effector is important in mechanisms of healing, but it is excessive in many chronic keeping these oscillations to a minimum. One example is the system that regulates arte- rial blood pressure (see Chapter 18). This system’s sensors Positive Feedback Promotes a (arterial baroreceptors) are located in the carotid sinuses Change in One Direction and aortic arch. Changes in stretch of the walls of the carotid sinus and aorta, which follow from changes in With positive feedback, a variable is sensed and action is blood pressure, stimulate these sensors. Positive feed- fibers transmit impulses to control centers in the medulla back does not lead to stability or regulation, but to the oblongata. Efferent nerve fibers send impulses from the opposite—a progressive change in one direction. One medullary centers to the system’s effectors, the heart and example of positive feedback in a physiological process is blood vessels. The output of blood by the heart and the re- the upstroke of the action potential in nerve and muscle sistance to blood flow are altered in an appropriate direc- (Fig. Depolarization of the cell membrane to a value tion to maintain blood pressure, as measured at the sensors, greater than threshold leads to an increase in sodium within a given range of values.

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Animal studies suggest a long-term depletion of 5-HT can occur and given the known roles of this monoamine in mood (Chapter 9) generic furosemide 100mg without a prescription, this is a plausible explanation generic 40mg furosemide overnight delivery. It is disturbing that a large number of people may be predisposed to mental problems as a result of this drug use buy furosemide 40 mg line. STIMULANTS General Amphetamines (speed sulph cheap furosemide 40 mg visa, sulphate buy 40 mg furosemide amex, uppers, wake-ups, billy whizz, whizz, whites, base) are synthetic stimulants which as medicines have been formed into a variety of tablets. Their current medical use is very limited and in fact only dexamphetamine sulphate, Dexedrine, is now available for use solely in the treatment of narcolepsy. The only other amphetamine available for medical use is methylphenidate (Ritalin) for the treatment of attention deficit syndrome in children. As a street drug, amphetamine usually comes as a white, grey, yellowish or pinky powder. The purity rate of street powders is less than 10%, the rest being made up of milder stimulants such as caffeine, other drugs such as paracetamol or substances like glucose, dried baby milk, flour or talcum powder. The powder form can be snorted up the nose, mixed in a drink or prepared for injection. During the 1990s, amphetamine was a popular drug among young people attending all-night raves and is probably the next most commonly used illegal drug after cannabis. Recent local surveys have shown between 5% and 18% of 16-year-olds claiming to have used it at least once. This is a crystallised form of meth (or methyl-) amphetamine that can be smoked or injected. It is very strong and can result in intense paranoia and a very unpleasant come-down. After heroin, amphetamine is probably the most commonly injected street drug in the UK. Amphetamines were first discovered in the 1800s but their medical uses were not recognised until the 1930s. Then they were used to counter low blood pressure, for asthmatics and to suppress appetite. Subsequently, amphetamines were prescribed for a whole range of disorders including inability to sleep, epilepsy, migraine, depression and hyperactivity in children. Until 1956 many amphetamine- based drugs could be bought over the counter without a prescription. In the 1970s and 1980s street use of amphetamine increased again and centred on a new generation of young people in the all-night club scene of punk rock and Northern Soul. Illicitly manufactured powdered amphetamine and sniffing replaced tablets stolen from factories as the main form of use. Legal All amphetamines are prescription only drugs under the Medicines Act. Doctors can prescribe them for patients but it is an offence to be in possession of amphetamines without a prescription. Most amphetamines are controlled as class B drugs under the Misuse of Drugs Act. If amphetamines are prepared for injection they become class A drugs and increased penalties apply. They increase breathing and heart rate, lessen appetite and dilate the pupils. Users tend to feel more alert, energetic, confident and cheerful and less bored or tired. With high doses people often experience a rapid flow of ideas and feel they have increased physical and mental powers although this is usually manifest as talking non-stop. Taking a lot, especially over a few days, can produce a temporary panic and paranoia and with high doses the amphetamine psychosis is like a transient episode of schizophrenia. The effects of a single dose last for about 3±4 h and tend to leave the user feeling tired. Users may feel depressed, lethargic, lacking in energy and incredibly hungry without taking the drug.

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The best studied of these is the lipopolysac- is not so cold that a blunted metabolic response would al- charide endotoxin of gram-negative bacteria buy cheap furosemide 100 mg. A thalamus (and perhaps elsewhere in the brain) to alter their lower core-to-skin conductance (i buy cheap furosemide 40 mg. This effect of climatization in which a reduction in the metabolic re- endogenous pyrogens is mediated by the local synthesis and sponse to cold occurred buy furosemide 40 mg amex. This increased insulation is not due to subcutaneous fat (in fact effective furosemide 40 mg, it has been observed in release of prostaglandin E2 order 100mg furosemide visa. Aspirin and other drugs that in- very lean subjects), but apparently results from lower blood hibit the synthesis of prostaglandins also reduce fever. In general, the cold liable indicator of the presence of disease that body tem- stresses that elicit a lower shell conductance after acclima- perature is probably the most commonly measured clinical tization involve either cold water immersion or exposure to index. Many of the body’s defenses against infection and air that is chilly but not so cold as to risk freezing the vaso- cancer are elicited by a group of polypeptides called cy- constricted extremities. However, other cytokines, par- ticularly tumor necrosis factor, interleukin-6, and the in- Cold-Induced Vasodilation and the Lewis Hunting Re- terferons, are also pyrogenic in certain circumstances. As the skin is cooled below about 15 C, its blood vated body temperature enhances the development of flow begins to increase somewhat, a response called cold- these defenses. If laboratory animals are prevented from de- induced vasodilation (CIVD). This response is elicited veloping a fever during experimentally induced infection, most easily in comfortably warm subjects and in skin rich in survival rates may be dramatically reduced. The this chapter, fever specifically means an elevation in core mechanism has not been established but may involve a di- temperature a resulting from pyrogens, some authors use rect inhibitory effect of cold on the contraction of vascular the term more generally to mean any significant elevation smooth muscle or on neuromuscular transmission. After repeated cold exposure, CIVD begins Many Factors Affect Thermoregulatory Responses earlier during cold exposure, produces higher levels of and Tolerance to Heat and Cold blood flow, and takes on a rhythmic pattern of alternating vasodilation and vasoconstriction. This is called the Lewis Regular physical exercise and heat acclimatization increase hunting response because the rhythmic pattern of blood heat tolerance and the sensitivity of the sweating response. This re- Aging has the opposite effect; in healthy 65-year-old men, sponse is often well developed in workers whose hands are the sensitivity of the sweating response is half of that in 25- CHAPTER 29 The Regulation of Body Temperature 547 year-old men. Heat exhaustion, also called heat col- ously those used for their anticholinergic effects, such as lapse, is probably the most common heat disorder, and rep- atropine and scopolamine. In addition, some drugs used for resents a failure of cardiovascular homeostasis in a hot en- other purposes, such as glutethimide (a sleep-inducing vironment. Collapse may occur either at rest or during drug), tricyclic antidepressants, phenothiazines (tranquil- exercise, and may be preceded by weakness or faintness, izers and antipsychotic drugs), and antihistamines, also confusion, anxiety, ataxia, vertigo, headache, and nausea or have some anticholinergic action. The patient has dilated pupils and usually sweats others have been associated with heatstroke. As in heat syncope, reduced diastolic filling of heart failure and certain skin diseases (e. Although blood pressure may be low patients with these diseases, heat exposure and especially during the acute phase of heat exhaustion, the baroreflex exercise in the heat may raise body temperature to danger- responses are usually sufficient to maintain consciousness ous levels. Lesions that affect the thermoregulatory struc- and may be manifested in nausea, vomiting, pallor, cool or tures in the brainstem can also alter thermoregulation. Patients with heat ex- Such lesions can produce hypothermia (abnormally low haustion usually respond well to rest in a cool environment core temperature) if they impair heat-conserving re- and oral fluid replacement. However, hyperthermia (abnormally high core intravenous replacement of fluid and salt may be required. However, heat exhaustion accompanied circadian rhythm of core temperature. Certain drugs, such as barbiturates, alcohol, and phe- Therefore, patients should be actively cooled if rectal tem- nothiazines, and certain diseases, such as hypothyroidism, perature is 40. Hypovolemia cially in debilitated patients, may be accompanied by hy- contributes if the patient is dehydrated, but heat exhaustion pothermia, instead of the usual febrile response to infec- often occurs without significant dehydration. This is reversed shortly before the maintenance of blood pres- failing appears to be due to an impaired ability to conserve sure fails. The most severe and dangerous heat disorder is characterized by high core temperature and the develop- Heat Stress Causes or Aggravates ment of serious neurological disturbances with a loss of Several Disorders consciousness and, frequently, convulsions. In the classical The harmful effects of heat stress are exerted through car- form, the primary factor is environmental heat stress that diovascular strain, fluid and electrolyte loss and, especially overwhelms an impaired thermoregulatory system, and in heatstroke, tissue injury whose mechanism is uncertain.

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