By F. Gorok. Ouachita Baptist University. 2019.

Areas that need more attention are improvement of infection-control measures to prevent transmission generic 50 mg cozaar, expansion of high-quality diagnostic services for timely detection of cases and expansion of community involvement to improve adherence buy discount cozaar 50 mg on line. However discount 25mg cozaar with amex, perhaps the most fundamental area for attention is the development of treatment programmes into which patients can be enrolled and treated successfully discount cozaar online mastercard. Unfortunately, there are few new drugs in the pipeline, making it unlikely that new compounds will be available to respond to the pressing need. The report also provides the most up-to-date trends from 47 countries, collected over a 13-year period. A report is published every three years because most countries require 12–18 months to complete a drug-resistance survey. However, the project has not met several of its initial goals, suggesting that it may be time to review some of the project methods. Adjustment of regimens is limited not by lack of data but by the lack of availability of new drugs and treatments. Interim drug- resistance surveillance guidelines were published in 2007, and a meeting planned for 2008 to review current methods in drug resistance surveillance will provide key input for revising these technical guidelines. Drug resistance among previously treated cases Resistance among previously treated cases is defined as the presence of resistant isolates of M. Combined proportion of drug resistance “Combined proportion of drug resistance” is the proportion of drug resistance in the population surveyed, regardless of prior treatment. Despite the importance of the distinction between drug resistance among new and previously treated cases, 36 countries reported data on cases with unknown treatment history. In most countries, this group of cases represented a small proportion of total cases; however, in eight countries (Australia, Fiji, Guam, New Caledonia, Puerto Rico, Qatar, Solomon Islands and the United States of America), and in one city in Spain (Barcelona), this was the only group reported or represented in most cases. Combined figures represent data collected on new and previously treated cases, and on all cases with an unknown treatment history. The countries Cuba, France, Italy and Japan operate sentinel networks for surveillance. Trend data from Germany and from the United Kingdom are evaluated from 2001 because surveillance methods changed in that year. Sentinel surveillance reports annual data from the same sites, with the exception of Japan, which conducts sentinel surveys every three years. Surveys are periodic, and reflect the population of registered pulmonary smear-positive cases. Depending on the area surveyed, a cluster-sampling technique may be adopted, or all diagnostic units may be included. While some countries, such as Botswana, repeat surveys every 3–5 years, for the purposes of this report they are considered as repeated surveys and not surveillance. Survey areas In both survey and surveillance settings, the coverage area is usually the entire country, but in some cases, subnational units are surveyed. Large countries, such as Brazil, China, India, Indonesia, the Russian Federation and South Africa, tend to survey large administrative units (e. Some countries have opted to limit surveys or surveillance to metropolitan areas, as in the case of Azerbaijan, China and Uzbekistan. Cuba, France, Italy and Japan) conduct sentinel surveillance, and some other countries have restricted surveys to subnational areas, either because of the remoteness of certain provinces or to avoid conflict areas. Separate sample sizes should be calculated for new cases and previously treated cases. However, the number of sputum-positive previously treated cases reported per year is usually small, meaning that a long intake period needed to achieve a statistically adequate sample size. Therefore, most countries have obtained an estimate of the drug-resistance level among previously treated cases by including all previously treated cases who present at centres during the intake period. While this may not provide a statistically adequate sample size, it can nevertheless give a reasonable estimate of drug resistance among previously treated cases. Surveys in Armenia, Baku City (Azerbaijan), Georgia, Gujarat state (India) were designed with separate sample sizes for re-treatment cases. Once fully implemented, these routine data will provide estimates of drug resistance in these populations. Survey protocols The quality of survey protocols has improved over the last 10 years. Most protocols reviewed in Phase 4 of the project were complete, and included detailed budgets, timelines and plans for quality assurance at several levels. Most of the protocols reviewed were submitted through a local ethics review board or through the ethics review board of a technical partner supporting the project. Survey data were reported from 35 countries or geographical settings, and surveillance data from 48 countries or geographical settings. Data from laboratory registers from South Africa were reported but not included in any analyses. These settings were Cuba, Honduras, Latvia, the Russian Federation (Tomsk Oblast), Spain (Barcelona and Galicia), Ukraine (Donetsk Oblast) and Uruguay. Among these settings, seven were able to report information for more than one year. Most countries cross-checked patient history collected in the survey with medical records, but fewer countries re- interviewed a percentage of patients. All new data reported have been returned to countries for verification before publication. The global project requests that survey protocols include a description of methods used for the quality assurance of data collection, entry and analysis. In surveillance settings, a combination of smear and culture was used for initial diagnosis. Some laboratories inoculated sodium hydroxide decontaminated specimen directly onto Ogawa medium without centrifugation. Laboratories in high-income countries generally used liquid medium or agar-based medium. The proportion method was most frequently used in all phases of the global project. Resistance was expressed as the percentage of colonies that grew on recommended critical concentrations of the drugs tested; that is, 0. The criterion used for drug resistance was growth of 1% or more of the bacterial population on media containing the critical concentration of each drug. Quality assurance of laboratories Proficiency testing and retesting of a proportion of survey strains are two components of external quality assurance of laboratories17. The percentage of isolates sent for checking is determined before the beginning of the survey. Adequate performance is defined as no more than one false-positive or false-negative result for rifampicin or isoniazid, and no more than two for streptomycin or ethambutol. Fiji and Vanuatu are supported by Queensland Mycobacterium Reference Laboratory, Brisbane, Australia. The Solomon Islands are supported by the Mycobacterium Reference Laboratory, Institute of Medical and Veterinary Science, Adelaide, Australia. The Commonwealth of the Northern Marianas Island is supported by the Hawaii State Laboratory, Honolulu, Hawaii, United States. Guam is supported by the Microbial Diseases Laboratory, San Francisco, California, United States. Information on methods used and quality assurance were not collected for this report. All data (in the form of annexed tables) were returned to the country for a final review before publication, and were then entered into a Microsoft Access database. Statistical analysis Drug-resistance data for new, previously treated and combined cases were analysed. Arithmetic means, medians and ranges were determined as summary statistics for new, previously treated and combined cases; for individual drugs; and for pertinent combinations. For geographical settings reporting more than a single data point since the third report, only the latest data point was used for the estimation of point proportion. Population- 31 weighted means from the last data point of all countries reporting to the project were calculated to reflect the mean proportion of resistance by region, based on countries within the region reporting data to the project.

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Neurofibrillary changes consist of tortuous purchase 50mg cozaar with visa, argyrophilic (stain with silver dyes) discount cozaar generic, tau positive fibrils found in the neuropil (neuropil threads) cheap 50 mg cozaar mastercard, in the halo of neuritic plaques (dystrophic neurites) 50mg cozaar overnight delivery, in the cytoplasm of pyramidal neurons (flame shaped neurofibrillary tangles) or oval neurons (globose tangles) and in the cytoplasm of oligodendrocytes or astrocytes (glial cytoplasmic tangles). Tau labeled glial cytoplasmic inclusions are observed in certain forms of familial frontotemporal dementia associated with parkinsonism due to a mutation involving the tau gene on chromosome 17. C) Bodian silver method: “ghost” tangles, which consist of residual, extracellular tangles following the subtotal or total resorption of the affected neurons. Neuritic plaques develop in the cerebral cortex, amygdala, hippocampal formation, and in the striatum especially in the nucleus accumbens. They may occur in the thalamus particularly within the dorsomedian and anterior nuclei; and in the cerebellar cortex. The ‘classical’ or ‘neuritic plaques’ are a spherical lesion, the diameter of which measures 50 to 180 µm (Fig. They are composed of a centrally located Congo red positive amyloid core (β-amyloid). Reactive astrocytes tend to be at the periphery of the plaques and in the parenchyma surrounding the plaques. They are more frequent in people with dementia than in intellectually normal subjects. They may derive from an age-related alteration of the microfilamentous actin system. Age related volume loss of the brain involves the white matter more than the gray matter. Extensive loss of the cerebral white matter with subsequent dementia may be caused by vasculopathies. Hypertensive vascular changes (fibrosis of the walls of the vessels) cause hypoperfusion of the centrum semi-ovale. A gradual loss of oligodendrocytes, myelin and neuronal processes occurs with a reactive gliosis and widening of the perivascular spaces. Prominent involvement of the subcortical white matter is termed Binswanger disease. Dementing illnesses with a destructive or demyelinating process include progressive multifocal leukoencephalopathy, the encephalopathy of the acquired immune deficiency syndrome, and multiple sclerosis. Formalin fixed, coronal slice of the right cerebral hemisphere of a 93-year-old, demented woman. The dorsal, elongated framed area includes part of the nucleus basalis of Meynert or substantia innominata. Among other areas, the substantia innominata including the nucleus basalis of Meynert, and the amygdala degenerate in Alzheimer disease, Alzheimer disease Lewy body variant, diffuse Lewy body disease, and in Parkinson disease. The rostral half of the thalamus may be atrophic (usually medial > lateral) in Pick disease. Formalin fixed, coronal slice of the left cerebral hemisphere of a 83-year-old demented man. The dorsomedian nucleus and the anterior nucleus of the thalamus, which are the limbic nuclei, are severely atrophic. The lateral ventricle is widened, as is the sylvian fissure reflecting the loss of parenchyma. Medial aspect of the hemi brainstem including the lower edge of the mesencephalon, which contains a portion of the substantia nigra, especially the pars compacta. The short (blue) bar within the fourth ventricle indicates the site of the locus coeruleus. Resting on the ventral aspect of the pons is the longitudinally sectioned, normal basilar artery. In summary, the areas that are vulnerable to degeneration causing dementing illnesses with or without movement disorders are amygdala; allocortex: entorhinal and pyriform cortices, hippocampal formation; mammillary bodies, anterior and dorsomedian nuclei of thalamus; neocortex (homotypical > heterotypical); neostriatum, nucleus coeruleus, and raphe nuclei. The growing awareness of the early signs of mental decline caused by neurodegeneration has increased the 7 8 incidence of the diagnosis of dementia. Likewise, the increasing life expectancy with the 9 growing number of elderly individuals raises the prevalance of dementing illnesses since dementia or neurodegeneration occurs primarily late in life. On external examination of the brain the hallmarks of atrophy are the narrowing of the gyri and widening of the sulci (Fig. The atrophy is diffuse with a predilection for the prefrontal, parietal, and temporal regions. On examination of the cut sections, the brunt of the atrophy involves the white matter and cortex notably in the areas mentioned above; the amygdaloid nucleus, hippocampal formation, and the anterior part of the thalamus. The ventricular system is widened proportionally to the volume loss of the parenchyma. The nucleus coeruleus is pale in contrast to the usually well-pigmented pars compacta of the substantia nigra. The microscopic changes are found almost throughout the brain; however, their severity varies according to the regions. Especially involved are the areas exhibiting the most prominent atrophy including the amygdaloid nucleus, hippocampal formation, and the following regions of the cerebral cortex: temporal, prefrontal, and parietal. The pathologic changes include: 1) A decrease of neuronal density the severity of which varies according to region 2) Neurofibrillary tangles of Alzheimer (Figure 8). In advanced stages of the disease they may be found within the motor or visual cortices or both. Neuronal tangles occur within the amygdaloid nucleus, hippocampus, substantia innominata (nucleus of Meynert), hypothalamus, thalamus, raphe nuclei, nucleus coeruleus, and reticular formation. Amyloid may gradually accumulate within the walls of medium size leptomeningeal or cortical vessels (Fig. Amyloid replaced the smooth muscle fibers as inferred by the absence of their nuclei within the media (Hematoxylin and eosin). Right: Section subjected to antibodies directed against β-amyloid, which labeled the abnormal deposits present within the wall of the vessel and within the surrounding parenchyma. The frequency of this vasculopathy increases with age and occurs often in elderly people including those without cognitive impairment. The mutations lie either within the amyloid peptide region itself or adjacent to it. These genes are highly homologous and encode for a transmembrane protein that is 64 part of the γ-secretase protein complex. The highest association is seen with e4 homozygous individuals, with a lesser association with e4 heterozygotes. Senile plaques typically exhibit varying degrees of reactive cellular response by microglia and astrocytes, both of which are known to produce cytokines. In the recent past there was considerable interest in the effects of aluminum, because neurons that contain tangles also appeared to contain high levels of aluminum, and 65 because the injection of aluminum salts into brains of experimental animals produced accumulations of neurofilaments in neuronal cell bodies and axons. Many kindreds have been linked to chromosome 17, with mutations identified in the tau gene and progranulin gene. The patients are phenotypically heterogeneous even within the same kindred, although consistent features occur. The atrophy usually predominates within the frontal, or fronto-temporal, or fronto- temporal-parietal regions (Fig. Right: Microphotograph of the stratum granulosum of the dentate gyrus showing ubiquitinated cytoplasmic inclusions involving scattered granular neurons. The hallmarks of Pick disease are: - Diffuse atrophy with regional, circumscribed accentuation of the atrophy (Fig. They are found in cortical pyramidal neurons and in the hippocampal formation; and in the amygdala, and occasionally within the striatum and brainstem. Pick bodies are found in about 30 to 50 percent of brains from demented patients with discrete, circumscribed atrophy. Left: Pyramidal neurons of the Sommer sector of the hippocampus, Bielschowsky, original magnification 200X. Ballooned neurons are found in a variety of neurodegenerative diseases included Pick disease and Alzheimer disease. Left: Micrographs of two ballooned neurons or Pick cells from the cingulate gyrus of a 88-year-old woman with dementia. Right: Ballooned neurons may represent a stage of the cell body during the degenerating process of the neuron starting at the distal end of the axon (neuronal dying-back phenomenon, or “nucleo distal” atrophy, or centripetal atrophy) Spatz H. The disease is characterized by a constellation of neurological symptoms collectively termed Parkinsonism, including resting tremor, bradykinesia, rigidity and postural instability (gait disturbance). Elderly individuals are predominantly involved (the exception being the rare form of juvenile Parkinson disease).

This rapid influx of positively charged ions raises the membrane potential to approximately +30 mV cheap cozaar 50mg with visa, at which point the sodium channels close purchase cozaar 50mg line. Depolarization is followed by the plateau phase discount cozaar 50 mg without prescription, in which membrane potential declines relatively 2+ 2+ + slowly buy cozaar in india. This is due in large part to the opening of the slow Ca channels, allowing Ca to enter the cell while few K + channels are open, allowing K to exit the cell. Once the 2+ + + membrane potential reaches approximately zero, the Ca channels close and K channels open, allowing K to exit the cell. At this point, membrane potential drops until it reaches resting levels once more and the cycle repeats. The absolute refractory period for cardiac contractile muscle lasts approximately 200 ms, and the relative refractory period lasts approximately 50 ms, for a total of 250 ms. This extended period is critical, since the heart muscle must contract to pump blood effectively and the contraction must follow the electrical events. Without extended refractory periods, premature contractions would occur in the heart and would not be compatible with life. The extended refractory period allows the cell to fully contract before another electrical event can occur. Their influx through slow calcium channels accounts for the prolonged plateau phase and absolute refractory period that enable cardiac muscle to function properly. Calcium ions also combine with the regulatory protein troponin in the troponin-tropomyosin complex; this complex removes the inhibition that prevents the heads of the myosin molecules from forming cross bridges with the active sites on actin that provide the power stroke of contraction. The bundle branches would have an inherent rate of 20–30 impulses per minute, and the Purkinje fibers would fire at 15–20 impulses per minute. While a few exceptionally trained aerobic athletes demonstrate resting heart rates in the range of 30–40 beats per minute (the lowest recorded figure is 28 beats per minute for Miguel Indurain, a cyclist), for most individuals, rates lower than 50 beats per minute would indicate a condition called bradycardia. Depending upon the specific individual, as rates fall much below this level, the heart would be unable to maintain adequate flow of blood to vital tissues, initially resulting in decreasing loss of function across the systems, unconsciousness, and ultimately death. Electrocardiogram By careful placement of surface electrodes on the body, it is possible to record the complex, compound electrical signal of the heart. The term “lead” may be used to refer to the cable from the electrode to the electrical recorder, but it typically describes the voltage difference between two of the electrodes. The 12-lead electrocardiograph uses 10 electrodes placed in standard locations on the patient’s skin (Figure 19. In continuous ambulatory electrocardiographs, the patient wears a small, portable, battery-operated device known as a Holter monitor, or simply a Holter, that continuously monitors heart electrical activity, typically for a period of 24 hours during the patient’s normal routine. Each component, segment, and interval is labeled and corresponds to important electrical events, demonstrating the relationship between these events and contraction in the heart. Since the Q wave may be difficult to view in some tracings, the measurement is often extended to the R that is more easily visible. Such an area, which may actually be a component of the conduction system or some other contractile cells, is known as an ectopic focus or ectopic pacemaker. An ectopic focus may be stimulated by localized ischemia; exposure to certain drugs, including caffeine, digitalis, or acetylcholine; elevated stimulation by both sympathetic or parasympathetic divisions of the autonomic nervous system; or a number of disease or pathological conditions. Occasional occurances are generally transitory and nonlife threatening, but if the condition becomes chronic, it may lead to either an arrhythmia, a deviation from the normal pattern of impulse conduction and contraction, or to fibrillation, an uncoordinated beating of the heart. In general, the size of the electrical variations, the duration of the events, and detailed vector analysis provide the most comprehensive picture of cardiac function. Additionally, it will not reveal the effectiveness of the pumping, which requires further testing, such as an ultrasound test called an echocardiogram or nuclear medicine imaging. External Automated Defibrillators In the event that the electrical activity of the heart is severely disrupted, cessation of electrical activity or fibrillation may occur. In fibrillation, the heart beats in a wild, uncontrolled manner, which prevents it from being able to pump effectively. The most common treatment is defibrillation, which uses special paddles to apply a charge to the heart from an external electrical source in an attempt to establish a normal sinus rhythm (Figure 19. These devices contain simple and direct verbal instructions that can be followed by nonmedical personnel in an attempt to save a life. In order to speed up the heart rate and restore full sinus rhythm, a cardiologist can implant an artificial pacemaker, which delivers electrical impulses to the heart muscle to ensure that the heart continues to contract and pump blood effectively. These artificial pacemakers are programmable by the cardiologists and can either provide stimulation temporarily upon demand or on a continuous basis. Oxygen from the lungs is brought to the heart, and every other organ, attached to the hemoglobin molecules within the erythrocytes. Normally, these two mechanisms, circulating oxygen and oxygen attached to myoglobin, can supply sufficient oxygen to the heart, even during peak performance. Both fatty acid droplets and glycogen are stored within the sarcoplasm and provide additional nutrient supply. The period of contraction that the heart undergoes while it pumps blood into circulation is called systole. Both the atria and ventricles undergo systole and diastole, and it is essential that these components be carefully regulated and coordinated to ensure blood is pumped efficiently to the body. Pressures and Flow Fluids, whether gases or liquids, are materials that flow according to pressure gradients—that is, they move from regions that are higher in pressure to regions that are lower in pressure. Accordingly, when the heart chambers are relaxed (diastole), blood will flow into the atria from the veins, which are higher in pressure. As blood flows into the atria, the pressure will rise, so the blood will initially move passively from the atria into the ventricles. When the action potential triggers the muscles in the atria to contract (atrial systole), the pressure within the atria rises further, pumping blood into the ventricles. During ventricular systole, pressure rises in the ventricles, pumping blood into the pulmonary trunk from the right ventricle and into the aorta from the left ventricle. Again, as you consider this flow and relate it to the conduction pathway, the elegance of the system should become apparent. Phases of the Cardiac Cycle At the beginning of the cardiac cycle, both the atria and ventricles are relaxed (diastole). Blood is flowing into the right atrium from the superior and inferior venae cavae and the coronary sinus. The two atrioventricular valves, the tricuspid and mitral valves, are both open, so blood flows unimpeded from the atria and into the ventricles. The two semilunar valves, the pulmonary and aortic valves, are closed, preventing backflow of blood into the right and left ventricles from the pulmonary trunk on the right and the aorta on the left. As the atrial muscles contract from the superior portion of the atria toward the atrioventricular septum, pressure rises within the atria and blood is pumped into the ventricles through the open atrioventricular (tricuspid, and mitral or bicuspid) valves. At the start of atrial systole, 862 Chapter 19 | The Cardiovascular System: The Heart the ventricles are normally filled with approximately 70–80 percent of their capacity due to inflow during diastole. Atrial contraction, also referred to as the “atrial kick,” contributes the remaining 20–30 percent of filling (see Figure 19. Atrial systole lasts approximately 100 ms and ends prior to ventricular systole, as the atrial muscle returns to diastole. At the end of atrial systole and just prior to atrial contraction, the ventricles contain approximately 130 mL blood in a resting adult in a standing position. Initially, as the muscles in the ventricle contract, the pressure of the blood within the chamber rises, but it is not yet high enough to open the semilunar (pulmonary and aortic) valves and be ejected from the heart. This increase in pressure causes blood to flow back toward the atria, closing the tricuspid and mitral valves. Since blood is not being ejected from the ventricles at this early stage, the volume of blood within the chamber remains constant. Consequently, this initial phase of ventricular systole is known as isovolumic contraction, also called isovolumetric contraction (see Figure 19. In the second phase of ventricular systole, the ventricular ejection phase, the contraction of the ventricular muscle has raised the pressure within the ventricle to the point that it is greater than the pressures in the pulmonary trunk and the aorta. Pressure generated by the left ventricle will be appreciably greater than the pressure generated by the right ventricle, since the existing pressure in the aorta will be so much higher. During the early phase of ventricular diastole, as the ventricular muscle relaxes, pressure on the remaining blood within the ventricle begins to fall. When pressure within the ventricles drops below pressure in both the pulmonary trunk and aorta, blood flows back toward the heart, producing the dicrotic notch (small dip) seen in blood pressure tracings. Since the atrioventricular valves remain closed at this point, there is no change in the volume of blood in the ventricle, so the early phase of ventricular diastole is called the isovolumic ventricular relaxation phase, also called isovolumetric ventricular relaxation phase (see Figure 19.

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There are also minute nerves within the walls of both types of vessels that control the contraction and dilation of smooth muscle cozaar 25mg amex. Both arteries and veins have the same three distinct tissue layers discount 25mg cozaar visa, called tunics (from the Latin term tunica) purchase cozaar, for the garments first worn by ancient Romans discount 50 mg cozaar overnight delivery; the term tunic is also used for some modern garments. From the most interior layer to the outer, these tunics are the tunica intima, the tunica media, and the tunica externa (see Figure 20. Comparison of Tunics in Arteries and Veins Arteries Veins General Thick walls with small lumens Thin walls with large lumens appearance Generally appear rounded Generally appear flattened Endothelium usually appears wavy due to constriction of Endothelium appears smooth Tunica intima smooth muscle Internal elastic membrane Internal elastic membrane present in larger vessels absent Normally thinner than the tunica externa Smooth muscle cells and Normally the thickest layer in arteries collagenous fibers Smooth muscle cells and elastic fibers predominate (the Tunica media predominate proportions of these vary with distance from the heart) Nervi vasorum and vasa External elastic membrane present in larger vessels vasorum present External elastic membrane absent Normally the thickest layer in veins Normally thinner than the tunica media in all but the largest Collagenous and smooth arteries Tunica externa fibers predominate Collagenous and elastic fibers Some smooth muscle fibers Nervi vasorum and vasa vasorum present Nervi vasorum and vasa vasorum present Table 20. Lining the tunica intima is the specialized simple squamous epithelium called the endothelium, which is continuous throughout the entire vascular system, including the lining of the chambers of the heart. Damage to this endothelial lining and exposure of blood to the collagenous fibers beneath is one of the primary causes of clot formation. Until recently, the endothelium was viewed simply as the boundary between the blood in the lumen and the walls of the vessels. Recent studies, however, have shown that it is physiologically critical to such activities as helping to regulate capillary exchange and altering blood flow. The endothelium releases local chemicals called endothelins that can constrict the smooth muscle within the walls of the vessel to increase blood pressure. Uncompensated overproduction of endothelins may contribute to hypertension (high blood pressure) and cardiovascular disease. Next to the endothelium is the basement membrane, or basal lamina, that effectively binds the endothelium to the connective tissue. The basement membrane provides strength while maintaining flexibility, and it is permeable, allowing materials to pass through it. The thin outer layer of the tunica intima contains a small amount of areolar connective tissue that consists primarily of elastic fibers to provide the vessel with additional flexibility; it also contains some collagenous fibers to provide additional strength. In larger arteries, there is also a thick, distinct layer of elastic fibers known as the internal elastic membrane (also called the internal elastic lamina) at the boundary with the tunica media. Like the other components of the tunica intima, the internal elastic membrane provides structure while allowing the vessel to stretch. It is permeated with small openings that 892 Chapter 20 | The Cardiovascular System: Blood Vessels and Circulation allow exchange of materials between the tunics. In addition, many veins, particularly in the lower limbs, contain valves formed by sections of thickened endothelium that are reinforced with connective tissue, extending into the lumen. Under the microscope, the lumen and the entire tunica intima of a vein will appear smooth, whereas those of an artery will normally appear wavy because of the partial constriction of the smooth muscle in the tunica media, the next layer of blood vessel walls. It is generally the thickest layer in arteries, and it is much thicker in arteries than it is in veins. The tunica media consists of layers of smooth muscle supported by connective tissue that is primarily made up of elastic fibers, most of which are arranged in circular sheets. Contraction and relaxation of the circular muscles decrease and increase the diameter of the vessel lumen, respectively. Specifically in arteries, vasoconstriction decreases blood flow as the smooth muscle in the walls of the tunica media contracts, making the lumen narrower and increasing blood pressure. Similarly, vasodilation increases blood flow as the smooth muscle relaxes, allowing the lumen to widen and blood pressure to drop. Both vasoconstriction and vasodilation are regulated in part by small vascular nerves, known as nervi vasorum, or “nerves of the vessel,” that run within the walls of blood vessels. These are generally all sympathetic fibers, although some trigger vasodilation and others induce vasoconstriction, depending upon the nature of the neurotransmitter and receptors located on the target cell. Parasympathetic stimulation does trigger vasodilation as well as erection during sexual arousal in the external genitalia of both sexes. Nervous control over vessels tends to be more generalized than the specific targeting of individual blood vessels. Together, these neural and chemical mechanisms reduce or increase blood flow in response to changing body conditions, from exercise to hydration. The smooth muscle layers of the tunica media are supported by a framework of collagenous fibers that also binds the tunica media to the inner and outer tunics. Along with the collagenous fibers are large numbers of elastic fibers that appear as wavy lines in prepared slides. Separating the tunica media from the outer tunica externa in larger arteries is the external elastic membrane (also called the external elastic lamina), which also appears wavy in slides. Tunica Externa The outer tunic, the tunica externa (also called the tunica adventitia), is a substantial sheath of connective tissue composed primarily of collagenous fibers. This is normally the thickest tunic in veins and may be thicker than the tunica media in some larger arteries. The outer layers of the tunica externa are not distinct but rather blend with the surrounding connective tissue outside the vessel, helping to hold the vessel in relative position. If you are able to palpate some of the superficial veins on your upper limbs and try to move them, you will find that the tunica externa prevents this. If the tunica externa did not hold the vessel in place, any movement would likely result in disruption of blood flow. All arteries have relatively thick walls that can withstand the high pressure of blood ejected from the heart. However, those close to the heart have the thickest walls, containing a high percentage of elastic fibers in all three of their tunics. Their abundant elastic fibers allow them to expand, as blood pumped from the ventricles passes through them, and then to recoil after the surge has passed. If artery walls were rigid and unable to expand and recoil, their resistance to blood flow would greatly increase and blood pressure would rise to even higher levels, which would in turn require the heart to pump harder to increase the volume of blood expelled by each pump (the stroke volume) and maintain adequate pressure and flow. The elastic recoil of the vascular wall helps to maintain the pressure gradient that drives the blood through the arterial system. An elastic artery is also known as a conducting artery, because the large diameter of the lumen enables it to accept a large volume of blood from the heart and conduct it to smaller branches. In terms of scale, the diameter of an arteriole is measured in micrometers compared to millimeters for elastic and muscular arteries. Farther from the heart, where the surge of blood has dampened, the percentage of elastic fibers in an artery’s tunica intima decreases and the amount of smooth muscle in its tunica media increases. Fortunately, because the blood pressure has eased by the time it reaches these more distant vessels, elasticity has become less important. Notice that although the distinctions between elastic and muscular arteries are important, there is no “line of demarcation” where an elastic artery suddenly becomes muscular. Arterioles have the same three tunics as the larger vessels, but the thickness of each is greatly diminished. With a lumen averaging 30 micrometers or less in diameter, arterioles are critical in slowing down—or resisting—blood flow and, thus, causing a substantial drop in blood pressure. The muscle fibers in arterioles are normally slightly contracted, causing arterioles to maintain a consistent muscle tone—in this case referred to as vascular tone—in a similar manner to the muscular tone of skeletal muscle. The importance of the arterioles is that they will be the primary site of both resistance and regulation of blood pressure. The precise diameter of the lumen of an arteriole at any given moment is determined by neural and chemical controls, and vasoconstriction and vasodilation in the arterioles are the primary mechanisms for distribution of blood flow. Capillaries A capillary is a microscopic channel that supplies blood to the tissues themselves, a process called perfusion. Exchange of gases and other substances occurs in the capillaries between the blood and the surrounding cells and their tissue fluid (interstitial fluid). The diameter of a capillary lumen ranges from 5–10 micrometers; the smallest are just barely wide enough for an erythrocyte to squeeze through. The wall of a capillary consists of the endothelial layer surrounded by a basement membrane with occasional smooth muscle fibers. There is some variation in wall structure: In a large capillary, several endothelial cells bordering each other may line the lumen; in a small capillary, there may be only a single cell layer that wraps around to contact itself. There are three major types of capillaries, which differ according to their degree of “leakiness:” continuous, fenestrated, and sinusoid capillaries (Figure 20. Continuous Capillaries The most common type of capillary, the continuous capillary, is found in almost all vascularized tissues. Continuous capillaries are characterized by a complete endothelial lining with tight junctions between endothelial cells. Although a tight junction is usually impermeable and only allows for the passage of water and ions, they are often incomplete in capillaries, leaving intercellular clefts that allow for exchange of water and other very small molecules between the blood plasma and 894 Chapter 20 | The Cardiovascular System: Blood Vessels and Circulation the interstitial fluid.

It highlights continued of malaria decreases through much of sub-Saharan Africa buy cozaar american express, the need progress made towards meeting international targets for malaria to diferentiate malaria from non-malarial fevers becomes more control to be achieved by 2010 and 2015 generic cozaar 25mg overnight delivery. A small number of countries have shown that it is possible to scale up rapidly the availability of malaria diag- International funding for malaria control has risen steeply in the nostic testing on a national scale purchase cozaar 25mg without a prescription, provided that attention is given to past decade generic 25mg cozaar otc. These fgures represent a substantial increase have been delivered to sub-Saharan Africa, enough to cover 76% of since 2005, when only 5 countries were providing sufcient courses the 765 million persons at risk of malaria. Nets delivered in 2006 and 2007 are therefore already few decades has led to an intensifcation of efcacy monitoring to due for replacement, and those delivered between 2008 and 2010 allow early detection of resistance. Failure to replace these nets could lead to a resurgence in parasite sensitivity to artemisinins, the clinical and parasitological of malaria cases and deaths. The widespread use of a single class of insecticide 2000 and 2009 was found in 32 of the 56 malaria-endemic countries increases the risk that mosquitoes will develop resistance, which outside Africa, while downward trends of 25%–50% were seen in 8 could rapidly lead to a major public health problem. It is estimated that the number of cases of malaria rose from 233 million in 2000 to 244 million in 2005 but decreased to 225 million in 2009. The number of deaths due to malaria is estimated to have decreased from 985 000 in 2000 to 781 000 in 2009. While progress in reducing the malaria burden has been remark- able, there was evidence of an increase in malaria cases in 3 countries in 2009 (Rwanda, Sao Tome and Principe, and Zambia). The increases in malaria cases highlight the fragility of malaria control and the need to maintain control programmes even if numbers of cases have been reduced substantially. The experiences in Rwanda and Zambia also indicate that monthly monitoring of disease surveillance data, both nationally and subnationally, is essential. Since many countries in sub-Saharan Africa had inadequate data to monitor disease trends, it is apparent that greater eforts need to be made to strengthen routine surveillance systems. Major epidemiological events could be occurring in additional countries without being detected and inves- tigated. On World Malaria Day 2008, the United Nations Secretary-Gen- countries in other Regions reported having a policy of parasito- eral called for eforts to ensure universal coverage with malaria logical testing of suspected malaria cases in persons of all ages, prevention and treatment programmes by the end of 2010. By November 2010, 25 countries were still allowing the marketing of  Policies and strategies for malaria control these products (down from 37 in 2009) and 39 pharmaceutical To attain the 2010 and 2015 targets, countries must reach all companies were manufacturing them. Spending by national governments on malaria transmission by vector control in all epidemiological settings. Of 106 malaria-endemic countries and areas, 77 received external quences, particularly pregnant women and infants. External fnancing appears to be Guinea, in the Western Pacifc Region, also adopted this policy concentrated on programme activities, particularly the procure- in 2009. The widespread use of a single class of insecticide to larger amounts of external fnancing, government fnancing increases the risk that mosquitoes will develop resistance, which exceeds that of external fnancing in countries in the pre-elimi- could rapidly lead to a major public health problem, particularly nation and elimination stages. The percentage of pregnant women who received the second 2010, sufcient to cover a further 10% of the population at risk. A model-based estimate showed that 42% of African households primarily to low coverage rates in Nigeria. There is no diference ularly in the African Region (from 26% to 35%), Eastern Mediterra- in usage rates between female and male children < 5 years of age nean Region (47% to 68%) and South-East Asia Region excluding (ratio girls: boys = 0. Data which corresponds to protection for 10% of the population at risk from a limited number of countries suggest that both microscopy in 2009. In 2009, the than fve-fold, and the total number of tests carried out (micros- European Region reported no cases of P. By combining household survey data with health facility data it be given to countries which harbour most of the malaria burden can be estimated that, on average, 65% of treatment needs are outside Africa. There were 8 countries in the pre-elimination stage of malaria are more difcult to construct for patients who are treated in the control in 2009 and 10 countries are implementing elimina- private sector, but household surveys indicate febrile patients tion programmes nationwide (8 having entered the elimina- treated in the private sector are 25% less likely to receive an anti- tion phase in 2008). A further 9 countries (Armenia, Bahamas, malarial than those visiting public sector facilities, while those Egypt, Jamaica, Morocco, Oman, Russian Federation, Syrian that stay at home are 60% less likely. The use of oral artemisinin-based monotherapies threatens and are in the phase of preventing re-introduction of malaria. It is estimated that the number of cases of malaria rose from 233 cal companies were manufacturing these products. Most of the million in 2000 to 244 million in 2005 but decreased to 225 million countries that still allow the marketing of monotherapies are in 2009. The number of deaths due to malaria is estimated to have located in the African Region and most of the manufacturers are decreased from 985 000 in 2000 to 781 000 in 2009. Parasite resistance has rendered previous antimalarial medicines largest proportional decreases noted in the European Region, inefective in most parts of the world, jeopardizing malaria followed by the Region of the Americas. Since 2008, containment activities to limit the spread of artemisinin-resistant parasites have been ongoing. Global control efforts have resulted in a reduction in the estimated number of deaths from nearly 1 million in 2000 to 781 000 in 2009. A total of 11 countries and one area in the African Region showed a reduction of more than 50% in either confrmed malaria cases or malaria admissions and deaths in recent years (Algeria, Botswana, Cape Verde, Eritrea, Madagascar, Namibia, Rwanda, Sao Tome and Principe, South Africa, Swaziland, Zambia, and Zanzibar, United Republic of Tanzania). No part of this book may be reproduced and/or distributed in any form without the express, written permission of the author. Readers are advised to check the product information currently pro- vided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the treating physician who relies on experience and knowledge about the patient to deter- mine dosages and the best treatment for the patient. The contributors to this site, including AmedeoGroup and Flying Publisher, disclaim responsibility for any errors or omissions or for results obtained from the use of information contained herein. It is the first major new infectious disease of this century, unusual in its high morbidity and mortality rates, and it is taking full advantage of the opportunities provided by a world of international travel. Fortunately, one by one, the outbreaks in the initial waves of infection have been brought under control. Surgery and vital treatments for patients with serious conditions had to be postponed; care in emergency rooms was disrupted. A significant proportion of patients required intensive care, thus adding to the considerable strain on hospital and healthcare sys- tems. There is no vaccine or treatment, and health authorities have to resort to control tools dating back to the earliest days of empirical microbiology: isolation, infection control and con- tact tracing. The early recognition of the etiologic agent has made the virus available for investigation of antiviral compounds and vaccines. What are the host or virus factors responsible for the "superspreader" phenomenon, in which a single patient may infect many people through brief casual contact or possibly environmental contamination? At this moment, a global epidemic of the magnitude of the 1918-19 influenza pandemic appears unlikely. It is the first major new infectious disease of this century and it is taking full advantage of the opportunities provided by a world of in- ternational travel. The early recognition of the etiologic agent has made the virus available for investigation of antiviral compounds and vaccines. Samples from one patient can be analysed in parallel by several laboratories and the results shared in real time. Fever followed by a rapidly progressive respiratory compromise is the key complex of signs and symptoms, which also include chills, muscular aches, head- ache and loss of appetite. In the great majority of countries, these measures have prevented imported cases from spreading the disease to others. February 14, 2003 A small notice in the Weekly Epidemiological Record reports 305 cases and 5 deaths from an unknown acute respiratory syndrome which occurred between 16 November and 9 February 2003 in the Guangdong Province, China. Two weeks later, at the end of February, the Chinese Ministry of Health reports that the infective agent causing the outbreak of the atypical pneumonia was probably Chlamydia pneumoniae. He had treated patients with atypical pneumonia prior to departure and is symptomatic upon arrival in Hong Kong. March 10 Eighteen healthcare workers on a medical ward in the Prince of Wales Hospital in Hong Kong report that they are ill. March 14 The Ministry of Health in Singapore reports 3 cases of atypical pneu- monia, including a former flight attendant who had stayed at the Hong Kong hotel. The alert includes a rare emergency travel advisory to international travelers, healthcare professionals and health authorities, advising all individuals traveling to affected areas to be watchful for the develop- ment of symptoms for a period of 10 days after returning (http://www. Samples from one patient can be analyzed in parallel by sev- eral laboratories and the results shared in real time. Although this guidance is primarily directed at air travel, the same procedures are recommended for international travel by road, rail or sea from affected areas. Electron- microscopic examination of cultures reveals ultrastructural features characteristic of coronaviruses.

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They function to carry these water-insoluble molecules from the intestine discount cozaar online amex, through the lymphatic system cheap cozaar 50 mg, and into the bloodstream purchase cozaar 50mg without prescription, which carries the lipids to adipose tissue for storage order cozaar without prescription. Lipolysis To obtain energy from fat, triglycerides must first be broken down by hydrolysis into their two principal components, fatty acids and glycerol. The resulting fatty acids are oxidized by β- oxidation into acetyl CoA, which is used by the Krebs cycle. Because one triglyceride molecule yields three fatty acid molecules with as much as 16 or more carbons in each one, fat molecules yield more energy than carbohydrates and are an important source of energy for the human body. Triglycerides yield more than twice the energy per unit mass when compared to carbohydrates and proteins. The breakdown of fatty acids, called fatty acid oxidation or beta (β)-oxidation, begins in the cytoplasm, where fatty acids are converted into fatty acyl CoA molecules. This fatty acyl CoA combines with carnitine to create a fatty acyl carnitine molecule, which helps to transport the fatty acid across the mitochondrial membrane. Once inside the mitochondrial matrix, the fatty acyl carnitine molecule is converted back into fatty acyl CoA and then into acetyl CoA (Figure 24. Ketogenesis If excessive acetyl CoA is created from the oxidation of fatty acids and the Krebs cycle is overloaded and cannot handle it, the acetyl CoA is diverted to create ketone bodies. Ketones serve as fuel in times of prolonged starvation or when patients suffer from uncontrolled diabetes and cannot utilize most of the circulating glucose. In both cases, fat stores are liberated to generate energy through the Krebs cycle and will generate ketone bodies when too much acetyl CoA accumulates. Ketone Body Oxidation Organs that have classically been thought to be dependent solely on glucose, such as the brain, can actually use ketones as an alternative energy source. The carbon dioxide produced can acidify the blood, leading to diabetic ketoacidosis, a dangerous condition in diabetics. The carbon within the acetoacetyl CoA that is not bonded to the CoA then detaches, splitting the molecule in two. These two acetyl CoA molecules are then processed through the Krebs cycle to generate energy (Figure 24. Lipogenesis When glucose levels are plentiful, the excess acetyl CoA generated by glycolysis can be converted into fatty acids, triglycerides, cholesterol, steroids, and bile salts. This process, called lipogenesis, creates lipids (fat) from the acetyl CoA and takes place in the cytoplasm of adipocytes (fat cells) and hepatocytes (liver cells). When you eat more glucose or carbohydrates than your body needs, your system uses acetyl CoA to turn the excess into fat. Although there are several metabolic sources of acetyl CoA, it is most commonly derived from glycolysis. Lipogenesis begins with acetyl CoA and advances by the subsequent addition of two carbon atoms from another acetyl CoA; this process is repeated until fatty acids are the appropriate length. However, the creation of triglycerides and lipids is an efficient way of storing the energy available in carbohydrates. Although lipogenesis occurs in the cytoplasm, the necessary acetyl CoA is created in the mitochondria and cannot be transported across the mitochondrial membrane. Oxaloacetate forms via the action of pyruvate carboxylase, whereas the action of pyruvate dehydrogenase creates acetyl CoA. Oxaloacetate and acetyl CoA combine to form citrate, which can cross the mitochondrial membrane and enter the cytoplasm. There is protein in bones (collagen), muscles, and tendons; the hemoglobin that transports oxygen; and enzymes that catalyze all biochemical reactions. Amid all these necessary functions, proteins also hold the potential to This OpenStax book is available for free at http://cnx. Proteins are not stored for later use, so excess proteins must be converted into glucose or triglycerides, and used to supply energy or build energy reserves. Although the body can synthesize proteins from amino acids, food is an important source of those amino acids, especially because humans cannot synthesize all of the 20 amino acids used to build proteins. The pancreas releases most of the digestive enzymes, including the proteases trypsin, chymotrypsin, and elastase, which aid protein digestion. In order to avoid breaking down the proteins that make up the pancreas and small intestine, pancreatic enzymes are released as inactive proenzymes that are only activated in the small intestine. Once released into the small intestine, an enzyme found in the wall of the small intestine, called enterokinase, binds to trypsinogen and converts it into its active form, trypsin. Trypsin and chymotrypsin break down large proteins into smaller peptides, a process called proteolysis. These smaller peptides are catabolized into their constituent amino acids, which are transported across the apical surface of the intestinal mucosa in a process that is mediated by sodium-amino acid transporters. The sodium can be reused in the transporter, whereas the amino acids are transferred into the bloodstream to be transported to the liver and cells throughout the body for protein synthesis. If amino acids exist in excess, the body has no capacity or 1176 Chapter 24 | Metabolism and Nutrition mechanism for their storage; thus, they are converted into glucose or ketones, or they are decomposed. Urea Cycle The urea cycle is a set of biochemical reactions that produces urea from ammonium ions in order to prevent a toxic level of ammonium in the body. In these reactions, an amine group, or ammonium ion, from the amino acid is exchanged with a keto group on another molecule. This transamination event creates a molecule that is necessary for the Krebs cycle and an ammonium ion that enters into the urea cycle to be eliminated. Because the processing of amino acids results in the creation of metabolic intermediates, including pyruvate, acetyl CoA, acetoacyl CoA, oxaloacetate, and α-ketoglutarate, amino acids can serve as a source of energy production through the Krebs cycle (Figure 24. Treatments can include diet modification, vitamin supplementation, and gene therapy; however, damage to the central nervous system usually cannot be reversed. Because of this, levels of phenylalanine rise to toxic levels in the body, which results in damage to the central nervous system and brain. Symptoms include delayed neurological development, hyperactivity, mental retardation, seizures, skin rash, tremors, and uncontrolled movements of the arms and legs. Babies exposed to excess phenylalanine in utero may present with heart defects, physical and/or mental retardation, and microcephaly. The person must closely follow a strict diet that is low in phenylalanine to avoid symptoms and damage. Some animal products and certain starches are also high in phenylalanine, and intake of these foods should be carefully monitored. Your body processes the food you eat both to use immediately and, importantly, to store as energy for later demands. If there were no method in place to store excess energy, you would need to eat constantly in order to meet energy demands. Distinct mechanisms are in place to facilitate energy storage, and to make stored energy available during times of fasting and starvation. The Absorptive State The absorptive state, or the fed state, occurs after a meal when your body is digesting the food and absorbing the nutrients (anabolism exceeds catabolism). Digestion begins the moment you put food into your mouth, as the food is broken down into its constituent parts to be absorbed through the intestine. The digestion of carbohydrates begins in the mouth, whereas the digestion of proteins and fats begins in the stomach and small intestine. The constituent parts of these carbohydrates, fats, and proteins are transported across the intestinal wall and enter the bloodstream (sugars and amino acids) or the lymphatic system (fats). From the intestines, these systems transport them to the liver, adipose tissue, or muscle cells that will process and use, or store, the energy. Depending on the amounts and types of nutrients ingested, the absorptive state can linger for up to 4 hours. The ingestion of food and the rise of glucose concentrations in the bloodstream stimulate pancreatic beta cells to release insulin into the bloodstream, where it initiates the absorption of blood glucose by liver hepatocytes, and by adipose and muscle cells. By doing this, a concentration gradient is established where glucose levels are higher in the blood than in the cells. Insulin also stimulates the storage of glucose as glycogen in the liver and muscle cells where it can be used for later energy needs of the body. If energy is exerted shortly after eating, the dietary fats and sugars that were just ingested will be processed and used immediately for energy. If not, the excess glucose is stored as glycogen in the liver and muscle cells, or as fat in adipose tissue; excess dietary fat is also stored as triglycerides in adipose tissues. The Postabsorptive State The postabsorptive state, or the fasting state, occurs when the food has been digested, absorbed, and stored. You commonly fast overnight, but skipping meals during the day puts your body in the postabsorptive state as well.

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