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Showing posts with label Organ. Show all posts
Showing posts with label Organ. Show all posts

Monday, April 12, 2021

AUTOINFLAMMATORY SYNDROMES

AUTOINFLAMMATORY SYNDROMES


AUTOINFLAMMATORY SYNDROMES
The autoinflammatory syndromes are a rare group of diseases for which the specific causes have been determined. The diseases in this category include hyper-immunoglobulin D (hyper-IgD) syndrome (HIDS), the cryopyrinopathies, familial Mediterranean fever (FMF), and tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS). The cryopyrinopathies are a group of conditions made up of Muckle-Wells syndrome, familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), and chronic infantile neurological cutaneous and articular syndrome (CINCA). These groupings were first proposed in the 1990s to bring together a collection of inflammatory disorders that are distinct in nature and pathophysiology from other forms of allergic, autoimmune, and immunodeficiency syndromes. Patients with these auto-inflammatory diseases lack the autoreactive immune cells (T and B cells) as well as autoantibodies. The identification of specific genes that are defective and the roles played by those genes in the development of these disorders has been critical in increasing understanding of these diverse diseases. The common link in these conditions is the fact that they all represent abnormalities of the innate immune system.

PATHOPHYSIOLOGY OF AUTOINFLAMMATORY SYNDROMES
PATHOPHYSIOLOGY OF AUTOINFLAMMATORY SYNDROMES

Clinical Findings: HIDS is inherited in an autosomal recessive fashion. Patients present with fever, arthralgias, abdominal pain, cervical adenopathy, and aphthous ulcers. Skin findings are consistent with a cutaneous vasculitis with palpable purpura and purpuric macules and nodules. Patients develop attacks of these symptoms with some evidence of periodicity. The attacks can last from 3 to 7 days, and typically the first attack occurs within the first year of life. As the child ages, the frequency and the severity of the attacks lessen. No reliable trigger has been found that initiates the attacks, and patients are completely normal between attack episodes.

Sunday, April 11, 2021

BUG BITES

BUG BITES


BUG BITES
Human skin is exposed to the environment on a constant basis and encounters multiple threats, including arthropods of many varieties. Each species of arthropod can inflict its own type of damage to the skin; some bites are mild and barely noticeable, and others can be life-threatening. The most common bites are those of mosquitoes, fleas, bedbugs, mites, ticks, and spiders. Not only can these bites cause direct damage to the skin, but these organisms may have the ability to transmit infectious diseases such as Lyme disease, leishmaniasis, and rickettsial diseases.
BUG BITES


Clinical Findings: Mosquitoes are prominent insects in the spring, summer, and early fall seasons. In warmer climates, they can be seen year round. Their bite is often not noticed until after the mosquito has gone. The recently bitten person is left with a pruritic urticarial papule that typically resolves by itself within an hour or so. Some individuals are prone to severe bite reactions and develop warm, red papules and nodules that can last for a week or two and can be associated with regional lymphadenopathy. Mosquitoes are essentially a nuisance for the most part, but in some areas of the world they are the major vectors for transmission of malaria and encephalitis viruses. Sand flies are similar, but they are the major vector for leishmaniasis.
Pathogen Recognition Receptors Provide The First Line Of Detection For Microbial Antigen

Pathogen Recognition Receptors Provide The First Line Of Detection For Microbial Antigen

Pathogen Recognition Receptors Provide The First Line Of Detection For Microbial Antigen

As we learned in Chapter 1, the innate immune system employs an impressive battery of defense mechanisms that specifically detect the presence of invading microbes, to coordinate a series of rapid responses that deal directly with the invader, while at the same time sowing the seeds for a more specific and long‐lasting adaptive immune response. Over many millennia of co‐evolution, vertebrate immune systems have become impressively adept at accurately identifying the presence of potentially harmful microbes, through the detection of microbial structures that are essential for viability and, therefore, refractive to the pressures of natural selection. These conserved microbial antigens, called pathogen‐associated molecular patterns (PAMPs), are unique to individual classes of microbes, and as such, convey pathogen‐specific information to the innate immune system, to facilitate an appropriate response tailored to the particular threat at hand.
Detection of PAMPs is facilitated by a family of evolutionarily conserved germline‐encoded receptors called pathogen recognition receptors (PRRs), expressed on innate immune cells such as DCs, macrophages, and neutrophils. PAMP detection is often the first indication to the innate immune system of microbial presence and consequently, PAMP‐induced PRR activation rapidly promotes the production of a host of cytokines, chemokines, and type 1 interferons that mobilize innate immune cells to directly confront the invader. Additionally, PRR stimulation acts as a crucial line of communication between the innate and adaptive immune systems by instructing antigen‐presenting cells, such as DCs, to effectively
license a T‐cell‐mediated adaptive immune response against a particular antigen. As will be discussed in later chapters, the particular mode of T‐cell activation is further shaped by PRR‐ induced DC‐derived cytokines, which effectively tailor the T‐ cell‐mediated response to the particular type of microbe. As PRR signaling has also been shown to be important for instructing B‐cells to respond to particular types of microbial antigen, it should be clear that the recognition of microbial PAMP by PRRs plays a crucial role in coordinating both innate and adaptive immune responses to infection.
To date, several different classes of PRRs have been charac­ terized, including Toll‐like receptors (TLRs), NOD‐like receptors (NLRs), RIG‐1‐like receptors (RLRs), DNA receptors, and C‐type lectin‐like receptors, which together sense a wide range of conserved microbial antigen. TLRs are among the best‐characterized PRRs and we will next turn our attention to this important immune receptor family.
TLR family structure, ligand specificity, and signaling mechanism (a) Structures of TLRs bound to ligand and arranged into a phylogenetic tree.
Figure 4.30 TLR family structure, ligand specificity, and signaling mechanism (a) Structures of TLRs bound to ligand and arranged into a phylogenetic tree. The ligands are colored red, and TLRs are blue and green. (b) Overview of LPS recognition by TLR4/MD‐2. LPS binding induces dimerization of the TLR4/MD‐2 complex, which is proposed to enable dimerization of the intracellular TIR domains and recruitment of adapter molecules such as MyD88. Aggregation of the death domains (DD) of MyD88 brings four IRAK4 and four IRAK2 molecules together forming a large tower‐like structure called the “Myddosome.” (Source: Park B.S. et al. (2013) Experimental and Molecular Medicine 45(12), 1–9. Reproduced with permission of Nature Publishing Group.)

Toll‐like receptors detect a wide range of conserved microbial PAMP
Named after a Drosophila protein that was originally discovered as important for embryogenesis and later, as required for anti­fungal immunity, Toll‐like receptors (TLRs) are a key family of mammalian PRRs involved in the detection of a wide variety of PAMPs. To date, 10 TLRs have been described in humans, and 12 have been characterized in mice. TLR1, 2, 4, 5, and 6 are expressed on the cell surface and detect ligands from bacteria, fungi, protozoa, and certain self antigens, whereas expression of TLR3, 7, 8, and 9 are confined to intracellular endocytotic compartments, where they recognize nucleic acids signatures unique to bacteria and viruses (Figure 4.30a).
What antibodies see

What antibodies see


The acquired immune responses mounted by lymphocytes depend upon specific recognition of antigen by the B‐cell receptor (BCR, a transmembrane version of the antibody molecule) or the T‐cell receptor (TCR). Following clonal selection the antigen‐specific lymphocytes undergo proliferation to produce sufficient numbers of effector cells and also to generate memory cells. In the case of B‐cells the main effector cells are the plasma cells that secrete a soluble version of the same antibody that was used as the BCR on the original B‐cell. In the case of T‐cells the effector cells are cytokine‐secreting helper or regulatory cells, or cell‐killing cytotoxic cells.
Introduction
In acquired immunity, specific antigens are recognized by two classes of molecules: (i) antibodies, present either as soluble proteins or as transmembrane molecules on the surface of
B‐cells; and (ii) T‐cell receptors, present as transmembrane molecules on the surface of T‐cells. Antibodies recognize antigens on the outside of pathogens or as soluble material such as toxins, whereas αβ T‐cell receptors recognize peptides in the context of MHC molecules on the surface of host cells. Antibodies can thus be thought of as scanning for foreign material directly whereas T‐cells (particularly cytotoxic T‐cells) are scanning for cells that are infected with pathogens.
 
Complementarity of the antibody combining site and the epitope recognized on the antigen
Figure 5.1 Complementarity of the antibody combining site and the epitope recognized on the antigen. The structure of the complex of the Fab of the antibody pertuzumab and its antigen HER2 is shown. HER2, the human epidermal growth factor receptor, is overexpressed on some breast cancer cells and pertuzumab is an antibody, similar to Herceptin®, with potential as a therapeutic against breast cancer. Below, the two molecules are shown separately with the interaction footprint shown on each. (Source: Robyn Stanfield. Reproduced with permission.)


What antibodies see
Antibodies recognize molecular shapes (epitopes) on antigens. Generally, the better the fit of the epitope (in terms of geometry and chemical character) to the antibody combining site, the more favorable the interactions that will be formed between the antibody and antigen and the higher the affinity of the antibody for antigen. The affinity of the antibody for the antigen is one of the most important factors in determining antibody efficacy in vivo.
OSTEOCHONDRITIS DISSECANS OF THE ELBOW

OSTEOCHONDRITIS DISSECANS OF THE ELBOW


Osteochondritis dissecans typically occurs in adolescent patients from repetitive high valgus stresses to the elbow, most commonly female gymnasts and male throwers. The repetitive valgus loads may create compressive forces across the lateral side of the elbow at the typical site of a pathologic process in the capitellum. It is thought that these forces cause repetitive micro-trauma and vascular insufficiency or injury to the capitellum that can lead to separation of the articular cartilage from the underlying subchondral bone. Genetic factors may also contribute in some cases. The condition occurs after the capitellum has almost completely ossified and involves both the articular cartilage and the underlying bone. If the articular cartilage becomes separated from the subchondral bone, it can become a loose body in the elbow joint.
OSTEOCHONDRITIS DISSECANS OF THE ELBOW

Symptoms include activity-related lateral elbow pain that may improve with rest from the offending activity. The pain may be dull and poorly localized. Mechanical symptoms, such as clicking or locking, may be present if a loose fragment develops. On examination, tenderness to palpation is noted over the capitellum and a joint effusion may be present. Range of motion of the elbow may produce crepitus, and patients commonly lack the terminal 10 to 30 degrees of elbow extension. Limitation of elbow flexion or of forearm pronation and supination may also occur but is less common. Plain radiographs can show lucency or fragmentation at the capitellum and a possible loose body if a fragment has broken off. If findings on plain radiographs are equivocal, advancing imaging (CT or MRI) can confirm the diagnosis. MRI is preferred and can delineate a stable versus unstable lesion by showing intervening fluid between the fragment and subchondral bone.
ROSIS OF THE ELBOW (PANNER DISEASE)

ROSIS OF THE ELBOW (PANNER DISEASE)


Panner disease also involves the capitellum and presents in a similar manner as a capitellar osteochondritis dissecans, but in a younger patient population and with a better long-term prognosis. Panner disease typically occurs in the dominant elbow of boys during the period of active ossification of the capitellar epiphysis at between 7 and 12 years of age, with a peak at age 9 years. 
ROSIS OF THE ELBOW (PANNER DISEASE)

The pathologic process is similar to that of Legg-Calvé-Perthes disease and is believed to be caused by interference in the blood supply to the growing epiphysis, which results in resorption and eventual repair and replacement of the ossification center. The exact cause of this avascular necrosis, or bone infarct, continues to be debated, with popular theories including chronic repetitive trauma, congenital and hereditary factors, embolism (particularly fat), and endocrine disturbances. Whatever factors are responsible, the end result is avascular necrosis. Signs and symptoms are similar to those seen with osteochondritis dissecans, including dull, aching lateral elbow pain that is aggravated by use and may improve with rest. Tenderness and swelling along the lateral side of the elbow with loss of terminal elbow extension are also common. Initial radiographic changes can appear similar to osteochondritis dissecans, with fragmentation of the capitellar epiphysis, but whereas lesions of osteochondritis dissecans can often progress to loose fragments, loose bodies are rare in Panner disease. Typically, the normal radiographic appearance of the capitellum will be reconstituted over time as growth progresses. Residual deformity of the capitellum is rare. MRI will demonstrate signal changes in the capitellar epiphysis but may be less useful than in osteochondritis dissecans owing to the lack of concern for an unstable lesion or a loose body.
CONGENITAL RADIOULNAR SYNOSTOSIS

CONGENITAL RADIOULNAR SYNOSTOSIS


CONGENITAL RADIOULNAR SYNOSTOSIS
Congenital radioulnar synostosis is an uncommon condition in which the proximal ends of the radius and ulna are joined, fixing the forearm in pronation. The deformity is due to a failure of the developing cartilaginous precursors of the forearm to separate during fetal development. Radioulnar synostosis is bilateral in 60% of patients and is frequently associated with other musculoskeletal abnormalities. Chromosomal abnormalities have been reported in some patients with bilateral involvement. Two types of synostosis are seen. In the first, called the headless type, the medullary canals of the radius and ulna are joined and the proximal radius is absent or malformed and fused to the ulna over a distance of several centimeters. The radius is anteriorly bowed and its diaphysis is larger and longer than that of the ulna. In the second type, the fused segment is shorter and the radius is formed normally but the radial head is dislocated anteriorly or posteriorly and fused to the diaphysis of the proximal ulna. The second type is often unilateral and sometimes associated with deformities such as syndactyly or supernumerary thumbs.
CONGENITAL RADIOULNAR SYNOSTOSIS

Radioulnar synostosis is present at birth but is usually not noticed until functional problems arise, most often in patients with bilateral involvement. Commonly, the only clinical finding is lack of rotation between the radius and the ulna, which fixes the forearm in a position of midpronation or hyperpronation. Range of motion in the elbow and wrist joints is usually normal or excessive, although some patients cannot completely extend the elbow. The degree of functional disability varies with the amount of fixed pronation and whether the condition is unilateral or bilateral. Unilateral deformity with less fixed pronation may be able to compensate with shoulder motion. However, in patients with bilateral involvement in which both hands are hyperpronated, many daily activities become problem- atic, such as turning a doorknob, buttoning clothing, drinking from a cup or eating, and personal hygiene.

Thursday, April 8, 2021

Immunology In The Laboratory

Immunology In The Laboratory


Immunology In The Laboratory
The ability to measure accurately and sensitively different aspects of immunological function is an important part of both experimental and clinical immunology (see Chapter 44). Some of the most commonly used techniques in the immunological laboratory (immunological assays) are shown in the figure. Some techniques, such as the differential blood count, have hardly changed in over a hundred years. Others, such as flow cytometry and the PCR continue to evolve at a rapid rate as new technologies are developed. In all cases, clinical laboratories are making increased use of robotics and sophisticated computational analysis to automate all aspects of the process, to make it faster, cheaper and more reliable. The ability to integrate many different measurements (immunological, haematological, psychological, genetic, etc.) taken from each patient rapidly and reliably is also driving the development of ‘personalized medicine’, where doctors will be increasingly able to tailor each treatment precisely to match the needs of individual patients.

Immunology In The Laboratory

Flow cytometry (Fig. 45.1–45.3) is one of the most powerful techniques in the immunologist’s repertoire. Cells are sucked into a fine jet of liquid so that they pass rapidly across a beam of one or, in more sophisticated machines, several lasers. Cells scatter the incoming beam of light by refraction and reflection. Light scattered through a small angle is called ‘forward scatter’ and is proportional to the size of the cells. Light scattered through a 90° angle is called ‘side scatter’ and depends on the granularity of the cell; e.g. a granulocyte has a much larger side scatter than a lymphocyte (see Fig. 45.1).
Investigating Immunity

Investigating Immunity


Investigating Immunity
As most of the cells and molecules of the immune system spend some or all of their time in the blood, sampling them is usually straightforward, and the standard tests illustrated here account for a substantial part of the routine work of the immunology and haematology laboratories, and often of microbiology and biochemistry too. The assays are mainly automated and a report will usually give the normal values and indicate which results are abnormal. Nevertheless, because of the considerable differences between individuals, and in the same individual with time, interpretation is not always obvious, even to those well versed in other aspects of medicine. The interpretation of tests for autoimmunity is particularly tricky.

Investigating Immunity

Assays of both immunological molecules (e.g. antibody) and cells mainly make use of standard reagents, which are themselves frequently monoclonal antibodies, designed to react with only one molecular feature or cell-surface marker. The use of antibodies, whether monoclonal or not, to detect antigens of any kind is referred to as immunoassay (see Fig. 45). For detection, antibodies may be labelled with a radio-isotope (radioimmunoassay), an enzyme (ELISA) or a fluorescent molecule (immunofluorescence).
Transplant Rejection

Transplant Rejection


Transplant Rejection
The success of organ grafts between identical (‘syngeneic’*) twins, and their rejection in all other cases, reflects the remarkable strength of immunological recognition of cell-surface antigens within a species. This is an unfortunate (and in the evolutionary sense unforeseeable) result of the specialization of T cells for detecting alterations of MHC antigens, upon which all adaptive responses depend (for a reminder of the central role of T-helper cells see Figs 19 and 21), plus the enormous degree of MHC polymorphism (different antigens in different individuals; see Fig. 11). It appears that when confronted with ‘non- self’ MHC molecules, T cells confuse them with ‘self plus antigen’, and in most cases probably ‘self plus virus’; several clear examples of this have already been found in mouse experiments. This may be one of the reasons for MHC polymorphism itself: the more different varieties of ‘self’ a species contains, the less likely is any particular virus to pass undetected and decimate the whole species. Differences in red cell (‘blood group’) antigens also give trouble in blood transfusion (top right) because of antibody; here the rationale for polymorphism is less obvious, but it is much more restricted (e.g. six ABO phenotypes compared with over 1012 for MHC). The ‘minor’ histocompatibility and blood group antigens appear to be both less polymorphic and antigenically weaker.

Transplant Rejection

Graft rejection can be mediated by T and/or B cells, with their usual non-specific effector adjuncts (complement, cytotoxic cells, macrophages, etc.), depending on the target: antibody destroys cells free in the blood, and reacts with vascular endothelium (e.g. of a grafted organ; centre) to initiate type II or III hypersensitivity, while T cells attack solid tissue directly or via macrophages (type IV). Unless the recipient is already sensitized to donor antigens, these processes do not take effect for a week or more, confirming that rejection is due to adaptive, not innate, immunity.
Antimicrobial Immunity: A General Scheme

Antimicrobial Immunity: A General Scheme


Antimicrobial Immunity: A General Scheme
At this point the reader will appreciate that the immune system is highly efficient at recognizing foreign substances by their shape but has no infallible way of distinguishing whether they are dangerous (‘pathogenic’). By and large, this approach works well to control infection, but it does have its unfortunate side, e.g. the violent immune response against foreign but harmless structures such as pollen grains, etc. (see Fig. 35).

Antimicrobial Immunity: A General Scheme

Would-be parasitic microorganisms that penetrate the barriers of skin or mucous membranes (top) have to run the gauntlet of four main recognition systems: complement (top right), phagocytic cells (centre), antibody (right) and cell-mediated immunity (bottom), together with their often interacting effector mechanisms. Unless primed by previous contact with the appropriate antigen, antibody and cell-mediated (adaptive) responses do not come into action for several days, whereas complement and phagocytic cells (innate), being ever present, act within minutes. There are also (top centre) specialized innate elements, such as lysozyme, interferons, etc., which act more or less non-specifically, much as antibiotics do. Innate molecules that have evolved to block virus infection are sometimes called restriction factors.

Saturday, April 3, 2021

Motor Control And The Cerebellum

Motor Control And The Cerebellum

Motor Control And The Cerebellum
Motor control
Motor control is defined as the control of movements by the body. These movements can be both influenced and guided by the many sensory inputs that are received, or can be triggered by sensory events. They can also be triggered by the need to move using internal mechanisms. The major division of the body into sensory and motor functions is artificial, because almost all motor areas in the central nervous system (CNS) receive sensory inputs.
The organization and physiology of motor systems have been represented as a number of hierarchical structures, but these must be viewed with caution, as they are again artificial and, by necessity, oversimplified.
Motor Control And The Cerebellum
        Figure 59a shows the major ascending sensory inputs and descending motor outputs, and Figure 59b shows the main looped pathways within the CNS.
Fertilization, Pregnancy And Parturition

Fertilization, Pregnancy And Parturition


Fertilization, Pregnancy And Parturition
Fertilization
The unfertilized ovum can survive for up to 24 h after ovulation, and sperm remain viable in the uterus for up to 5 days after ejaculation. The environment of the female tract triggers the capacitation of sperm. This is a prerequisite for fertilization that involves remodelling of the lipids and glycoproteins of the sperm plasma membrane, coupled with increased metabolism and motility. The ovum is surrounded by the zona pellucida, an acellular membrane bearing the glycoprotein ZP3 that acts as a sperm receptor. Fertilization occurs in the oviduct, when a single capacitated sperm binds to ZP3 and under-goes the acrosome reaction. The acrosome is a body containing proteolytic enzymes that is attached to the sperm head (Fig. 52a). When a sperm binds to ZP3, the acrosomal enzymes are released to digest a pathway for the sperm to penetrate the ovum, within which the contents of the sperm head, including its genetic material, are deposited. This event leads to a chain of reactions that denies access to further sperm penetration. The ovum first undergoes electrical depolarization and then discharges granules that impair further sperm binding at the zona pellucida (the cortical reaction). In this way, fertilization is normally restricted to one sperm per ovum. Some 2–3 h after penetrating the ovum, the sperm head forms the male pronucleus which joins with the female pronucleus from the ovum (Fig. 52a). Fusion of the pronuclei combines the parental genetic material from the gametes to form the zygote.

Fertilization, Pregnancy And Parturition

Pregnancy
The zygote is propelled by cilia and muscular contractions of the Fal-lopian tube into the uterus, where it implants in the endometrium. During this journey, the zygote undergoes a number of cell divisions to form the morula, a solid ball of 16 cells that ‘hatches’ from the zona pellucida and develops into the blastocyst, in which embryonic cells are surrounded by trophoblasts (Fig. 52a). The trophoblasts are responsible for implantation, digesting away the uterine endometrial wall to form a space for the embryo, opening up a pathway to the maternal circulation (via the spiral arteries of the uterus) and forming the fetal portion of the placenta. The tissue engineering activities of trophoblasts are mediated by epidermal growth factor (EGF) (Chapter 46) and interleukin-1β. Implantation is complete within 7–10 days of fertilization, at which time the embryo and early placenta begin to secrete human chorionic gonadotrophin (hCG). The appearance of hCG in the plasma and urine is one of the earliest signs of successful conception, and its detection forms the basis of pregnancy testing kits. hCG is a glycoprotein similar to LH that stimulates progesterone secretion from the corpus luteum. Progesterone levels rise steadily throughout pregnancy and fall sharply at term (Fig. 52b). This steroid ensures that the smooth muscle of the uterus remains quiescent during gestation (essential for a successful pregnancy), stimulates mammary gland development and prepares the maternal brain for motherhood. The  placenta  also  secretes  chorionic  somatomammotrophin,  a growth hormone-like protein that mobilizes metabolic fuels (Chapter 43) and promotes mammary gland growth, and oestrogen (mainly oestriol) that stimulates uterine expansion to accommodate the growing fetus. Fetal development occurs within a fluid-filled sac, known as the amniotic membrane, which provides a protective buffer against physical trauma. Pregnancy makes many physiological demands on the mother. The ventilation rate, cardiac output and plasma volume increase to supply fetal–maternal oxygen and water demands; the gastrointestinal absorption of minerals is enhanced; and the renal glomerular filtration rate (Chapter 32) rises to cope with fetal waste production.
Endocrine Control Of Reproduction

Endocrine Control Of Reproduction


Endocrine Control Of Reproduction
Reproductive function in males and females is controlled by common hormonal systems based on the hypothalamic control of the pituitary gonadotrophins, individually known as luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These glycoproteins are released from the gonadotrophs of the anterior pituitary gland under the influence of gonadotrophin-releasing hormone (GnRH; Chapter
44) (Fig. 50a,b). Failure of GnRH release is one cause of infertility. It is released in pulses at intervals of 1–3 h in both males and females, a pattern that is accurately reflected in plasma levels of LH. The pulsatile pattern of GnRH secretion is essential for normal reproductive activity, as continuous exposure of gonadotrophs to the hormone leads to a rapid desensitization of the gonadotrophs and a reduction in the release of gonadotrophins. The releasing hormone acts through receptors coupled to Gq (Chapter 3) to stimulate the release and manufacture of the gonadotrophins.

Endocrine Control Of Reproduction

Actions of gonadotrophins
The gonadotrophins produce their effects via interactions with guanosine triphosphate-binding protein (G-protein)-coupled receptors that activate the intracellular production of cyclic adenosine monophosphate (cAMP) (Chapter 3). In the male, LH acts on the Leydig cells of the testes to stimulate the production of the steroid testosterone, which acts in concert with FSH on Sertoli cells of the seminiferous tubules to support spermatogenesis (Fig. 50a). Sperm are generated in a two-stage meiosis from spermatocytes via spermatids. Spermatogenesis proceeds most efficiently at a temperature of 34 °C, which is why the testes are located outside the body cavity. A normal adult male produces some 2 × 108 sperm per day, a process that carries on from puberty until the end of life. Sertoli cells also produce inhibin, a peptide feedback signal that specifically inhibits the release of FSH from the anterior pituitary.
The Adrenal Glands And Stress

The Adrenal Glands And Stress


The Adrenal Glands And Stress
The adrenal glands are located just above each kidney (hence the name; Fig. 49a) and consist of two endocrine tissues of distinct developmental origins. The inner core (the adrenal medulla) releases the catecholamine hormones adrenaline (epinephrine) and noradrenaline (norepinephrine). It develops from neuronal tissue and is functionally part of the sympathetic nervous system (Chapter 7). The outer layers of the gland (the adrenal cortex) originate from mesodermal tissue and secrete steroid hormones, primarily under the control of the anterior pituitary gland (Chapter 44). Removal of the adrenal glands in animals results in death within a few days, which is thought to result from the loss of the ability to cope with stress.

The Adrenal Glands And Stress

The adrenal medulla
The chromaffin cells of the adrenal medulla manufacture and secrete noradrenaline (20%) and adrenaline (80%). These catecholamine hormones are derived from tyrosine by a series of steps catalysed by specific enzymes (Fig. 49b). The production of the rate-limiting enzyme, phenylethanolamine-N-methyl transferase, is stimulated by cortisol, providing a direct link between the functioning of the medulla and cortex. The secretion of catecholamines is stimulated by sympathetic preganglionic neurones located in the spinal cord (Chapter 7), so that the adrenal medulla functions in concert with the sympathetic nervous system, of which noradrenaline is the main neurotransmitter. Catecholamine release contributes to normal physiological functions, but is enhanced by stress (see below). Adrenaline and noradrenaline act through guanosine triphosphate-binding protein (G-protein)-coupled adrenoceptors. These are classified as α1, α2 and β1–β3. The hormones have the same effects in tissues as the stimulation of sympathetic nerves, with important stress-related responses being vasoconstriction (α1), increased cardiac output (β1) and increased glycolysis and lipolysis (β2, β3). These actions support increased physical activity. Noradrenaline has equal potency at all adrenoceptors, but adrenaline, at normal plasma concentrations, will only activate β-receptors (NB: higher levels do stimulate α-receptors). Phaeochromocytoma is a tumour of the adrenal medulla that leads to the excess production of catecholamines, with high blood pressure as the most immediately threatening symptom. It is treated by α-adrenoceptor antagonists and/or surgery.
Thyroid Hormones And Metabolic Rate

Thyroid Hormones And Metabolic Rate


Thyroid Hormones And Metabolic Rate
The thyroid gland is attached to the anterior surface of the trachea just below the larynx. It releases two iodine-containing hormones, thyroxine (also known as T4) and tri-iodothyronine (T3; Fig. 45a), the main effect of which is to increase heat production (thermogenesis) throughout the body and thereby induce an increase in metabolic rate. The hormones also have a crucial role in growth and development.
Thyroid Hormones And Metabolic Rate

Synthesis and release
The thyroid gland is formed from clusters of cells (follicles) that surround a gel-like matrix or colloid, the primary constituent of which is the glycoprotein thyroglobulin. The follicle cells actively accumulate iodide (I−) ions by means of an Na+–I− symporter (Chapter 4) driven by the inward sodium gradient (Fig. 45b). The formation of T3 and T4 occurs in two steps: (i) the amino acid tyrosine is iodinated to form mono- (T1) or di-iodotyrosine (T2) (Fig. 45a); (ii) T2 is then coupled to T1 or T2 by thyroperoxidase to form the thyroid hormones. This process occurs with the tyrosine residues attached to thyroglobulin, so that, at any one time, this protein is festooned with molecules of T1, T2, T3 and T4 (Fig. 45b). The thyroid hormones and their intermediates are highly lipophilic and would escape from the gland were they not incorporated into thyroglobulin, which thus acts as a nucleus for the manufacture of the hormones and as a storage site. The hormones are released under the control of thyroid-stimulating hormone (TSH) from the anterior pituitary, which is obligatory for normal thyroid function (Chapter 44; Fig. 45c). Under the action of TSH, thyroid follicle cells pinch off small quantities of colloid by pinocytosis. Lysozymal protease enzymes then act on the thyroglobulin to liberate the iodinated compounds into the cell and thence into the bloodstream (Fig. 45b). Free T1  and T2 are deiodinated by enzymatic action before they can leave the cell. The average plasma concentration of T3 is roughly one-sixth of that of T4, and much of that derives from deiodinated T4. Most of the thyroid hormones in the blood are bound to thyroxine-binding protein and are thus unavailable to their receptors, which are located inside target cells, attached directly to deoxyribonucleic acid (DNA). The small amounts of free T3 and T4 in plasma readily cross the cell membranes to bind to thyroid hormone receptors (the most important of which is TRa1). Thyroid receptors are linked to a DNA sequence known as the thyroid-response element (TRE) which initiates the transcription of thyroid-responsive genes. T3 is some 10 times more potent than T4 in activating TRα1 and consequently mediates most thyroid hormone actions, notwithstanding its lower levels in plasma. Thyroid receptors are present in almost all tissues, with particularly high levels in the liver and low levels in the spleen and testes.
Endocrine Control

Endocrine Control


Endocrine Control
Multicellular organisms must coordinate the diverse activities of their cells, often over large distances. In animals, such coordination is achieved by the nervous and endocrine systems, the former providing rapid, precise but short-term control and the latter providing generally slower and more sustained signals. The two systems are intimately integrated and in some places difficult to differentiate. Endocrine control is mediated by hormones, signal molecules usually secreted in low concentrations (10−12–10−7 m) into the bloodstream, so that they can reach all parts of the body. Other types of chemical communication are mediated over smaller distances. Chemical signals can act locally on neighbouring cells (paracrine signals) or can act on the same cell that produced the signal (autocrine signals); juxtacrine communication requires direct physical contact between signal chemicals on the surface of one cell and receptor molecules on the surface of a neighbour. Many hormones are secreted by discrete glands (Table 42), while others are released from tissues with other primary functions. For instance, several of the cytokines released by immune cells (Chapter 10) act at some distance from their site of release and can fairly be considered as hormones.
Endocrine Control

Endocrine Control

Features of hormonal signalling
Hormonal molecules can be: (i) modified amino acids [e.g. adrenaline (norepinephrine); Chapter 49]; (ii) peptides (e.g. somatostatin; Chapter 44); (iii) proteins (e.g. insulin; Chapter 43); or (iv) derivatives of the fatty acid cholesterol, such as steroids (e.g. cortisol; Chapter 49; Table 42). Protein and peptide hormones are cleaved from larger gene products, whereas smaller molecules require the precursor to be transported into endocrine cells so that it can be modified by sequences of enzymes to generate the final product (e.g. Chapter 49). Most hormones are stored in intracellular membrane-bound secretory granules, to be released by a calcium-dependent mechanism similar to the release of neurotransmitters from nerve cells (Chapter 7; Fig. 43b) when the cell is activated. However, thyroid hormones and steroids, which are highly lipid soluble, cannot be stored in this way. Most steroids are made immediately before release, whereas the thyroid hormones are bound within a glycoprotein matrix (Chapter 45). After secretion, some hormones bind to plasma proteins. In most cases this involves non-pecific binding to albumin, but there are specific binding proteins for some hormones, such as cortisol or testosterone. A hormone bound to a plasma protein cannot reach its site of action and is protected from metabolic degradation, but is freed when the plasma level of the hormone falls. The bound fraction thus acts as a reservoir that helps to maintain steady plasma levels of the free hormone.

Thursday, April 1, 2021

Special Senses: Vision

Special Senses: Vision

Special Senses: Vision
Vision in humans involves the detection of a very narrow band of light ranging from about 400 to 750 nm in wavelength. The shortest wave-lengths are perceived as blue and the longest as red. The eye contains photoreceptors that detect light, but, before the light hits the receptors responsible for this detection, it has to be focused onto the retina (200 μm thick) by the cornea and the lens (Fig. 57a).

Special Senses: Vision


The photoreceptors can be divided into two distinct types called rods and cones. Rods respond to dim light and cones respond in brighter conditions and can distinguish red, green or blue light. The rods and cones are found in the deepest part of the retina, and light has to travel through a number of cellular layers to reach these photoreceptors. Each photoreceptor contains molecules of the visual pigments (rods: rhodopsin; cones: erythrolabe (red), chlorolabe (green) and cyanolabe (blue)); these absorb light and trigger receptor potentials which, unlike other receptor systems, lead to a hyperpolarization of the cell and not depolarization.
Special Senses: Hearing And Balance

Special Senses: Hearing And Balance

Special Senses: Hearing And Balance
Hearing
The young healthy human can detect sound wave frequencies of between 40 Hz and 20 kHz, but the upper frequency limit declines with age. When sound waves reach the ear, they pass down the external auditory meatus (the external ear) to the tympanic membrane that vibrates at a frequency and strength determined by the magnitude and pitch of the sound. The vibration of the membrane causes three ear ossicles (malleus, incus and stapes) in the middle ear (an air-filled cavity) to move, which, in turn, displaces fluid within the cochlea (the inner ear) as the foot of the stapes moves the oval window at the base of the cochlea. This mechanical link prevents the incoming sound energy from being reflected back, and the ossicles improve the efficiency with which the sound energy is transferred from the air to the fluid. Small muscles are attached to the ossicles and contract reflexly in response to loud sounds, thereby dampening the vibration and attenuating the transmission of the sound (Fig. 58a).


Special Senses: Hearing And Balance

The inner ear includes the cochlea and also the vestibular organs responsible for balance (see later). The receptors involved in both hearing and balance are specialized mechanoreceptors called hair cells. Projecting from the apical surface of the hair cell is a bundle of over 100 small hair-like structures called stereocilia and a larger stere- ocilium called the kinocilium. Deflection of the stereocilia towards the kinocilium leads to a potential change in the cell (depolarization), the release of a transmitter substance from the base of the hair cell, and activation of the nerve fibres that convey impulses to the higher centres of the brain.
Sensory Receptors

Sensory Receptors

Sensory Receptors
The sensory receptor is a specialized cell. In mammals, receptors fall into five groups: mechanoreceptors, thermoreceptors, nociceptors, chemoreceptors (Chapter 56) and photoreceptors (Chapter 57). There is further specialization within these groups. Each receptor responds to one stimulus type; this property is called the specificity of the receptor. The stimulus that is effective in eliciting a response is called the adequate stimulus.
Transduction processes. Some receptors consist of a nerve fibre alone (e.g. free nerve endings), others consist of a specialized accessory structure (e.g. olfactory receptors, Pacinian corpuscles), and others are more complex and consist of a specialized receptor cell which synapses with a neurone, in other words a secondary sensory cell (e.g. gustatory receptors and Merkel’s discs).
Sensory Receptors

Mechanoreceptors. These are found all over the body. Those in the skin have three main qualities: pressure, touch and vibration (or acceleration) (Fig. 55a,b). When the responses to constant stimuli are studied in the various receptors, the receptors can be divided into three types on the basis of their adaptive properties: slowly adapting receptors that continue to fire action potentials even when the pressure is maintained for a long period (e.g. Ruffini’s endings, tactile discs, Merkel’s discs); moderately rapidly adapting receptors that fire for about 50–500 ms after the onset of the stimulus, even when the pressure is maintained (e.g. hair follicle receptors, Meissner’s corpuscles); and very rapidly adapting receptors that fire only one or two impulses (e.g. Pacinian corpuscles) (Fig. 55b). These three types of receptor are examples of receptors in the skin that detect intensity, velocity and vibration (or acceleration), respectively.

ANATOMY PHYSIOLOGY

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