Patricia B. Crawford DrPH, RD

• Adjunct Professor

https://publichealth.berkeley.edu/people/patricia-crawford/

The other approved nanoparticle is Abraxane anxiety symptoms in 12 year old boy 25 mg phenergan amex, an albumin-bound form of paclitaxel that treats breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy anxiety reduction techniques purchase 25 mg phenergan otc. Prior therapy should have included an anthracycline unless clinically contraindicated anxiety gif purchase 25 mg phenergan. The primary goals are to study the safety and pharmacokinetics of the drug for 1­2 years and to determine the maximum tolerated dose anxiety symptoms vertigo phenergan 25 mg buy cheap. The hypothesis is that lapatinib will work synergistically with the paclitaxel nanoparticle to increase antitumor efficacy anxiety symptoms returning 25 mg phenergan purchase otc. The study will enroll 15 patients, measure the maximum tolerated dose of a 2-day pulse of lapatinib given prior to paclitaxel nanoparticles, and yield preliminary data for antitumor efficacy. Another currently registered trial is a diagnostic study utilizing ferrimoxytol, a superparamagnetic iron oxide nanoparticle, to assess differences in the effects of antiangiogenic chemotherapy and steroid on tumor imaging (U. Nanoparticles are being aggressively studied for use in humans; however, the possible risks to human health have not been elucidated. Other questions remain to be answered: How will the immune system react to these very small structures? Can nanoparticles act like haptens, potentially evoking unpredictable autoimmune effects? On the other hand, nanoparticles may go undetected by the immune system, gaining access to unintended tissues and resulting in toxicity to normal structures. Presently, biotoxicity studies are elucidating the interaction of nanoparticles with the human body and hopefully will yield strategies to design nanoparticles of increased efficacy and reduced toxicity (Invernici et al. The search for more effective and less toxic treatments for primary brain tumors is driven by the limited effect of the present treatment. The studies reviewed in this chapter reveal a new treatment paradigm for primary brain tumors using tumor-targeted nanodrugs. Undoubtedly, more research is needed to evaluate and develop the use of nanodrugs. As we explore potential applications for these agents, we will come to better understand their pharmacokinetics in valid animal models. Human trials can be performed with select nanodrugs that appear to be promising candidates based on preclinical testing. There is optimism that the unique targeting properties of nanodrugs will lead to advances in the treatment of primary brain tumors to improve prognosis and to reduce the suffering of affected patients. Delivery of superparamagnetic nanoparticles for local chemotherapy after intraarterial infusion and magnetic drug targeting. Interaction of poly(butylcyanoacrylate) nanoparticles with the blood­brain barrier in vivo and in vitro. Significant entry of tubocurarine into the brain of rats by adsorption to polysorbate 80-coated polybutylcyanoacrylate nanoparticles: an in situ brain perfusion study. Biodistribution of polysorbate 80-coated doxorubicinloaded [14C]-poly(butyl cyanoacrylate) nanoparticles after intravenous administration to glioblastomabearing rats. Body distribution of polysorbate-80 and doxorubicinloaded [14C]poly(butyl cyanoacrylate) nanoparticles after i. Indomethacin-loaded nanocapsules treatment reduces in vivo glioblastoma growth in a rat glioma model. Selective cytotoxicity of indomethacin and indomethacin ethyl ester-loaded nanocapsules against glioma cell lines: an in vitro study. Organically modified silica nanoparticles: a nonviral vector for in vivo gene delivery and expression in the brain. Negative preclinical results with stealth nanospheresencapsulated doxorubicin in an orthotopic murine brain tumor model. Assembly automation with evolutionary nanorobots and sensor-based control applied to nanomedicine. Interaction of functionalized superparamagnetic iron oxide nanoparticles with brain structures. Three-step radioimmunotherapy with yttrium-90 biotin: dosimetry and pharmacokinetics in cancer patients. Cyclooxygenase-2 inhibitor celecoxib augments chemotherapeutic drug-induced apoptosis by enhancing activation of caspase-3 and -9 in prostate cancer cells. Biotinylation of membrane proteins accessible via the pulmonary circulation in normal and hyperoxic rats. Nanoparticles of biodegradable polymers for clinical administration of paclitaxel. Inhibition of laminin-8 in vivo using a novel poly(malic acid)-based carrier reduces glioma angiogenesis. Brain tumor tandem targeting using a combination of monoclonal antibodies attached to biopoly(beta-l-malic acid). Influence of particle size on transport of methotrexate across blood brain barrier by polysorbate 80-coated polybutylcyanoacrylate nanoparticles. In Nanoparticle Technology for Drug Delivery, Drugs, and the Pharmaceutical Sciences, ed. Toxicological studies of doxorubicin bound to polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles in healthy rats and rats with intracranial glioblastoma. Chemotherapy of brain tumours using doxorubicin bound to polysorbate 80-coated nanoparticles. Immunogenicity and pharmacokinetic attributes of poly(ethylene glycol)-grafted immunoliposomes. Efficient systemic therapy of rat glioblastoma by nanoparticle-bound doxorubicin is due to antiangiogenic effects. Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance. A novel intravascular drug delivery method using endothelial biotinylation and avidin­biotin binding. Selective photothermal therapy for mixed cancer cells using aptamer-conjugated nanorods. Liposomes bearing polyethyleneglycol-coupled transferrin with intracellular targeting property to the solid tumors in vivo. The targeted delivery of cancer drugs across the blood­brain barrier: chemical modifications of drugs or drug-nanoparticles? Transferrin-conjugated nanoparticles for increasing efficacy of a therapeutic agent. Polycefin, a new prototype of a multifunctional nanoconjugate based on poly(beta-l-malic acid) for drug delivery. Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Association between laminin-8 and glial tumor grade, recurrence, and patient survival. Overexpression of alpha4 chain-containing laminins in human glial tumors identified by gene microarray analysis. Mechanisms regulating body distribution of nanospheres conditioned with pluronic and tetronic block-copolymers. Self-assembled hydrogel nanoparticles responsive to tumor extracellular pH from pullulan derivative/sulfonamide conjugate: characterization, aggregation, and adriamycin release in vitro. Micellar formulations for drug delivery based on mixtures of hydrophobic and hydrophilic pluronic block copolymers. Combined treatment of advanced oropharyngeal cancer with external radiotherapy and three-step radioimmunotherapy. Tumor-Targeted Nanodrugs for Treatment of Primary Brain Tumors 393 Panzenboeck, U. Influence of the formulation on the tolerance profile of nanoparticle-bound doxorubicin in healthy rats: focus on cardio- and testicular toxicity. Intravenous tolerance of a nanoparticle-based formulation of doxorubicin in healthy rats. Chemotherapy of brain tumour using doxorubicin bound to surfactant-coated poly(butyl cyanoacrylate) nanoparticles: revisiting the role of surfactants. Binding specificity and internalization properties of an antibody­avidin fusion protein targeting the human transferrin receptor. Body distribution of 3H-labelled dalargin bound to poly(butyl cyanoacrylate) nanoparticles after i. Tumour targeting: biological factors and formulation advances in injectable lipid nanoparticles. Transferrin coupled liposomes as drug delivery carriers for brain targeting of 5-florouracil. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Selective uptake of multi-walled carbon nanotubes by tumor macrophages in a murine glioma model. Uptake of adriamycin in tumour and surrounding brain tissue in patients with malignant gliomas. Magnetic paclitaxel nanoparticles inhibit glioma growth and improve the survival of rats bearing glioma xenografts. Surgery and radiation comprise the cornerstone of current treatment for brain metastases, and clinical context determines individualized treatments. Surgery is well suited for addressing solitary lesions or symptomatic lesions because it can remove a large mass of tumor and relieve mass effect when present. However, the recurrence rates of tumors are high in the absence of adjuvant radiation, and the role of surgery is somewhat limited in patients with multiple metastases or extensive leptomeningeal diseases in which intrathecal chemotherapy plays a significant role. However, the sequelae associated with radiating large expanses of normal parenchyma are considerable and limit the radiation dose that can be delivered in a single session. In particular, cognitive impairment, such as dementia, is a worrisome complication of this treatment (DeAngelis et al. It avoids the complications of surgery, such as cerebrospinal fluid leaks and surgical wound infections, and can target multiple lesions. Despite this diverse array of therapeutic strategies, there is considerable room for progress. Nanotechnology is an exciting discipline that can augment existing strategies and open new therapeutic avenues. In the following sections, we will discuss the current state of this field as it applies to brain metastases and highlight areas of nanotechnology research that can be adapted to combat brain metastases. Gold nanoparticles come in many shapes, including nanospheres, nanoshells, and nanorods. This property is tunable based on size, allowing the selection of appropriate absorption bands for imaging applications. Bulk gold is chemically inert and relatively nontoxic, and has great potential as an imaging agent and for photothermal therapy (Alkilany and Murphy 2010). Gold nanoparticles, such as nanorods or nanorodin-shell nanostructures, are excitable by near-infrared light. When excited, they produce intense 398 the Textbook of Nanoneuroscience and Nanoneurosurgery localized heat that is able to destroy tumor cells. Near-infrared light can penetrate into brain tissue to a depth of between 2 and 3 mm (Stolik et al. In addition, the surface of colloidal gold is readily modified by molecules containing thiol groups, allowing rapid and diverse modulation of surface properties and conjugation of a variety of cargoes and targeting agents to its surface. The mechanism for the endocytosis of these nanoparticles has been proposed to be due to the surface adsorption of apolipoproteins B and E on the surface of the nanoparticles, thereby enabling the nanoparticles to be taken up by brain capillary endothelial cells via receptor-mediated endocytosis (Kreuter 2001). This is especially powerful because maximal brain delivery occurred with around 30 antibodies/immunoliposomes; since each liposome can deliver tens of thousands of small-molecule drugs, conjugation of the antibodies to immunoliposomes increased the carrying capacity of the antibody by four log orders in magnitude (Huwyler et al. This impressive targeting has also been demonstrated successfully for melanoma brain metastases (Aboody et al. Magnetic microparticles that can 400 the Textbook of Nanoneuroscience and Nanoneurosurgery be used for ex vivo stimulation and removed magnetically before the cells are administered have been developed and show strong stimulation and good antitumor effect both in vitro and in vivo (Durai et al. At this point, 4- to 5-m particles appear to be most effective in inducing a strong immune response but are only useful for ex vivo applications due to the potential for particles of that size to be trapped in and occlude microvessels (Steenblock et al. However, there is ongoing work to develop nanoparticles of similar efficacy (to take advantage of the pharmacological benefits of nanoparticles) and the ability to deliver them systemically. Magnetic, metallic, and organic nanoparticles each have unique characteristics that favor their use in select clinical scenarios. Nanotechnology can be effective for both diagnosing and treating brain metastases. These novel approaches could potentially improve patient outcomes alone or in combination with conventional modalities such as surgery, radiation, or chemotherapy. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Neural stem cells as a novel platform for tumor-specific delivery of therapeutic antibodies. Significant transport of doxorubicin into the brain with polysorbate 80-coated nanoparticles. The optical properties of metal nanoparticles: the influence of size, shape, and dielectric environment. Targeting rat brainstem glioma using human neural stem cells and human mesenchymal stem cells. Magnetic resonance imaging of mesenchymal stem cells homing to pulmonary metastases using biocompatible magnetic nanoparticles. Ag-doped manganite nanoparticles: new materials for temperature-controlled medical hyperthermia.

Juxtamedullary nephrons have longer loops of Henle Glomerulus Renal Blood Flow the renal artery supplies blood to the kidney anxiety symptoms 2 buy phenergan 25 mg with amex. The human kidneys receive approximately 25% of the blood pumped through the heart at all times anxiety jelly legs purchase genuine phenergan. The varying sizes of these arterioles help to create the hydrostatic pressure differential important for glomerular filtration and to maintain consistency of glomerular capillary pressure and renal blood flow within the glomerulus anxiety 9gag discount 25 mg phenergan overnight delivery. The peritubular capillaries surround the proximal and distal convoluted tubules anxiety upset stomach phenergan 25 mg order, providing for the immediate reabsorption of essential substances from the fluid in the proximal convoluted tubule and final adjustment of the urinary composition in the distal convoluted tubule anxiety x rays order genuine phenergan. The vasa recta are located adjacent to the ascending and descending loops of Henle in juxtamedullary nephrons. In this area, the major exchanges of water and salts take place between the blood and the medullary interstitium. This exchange maintains the osmotic gradient (salt concentration) in the medulla, which is necessary for renal concentration. Variations in normal values have been published for different age groups and should be considered when evaluating renal function studies. Therefore, the actions Glomerular Pressure As mentioned previously, the presence of hydrostatic pressure resulting from the smaller size of the efferent arteriole and the glomerular capillaries enhances filtration. By increasing or decreasing the size of the afferent and efferent arterioles, an autoregulatory mechanism within the juxtaglomerular apparatus maintains the glomerular blood pressure at a relatively constant rate regardless of fluctuations in systemic blood pressure. Triggers antidiuretic hormone release by the hypothalamus to stimulate water reabsorption in the collecting duct is the absence of plasma protein, any protein-bound substances, and cells. Analysis of the fluid as it leaves the glomerulus shows the filtrate to have a specific gravity of 1. This information provides a useful baseline for evaluating the renal mechanisms involved in converting the plasma ultrafiltrate into the final urinary product. Note the smaller size of the afferent arteriole indicating increased blood pressure. Therefore, when the plasma ultrafiltrate enters the proximal convoluted tubule, the nephrons, through cellular transport mechanisms, begin reabsorbing these essential substances and water (Table 3­2). Because this filtration is nonselective, the only difference between the compositions of the filtrate and the plasma Reabsorption Mechanisms the cellular mechanisms involved in tubular reabsorption are termed active transport and passive transport. A nonfasting patient with high glucose intake would not have a normal blood glucose. Passive transport Urea Sodium Ascending loop of Henle Proximal and distal convoluted tubules Proximal convoluted tubule Descending loop of Henle Collecting duct Proximal convoluted tubule Ascending loop of Henle Ascending loop of Henle Tubular Concentration Renal concentration begins in the descending and ascending loops of Henle, where the filtrate is exposed to the high osmotic gradient of the renal medulla. Excessive reabsorption of water as the filtrate passes through the highly concentrated medulla is prevented by the water-impermeable walls of the ascending loop. The sodium and chloride leaving the filtrate in the ascending loop prevent dilution of the medullary interstitium by the water reabsorbed from the descending loop. The electrochemical energy created by this interaction transfers the substance across the cell membranes and back into the bloodstream. Active transport, like passive transport, can be influenced by the concentration of the substance being transported. The plasma concentration at which active transport stops is termed the renal threshold. For glucose, the plasma renal threshold is 160 to 180 mg/dL, and glucose appears in the urine when the plasma concentration reaches this level. Knowledge of the renal threshold and the plasma concentration can be used to distinguish between excess solute filtration and renal tubular damage. Collecting Duct Concentration the final concentration of the filtrate through the reabsorption of water begins in the late distal convoluted tubule and continues in the collecting duct. One would expect that as the dilute filtrate in the collecting duct comes in contact with the higher osmotic concentration of the medullary interstitium, passive reabsorption of water would occur. Therefore, the chemical balance in the body is actually the final determinant of urine volume and concentration. Tubular secretion serves two major functions: eliminating waste products not filtered by the glomerulus and regulating the acid­base balance in the body through the secretion of hydrogen ions. Many foreign substances, such as medications, cannot be filtered by the glomerulus because they are bound to plasma proteins. When these protein-bound substances enter the peritubular capillaries, they develop a stronger affinity for the tubular cells and dissociate from their carrier proteins, which results in their transport into the filtrate by the tubular cells. Should there be additional need for elimination of hydrogen ions, the distal convoluted tubule and the collecting duct are also able to produce ammonium ion. All three of these processes occur simultaneously at rates determined by the acid­base balance in the body. Renal tubular cell Peritubular plasma Renal Function Tests this brief review of renal physiology shows that there are many metabolic functions and chemical interactions to be evaluated through laboratory tests of renal function. To ensure that glomerular filtration is being measured accurately, the substance analyzed must be one that is neither reabsorbed nor secreted by the tubules. Newer methods that eliminate many of the problems mentioned above have replaced some of these tests. At present, creatinine, beta2-microglobulin, cystatin C, and possibly radioisotopes are the primary substances used in clearance tests. A test that requires an infused substance is termed an exogenous procedure and is seldom the method of choice if a suitable test substance is already present in the body (endogenous procedure). Because creatinine is normally found at a relatively constant level in the blood, it provides the laboratory with an endogenous procedure for evaluating glomerular function. The use of creatinine has several disadvantages and careful consideration should be given to them. Medications, including gentamicin, cephalosporins, and cimetidine (Tagamet), inhibit tubular secretion of creatinine, thus causing falsely low serum levels. Measurement of creatinine clearance is not a reliable indicator in patients suffering from muscle-wasting diseases or persons involved in heavy exercise or athletes supplementing with creatine. It must be corrected for body surface area, unless normal is assumed, and must always be corrected for children. Newer methods that do not require the collection of timed (24-hour) urine specimens have been developed using just the serum creatinine, cystatin C, or beta2-microglobulin values. Procedure By far the greatest source of error in any clearance procedure using urine is the use of improperly timed urine specimens. The urine volume is calculated by dividing the number of milliliters in the specimen by the number of minutes used to collect the specimen. The formula has been modified several times to make it more accurate and standardized. V = 1440 mL = 1 mL/min 60 minutes Ч 24 = 1440 minutes 120 mg/dL Ч 1 mL/min (V) = 120 mL/dL 1. Chapter 3 Renal Function 440 420 400 380 360 340 320 300 290 280 270 260 250 240 230 220 210 200 190 180 170 160 150 140 Weight in pounds 130 120 110 100 90 80 35 70 30 60. Cystatin C is a small protein (molecular weight 13,359) produced at a constant rate by all nucleated cells. It is readily filtered by the glomerulus and reabsorbed and broken down by the renal tubular cells. However, the test is not reliable in patients who have a history of immunologic disorders or malignancy. They have also been shown to be most accurate when results are lower than 60 mL/min. Neither test is used now because the information provided by specific gravity measurements is most useful as a screening procedure, and quantitative measurement of renal concentrating ability is best assessed through osmometry. Currently renal concentrating testing is performed after various periods of fluid deprivation, measuring urine and often serum osmolality. Controlled intake procedures can include after dinner overnight deprivation of fluid for 12 hours followed by collection of a urine sample. A urine osmolality reading of 800 mOsm or higher is normal and the test can be discontinued. If the urine test is abnormal, the fluid is restricted for another two hours and both urine and serum species are collected for osmolality testing. A urine to serum ratio (U:S ratio) of 3:1 or greater or a urine osmolality of 800 mOsm or greater indicates normal tubular reabsorption. As mentioned, the ultrafiltrate that enters the tubules has a specific gravity of 1. Throughout the years, various methods have been used to produce water deprivation, including the Fishberg and Mosenthal concentration tests, which measured specific gravity. In the Fishberg test, patients were deprived of fluids for 24 hours before measuring specific gravity. The Mosenthal test compared Patient A Water (1 glass) Patient B Water (4 glasses) Osmolality As will be discussed in Chapter 4, osmolality measures only the number of particles in a solution, whereas specific gravity is influenced by the number and density (molecular weight) of the particles. Largemolecular-weight molecules such as glucose and urea do not contribute to the evaluation of renal concentration. Glomerulus Glomerulus Ultrafiltrate 120 mL Water 300 mg Solute Reabsorption 119 mL Water 100 mg Solute Ultrafiltrate 120 mL Water 300 mg Solute Reabsorption 110 mL Water 100 mg Solute Urine 1 mL Water 200 mg Solute Urine 10 mL Water 200 mg Solute Specific gravity 1. Temperatures are compared with those of the NaCl standards and converted into milliosmoles. Correlation studies have shown more variation with vapor pressure osmometers, stressing the necessity of careful technique. In lipemic serum, the serum water displacement by insoluble lipids produces erroneous results with both vapor pressure and freezing point osmometers. Freezing Point Osmometers Measurement of freezing point depression was the first principle incorporated into clinical osmometers, and many instruments employing this technique are available. These osmometers determine the freezing point of a solution by supercooling a measured amount of sample to approximately 27°C. The supercooled sample is vibrated to produce crystallization of water in the solution. These evaluations may require determination of serum in addition to urine osmolarity. Reference values for urine osmolality are difficult to establish, because factors such as fluid intake and exercise can greatly influence the urine concentration. The actual measurement performed, however, is that of the dew point (temperature at which water vapor condenses to a liquid). Samples are absorbed into small filter paper disks that are placed in a sealed chamber containing a temperature-sensitive thermocoupler. When the temperature in the chamber is lowered, water condenses in the chamber and on the thermocoupler. Free Water Clearance the ratio of urine to serum osmolarity can be further expanded by performing the analyses using water deprivation and a timed urine specimen and calculating the free water clearance. The ultrafiltrate contains the same osmolality as the plasma; therefore, the osmotic differences in the urine are the result of renal concentrating and diluting mechanisms. By comparing the osmolar clearance with the actual urine volume excreted per minute, it can be determined whether the water being excreted is more or less than the amount needed to maintain an osmolality the same as that of the ultrafiltrate. The calculation of the free water clearance is used to determine the ability of the kidney to respond to the state of body hydration. Also, the term "effective" is included because approximately 8% of the renal blood flow does not come into contact with the functional renal tissue. Impaired tubular secretory ability or inadequate presentation of the substance to the capillaries owing to decreased renal blood flow may cause an abnormal result. Titratable Acidity and Urinary Ammonia the ability of the kidney to produce an acid urine depends on the tubular secretion of hydrogen ions and production and secretion of ammonia by the cells of the distal convoluted tubule. Chachati, A, et al: Rapid method for the measurement of differential renal function: Validation. The inability to produce an acid urine in the presence of metabolic acidosis is called renal tubular acidosis. Urine pH, titratable acidity, and urinary ammonia measurements can be used to determine the defective function. The renin-angiotensin-aldosterone system is responsible for all of the following except: A. Concentration of the tubular filtrate by the countercurrent mechanism depends on all of the following except: A. If ammonia is not produced by the distal convoluted tubule, the urine pH will be: A. Substances that may interfere with freezing point measurement of urine and serum osmolarity include all of the following except: A. After controlled fluid intake, the urine-to-serum osmolarity ratio should be at least: A. To provide an accurate measure of renal blood flow, a test substance should be completely: A. Production of excessively acidic urine due to increased filtration of hydrogen ions B. A 44-year-old man diagnosed with acute tubular necrosis has a blood urea nitrogen of 60 mg/dL and a blood glucose level of 100 mg/dL. Diagram the reactions that take place to ensure adequate blood pressure within the nephrons. How can the physician determine whether it is safe to prescribe this medication before the patient leaves the office? State two additional blood tests that the physician could use to continue monitoring this patient. If the patient has a history of prostate malignancy, would both of these methods provide reliable results? A laboratory is obtaining erratic serum osmolarity results on a patient who is being monitored at 6 a.

In the presence of massive hemoglobinuria or myoglobinuria anxiety remedies order phenergan pills in toronto, homogenous orange-red or red-brown casts may be observed anxiety videos purchase generic phenergan line. They are associated with the acute tubular necrosis often caused by the toxic effects of massive hemoglobinuria that can lead to renal failure anxiety symptoms diarrhea phenergan 25 mg order line. When tubular damage is present anxiety 4 hereford bull 25 mg phenergan order amex, some cells may be incorporated into the cast matrix anxiety 37 weeks discount 25 mg phenergan fast delivery, but the majority will be very noticeably attached to the cast surface. These structures should be carefully examined to determine that a cast matrix is present. Fatty Casts Fatty casts are seen in conjunction with oval fat bodies and free fat droplets in disorders causing lipiduria. The cast matrix may contain few or many fat droplets, and intact oval fat bodies may be attached to the Bacterial Casts Bacterial casts containing bacilli both within and bound to the protein matrix are seen in pyelonephritis. When mixed casts are present, there should also be homogenous casts of at least one of the cell types, and they will be the primary diagnostic marker. However, final identification should be performed using high power to determine the presence of a cast matrix. When granular casts remain in the tubules for extended periods, the granules further disintegrate, and the cast matrix develops a waxy appearance. Broad Casts Often referred to as renal failure casts, broad casts like waxy casts represent extreme urine stasis. As a mold of the distal convoluted tubules, the presence of broad casts indicates destruction (widening) of the tubular walls. The primary reason for the identification of urinary crystals is to detect the presence of the relatively few abnormal types that may represent such disorders as liver disease, inborn errors of metabolism, or renal damage caused by crystallization of medications compounds within the tubules. Chapter 6 Microscopic Examination of Urine 129 Crystal Formation Crystals are formed by the precipitation of urine solutes, including inorganic salts, organic compounds, and medications (iatrogenic compounds). Precipitation is subject to changes in temperature, solute concentration, and pH, which affect solubility. Crystals are extremely abundant in refrigerated specimens and often present problems because they obscure clinically significant sediment constituents. The presence of crystals in freshly voided urine is most frequently associated with concentrated (high specific gravity) specimens. A valuable aid in the identification of crystals is the pH of the specimen because this determines the type of chemicals precipitated. General Identification Techniques the most commonly seen crystals have very characteristic shapes and colors; however, variations do occur and can present identification problems, particularly when they resemble abnormal crystals. As discussed previously, the first consideration when identifying crystals is the urine pH. Additional aids in crystal identification include the use of polarized microscopy and solubility characteristics of the crystals. Although the size of a particular crystal may vary (slower crystallization produces larger crystals), the basic structure remains the same. Chapter 6 Microscopic Examination of Urine 131 prevent destruction of other elements. In Table 6­6, characteristics for the most commonly encountered crystals are provided. Amorphous urates are frequently encountered in specimens that have been refrigerated and produce a very characteristic pink sediment. Accumulation of the pigment, uroerythrin, on the surface of the granules is the cause of the pink color. Increased amounts of uric acid crystals, particularly in fresh urine, are associated with increased levels of purines and nucleic acids and are seen in patients with leukemia who are receiving chemotherapy, in patients with Lesch-Nyhan syndrome (see Chapter 8), and sometimes in patients with gout. Uric acid crystals are seen in a variety of shapes, including rhombic, four-sided flat plates (whetstones), wedges, and rosettes. Calcium oxalate crystals are sometimes seen in clumps attached to mucous strands and may resemble casts. The monohydrate form is most frequently seen in children and pets because antifreeze tastes sweet and uncovered containers left in the garage can be very tempting! When present in large quantities following specimen refrigeration, they cause a white precipitate that does not dissolve on warming. They can be differentiated from amorphous urates by the color of the sediment and the urine pH. Triple phosphate (ammonium magnesium phosphate) crystals are commonly seen in alkaline urine. They have no clinical significance; however, they are often seen in highly alkaline urine associated with the presence of ureasplitting bacteria. They may appear as colorless, flat rectangular plates or thin prisms often in rosette formations. The rosette forms may be confused with sulfonamide crystals when the urine pH is in the neutral range. They have no clinical significance, although calcium phosphate is a common constituent of renal calculi. Abnormal Urine Crystals Abnormal urine crystals are found in acidic urine or rarely in neutral urine. However, their identity can be confirmed by patient information, including disorders and medication (Table 6­7). Iatrogenic crystals can be caused by a variety of compounds, particularly when they are administered in high concentrations. Uric acid crystals are very birefringent under polarized microscopy, whereas only thick cystine crystals have polarizing capability. Cholesterol Crystals Cholesterol crystals are rarely seen unless specimens have been refrigerated, because the lipids remain in droplet form. They are associated with disorders producing lipiduria, such as the nephrotic syndrome, and are seen in conjunction with fatty casts and oval fat bodies. Differentiation is best made by comparison of the other urinalysis results and the patient history. As mentioned previously, cholesterol crystals should be accompanied by other lipid elements and heavy proteinuria. Likewise, the specific gravity of a specimen containing radiographic contrast media is markedly elevated when measured by refractometer. Crystals Associated With Liver Disorders In the presence of severe liver disorders, three rarely seen crystals may be found in the urine sediment. They are usually seen in conjunction with leucine crystals in specimens with positive chemical test results for bilirubin. Tyrosine crystals may also be encountered in inherited disorders of amino acid metabolism (see Chapter 8). The appearance of sulfonamide crystals in fresh urine can suggest the possibility of tubular damage if crystals are forming in the nephron. A variety of sulfonamide medications are currently on the market; therefore, one can expect to encounter a variety of crystal shapes and colors. Ampicillin Crystals Precipitation of antibiotics is not frequently encountered except for the rare observation of ampicillin crystals following massive doses of this penicillin compound without adequate hydration. Urinary Sediment Artifacts Contaminants of all types can be found in urine, particularly in specimens collected under improper conditions or in dirty containers. Chapter 6 Microscopic Examination of Urine 139 Starch granule contamination may occur when cornstarch is the powder used in powdered gloves. Like many artifacts, their large size may cause them to be out of focus with true sediment constituents. Improperly collected specimens or rarely the presence of a fistula between the intestinal and urinary tracts may produce fecal specimen contamination. Addis, T: the number of formed elements in the urinary sediment of normal individuals. Olympus Microscopy Resource Center: Specialized Microscopy Techniques: Fluorescence. Kohler, H, Wandel, E, and Brunch, B: Acanthocyturia: A characteristic marker for glomerular bleeding. Graber, M, et al: Bubble cells: Renal tubular cells in the urinary sediment with characteristics of viability. Variations in the microscopic analysis of urine include all of the following except: A. When using the glass slide and cover-slip method, which of the following might be missed if the cover slip is overflowed? Initial screening of the urine sediment is performed using an objective power of: A. Which of the following should be used to reduce light intensity in bright-field microscopy? The Sternheimer-Malbin stain is added to urine sediments to do all of the following except: A. Leukocytes that stain pale blue with Sternheimer-Malbin stain and exhibit brownian movement are: A. Match the following crystals seen in acidic urine with their description/identifying characteristics: Amorphous urates Uric acid Calcium oxalate monohydrate Calcium oxalate dihydrate 1. Match the following crystals seen in alkaline urine with their description/identifying characteristics: Triple phosphate Amorphous phosphate Calcium phosphate Ammonium biurate Calcium carbonate 1. Detects specific wavelengths of light emitted from objects Chapter 6 Microscopic Examination of Urine 145 Case Studies and Clinical Situations 1. Results of an ancillary blood glucose test are 250 mg/dL, and her physician orders additional blood tests and a routine urinalysis. Is there a discrepancy between the negative nitrite and the positive leukocyte esterase results? Reagent strip testing indicates the presence of moderate blood and leukocytes, but the student is also observing some large unusual objects resembling crystals and possible casts. What microscopy technique could be used to aid in differentiating a cast and an artifact? A prisoner sentenced to 10 years for selling illegal drugs develops jaundice, lethargy, and hepatomegaly. When his condition appears to worsen and a low urinary output is observed, the patient is transferred to a local hospital. The nurse on duty tells her that the specimen will be refrigerated and tested by the technologist the next morning. What could have caused the technologist to have difficulty interpreting the reagent strip results? A 2-year-old left unattended in the garage for 5 minutes is suspected of ingesting antifreeze (ethylene glycol). Identify a chemical result in the urinalysis that confirms your reason for the discrepancies. What course of action should the laboratory take to obtain accurate results for this patient? A high school student is taken to the emergency room with a broken leg that occurred during a football game. The presence of waxy casts and a negative protein in urine from a 6­month-old girl b. Considering that the major function of the kidneys is filtration of the blood to remove waste products, it becomes evident that the kidneys are consistently exposed to potentially damaging substances. As toxicity to the glomerular membrane subsides, urinalysis results return to normal, with the possible exception of microscopic hematuria that lasts until the membrane damage has been repaired. Demonstration of positive anti­group A streptococcal enzyme tests provides evidence that the disease is of streptococcal origin. Immune complexes formed as a result of immunologic reactions and increased serum immunoglobulins, such as immunoglobulin A (IgA), circulate in the bloodstream and are deposited on the glomerular membranes. Rapidly Progressive (Crescentic) Glomerulonephritis A more serious form of acute glomerular disease is called rapidly progressive (or crescentic) glomerulonephritis and has a much poorer prognosis, often terminating in renal failure. Some forms may demonstrate increased fibrin degradation products, cryoglobulins, and the deposition of IgA immune complexes in the glomerulus. Goodpasture Syndrome Morphologic changes to the glomeruli resembling those in rapidly progressive glomerular nephritis are seen in conjunction with the autoimmune disorder termed Goodpasture syndrome. A cytotoxic autoantibody can appear against the glomerular and alveolar basement membranes after viral respiratory infections. Referred to as antiglomerular basement membrane antibody, the autoantibody can be detected in patient serum. Initial pulmonary complaints are hemoptysis and dyspnea, followed by the development of hematuria. These may include fever, edema (most noticeably around the eyes), fatigue, hypertension, oliguria, and hematuria. Wegener Granulomatosis Wegener granulomatosis causes a granuloma-producing inflammation of the small blood vessels primarily of the kidney and respiratory system. Many of the patients are children, and the disease has a poor prognosis: type 1 patients progress to the nephrotic syndrome and type 2 patients experience symptoms of chronic glomerulonephritis. There appears to be an association with autoimmune disorders, infections, and malignancies. Gradually worsening symptoms include fatigue, anemia, hypertension, edema, and oliguria. Examination of the urine reveals hematuria, proteinuria, glucosuria as a result of tubular dysfunction, and many varieties of casts, including broad casts. Henoch-Schцnlein Purpura Henoch-Schцnlein purpura disease occurs primarily in children after upper respiratory infections. In other patients, progression to a more serious form of glomerulonephritis and renal failure may occur. Urinalysis and renal function assessment should be used to monitor patients following recovery from the original symptoms. Patients have increased serum levels of IgA, which may be a result of a mucosal infection. Recovery from the macroscopic hematuria is spontaneous; however, asymptomatic microhematuria and elevated serum levels of IgA remain.

Otoliths may be dislodged by head injury or infection or due to the normal degeneration of aging anxiety symptoms 6 weeks buy phenergan 25 mg mastercard. The head movements are designed to use the force of gravity to dislodge loose otoliths from the semicircular canals and move them back into the gelatinous membranes within the utricle and saccule anxiety symptoms throwing up order phenergan 25 mg without prescription. Because multiple treatments are sometimes required anxiety symptoms change cheap phenergan online, he was given instructions on how to self-administer a modified Epley maneuver at home; within 3 weeks anxiety symptoms like heart attack 25 mg phenergan order amex, his vertigo was gone anxiety vision purchase phenergan cheap online. When the frequency of action potentials along sensory neurons is constant as long as a stimulus continues, it is called "adaptation. When sensory units have large receptive fields, the acuity of perception is greater. The modality of energy a given sensory receptor responds to in normal functioning is known as the "adequate stimulus" for that receptor. Receptor potentials are "all or none," that is, they have the same magnitude regardless of the strength of the stimulus. Using a single intracellular recording electrode, in what part of a sensory neuron could you simultaneously record both receptor potentials and action potentials? Presynaptic axo­axonal synapses reduce neurotransmitter release at excitatory synapses. When a stimulus is maintained for a long time, action potentials from sensory receptors decrease in frequency with time. Descending inputs from the brainstem inhibit afferent pain pathways in the spinal cord. Inhibitory interneurons decrease action potentials from receptors at the periphery of a stimulated region. The eyeball is too long; far objects focus on the retina when the ciliary muscle contracts. The eyeball is too long; near objects focus on the retina when the ciliary muscle is relaxed. The eyeball is too short; near objects focus on the retina when the ciliary muscle is relaxed. If a patient suffers a stroke that destroys the optic tract on the right side of the brain, which of the following visual defects will result? There will be no vision in the left eye, but vision will be normal in the right eye. The patient will not perceive images of objects striking the left half of the retina in the left eye. The patient will not perceive images of objects striking the right half of the retina in the right eye. Displacement of the basilar membrane with respect to the tectorial membrane stimulates stereocilia on the hair cells. Pressure waves on the oval window cause vibrations of the malleus, which are transferred via the stapes to the round window. Movement of the stapes causes oscillations in the tympanic membrane, which is in contact with the endolymph. Oscillations of the stapes against the oval window set up pressure waves in the semicircular canals. A standing subject looking over her left shoulder suddenly rotates her head to look over her right shoulder. The utricle goes from a vertical to a horizontal position, and otoliths stimulate stereocilia. Stretch receptors in neck muscles send action potentials to the vestibular apparatus, which relays them to the brain. Fluid within the semicircular canals remains stationary, bending the cupula and stereocilia as the head rotates. The movement causes endolymph in the cochlea to rotate from right to left, stimulating inner hair cells. A key general principle of physiology is that homeostasis is essential for health and survival. How might sensory receptors responsible for detecting painful stimuli (nociceptors) contribute to homeostasis? Elaboration of surface area to maximize functional capability is a common motif in the body illustrating the general principle of physiology that structure is a determinant of - and has coevolved with - function. Describe several mechanisms by which pain could theoretically be controlled medically or surgically. At what two sites would central nervous system injuries interfere with the perception that heat is being applied to the right side of the body? At what single site would a central nervous system injury interfere with the perception that heat is being applied to either side of the body? Damage to what parts of the cerebral cortex could explain the following behaviors? Because retinal is also used in cone photopigments, a severe vitamin A deficiency eventually results in impairment of vision under all lighting conditions, being generally most noticeable at night when less light is available. Action potential propagation to the central nervous system would also be normal because it depends only on voltage-gated Na1 and K1 channels. The drug would inhibit neurotransmitter release from the central axon terminal, however, because vesicle exocytosis requires Ca21 entry through voltage-gated channels. The outer half of the visual field seen by each eye would be dark because neurons from the inner half of the retinas that cross at the optic chiasm would not reach the visual cortex. The right half of the visual field seen by each eye would be perceived as dark because the left occipital lobe processes neuronal input from the left half of each retina. When pressure is initially applied, the fluid in the capsule compresses the nerve ending, opening mechanically gated nonspecific cation channels and causing depolarization and action potentials. However, fluid then redistributes within the capsule, taking the pressure off the nerve ending; consequently, the channels close and the neuron repolarizes. When the pressure is removed, redistribution of the capsule back to its original shape briefly deforms the nerve ending once again and a brief depolarization results. Without the specialized capsule, the afferent nerve ending becomes a slowly adapting receptor; as long as pressure is applied, the mechanoreceptors remain open and the receptor potential and action potentials persist. When you shift your gaze to the white background (white light contains all wavelengths of light), only the blue cones are available to respond, so you perceive a blue circle until the red and green cones recover. Lung infections are often accompanied by an accumulation of fluid in the lungs, which is detectable with a stethoscope as crackling or bubbling sounds during breathing. With those muscles contracted, the movement of the middle ear bones is dampened during the 140 dB gun blast, thus reducing the transmission of that harmfully loud sound to the inner ear. Below the level of the injury, however, there would be a mixed pattern of sensory loss. Fine touch, pressure, and body position sensation would be lost from the left side of the body below the level of the injury because that information ascends in the spinal cord on the side that it enters without crossing the midline until it reaches the brainstem. Pain and temperature sensation would be lost from the right side of the body below the injury because those pathways cross immediately upon entry and ascend in the opposite side of the spinal cord. It appears to play a role in generating the unusually high K1 concentration found in the endolymph. Inhibiting this transporter with furosemide reduces the K1 concentration in the endolymph, which reduces the ability of hair cells to depolarize when sound waves bend the tip links. Less depolarization reduces Ca21 entry, glutamate release, and action potentials in the cochlear nerve, which in turn would reduce the perception of sound. It would not be visible, because visible light frequencies are in the range of 1014 to 1015 Hz. Altered States of Consciousness Schizophrenia the Mood Disorders: Depressions and Bipolar Disorders Psychoactive Substances, Dependence, and Tolerance 8 C 8. We discuss the general phenomenon of consciousness and its variable states of existence, as well some of the important neural mechanisms involved in the processing of our experiences. Although advances in electrophysiological and brain-imaging techniques are yielding fascinating insights, there is still much that we do not know about these topics. If you can imagine that, for any given neuron, there may be as many as 200,000 other neurons connecting to it through synapses, you can begin to appreciate the complexity of the systems that control even the simplest behavior. The general principle of physiology most obviously on display in this chapter is that information f low between cells, tissues, and organs is an essential feature of homoeostasis and allows for integration of physiological processes. The nervous system "information" discussed previously involved phenomena like chemical and electrical gradients, graded potentials, and 234 action potentials. Those are the essential physiological building blocks for the higher-order processes discussed in this chapter, which include our abilities to consciously pay attention, be motivated, learn, remember, and communicate with others. These abilities are essential determinants of many complex behaviors that help us maintain homeostasis. The first concept refers to levels of alertness such as being awake, drowsy, or asleep. The second refers to experiences a person is aware of - thoughts, feelings, perceptions, ideas, dreams, reasoning - during any of the states of consciousness. Electroencephalogram Neural activity is manifested by the electrical signals known as graded potentials and action potentials (Chapter 6). In other words, it indicates the degree of synchronous firing of the neurons that are generating the synaptic activity. On the other hand, a small amplitude indicates that these neurons are less activated or are firing asynchronously. The frequency of the wave indicates how often it cycles from the maximal to the minimal amplitude and back. The frequency is measured in hertz (Hz, or cycles per second) and may vary from 0. Wave patterns vary not only as a function of state of consciousness but also according to where on the scalp they are recorded. Current thinking is that clusters of neurons in the thalamus play a critical role; they provide a fluctuating action potential frequency output through neurons leading from the thalamus to the cortex. This output, in turn, causes a rhythmic pattern of synaptic activity in the pyramidal neurons of the cortex. These clusters receive input from brain areas involved in controlling the conscious state. It was formerly also used in the detection of brain areas damaged by tumors, blood clots, or hemorrhage. Epilepsy is a common neurological disease, occurring in about 1% of the population. It manifests in mild, intermediate, and severe forms and is associated with abnormally synchronized discharges of cerebral neurons. Epilepsy is also associated with changes in behavior that vary according to the part of the brain affected and severity and can include involuntary muscle contraction and a temporary loss of consciousness. Among the known triggers are traumatic brain injury, abnormal prenatal brain development, diseases that alter brain blood flow, heavy alcohol and illegal drug use, infectious diseases like meningitis and viral encephalitis, extreme stress, sleep deprivation, and exposure to environmental toxins such as lead or carbon monoxide. Alpha waves vary from 8 to 13 Hz and have larger amplitudes than beta waves, which have frequencies above 13 Hz. The Waking State Behaviorally, the waking state is far from homogeneous, reflecting the wide variety of activities you may be engaged in at any given moment. The alpha rhythm is recorded best over the parietal and occipital lobes and is associated with decreased levels of attention. When alpha rhythms are generated, subjects commonly report that they feel relaxed and happy. However, people who normally experience more alpha rhythm than usual have not been shown to be psychologically different from those with less. These are high-frequency oscillations (30­100 Hz) that spread across large regions of the cortex, which seem in some cases to emanate from the thalamus. They often coincide with the occurrence of combinations of stimuli like hearing noises and seeing objects and are thought to be evidence of large numbers of neurons in the brain actively tying together disparate parts of an experienced scene or event. As a person becomes increasingly drowsy, his or her wave pattern transitions from a beta rhythm to a predominantly alpha rhythm. In stage N2, high-frequency bursts called sleep spindles and large-amplitude K complexes occasionally interrupt the theta rhythm. The large-amplitude delta waves of slow-wave sleep demonstrate the synchronous activity pattern in cortical neurons. This is true even in people who usually do not remember dreaming when they awaken on their own. Initially, as you transition from drowsiness to stage N1 sleep, there is a considerable tension in the postural muscles, and brief muscle twitches called hypnic jerks sometimes occur. Exceptions include the eye muscles, which undergo rapid bursts of contractions and cause the sweeping eye movements that give this sleep stage its name. Experiments suggest that they do not seem to rigorously correlate with the content of dreams; that is, what the sleeper is "seeing" in a dream does not seem to affect the eye movements. In one form of a disease known as sleep apnea, however, stimulation of the respiratory muscles temporarily ceases, sometimes hundreds of times during a night. As a result, this disease is associated with excessive - and sometimes dangerous - sleepiness during the day (refer to Chapter 13 for a more complete discussion of sleep apnea). Consciousness, the Brain, and Behavior 237 During the sleep cycle, many changes occur throughout the body in addition to altered muscle tension, providing an excellent example of the general principle of physiology that the functions of organ systems are coordinated with each other. Moreover, twitches of the facial muscles or limb muscles may occur - despite the generalized lack of skeletal muscle tone - as may erection of the penis and engorgement of the clitoris. Although we spend about one-third of our lives sleeping, the functions of sleep are not completely understood. Many lines of research, however, suggest that sleep is a fundamental necessity of a complex nervous system. Sleep, or a sleeplike state, is a characteristic found throughout the animal kingdom, including insects, reptiles, birds, mammals, and others. Studies of sleep deprivation in humans and other animals suggest that sleep is a homeostatic requirement, similar to the need for food and water. Deprivation of sleep impairs the immune system, causes cognitive and memory deficits, and ultimately leads to psychosis and even death.

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