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The products of aromatization of testosterone and androstenedione are Steroid hormones are produced from cholesterol by the ad- estradiol and estrone buy zoloft 100mg cheap anxiety attack help, respectively (see Fig buy zoloft 100 mg line mood disorder 7 year old. Cholesterol, a testis, the Sertoli cell is the main site of aromatization, 27-carbon (C27) steroid, can be obtained from the diet or which is stimulated by FSH; however, aromatization may synthesized within the body from acetate. Each organ uses also occur in peripheral tissues that lack FSH receptors a similar steroid biosynthetic pathway, but the relative (e. The major steroid produced by the testis is Primarily Mediated by cAMP testosterone, but other androgens, such as androstenediol, androstenedione, and dehydroepiandrosterone (DHEA), as The action of LH on Leydig cells is mediated through spe- well as a small amount of estradiol, are also produced. A Leydig cell Cholesterol from low-density lipoprotein (LDL) and has about 15,000 LH receptors, and occupancy of less than high-density lipoprotein (HDL) is released in the Leydig 5% of these is sufficient for maximal steroidogenesis. This cell and transported from the outer mitochondrial mem- is an example of “spare receptors” (see Chapter 31). Excess brane to the inner mitochondrial membrane, a process reg- receptors increase target cell sensitivity to low circulating ulated by steroidogenic acute regulatory protein (StAR). After senger, cholesterol is converted to pregnenolone (C21) by exposure to a high LH concentration, the number of LH re- cholesterol side-chain cleavage enzyme (CYP11A1), which ceptors and testosterone production decrease. Preg- response to the initial high concentration of LH, testos- nenolone is a key intermediate for all steroid hormones in terone production will increase and then decrease. The pregnenolone then moves by volves a loss of surface LH receptors as a result of internal- diffusion to the smooth ER, where the remainder of sex ization and receptor modification by phosphorylation. The LH receptor is a single 93-kDa glycoprotein com- Pregnenolone can be converted to testosterone via two posed of three functional domains: a glycosylated extracel- pathways, the delta 5 pathway and the delta 4 pathway. In lular hormone-binding domain, a transmembrane spanning the delta 5 pathway, the double bond is in ring B; in the domain that contains seven noncontiguous segments, and delta 4 pathway the double bond is in ring A (see Fig. The receptor is coupled to a stim- The delta 5 intermediates include 17 -hydroxypreg- ulatory G protein (Gs) via a loop of one of the LH receptor nenolone, DHEA, and androstenediol, while the delta 4 in- transmembrane segments. The activation of Gs results in in- termediates are progesterone, 17 -hydroxyprogesterone, creased adenylyl cyclase activity, the production of cAMP, and androstenedione. The conversion of C21 steroids (the progestins) to an- Low doses of LH can stimulate testosterone production drogens (C19 steroids) proceeds in two steps: first, 17 - without detectable changes in total cell cAMP concentra- hydroxylation of pregnenolone (to form 17 -hydrox- tion. However, the amount of cAMP bound to the regula- ypregnenolone) and second, C17,20 cleavage; thus, two tory subunit of protein kinase A (PKA) increases in response carbons are removed to form DHEA. This response emphasizes the im- and cleavage is accomplished by a single enzyme, 17 - portance of compartmentalization for both enzymes and hydroxylase or 17,20-lyase (CYP17). Other intracellular to androstenedione by another two-step enzymatic reac- mediators, such as the phosphatidylinositol system or cal- tion: dehydrogenation in position 3 (catalyzed by 3 -hy- cium, have roles in regulating Leydig cell steroidogenesis, droxysteroid dehydrogenase [3 -HSD]) and shifting of but it appears that the PKA pathway may predominate. The final reaction yielding testosterone is carried ment binding protein (CREB), which functions as a DNA- out by 17-ketosteroid reductase (17 -hydroxysteroid de- binding protein, regulate the transcription of cholesterol 660 PART X REPRODUCTIVE PHYSIOLOGY CH3 17 CH3 Leydig A HO 3 5 cell 4 6 Cholesterol Cholesterol side- chain cleavage CH3 CH3 enzyme CHCO CO (CYPllAl) 3 CH3 CH3 3β-HSD CH3 HO O Progesterone Pregnenolone 17α-Hydroxylase 17α-Hydroxylase CH3 (CYP17) CH3 (CYP17) CO CO CH3 OH CH3 OH CH3 3β-HSD CH3 HO O 17α-Hydroxypregnenolone 17α-Hydroxyprogesterone 17,20-Lyase 17,20-Lyase (CYP17) O (CYP17) O O CH3 CH3 CH3 3β-HSD Aromatase CH3 CH3 HO O HO Dehydroepiandrosterone Androstenedione Estrone 17β-OH steroid 17 Ketosteroid 17-Ketosteroid dehydrogenase reductase reductase CH OH OH OH 3 CH3 CH3 CH 3β-HSD Aromatase 3 CH3 HO O HO Androstenediol Testosterone 17β-Estradiol 5α-Reductase CHOH 3 Steroidogen- FIGURE 37. This Leydig cells also contain receptors for prolactin enzyme plays a major role in regulating LH (and, possibly, (PRL). Hyperprolactinemia in men with pituitary tumors, FSH) responses because phosphodiesterase is activated by usually microadenomas, is associated with decreased gonadotropin stimulation. This condition is due to a direct ef- esterase reduces the response to LH (and FSH). Certain fect of elevated circulating levels of PRL on Leydig cells, drugs can inhibit phosphodiesterase; gonadotropin hor- reducing the number of LH receptors or inhibiting down- mone responses will increase dramatically in the presence stream signaling events. Numerous isoforms of phosphodiesterase may decrease LH secretion by reducing the pulsatile na- and adenylyl cyclase exist; specific types of each in the ture of its release. THE ACTIONS OF ANDROGENS the circulation much more slowly if bound to a protein. Any type of liver damage or disease will generally reduce DHT enhances development of the male reproductive SHBG production. The latter can upset the hormonal bal- tract, accompanying accessory ducts and glands, and male ance between LH and testosterone. A lack of androgen declines acutely, then free testosterone may increase secretion or action causes feminization. In response to the increase in free testosterone, LH levels would decline in a homeostatic attempt to re- Peripheral Tissues Process and duce testosterone production. Metabolize Testosterone Once testosterone is released into the circulation, its Testosterone is not stored in Leydig cells but diffuses into fate is variable.

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We here present a set of practical guidelines cheap zoloft 100 mg on line depression legere definition, based on evidence and the expertise of the Cochrane Collaboration buy discount zoloft 50mg line depression symptoms morning, to facilitate the understanding of and appropriate adherence to methodological principles when conducting diagnostic systematic reviews. We reviewed reports of systematic searches of the literature for diagnostic research,8–11 methodological criteria to evaluate diagnostic research,1,4–7 methods for statistical pooling of data on diagnostic accuracy,12–20 and methods for exploring heterogeneity. Examples are given using the results of two systematic reviews on the accuracy of the urine dipstick in the diagnosis of urinary tract infections,26 and on the accuracy of the straight-leg raising test in the diagnosis of intervertebral disc hernia. The reviewer has to design a search strategy based on a clear and explicit description of the subjects receiving the test of interest, the diagnostic test and its accuracy estimates, the target disease, and the study design. These elements are usually specified in the criteria for inclusion of primary studies in the review. However, because computerised databases only index a subset of all the available literature, the search should be extended using other sources. A search strategy begins by creating a list of database specific keywords and text words that describe the diagnostic test and the target disease of interest (subject specific strategy). Because the number of diagnostic accuracy studies is often small, the subject specific strategy usually yields a limited number of publications to be screened. We found a combination of two published generic strategies adapted for use in PubMed (MEDLINE) to be more sensitive and precise than previously published strategies8,10 (Box 8. Each electronic database will need to be searched using a specially designed search strategy. The reference section of primary studies, narrative reviews, and systematic reviews should be checked to search for additional primary studies that could have been missed by the electronic search. Consultation of experts in the disease of interest to identify further published and unpublished primary studies. As diagnostic accuracy studies are often based on routinely collected data, publication bias may be more prevalent in diagnostic than in therapeutic research. Diagnostic research reports – older publications in particular – are often poorly indexed in the electronic databases. It is often fruitful to conduct pilot searches using the subject specific strategy. This process is repeated after identifying and incorporating additional keywords and text words to describe and index the retrieved reports. Studies found only in the reference sections of the retrieved reports but missed by the search strategy should be searched for in the database, using the article title or the first author’s name. If a study is found in the database, its keywords should be noted and added to the strategy. Citation tracking may provide additional 148 GUIDELINES FOR SYSTEMATIC REVIEWS studies. The Science Citation Index could be searched forward in time to identify articles citing relevant publications. If disagreements cannot be resolved by consensus, or if insufficient information is available, a third reviewer and/or the full papers should be consulted. Inclusion criteria q Reference test The accuracy of a diagnostic or screening test should be evaluated by comparing its results with a “gold standard”, criterion standard, or reference test accepted as the best available by content experts. The reference test may be a single test, a combination of different tests, or the clinical follow up of patients. Participants should be defined explicitly in terms of age, gender, complaints, signs, and symptoms, and their duration. At least a definition of participants with and without the disease, as determined by the reference test, should be available. The minimal number of participants needed with and without the disease depends on the type of study, the estimates of diagnostic accuracy, and the precision used to estimate these parameters. Comments As the patient mix (spectrum of disease severity) is different at different levels of care, a diagnostic review may focus on a specific setting (primary care, etc. This information may be important for subgroup analyses in case of heterogeneity. All evidence available should be reviewed, regardless of the language of publication. It is not easy to identify non-English publications, as they are often not indexed in computerised databases. In the field of intervention research there is some evidence of bias when excluding non-English publications.

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The number of platelets circulating in Blood has many important functions: the blood normally does not change 50 mg zoloft for sale mood disorder lamictal. If there should be a decrease in the number • It carries oxygen and nutrients to the of platelets discount zoloft 25mg overnight delivery depression negative thoughts, however, the condition is body tissues. It contains no blood cells but is sues to the organs of excretion, such essential for carrying blood cells and nutri- as the lungs and the kidneys. Approximately three-fifths of the total • It promotes clotting to minimize blood volume is plasma. Normal Structure and Function of Several different types of cells make up Red Blood Cells the blood. Approximately two-fifths of the total blood volume is composed of cells Erythrocytes (red blood cells) carry oxy- that are formed by a process called hemo- gen to the tissues. They are normally 231 232 CHAPTER 8 CONDITIONS OF THE BLOOD AND IMMUNE SYSTEM disk shaped, with a thin center and thick- Normal Structure and Function of er edges. Their flexible shape allows them White Blood Cells and Immunity to fit through blood vessels of differing sizes. Hemoglobin is the red-pigmented The immune system is a complex organ- protein contained within the erythrocytes ization of specialized cells and organs that and is the specific part of the red blood cell distinguishes between self and nonself, that carries oxygen. Although the body is exposed to Special cells in the bone marrow pro- a number of microorganisms each day, the duce erythrocytes. Several vitamins, such immune system helps it fight off bacteria, as vitamin B12 and folic acid (which is part viruses, and other microbes. Although of the vitamin B complex), are necessary constantly bombarded by microorganisms for the formation of erythrocytes. They are or trauma that can result in infection, dis- obtained from the diet. Iron, which is also ease, or injury, the body has specific de- obtained from the diet, is important for fenses to protect it against such invasions. Excess The immune system has traditionally amounts of iron and vitamin B12 are been divided into innate and adaptive com- stored in the liver. Although most erythrocytes are body’s first line of defense against foreign released into the blood, some are taken up material is called nonspecific or innate im- by the spleen to be stored for emergency munity. This type of immunity includes the use when the red blood cell count drops protection provided by the skin, which significantly below normal levels, such as acts as a barrier to organisms, and by the during hemorrhage. Newly formed red mucous membranes, gastric secretions, blood cells enter the bloodstream before and tears, which contain special chemicals they are totally mature. At this stage, they that destroy potentially harmful organ- are called reticulocytes. Innate immunity requires no previ- days, the cells mature to become erythro- ous exposure to the foreign substance or cytes. The life cycle of erythrocytes is recognition of any specific properties of approximately 120 days. When, despite exter- cytes reach the end of their life cycle, they nal and chemical barriers, an organism or become more fragile and rupture. Some of other foreign material gains entry into the the old erythrocytes are destroyed in the body, an inflammatory response results (the spleen. The main purpose of liver absorb the old erythrocytes, making the inflammatory response is to bring room for more new cells. For example, at higher alti- Also important to the body’s defense is tudes, where less oxygen is available in the a circulatory system called the lymphatic air, the bone marrow reacts by producing system. The lymphatic system is a circula- more red blood cells, even if there is an tory system separate from the general cir- adequate number of red blood cells in the culation and consists of lymph vessels, circulation. This is part of the adaptive component porary storage reservoirs for lymphocytes of the immune system. Lymphocytes are (white blood cells that fight infection) white blood cells formed by the lymph and, with appropriate stimulus, as manu- nodes, spleen, thymus, and sometimes the facturers of lymphocytes.

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The ataxia and tremor are re- cles of the pharynx and larynx effective zoloft 100mg anxiety xanax, including what is commonly called lated primarily to damage to these cerebellar efferent fibers generic 100mg zoloft with mastercard mood disorder jesse jackson. A lesion of this nucleus is one cause of motor deficit is contralateral to the lesion because the corti- dysarthria. The solitary tract and nuclei are concerned with vis- cospinal fibers, through which the deficit is expressed, cross at the ceral afferent information including taste, and the spinal trigemi- motor (pyramidal) decussation. Lesions at the other choices nal tract is made the central processes of primary sensory fibers would not result in a paucity of eye movement and are, therefore, conveying general somatic afferent (GSA) information from the not potential candidates. Proprioceptive infor- mation from the ipsilateral upper extremity is transmitted via the 9. Answer C: The lesion on the exiting oculomotor fibers (on the cuneate nucleus; the vestibular nuclei are related to balance, equi- left) damages the preganglionic fibers from the Edinger-Westphal librium, and control of eye movement. Consequently, the intact postganglionic sympathetic fibers from the ipsilateral su- 15. Answer C: The area of the brainstem that contains the nucleus perior cervical ganglion predominate, and the pupil dilates. Occlusion of this vessel usually gives rise to the thalamospinal fibers would remove sympathetic influence at the PICA (lateral medullary or Wallenberg) syndrome. The anterior intermediolateral cell column, and the pupil would constrict inferior cerebellar artery (AICA) serves the lateral and inferior (parasympathetic domination). Answer C: Cerebellar efferent fibers exit the cerebellum via the artery, a branch of AICA, serves the inner ear. The posterior superior cerebellar peduncle, cross in its decussation, and termi- spinal artery serves the posterior columns and their nuclei. Consequently, 110–111, 202–203) the cerebellar nuclei on the left project to the right VL. The ven- tral anterior nucleus does not receive significant cerebellar input. Answer D: Glutamate is found in many efferent fibers of the While the ventral posterolateral nucleus receives a limited amount cerebral cortex including those of the corticospinal tract. Conse- of cerebellar input, its major role is the relay of somatosensory in- quently, there are many glutaminergic terminals in the spinal formation to the primary somatosensory cortex (postcentral cord. Answer B: The jerking movements of the upper extremity (as- their nigrostriatal terminals. Gamma aminobutyric acid (GAMA) terixis) are also called a flapping tremor and are seen in patients is an inhibitory neurotransmitter and is found in many interneu- with hepatolenticular degeneration (Wilson disease). Resting tremor is seen in patients with disease pothalamus, basal nuclei, and the raphe nuclei. Answer A: The loss of sensation on one side of the face and the tonia is the result of sustained muscle contractions that twist the opposite side of the body is an alternating hemianesthesia (also extremities, trunk, and neck into distorted and abnormal pos- called an alternate hemianesthesia or a crossed hemianesthesia). Answer A: This man is unable to recognize or comprehend the motor abnormalities. Answer D: Lesions in the lateral portions of the brainstem dam- ditory agnosia. Agraphia is the inability to write in a person with age descending projections from the hypothalamus to the ipsilat- no paralysis, and alexia is the inability to comprehend the mean- eral intermediolateral cell column at spinal levels T1-T4, these be- 288 Q & A’s: A Sampling of Study and Review Questions with Explained Answers ing the hypothalamospinal fibers. Weakness of the extremities may be seen, but on the side ipsilateral to the lesion. Horner syndrome may also be this almost always follows ocular movement disorders. A contralateral hemi- is most commonly seen in cerebellar disease and may be present plegia is not seen in lesions in lateral areas of the brainstem. Tremor is other choices are syndromes or deficits specific to medial brain- commonly seen in diseases or lesions of the basal nuclei and the stem areas or to only a particular level. Answer C: The denticulate ligament is located on the lateral as- sensory loss on the body (excluding the head) is on her left side; a pect of the spinal cord at a midpoint in the posterior-anterior ex- lesion in the medulla on the right side, involving fibers of the an- tent of the spinal cord. The anterolateral system, the tract divided terolateral system (ALS), accounts for this sensory deficit. A le- in the anterolateral cordotomy, is located in the anterolateral por- sion of the ALS on the left side of the medulla would result in sen- tion of the spinal cord just inferior to the position of the denticu- sory deficits on the right side of the body. The posterolateral sulcus is the entrance point for tract and nucleus convey pain and thermal sensations from the ip- sensory fibers of the posterior roots; the anterolateral sulcus is the silateral side (right side in this case) of the face, and the medial exit point for motor fibers of the anterior root; and the posterior lemniscus conveys vibratory and discriminative touch sensations intermediate sulcus separates the gracile and cuneate fasciculi.