Cindy L. OﾒBryant, PharmD, BCOP

• Associate Professor, Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
• Clinical Pharmacy Specialist, University of Colorado Cancer Center, Aurora, Colorado

http://www.ucdenver.edu/academics/colleges/pharmacy/Departments/ClinicalPharmacy/DOCPFaculty/H-P/Pages/OBryantCindyPharmD.aspx

Recall that the usual components of a reflex pathway include sensory receptors, afferent pathways, integrating centers in the central nervous system, efferent pathways, and effector organs pain treatment in pancreatitis buy cheap rizatriptan online. Their spontaneous activity is modulated by inputs from adjacent centers in the brainstem pacific pain treatment center victoria bc rizatriptan 10 mg order online. The neural interconnections between the diffuse structures in this area are complex and not completely mapped anterior knee pain treatment exercises cheap rizatriptan online mastercard. Moreover, these structures appear to serve multiple functions including respiratory control midsouth pain treatment center reviews discount rizatriptan 10 mg. What is known with a fair degree of certainty is where the cardiovascular afferent and efferent pathways enter and leave the medulla canadian pain treatment guidelines order rizatriptan with amex. The cell bodies of the efferent vagal parasympathetic cardiac nerves are located primarily in the medullary nucleus ambiguus. The sympathetic autonomic efferent information leaves the medulla predominantly from the rostral ventrolateral medulla group of neurons (via an excitatory spinal pathway) or the raphe nucleus (via an inhibitory spinal pathway). The intermediate processes involved in the actual integration of the sensory information into appropriate sympathetic and parasympathetic responses are not well understood. Much of this integration takes place within the medulla, but higher centers such as the hypothalamus are probably involved as well. In this context, knowing the details of the integration process is not as important as appreciating the overall effects that changes in arterial baroreceptor activity have on the activities of parasympathetic and sympathetic cardiovascular nerves. Because the arterial baroreceptors are active at normal arterial pressures, they supply a tonic input to the central integration centers. Thus, an increase in the arterial baroreceptor discharge rate (caused by increased arterial pressure) causes a decrease in the tonic activity of cardiovascular sympathetic nerves and a simultaneous increase in the tonic activity of cardiac parasympathetic nerves. Conversely, decreased arterial pressure causes increased sympathetic and decreased parasympathetic activity. Afferent Pathways Sensory receptors, called arterial baroreceptors, are found in abundance in the walls of the aorta and carotid arteries. Major concentrations of these receptors are found near the arch of the aorta (the aortic baroreceptors) and at the bifurcation of the common carotid artery into the internal and external carotid arteries on either side of the neck (the carotid sinus baroreceptors). The receptors are mechanoreceptors that sense arterial pressure indirectly from the degree of stretch of the elastic arterial walls. Baroreceptors actually sense not only absolute stretch, but also the rate of change of stretch. The dashed curve shows how baroreceptor firing rate is affected by different levels of a steady arterial pressure. The solid curve indicates how baroreceptor firing rate is affected by the mean value of a pulsatile arterial pressure. Note that the presence of pulsations increases the baroreceptor firing rate at any given level of mean arterial pressure. Note also that changes in mean arterial pressure near the normal value of 100 mm Hg produce the largest changes in baroreceptor discharge rate and there is very little output at low pressures. If arterial pressure remains above normal over a period of several days, the arterial baroreceptor firing rate will gradually return toward normal. Thus, arterial baroreceptors are said to adapt to long-term changes in arterial pressure. For this reason, the arterial baroreceptor reflex does not serve as a mechanism for the long-term regulation of arterial pressure. The arterial baroreceptor reflex mechanism acts to regulate arterial pressure in a negative feedback fashion as was described in Chapter 1. Recall that neural control of vessels is more important in some areas such as the kidney, the skin, and the splanchnic organs than in the brain and heart muscle. Thus, the reflex response to a decrease in arterial pressure may, for example, include a significant increase in renal vascular resistance and a decrease in renal blood flow without changing the cerebral vascular resistance or blood flow. The peripheral vascular adjustments associated with the arterial baroreceptor reflex take place primarily in organs with strong sympathetic vascular control. These reactions are caused by influences on the medullary cardiovascular centers other than those from the arterial baroreceptors. An analogy was made between the arterial baroreceptor reflex operating to control arterial pressure to a home heating system acting to control room temperature (see Chapter 1). The temperature setting on the thermostat determines the set point for temperature regulation. The role of these cardiopulmonary receptors in the control of the cardiovascular system is, in most cases, incompletely understood, but they are likely involved in many physiological and pathological states. Cardiopulmonary baroreceptors (sometimes referred to as low-pressure receptors) sense the pressure (or volume) in the atria and central venous pool. Increased central venous pressure (or volume) causes activation of these receptors by stretch, and elicits a reflex decrease in sympathetic activity. These cardiopulmonary baroreflexes normally exert a tonic inhibitory influence on sympathetic activity. Alterations in sympathetic activity evoked by increases or decreases in central venous pressure not only have short-term influences on arterial pressure, but also influence renal mechanisms that influence blood volume and long-term regulation of arterial pressure. However, if cerebral blood flow is severely inadequate for several minutes, the cerebral ischemic response wanes and is replaced by marked loss of sympathetic activity. This results when function of the nerve cells in the cardiovascular centers becomes directly depressed by the unfavorable chemical conditions in the cerebrospinal fluid. It can cause mean arterial pressures of more than 200 mm Hg in severe cases of increased intracranial pressure. The benefit of the Cushing reflex is that it prevents collapse of cranial vessels and thus preserves adequate brain blood flow in the face of large increases in intracranial pressure. The mechanisms responsible for the Cushing reflex are not known but could involve the central chemoreceptors. A hallmark of the Cushing reflex is acutely increased arterial pressure in spite of accompanying bradycardia. These responses originate in the cerebral cortex and reach the medullary cardiovascular centers through corticohypothalamic pathways. The blushing response involves a loss of sympathetic vasoconstrictor activity only to particular cutaneous vessels, and this produces the blushing by allowing engorgement of the cutaneous venous sinuses. Excitement or a sense of danger often elicits a complex behavioral pattern called the alerting reaction (also called the "defense" or "fight-or-flight" response). The alerting reaction involves a host of responses such as pupillary dilation and increased skeletal muscle tenseness that are generally appropriate preparations for some form of intense physical activity. The cardiovascular component of the alerting reaction is an increase in blood pressure caused by a general increase in cardiovascular sympathetic nervous activity and a decrease in cardiac parasympathetic activity. Some individuals respond to situations of extreme stress by fainting, a situation referred to clinically as vasovagal syncope. The loss of consciousness is due to decreased cerebral blood flow that is itself produced by a sudden dramatic loss of arterial blood pressure that occurs as a result of a sudden loss of sympathetic tone and a simultaneous large increase in parasympathetic tone and decrease in heart rate. These responses appear to be a result of increased activity of arterial chemoreceptors, located in the carotid arteries and the arch of the aorta, and central chemoreceptors, located within the central nervous system. Chemoreceptors probably play little role in the normal regulation of arterial pressure because arterial blood Po2 and Pco2 are normally held very nearly constant by respiratory control mechanisms. An extremely strong reaction called the cerebral ischemic response is triggered by inadequate blood flow (ischemia) to the brain and can produce a more intense sympathetic vasoconstriction and cardiac stimulation than is elicited by any other influence on the cardiovascular control centers. The concept is that the same cortical drives that initiate somatomotor (skeletal muscle) activity also simultaneously initiate cardiovascular (and respiratory) adjustments appropriate to support that activity. Generally, superficial or cutaneous pain causes an increase in blood pressure in a manner similar to that associated with the alerting response and perhaps over many of the same pathways. Deep pain from receptors in the viscera or joints, however, often causes a cardiovascular response similar to that which accompanies vasovagal syncope, that is, decreased sympathetic tone, increased parasympathetic tone, and a significant decrease in blood pressure. First is the fact that the baroreceptor reflex, however well it counteracts temporary disturbances in arterial pressure, cannot effectively regulate arterial pressure in the long term for the simple reason that the baroreceptor firing rate adapts to prolonged changes in arterial pressure. The second pertinent fact is that circulating blood volume can influence arterial pressure because: blood volume peripheral venous pressure right shift of venous function curve central venous pressure cardiac output arterial pressure. Arterial pressure has a profound influence on urinary output rate and thus affects total body fluid volume. Because blood volume is one of the components of the total body fluid, blood volume alterations accompany changes in total body fluid volume. The mechanisms are such that a decrease in arterial pressure causes a decrease in urinary output rate and thus an increase in blood volume. But, as outlined in the preceding sequence, increased blood volume tends to increase arterial pressure. Thus, the complete sequence of events that are initiated by a decrease in arterial pressure can be listed as follows: Arterial pressure (disturbance) urinary output rate fluid volume blood volume cardiac output arterial pressure (compensation). Whereas the arterial baroreceptor reflex is very quick to counteract disturbances in arterial pressure, hours or even days may be required before a change in urinary output rate produces a significant accumulation or loss of total body fluid volume. What this fluid volume mechanism lacks in speed, however, it more than makes up for in persistence. As long as there is any inequality between the fluid intake rate and the urinary output rate, body fluid volume is changing and this fluid volume mechanism has not completed its adjustment of arterial pressure. The fluid volume mechanism is in equilibrium only when the urinary output rate equals the fluid intake rate. The processes that regulate thirst are not well understood but seem to involve many of the same factors that influence urinary output. The arterial baroreceptor reflex is, of course, essential for counteracting rapid changes in arterial pressure. The fluid volume mechanism, however, determines the long-term level of arterial pressure because it slowly overwhelms all other influences. In a steady state, urine output (plus fluid lost from the body by other means) is equal to fluid intake (point N in this figure). At arterial pressures below point N, fluid intake exceeds urinary output and bodily fluid volume will necessarily be increasing. At present, he has no specific complaints about health conditions, but admits to not getting as much exercise as he did while in his twenties. His father had a mild heart attack at 50 years of age, received a coronary artery stent, and has been treated for hypertension for the 15 years since that time. He is 511 (180 cm), 240 lb (109 kg), and has a heart rate of 64 beats/min and an arterial pressure of 150/92 mm Hg. He has access to blood pressure monitoring equipment at home and was instructed to monitor his blood pressure daily for 1 week and to report his results to the doctor. Systemic hypertension is defined as a chronic increase in mean systemic arterial pressure above 140/90 mm Hg. It is an extremely common cardiovascular problem, affecting more than 20% of the adult population of the Western world. It has been established that hypertension increases the risk of coronary artery disease, myocardial infarction, heart failure, stroke, and many other serious cardiovascular problems. In approximately 90% of cases, the primary abnormality that produces high blood pressure is unknown. Structural changes in the left heart and arterial vessels occur in response to hypertension. Early alterations include hypertrophy of muscle cells and thickening of the walls of the ventricle and resistance vessels. Late changes associated with deterioration of function include increases in connective tissue and increased tissue stiffness. The established phase of hypertension is associated with increased total peripheral resistance. Cardiac output and/or blood volume may be increased during the early developmental phase, but are usually normal after the hypertension is established. The increased total peripheral resistance associated with established hypertension may be due to microvessel rarefaction (decrease in density), pronounced structural adaptations of the peripheral vascular bed, increased basal vascular smooth muscle tone, increased sensitivity and reactivity of the vascular smooth muscle cells to external vasoconstrictor stimuli, and/or diminished production and/or effect of endogenous vasodilator substances. Chronic hypertension is not due to a sustained increase in sympathetic vasoconstrictor neural discharge nor is it due to a sustained increase of any blood-borne vasoconstrictive factor. Disturbances in renal function contribute importantly to the development and maintenance of primary hypertension. Recall that, in the long term, arterial pressure can stabilize only at the level that makes urinary output rate equal to fluid intake rate. Higher-than-normal arterial pressure is required to produce a normal urinary output rate in a hypertensive individual. With a normal fluid intake rate, this untreated hypertensive patient retains fluid to ultimately stabilize at point A (mean arterial pressure = 150 mm Hg). Baroreceptors adapt within days so that they will have a normal discharge rate at the prevailing average arterial pressure. Thus, once the hypertensive individual has been at point A for a week or more, even the baroreceptor mechanism will begin resisting acute changes from the 150-mm Hg pressure level. In certain hypertensive individuals, dietary salt restriction produces a substantial reduction in blood pressure because of the reduced requirement for water retention to osmotically balance the salt load. The arterial pressure of a normal individual, for example, is affected only slightly by changes in salt intake because the normal renal function curve is so steep. A second common treatment of hypertension is diuretic therapy (see Chapters 44 and 46). The net effect of diuretic therapy is that the urinary output rate for a given arterial pressure is increased, that is, diuretic therapy shifts the renal function curve upward. Alterations in lifestyle, including reduction of stress, decreases in caloric intake, limitation of the amount of saturated fats in the diet, and establishment of a regular exercise program, may also help reduce blood pressure in certain individuals. The arterial baroreceptor reflex involves the following: pressure sensing by stretch-sensitive baroreceptor nerve endings in the walls of arteries, neural integrating centers in the brainstem that adjust autonomic nerve activity in response to the pressure information they receive from the arterial baroreceptors, and responses of the heart and vessels to changes in autonomic nerve activity. Overall, the arterial baroreflex operates such that increases in arterial pressure lead to an essentially immediate decrease in sympathetic nerve activity and a simultaneous increase in parasympathetic nerve activity (and vice versa). The brainstem integrating centers also receive nonarterial baroreceptor inputs that can raise or lower the set point for short-term arterial pressure regulation.

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This probably explains the higher efficacy of this treatment, albeit at the cost of increased therapy-related toxicity a better life pain treatment center flagstaff az purchase 10 mg rizatriptan visa. The regimen was generally well tolerated, although significant myelosuppression occurred, and rest periods of weeks to months were intermittently required to allow marrow recovery pain medication safe dogs buy 10 mg rizatriptan with visa. In this study, neither the spleen size nor the degree of marrow involvement was predictive of response, although others have observed a correlation between spleen size and the improvement in blood counts after splenectomy pain treatment center franklin tn proven 10 mg rizatriptan. In addition, more individuals may now be candidates for this procedure as laparoscopic splenectomies become routine pain treatment ms best order rizatriptan. Although almost all patients experience a reduction in spleen size and relief from pain with irradiation, the effects on hemoglobin and platelets are more variable over the counter pain treatment for dogs cheap rizatriptan online visa. The addition of steroids markedly increases the risk of infections with fludarabine and should be avoided. These patients should be watched for all the usual complications of prednisone, such as gastric irritation, diabetes mellitus, an increased risk of opportunistic infections, and osteoporosis. Thus, these patients may need to be maintained on an H2-blocker or proton pump inhibitor, may require oral hypoglycemics/insulin, and should be maintained on prophylaxis against Pneumocystis jirovecii [e. Many of these patients are elderly, and the prolonged course of prednisone increases the risk of osteoporosis and vertebral collapse. The authors prefer an intravenous formulation to reduce the risk of the gastric irritation that may result from corticosteroids. Immune cytopenias also may be treated with other immunosuppressive drugs, such as 6-mercaptopurine or cyclophosphamide, although no controlled trials related to their use have been published. Patients receiving gammaglobulin had a reduced number of infections, but the effectiveness did not correlate with restoration of the IgG levels. Thus, it is recommended that selected patients with hypogammaglobulinemia and frequent bacterial infections may receive prophylactic Ig. Prophylactic antibiotics may be of benefit, particularly when patients are receiving nucleoside analogues, monoclonal antibodies, and steroids, and frequently, antibiotics are incorporated into the newer and more immunosuppressive regimens. However, the use of these antibiotics varies widely and whether all patients should receive prophylactic antibiotics or only older patients or those with a history of shingles is still unclear. It is thus important to be constantly aware of the potential development of these disorders and to treat them appropriately. The immune cytopenias are treated initially with steroids, using prednisone 1 mg/kg/day, and 75% of patients respond to this therapy. Preferably, the diagnosis should be made on a lymph node biopsy but in sick patients a needle aspirate of a node with cytology demonstrating large cells is sufficient. Steroids should primarily be reserved to treat immune cytopenias and should be avoided, if possible, when patients are receiving chemotherapy. There is no evidence that steroids increase the response rate obtained with alkylating agents or nucleoside analogues alone, and they increase the risk of infection. However, if used judiciously, prednisone may be combined with chlorambucil to enhance marrow clearing of tumor and to reduce organomegaly. Patients with immune cytopenias or red cell aplasia should initially be treated with prednisone 1 mg/kg/day orally, but may also benefit from gammaglobulin, cyclosporine, cyclophosphamide, or rituximab. Radiotherapy is reserved for local lesions that are particularly bulky and troublesome and is used only when chemotherapy is not required for control of more disseminated disease. The lowest dose of radiotherapy capable of shrinking the tumor mass should be used. Splenic irradiation may be helpful in patients who require a splenectomy but who are not surgical candidates. Splenectomy may be useful in patients with painful splenomegaly or who have cytopenias that are unresponsive to other therapies. Prophylactic gammaglobulin is useful in reducing the frequency of infections in patients with hypogammaglobulinemia and frequent bacterial infections. Thus, patients need to be monitored for these complications with each visit and second malignancies promptly treated. If the patient is not participating in a clinical trial, the following are general guidelines. Approximately half the patients who become refractory to the above regimens have a deletion 17p13 and treatment options for resistant patients include alemtuzumab alone, or high-dose steroids in combination with rituximab or alemtuzumab. Ofatumumab is used for patients who are refractory to alemtuzumab or with lymph nodes >5 cm, but is not very effective for patients with loss of p53 function. Prophylaxis against Pneumocystic jirovecii and herpes infections should be given to patients receiving nucleoside analogues, steroids, or alemtuzumab and continued for 6 months following therapy. The authors use trimethoprimsulfamethoxazole (co-trimoxazole) 1 double strength twice a day on Saturdays and Sundays with valacyclovir 500 mg/day (or an equivalent). For patients allergic to trimethoprim-sulfamethoxazole, dapsone 100 mg 3 times a week or pentamidine by aerosol once a month may be used. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1995 Guidelines. Trends in long-term survival of patients with chronic lymphocytic leukemia from the 1980s to the early 21st century. Age at diagnosis and utility of prognostic testing in patients with chronic lymphocytic leukemia. Over 20% of patients with chronic lymphocytic leukemia carry sterotypded receptors: pathogenetic implication and clinical correlations. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. B-cell monoclonal lymphocytosis and B-cell abnormalities in the setting of familial B-cell chronic lymphocytic leukemia. Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia. Circulating microvesicles in B-cell chronic lymphocytic leukemia can stimulate marrow stromal cells: implications for disease progression. The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy. Interactions between bone marrow stromal microenvironment and B-chronic lymphocytic leukemia cells: any role for Notch, Wnt and Hh signaling pathways Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration. Targeting the microenvironment in chronic lymphocytic leukemia offers novel therapeutic options. In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. The prognostic significance of various 13q14 deletions in chronic lymphocytic leukemia. Genomic complexity identifies patients with aggressive chronic lymphocytic leukemia. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukemia. The cumulative amount of serumfree light chain is a strong prognosticator in chronic lymphocytic leukemia. Infectious complications of chronic lymphocytic leukemia: pathogenesis, spectrum of infection, preventive approaches. The prognostic significance of cytopenia in chronic lymphocytic leukaemia/small lymphocytic lymphoma. Immune anaemias in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab: incidence and predictors. Improving survival in patients with chronic lymphocytic leukemia (1980­2008): the Hospital Clínic of Barcelona experience. Short telomeres are associated with genetic complexity, high-risk genomic aberrations, and short survival in chronic lymphocytic leukemia. Antibody-induced nonapoptotic cell death in human lymphoma and leukemia cells is mediated through a novel reactive oxygen species-dependent pathway. Cyclosporin A for the treatment of cytopenia associated with chronic lymphocytic leukemia. A combination of rituximab, cyclophosphamide and dexamethasone effectively treats immune cytopenias of chronic lymphocytic leukemia. Rituximab-cyclophosphamidedexamethasone combination in the managements of autoimmune cytopenias associated with chronic lymphocytic leukemia. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Second cancer incidence and cancer mortality among chronic lymphocytic leukaemia patients: a population-based study. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Several case-controlled studies have identified possible relationships to radiation exposure,7,8 exposure to benzene,9 to farm animals, and to commercial herbicides and pesticides. Fluctuations in the expression of T- and B-cell markers have been demonstrated both in vivo and under various in vitro culture conditions. In addition, until recently it has been difficult to induce hairy cells to proliferate and to obtain hairy cells in metaphase. Clonal abnormalities of chromosome 5 were found in 40% of cases (most commonly trisomy 5, pericentric inversions, and interstitial deletions involving 5q13). The frequency with which these abnormalities occur is unique and is not found in other B-cell malignancies. Abnormalities in 5q13 thus occur in one third of patients, and subsequent studies have identified three expressed sequences as candidates for a putative tumor-suppressor gene at 5q13. Thus, individual hairy cells may express IgG alone or in combination with IgM and/or IgD and/or IgA. These studies have suggested that the hairy cell is in maturation arrest before deletional recombination within the heavy chain locus. A proportion of these selected B-cells then undergo switch recombination of the Ig constant region, which changes the isotype and, consequently, the antibody-effector function. Up-regulation of annexin1 mediates phagocytic function and c-Maf transcription factor for macrophage differentiation. The incidence at presentation is 17%, but increases to 56% at relapse after chemotherapy. First, the major factor responsible for the cytopenias is pooling (sequestration, margination) of normal peripheral blood cells in the enlarged spleen. Approximately 30% of patients present with infection, and 70% have either documented or suspected infections during the course of the disease. Monocytopenia is often a prominent feature,101,102 and functional abnormalities of monocytes and granulocytes may occur. Immune suppression is a result of T-cell dysfunction and impaired hematopoiesis with pancytopenia, bone marrow fibrosis, and hypersplenism. T-cell activation, decreased numbers of memory T-cells, restricted T-cell repertoire, and opportunistic infections are the result of inappropriate activation and suppression of T-cell responses directly by cytokines produced by the neoplastic B-cells. Finally, an expanded plasma volume contributes to the appearance of cytopenia with splenomegaly; this is particularly true for the observed anemia. Biopsy shows the infiltrates to be perivascular, involving the dermis but not the epidermis. Most frequently, patients present with arthritis, arthralgias, palpable purpura, or nodular skin lesions resulting from cutaneous vasculitis, and low-grade fever. In a series of 725 cases studied by the Italian Cooperative Group, 80% of patients had pancytopenia at presentation, with one third of all patients having a hemoglobin level <8. The cytoplasm is pale blue-gray and agranular with a variable number of elongated (hairy) projections. On both transmission and scanning electron microscopy, the cytoplasmic projections appear as elongated slender microvilli or broad-based ruffles or pseudopods. Nucleus is round, oval, or reniform with light-staining homogeneous nuclear chromatin (Wright stain, × 1,500). The hairy cells are monoclonal and, in contrast with most other lymphoid malignancies, cases with k or l expression are equally represented or there is a predominance of cases with k expression. Recently, it has been demonstrated that this feature is related to the ability of hairy cells to synthesize fibronectin. The overall marrow cellularity is increased in 55% of patients and normal in 38% of patients. Pattern of the infiltration gives a "honeycomb" appearance with the nucleus of each hairy cell surrounded by a halo of cytoplasm. Blood-filled pseudosinuses lined by hairy cells are a characteristic feature, and, despite monocytopenia, the number of histiocytes is increased in the red pulp. The marrow aspirate is "dry," and the bone biopsy should reveal the classic pattern of infiltration that may be diffuse, focal, or interstitial with increased reticulin and the cells staining positively for annexin A1. When hairy cells cannot be demonstrated in the peripheral blood, the bone marrow findings are critical for diagnosis. In addition to the typical bone marrow findings, immunophenotypic analysis may be helpful in identifying the leukemic cells (Table 91. However, it is expressed in myeloid and T-cells and thus not useful to detect residual disease. Surg Path 2010;3:933­954, and Jones G, Parry-Jones N, Wilkins B, Else M, Catovsky D. The leukemia cell is smaller and frequently contains a nucleolus, and the villi are shorter, fewer, and more uneven than in a typical hairy cell and are frequently concentrated at one end of the cell. A small monoclonal band is found in the serum or urine in two thirds of patients and patients may develop a Coombs-positive autoimmune hemolytic anemia. Bone marrow involvement is less frequent and usually is paratrabecular; peripheral blood involvement is rare. In lymph nodes, the infiltration is interfollicular and sinusoidal, often with preservation of some lymph follicles, a finding similar to that seen in hairy cell involvement of lymph nodes. The spleen shows not only white pulp expansion, but also a variable degree of red pulp expansion.

It is noteworthy that distinct differences between right and left ventricular mass and wall thickness develop only after birth pain management for arthritis in dogs buy rizatriptan 10 mg without a prescription. Presumably these differences arise because of a hypertrophic response of the left ventricle to the increased afterload it must assume at birth joint and pain treatment center fresno ca purchase rizatriptan 10 mg online. This may result from their lower arterial blood pressure, greater aortic compliance, and improved ability to induce vasodilatory mechanisms (such as endothelial-dependent flowmediated vasodilation) natural treatment for shingles nerve pain discount rizatriptan 10 mg on line. These differences are thought to be related to protective effects of estrogen and may account for the lowered risk of premenopausal women for developing cardiovascular disease pain medication for dogs metacam discount rizatriptan 10 mg buy on-line. They are also twice as likely as men to have atrioventricular nodal reentry tachycardias pain treatment drugs 10 mg rizatriptan buy amex. This resulted in a significant loss of blood and, by the time he was brought to the hospital, he was very weak and pale, his skin was cold and clammy, and he was somewhat confused. His breathing was rapid and shallow and jugular venous pulses could not be observed when he was recumbent. An intravenous catheter advanced from a peripheral vein into his right atrium recorded central venous pressure to be 0 mm Hg (normal 2­6 mm Hg). The most immediate problem was determined to be hemorrhagic hypovolemic shock and he was given a liter of blood. Within an hour, his heart rate was 90 beats/min and his blood pressure was 115/85 mm Hg. Circulatory shock exists whenever there is a severe reduction in blood supply to the body tissues and the metabolic needs of the tissues are not met. Even with all cardiovascular compensatory mechanisms activated, arterial pressure is usually (though not always) low in shock. The shock state is precipitated by one of the following two conditions: (1) severely depressed myocardial function or (2) grossly inadequate cardiac filling due to low mean circulatory filling pressure. The former situation is called cardiogenic shock and the latter situation can result from a variety of non-cardiac causes. These shock states are described in Table 30­1 along with the primary disturbance on the cardiovascular system and the consequences on cardiac filling pressure. The common primary disturbances in all forms of shock lead to decreased mean arterial pressure and decreased arterial baroreceptor discharge rate. In the case of hypovolemic, anaphylactic, and septic shock, diminished activity of the cardiopulmonary baroreceptors due to a decrease in central venous pressure and/or volume acts on the medullary cardiovascular centers to stimulate sympathetic output. If arterial pressure decreases below the autoregulatory range for cerebral blood flow (below about 60 mm Hg), perfusion of the brain begins to decrease, eliciting the cerebral ischemic response that causes the most intense of all signals to activate sympathetic nerves. Unless the primary disturbance precludes these compensatory responses, the increase in sympathetic activity (and decrease in parasympathetic activity) will lead to an increase in cardiac output (by increasing heart rate and cardiac contractility), an increase in total peripheral resistance (by generalized arteriolar constriction), and an increase in peripheral venous tone (which will shift blood into the central venous pool). When the immediate compensatory processes are inadequate, the individual may also show signs of abnormally low arterial pressure, such as dizziness, confusion, or loss of consciousness. The latter two processes result in a sort of autotransfusion that can move as much as a liter of fluid into the vascular space in the first hour after the onset of the shock episode (see Chapter 26). This fluid shift accounts for the reduction in hematocrit that is commonly observed in hemorrhagic shock. In addition to the immediate compensatory responses described above, fluid retention mechanisms are evoked that promote renal retention of fluid and an increase in circulating blood volume. These processes are described in detail in Chapter 45 and contribute to the replenishment of extracellular fluid volume within a few days of the shock episode. If the primary disturbances are not corrected soon, the strong compensatory responses can reduce perfusion of tissues (other than the heart and brain) despite nearly normal arterial pressure. Intense sympathetic activation can lead to renal, splanchnic, or hepatic ischemic damage. If this ischemia is prolonged, self-reinforcing decompensatory mechanisms (positive feedback described in Chapter 1) will progressively drive arterial pressure down and unless corrective measures are taken quickly, death will ultimately result. Gravity, and hence body position, has a significant effect on the cardiovascular system, and various reflex compensatory mechanisms are required to overcome venous pooling that accompanies the upright position. Long-term bed rest causes decreases in circulating blood volume that contributes to orthostatic hypotension. Cardiovascular characteristics are influenced by a variety of conditions including respiratory activity, gender, pregnancy, growth and development from the fetal period, through birth, pediatric stages, adulthood, and old age. A 35-year-old man has had a severe bout of the flu with vomiting and diarrhea for several days. All of the following conditions would be expected to be present except A) orthostatic hypotension. Vertical immersion to the chest in tepid water produces a diuresis in many individuals. A) an increase in sympathetic activity to the kidney B) an increase in mean arterial pressure C) a shift of blood from the central to the peripheral venous pool D) decreased firing of arterial baroreceptors E) increased firing of the cardiopulmonary baroreceptors 303 5. All of the following help maintain circulation during states of hypovolemic shock except A) an increase in heart rate. Describe functions and structures of the conducting airways, the alveolar­capillary unit, and the chest wall. Describe the central nervous system initiation of breathing and the innervation of the respiratory muscles. The main functions of the respiratory system are to obtain oxygen from the external environment and supply it to the cells, and to remove from the body the carbon dioxide produced by cellular metabolism. The respiratory system is composed of the lungs, the conducting airways, the parts of the central nervous system concerned with the control of the muscles of respiration, and the chest wall. The chest wall consists of the muscles of respiration- the diaphragm, the intercostal muscles, and the abdominal muscles-and the rib cage. The forces needed to cause the air to flow are generated by the respiratory muscles, acting on commands initiated by the central nervous system. At the same time, venous blood returning from the various body tissues is pumped into the lungs by the right ventricle of the heart. This mixed venous blood has a high carbon dioxide content and a low oxygen content. The blood leaving the lungs, which now has a high oxygen content and a lower carbon dioxide content, is distributed to the tissues of the body by the left side of the heart. During expiration, gas with a high concentration of carbon dioxide is expelled from the body. Acid­base balance is discussed in greater detail in Chapter 37; the control of breathing is discussed in Chapter 38. Phonation Phonation is the production of sounds by the movement of air through the vocal cords. Speech, singing, and other sounds are produced by the actions of the central nervous system controllers on the muscles of respiration, causing air to flow through the vocal cords and the mouth. Pulmonary Defense Mechanisms Each breath brings into the lungs a small sample of the local atmospheric environment. This may include microorganisms such as bacteria, dust, particles of silica or asbestos, toxic gases, smoke (cigarette and other types), and other pollutants. In addition, the temperature and humidity of the local atmosphere can vary tremendously. The mechanisms by which these impurities are removed from the respiratory tract are described in the section "Structure of the Respiratory System. Some specialized pulmonary cells also produce substances necessary for normal pulmonary function. Surfactant plays an important role in reducing the alveolar elastic recoil due to surface tension and in stabilizing the alveoli, as discussed later in Chapter 32. Histamine, lysosomal enzymes, prostaglandins, leukotrienes, plateletactivating factor, neutrophil and eosinophil chemotactic factors, and serotonin can be released from mast cells in the lungs in response to conditions such as pulmonary embolism (see Chapter 34) and anaphylaxis (an acute life-threatening systemic allergic reaction). These substances may cause bronchoconstriction or immune or inflammatory responses, or they may initiate cardiopulmonary reflexes. Many substances are also produced by cells of the lung and released into the alveoli and airways, including mucus and other tracheobronchial secretions; surface enzymes, proteins, and other factors; and immunologically active substances. These substances are produced by goblet cells, submucosal gland cells, Clara cells, and macrophages. Substances produced by lung cells and released into the blood under various circumstances include bradykinin, histamine, serotonin, heparin, prostaglandins E2 and F2, and the endoperoxides (prostaglandins G2 and H2). In addition, the pulmonary capillary endothelium contains a great number of enzymes that can produce, metabolize, or modify naturally occurring vasoactive substances. For exam- ple, prostaglandins E1, E2, and F2 are nearly completely removed in a single pass through the lungs. On the other hand, prostaglandins A1, A2, and I2 (prostacyclin) are not affected by the pulmonary circulation. Similarly, about 30% of the norepinephrine in mixed venous blood is removed by the lung, but epinephrine is unaffected. It appears that some substances released into specific vascular beds for local effects are inactivated or removed as they pass through the lungs, preventing them from entering the systemic circulation; other substances, apparently intended for more general effects, are not affected. Air entering through the nose is filtered, warmed to body temperature, and humidified as it passes through the nose and nasal turbinates. The mucosa of the nose, the nasal turbinates, the oropharynx, and the nasopharynx have a rich blood supply and constitute a large surface area. As inspired air passes through these areas and continues through the tracheobronchial tree, it is warmed to body temperature and humidified. This protective function is more effective if one is breathing through the nose than through the mouth. Because the olfactory receptors are located in the posterior nasal cavity rather than in the trachea or alveoli, a person can sniff to attempt to detect potentially hazardous gases or dangerous material in the inspired air. This rapid, shallow inspiration brings gases into contact with the olfactory sensors without bringing them into the lung. Name of branches Trachea Bronchi Conducting zone Number of tubes in branch 1 2 Structure of the Airways the structure of the airways varies considerably, depending on their location in the tracheobronchial tree. The trachea is a fibromuscular tube supported ventrolaterally by C-shaped cartilage and completed dorsally by smooth muscle. The cartilage of the large bronchi is semicircular, like that of the trachea, but as the bronchi enter the lungs, the cartilage rings disappear and are replaced by irregularly shaped cartilage plates. They completely surround the bronchi and give the intrapulmonary bronchi their cylindrical shape. These plates, which help support the larger airways, diminish progressively in the distal airways and disappear in airways about 1 mm in diameter. Because the bronchioles and alveolar ducts contain no cartilage support, they are subject to collapse when compressed, as will be discussed later in this chapter. As the cartilage plates become irregularly distributed around distal airways, the muscular layer completely surrounds these airways. As the bronchioles proceed toward the alveoli, the muscle layer becomes thinner, although smooth muscle can even be found in the walls of the alveolar ducts. The outermost layer of the bronchiolar wall is surrounded by dense connective tissue with many elastic fibers. The entire respiratory tract, except for part of the pharynx, the anterior third of the nose, and the respiratory units distal to the terminal bronchioles, is lined with ciliated cells interspersed with mucus-secreting goblet cells and other secretory cells. In the bronchioles, the goblet cells become less frequent and are replaced by another type of secretory cell, the Clara cell. The ciliated epithelium, along with mucus secreted by glands along the airways and the goblet cells and the secretory products of the Clara cells, constitutes an important mechanism for the protection of the lung called the mucociliary escalator. After passing through the conducting airways, the inspired air enters the alveoli, where it comes into contact with the mixed venous blood in the pulmonary capillaries. Starting with the trachea, the air may pass through as few as 10 or as many as 23 generations, or branchings, on its way to the alveoli. The first 16 generations of airways, the conducting zone, contain no alveoli and thus are anatomically incapable of gas exchange with the venous blood. Alveoli start to appear at the 17th to the 19th generations, in the respiratory bronchioles, which constitute the transitional zone. These alveolar ducts and the alveolar sacs, which terminate the tracheobronchial tree, are referred to as the respiratory zone. The portion of the lung supplied by a primary respiratory bronchiole is called an acinus. The numerous branchings of the airways result in a tremendous total cross-sectional area Filtration and Removal of Inspired Particles by the Airways Filtration of Inspired Air Air passing through the nose is first filtered by passing through the nasal hairs, or vibrissae. The inspired air stream changes direction abruptly at the nasopharynx so that many of these larger particles impact the posterior wall of the pharynx. The tonsils and adenoids are located near this impaction site, providing immunologic defense against biologically active material filtered at this point. Sedimentation of most particles in the size range of 2­5 m occurs by gravity in the smaller airways, where airflow rates are extremely low. Thus, most of the particles between 2 and 10 m in diameter are removed by impaction or sedimentation and become trapped in the mucus that lines the upper airways, trachea, bronchi, and bronchioles. Removal of Filtered Material Filtered or aspirated material trapped in the mucus that lines the respiratory tract can be removed in several ways. Mechanical or chemical stimulation of receptors in the nose, trachea, larynx, or elsewhere in the respiratory tract may produce bronchoconstriction to prevent deeper penetration of the irritant into the airways and may also produce a cough or a sneeze. A sneeze results from stimulation of receptors in the nose or nasopharynx; a cough results from stimulation of receptors in the trachea. In either case, a deep inspiration is followed by a forced expiration against a closed glottis. Pressure in the chest surrounding the lungs (intrapleural pressure) may rise to more than 100 mm Hg during this phase of the reflex. The glottis opens suddenly, and pressure in the airways decreases rapidly, resulting in compression of the airways and an explosive expiration, with linear airflow velocities said to approach the speed of sound. Such high airflow rates through the narrowed airways are likely to carry the irritant, along with some mucus, out of the respiratory tract. In a sneeze, the expiration is via the nose; in a cough, the expiration is via the mouth. The cough or sneeze reflex is also useful in helping to move the mucous lining of the airways toward the nose or mouth.

Diseases

• Benzodiazepine dependence
• Limb reduction defect
• Erysipelas
• Spastic paraplegia mental retardation corpus callosum
• Cleft palate colobomata radial synostosis deafness
• Mental retardation short stature unusual facies
• Cerebral gigantism jaw cysts
• Parasitophobia
• Cardioauditory syndrome
• Niemann Pick C1 disease

He now experiences chest pain and some dizziness with only mild exertion and, the day before his appointment, he fainted when getting out of bed pain treatment uti buy 10 mg rizatriptan visa. A loud systolic murmur is heard using a stethoscope placed above the aorta, and a slowly rising pulse is detected in his radial artery pain treatment center az discount rizatriptan 10 mg buy on line. Echocardiography indicated significant left ventricular wall thickening and significant narrowing of the aortic valve opening during systole wrist pain treatment tendonitis 10 mg rizatriptan buy visa. Because of the elevated resistance to outflow (essentially an increased afterload), the left ventricular muscles must develop more force to generate sufficient pressure to eject blood during systole pain treatment for endometriosis buy rizatriptan 10 mg on line. Left ventricular pressure during systole will be much higher than aortic pressure during systole, thereby producing a significant pressure gradient pain medication for small dogs order rizatriptan with a mastercard. Over time, this increased workload induces hypertrophy of the left ventricular muscle that accounts for the leftward shift in the mean electrical axis. When the leaflets of the aortic valve do not provide an adequate seal, blood regurgitates from the aorta back into the left ventricle during the diastolic period. Aortic pressure falls faster and further than normal during diastole, which causes a low diastolic pressure and a large pulse pressure. Tachycardias may originate either in the atria or ventricles and are a result of increased pacemaker automaticity or of continuously circling pathways setting up a reentrant circuit. A variety of methods are available for measuring various aspects of cardiac mechanical function. These methods are based on the Fick principle and various imaging techniques including echocardiography. The ejection fraction (which is the stroke volume divided by the end-diastolic volume) and the ventricular end-systolic pressure­volume relationship are very useful indices of cardiac contractility. Failure of cardiac valves to open fully (stenosis) can result in elevated upstream chamber pressure and abnormal pressure gradients, congestion in upstream vascular beds, chamber wall hypertrophy, turbulent forward flow across the valve, and murmurs during systole or diastole. Failure of cardiac valves to close completely (insufficiency, incompetence, regurgitation) can result in large stroke volumes, abnormal pressure pulses, congestion in upstream vascular beds, turbulent backward flow across the valve, and murmurs during systole or diastole. Fainting may be a common symptom in patients with aortic stenosis and, although it certainly reflects a decrease in brain blood flow, the specific causes are not entirely clear. Other possibilities include a hypertrophyinduced predisposition to arrhythmias or a vasodilator reflex evoked by high left ventricular pressures. The chest pain (angina pectoris) is a result of inadequate coronary blood flow to meet the myocardial metabolic demands. Ischemia can be a result of either an impediment to coronary flow (as might occur with coronary artery disease or atherosclerosis) or an increase in metabolic demands. In this case, the increase in myocardial work because of the aortic stenosis plus the accompanying hypertrophy outstrips the ability of the coronary bed to provide sufficient flow. The magnitude and direction of the net dipole formed by the wavefront of the action potential at any instant in time can be deduced from the magnitude and orientation of the electrocardiographic deflections. The mean electrical axis describes the orientation of the net dipole at the instant of maximum wavefront propagation during ventricular depolarization and normally falls between 0° and +90° on a polar coordinate system. The standard 12-lead electrocardiogram is widely used to evaluate cardiac electrical activity and consists of a combination of bipolar and unipolar records from limb electrodes and chest electrodes. Cardiac arrhythmias can often be detected and diagnosed from a single electrocardiographic lead. A) aortic stenosis B) aortic insufficiency C) mitral stenosis D) mitral insufficiency E) right ventricular hypertrophy 2. A) 10 L/min that is normal for mild exercise B) 10 L/min that is abnormally low at rest C) 6 L/min that is close to a normal resting value D) 0. Given data, use the Fick principle to calculate the rate of removal of a solute from blood as it passes through an organ. Describe how capillary wall permeability to a solute is related to the size and lipid solubility of the solute. List the factors that influence transcapillary fluid movement and, given data, predict the direction of transcapillary fluid movement. Describe the lymphatic vessel system and its role in preventing fluid accumulation in the interstitial space. Given data, calculate the vascular resistances of networks of vessels arranged in parallel and in series. Describe differences in the blood flow velocity in the various segments and how these differences are related to their total cross-sectional area. Describe laminar and turbulent flow patterns and the origin of flow sounds in the cardiovascular system. Identify the approximate percentage of the total blood volume that is contained in the various vascular segments in the systemic circulation. Describe the pressure changes that occur as blood flows through a vascular bed and relate them to the vascular resistance of the various vascular segments. Define total peripheral resistance (systemic vascular resistance) and state the relationship between it and the vascular resistance of each systemic organ. Define vascular compliance and state how the volume­pressure curves for arteries and veins differ. Predict what will happen to venous volume when venous smooth muscle contracts or when venous transmural pressure increases. Indicate the relationship between arterial pressure, cardiac output, and total peripheral resistance and predict how arterial pressure will be altered when cardiac output and/or total peripheral resistance change. Indicate the relationship between pulse pressure, stroke volume, and arterial compliance and predict how pulse pressure will be changed by changes in stroke volume, or arterial compliance. Describe how arterial compliance changes with age and how this affects arterial pulse pressure. Blood flow is continuously delivering nutrients to and removing waste products from the local interstitial environment throughout the body. Everywhere within the vascular system, blood always flows from higher pressure to lower pressure according to well-known physical rules. Like water flowing downhill, blood seeks to travel along the path of least resistance. Consequently, the peripheral vascular system changes the resistance of its various pathways to direct blood flow to where it is needed. This chapter begins with a description of the mechanisms responsible for the transport of dissolved substances through the vascular system and the movement of these substances and fluid from capillaries to and from the interstitial space. Next, the basic equation for flow though a single vessel (Q = P/R, presented in Chapter 22) is applied to the complex network of branching vessels that actually exists in the cardiovascular system. Then, the consequences of the elastic properties of the large diameter arteries and veins on overall cardiovascular system operation are considered. Finally, the principles of the routine clinical measurement of arterial blood pressure are presented along with the conclusions about overall cardiovascular function that can be made from the information. The rate at which a substance (X) is transported by this process depends solely on the concentration of the substance in the blood and the blood flow: Transport rate = Flow × Concentration or (1). It is evident from the preceding equation that only two methods are available for altering the rate at which a substance is carried to an organ: (1) a change in the blood flow through the organ or (2) a change in the arterial blood concentration of the substance. Note, however, that this calculation would not indicate whether the muscle actually used the oxygen carried to it. The relationship that results is referred to as the Fick principle and may be formally stated as follows. In that case, the known variables included the systemic tissue oxygen consumption rate and the concentrations of oxygen in arterial blood and mixed venous blood and the above equation was. There are four factors that determine the diffusion rate of a substance between the blood and the interstitial fluid: (1) the concentration difference, [X], (2) the surface area for exchange, A, (3) the diffusion distance, L, and (4) the permeability of the capillary wall to the diffusing substance represented as the diffusion coefficient, D. Capillaries are extremely fine vessels with a lumen (inner) diameter of about 5 m, a wall thickness of approximately 1 m, and an average length of perhaps 0. It is estimated that there are about 1010 capillaries in the systemic organs with a collective surface area of about 100 m2. Recall from Chapter 22 that most cells are no more than about 10 m (less than one tenth the thickness of paper) from a capillary. Diffusion is a tremendously powerful mechanism for material exchange when operating over such a short distance and through such a large area. We are far from being able to duplicate-in an artificial lung or kidney, for example-the favorable geometry for diffusional exchange that exists in our own tissues. The ease with which a particular solute crosses the capillary wall is expressed in a parameter called its capillary permeability. Fluid flows through transcapillary channels in response to pressure differences between the interstitial and intracapillary fluids according to the basic flow equation. How hydrostatic pressure provides the driving force for causing blood flow along vessels has been discussed previously. The hydrostatic pressure inside capillaries, Pc, is about 25 mm Hg and is the driving force that causes blood to return to the right heart from the capillaries of systemic organs. In addition, however, the 25-mm Hg hydrostatic intracapillary pressure tends to cause fluid to flow through the transcapillary pores into the interstitium where the hydrostatic pressure (Pi) is near 0 mm Hg. Thus, there is normally a large hydrostatic pressure difference favoring fluid filtration across the capillary wall. Our entire plasma volume would soon be in the interstitium if there were not some counteracting force tending to draw fluid into the capillaries. The balancing force is an osmotic pressure that arises from the fact that plasma has a higher protein concentration than interstitial fluid. Also recall that the driving force for osmotic water movement between one solution and another can be expressed as an osmotic pressure difference between the two. The osmotic pressure difference is directly related to the difference in total solute concentration in the two solutions in question. Because plasma and interstitial fluid are essentially identical except for their protein concentrations, plasma proteins are primarily responsible for the net osmotic pressure difference across capillary walls. The component of total osmotic pressure due to proteins has been given the special name, oncotic pressure (or colloid osmotic pressure). Due to the absence of proteins, the oncotic pressure of the interstitial fluid (i) is near 0 mm Hg. Thus, there is normally a large osmotic force for fluid reabsorption into capillaries. The capillary permeability to small polar particles such as sodium and potassium ions is about 10,000-fold less than that for oxygen. Nevertheless, the capillary permeability to small ions is several orders of magnitude higher than the permeability that would be expected if the ions were forced to move through the lipid plasma membranes. It is therefore postulated that capillaries are somehow perforated at intervals with waterfilled channels or pores (which may actually be clefts between the endothelial cells). Calculations from diffusion data indicate that the collective cross-sectional area of the pores relative to the total capillary surface area varies greatly between capillaries in different organs. Brain capillaries appear to be very tight (have few pores), whereas capillaries in the kidney and fluid-producing glands are much more leaky. On the average, however, pores constitute only a very small fraction of total capillary surface area-perhaps 0. This area is, nevertheless, sufficient to allow very rapid equilibration of small watersoluble substances between the plasma and interstitial fluids of most organs. Thus, the concentrations of inorganic ions measured in a plasma sample can be taken to indicate their concentrations throughout the entire extracellular space. In general, albumin and other large plasma proteins cannot easily cross capillary walls. The precise mechanism for the low capillary permeability to proteins is in dispute. One hypothesis is that capillary pores are just physically smaller than the diameter of plasma protein molecules. Whatever the mechanism(s), the result is that much higher protein concentrations normally exist in blood plasma than in interstitial fluid. Because of their ubiquitous and intimate contact with blood, endothelial cells have evolved to serve many functions in addition to acting as a barrier to transcapillary solute and water exchange. For example, endothelial cell membranes contain specific enzymes that convert some circulating hormones from inactive to active forms. Endothelial cells are also intimately involved in producing substances that lead to blood clot formation and the stemming of bleeding in the event of tissue injury. Moreover, and as will be discussed in the next chapter, the endothelial cells lining muscular vessels such as arterioles can produce vasoactive substances that act on the smooth muscle cells that surround them to influence arteriolar diameter. In most tissues, rapid net filtration of fluid is abnormal and causes tissue swelling as a result of excess fluid in the interstitial space (edema). One of the actions of histamine is to increase capillary permeability to the extent that proteins leak into the interstitium. Net filtration and edema accompany histamine release, in part because the oncotic pressure difference (c ­ i) is reduced below normal. Indeed, fluid-producing organs such as salivary glands and kidneys utilize high intracapillary hydrostatic pressure to produce continuous net filtration. Moreover, in certain abnormal situations, such as severe loss of blood volume through hemorrhage, the net fluid reabsorption accompanying diminished intracapillary hydrostatic pressure helps restore the volume of circulating fluid. The lymphatic system begins in the tissues with blind-end lymphatic capillaries that are roughly equivalent in size to but less numerous than regular capillaries. This fluid, called lymph, moves through the converging lymphatic vessels, is filtered through lymph nodes where bacteria and particulate matter are removed, and reenters the circulatory system through the thoracic duct near the point where the blood enters the right heart. Flow of lymph from the tissues toward the entry point into the circulatory system is promoted by (1) increases in tissue interstitial pressure (due to fluid accumulation or to movement of surrounding tissue), (2) contractions of the lymphatic vessels, and (3) valves located in these vessels to prevent backward flow. In the steady state, this indicates a total body net transcapillary fluid filtration rate of 2.

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