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For example order 100mg clozaril visa, if the slope of diastolic depolarization steepens buy genuine clozaril on line, and if the resting membrane potential becomes less negative or the threshold potential more negative (within limits) purchase clozaril american express, the discharge rate increases (e. The same mechanism reduces input resistance at diastolic potentials, which means that a greater depolarizing current would be required to achieve the “threshold” for firing an action potential. Passive membrane properties, including membrane resistance, capacitance, and cable properties, play an important role in cardiac electrophysiology. Although the cardiac cell membrane is resistant to current flow, it also has capacitive properties, which means that it behaves like a battery and can store charges of opposite signs on its two sides—an excess of negative charges inside the membrane balanced by equivalent positive charges outside the membrane. These resistive and capacitive properties cause the membrane to take a certain amount of time to respond to an applied stimulus, rather than responding instantly, because the charges across the capacitive membrane must be altered first. A subthreshold rectangular current pulse applied to the membrane produces a slowly rising and decaying change in membrane voltage rather than a rectangular voltage change. A value called the time constant of the membrane reflects its capacitive property. The time constant tau (τ) is equal to the product of membrane resistance (R ) and cell capacitance (C ):m m This is the time taken by the membrane voltage to reach 63% of its final value after application of a steady current. The time course of changes in membrane potential after the application of a hyperpolarizing or depolarizing subthreshold current step is typically monoexponential in all myocyte types, thus indicating that the entire sarcolemma (including the T-tubular membrane; see eFig. Constitutive intracellular Na excess in Purkinje cells+ V promotes arrhythmogenesis at lower levels of stress than ventricular myocytes from mice with catecholaminergic polymorphic ventricular tachycardia. When current is injected at a point, most of it flows parallel to the long axis inside the cell, but some leaks out. Because of this loss of current, the change in voltage of a cell at a site distant from the point of applied current is less than the change in membrane voltage at the point where the stimulus was applied. A measure of this property of a cable is called the space or length constant lambda (λ), which is the distance along the cable from the point of stimulation at which the voltage at steady state is 1/e (37%) of its value at the point of stimulation. Because the current loop in any circuit must be closed, current must flow back to its point of origin. Local circuit currents pass across gap junctions between cells and exit across the sarcolemmal membrane + to close the loop and complete the circuit. Inward excitation currents in one area (carried by Na in most + regions) flow intracellularly along the length of the tissue (carried mostly by K ), escape across the membrane, and flow extracellularly in a longitudinal direction. Through these local circuit currents, the transmembrane potential of each cell influences the transmembrane potential of its neighbor, because of the passive flow of current from one segment of the fiber to another across the low-resistance gap junctions (see Gap Junction Channels and Intercalated Discs and Fig. The speed of conduction in cardiac tissue depends on active membrane properties such as the + magnitude of the Na current, a measure of which is V̇max. Passive membrane properties also contribute to conduction velocity and include the excitability threshold, which influences the capability of cells adjacent to the one that has been discharged to reach threshold; the intracellular resistance of the cell, determined by free ions in the cytoplasm; the resistance of the gap junction; and the cross-sectional area of the cell. The direction of propagation is crucial because of the influence of anisotropy, in which conduction is faster parallel to the fiber axis compared to that across fibers. Loss of Membrane Potential and Development of Arrhythmias Many acquired abnormalities of cardiac muscle or specialized fibers that result in arrhythmias produce a loss of the resting membrane potential (less negative). This change should be viewed as a symptom of an underlying abnormality, analogous to fever or jaundice, rather than as a diagnosis in and of itself, because both the ionic changes resulting in cellular depolarization and the more fundamental biochemical or metabolic abnormalities responsible for the ionic alterations probably have a number of causative factors. For + + example, acute myocardial ischemia results in decreased [K ] and increased [K ] , release ofi o 2+ 2+ norepinephrine, and acidosis, which may be related to an increase in intracellular Ca and Ca -induced transient inward currents and accumulation of amphipathic lipid metabolites and oxygen free radicals. All these changes can contribute to the development of an abnormal electrophysiologic environment and arrhythmias during ischemia and reperfusion. The reduced resting membrane potential alters the depolarization and repolarization phases of the cardiac action potential. The subsequent reduction in action potential amplitude prolongs the conduction time of the propagated impulse, at times to the point of block. Membrane depolarization to levels of + −60 to −70 mV can inactivate a substantial portion of the available voltage-gated Na channels, and + depolarization to −50 mV or less can almost completely inactivate all the Na channels (see Fig. These changes in the action potential are likely to be heterogeneous, with unequal degrees of + Na inactivation that create areas with minimally reduced velocity, more severely depressed zones, and areas of complete block. Cells with reduced membrane potentials can exhibit postrepolarization refractoriness. Furthermore, if conduction block occurs in a fairly localized area without significant slowing of conduction proximal to the site of block, cells in this proximal zone exhibit short action potentials and refractory periods because unexcited cells distal to the block (still in a polarized state) electrotonically speed recovery in cells proximal to the site of block. If conduction slows gradually proximal to the site of block, the duration of these action potentials and their refractory periods can be prolonged. Molecular Structure of Ion Channels Ion channels are building blocks of biologic electricity in the heart, brain, skeletal muscle, and other excitable tissues. Ion channels are transmembrane glycoproteins that form ion-selective pores in cell membranes that open and close (gating) in response to an appropriate biologic signal. The most abundant ion channels in the heart gate in response to changes in transmembrane voltage. Electrophysiologic studies have detailed the functional properties of + 2+ + Na , Ca , and K currents in cardiomyocytes, and molecular cloning has revealed a large number of pore-forming (α) and auxiliary (β, γ, and δ) subunits thought to contribute to formation of ion channels. These studies have demonstrated that distinct molecular entities give rise to the various cardiac ion channels and shape the myocardial action potential. Mutations in the genes encoding subunits of cardiac 10 ion channels are responsible for several inherited cardiac arrhythmias (see Chapter 33). The expression and functional properties of myocardial ion channels also change in a number of acquired 11 disease states, and these alterations can predispose to cardiac arrhythmias. The name of the voltage- + gated sodium channel consists of the chemical symbol of the principal permeating ion (Na ) and v, which indicates its principal physiologic regulator (voltage). The number following v indicates the gene subfamily (Nav1), and the number following the decimal point identifies the specific channel isoform (e. An identical nomenclature applies to voltage-gated calcium and potassium channels. Brugada syndrome mutations result in reduced Nav current amplitude, which leads to slowing of phase 0 action potential upstroke, reduced action potential amplitude, and altered phase 1 early repolarization. A, Voltage-gated + 2+ Na and Ca channels are composed of a single tetramer consisting of four covalently linked repeats of + the six-transmembrane–spanning motifs, whereas B, voltage-gated K channels are composed of four + separate subunits, each containing a single six-transmembrane–spanning motif. Inwardly rectifying K + channels are formed by inward rectifier K channel pore-forming (alpha) subunits (Kir). In contrast to + voltage-gated K channel alpha subunits, the Kir alpha subunits have only two (not six) transmembrane domains. C, All ion channels are multisubunit proteins, as exemplified by the schematic subunit structure of L-type Ca channels. Nav β subunits appear to play an important role in anchoring ion channel proteins to the outer cell membrane. Kv channels are composed of four separate pore-forming (α) subunits, each containing six-membrane– 17 spanning domains (S through S )1 6 (see Fig.

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The degree and type of injury that occurs usually depends on the volume of urine in the bladder purchase 50mg clozaril with amex. Extraperitoneal occurs when the bladder is empty or contains only a small amount of urine clozaril 100 mg without a prescription. In extraperitoneal rupture clozaril 50 mg low cost, the bladder lies within the pelvis and is protected by the strong bony pelvis. Here lacerations of the urinary bladder are associated with fractures of the pelvis. This is when blunt force is applied to the lower abdominal wall in a downward direction. Intraperitoneal rupture of the urinary bladder occurs when the bladder is markedly distended by urine. At this time, a kick, a blow, or any blunt force to the lower abdominal wall can compress the posterior wall of the 140 Forensic Pathology bladder against the sacrum, raising the pressure within the bladder lumen and rupturing it, with urine entering the abdominal cavity. When they do occur, they are usually associated with extensive fractures of the pelvis. Blunt trauma injuries to the pregnant uterus and/or fetus are usually caused by automobile accidents, with falls and assaults accounting for a significantly smaller num- ber of cases. Sep- aration occurs at the moment of trauma but may not become evident for a few hours. This is probably due to a small separation at the edge of the placenta, with development of a retroplacental hematoma that takes a while to grow and kill the fetus. In the absence of any direct trauma, the cause for the separation is severe distortion of the uterus that can occur with violent motion. Following the death of the fetus, labor usually begins within 48 h, though it may be delayed up to a few weeks. During this time, the mother may develop a disseminated intravascular coagulopathy. With fractures of the pelvis, there may be not only placental separation but direct fetal injury, for example, fracture of the fetal skull and/or internal injuries to the fetus. Blunt Force Injuries of the Extremities These injuries may be limited to the skin and subcutaneous tissues or extend to muscles, blood vessels, nerves, bones, and joints. Avulsive wounds of the lower extremities are most frequently seen in automobile–pedestrian accidents. If an automobile wheel passes over the lower extremities, it can exert tangential pressure on the skin and subcu- taneous tissues, separating them from the underlying muscles. In other instances, the skin and subcutaneous tissue are also torn, forming a large flap of skin (Figure 5. A blood-filled pocket may also be produced in the back and/or lateral (outer) aspect of the thigh in pedestrians impacted by the front of the hood. The tangential force of the hood impacting the thigh strips the skin and subcutaneous tissue from the muscle, creating a blood-filled pocket (Figure 5. Complications of Blunt Force Injuries to the Lower Extremities Shock — caused by severe crushing, soft tissue injuries, and/or com- pound fracture. Hemorrhage — occurs from traumatic amputation, compound fracture with severing of a large vessel, multiple lacerations, or severe avulsive wounds Blunt Trauma Injuries of the Trunk and Extremities 141 A B C Figure 5. Venous thrombosis with fatal pulmonary embolism — Veins may be injured directly by fracture of the lower extremity, with resultant thrombosis. Thrombosis may also be secondary to venous stasis following prolonged immobilization of the lower extremity when the patient is confined to bed with a fractured extremity. There may be crushing injuries rather than frac- tures of the lower extremity with either direct injury to the veins or stasis bv compressing hemorrhage and edema resulting from the leg injury. Fat embolism — Fat embolism follows mechanical trauma that mobi- lizes the fat from an injured fat deposit in the body. A few heartbeats are sufficient to bring fat to the lungs and even to the systemic circulation. For this reason, fat may be found even when death seems to be instantaneous —although, with sudden death, the amount of fat is usually small. The amount of fat in those surviving injury is proportional to the degree of injury and to the time of survival up to 24 h. Microscopic sections of the lungs show massive amounts of intravascular fat droplets, as well as free fat in the alveoli. Outside the lungs, fat emboli are more frequently seen in the kidney than in the brain. Micro- scopic sections of the brain show petechiae (small hemorrhages) throughout, with fat droplets within the capillaries. Blunt Trauma Injuries of the Trunk and Extremities 143 Infection — Compound fractures are frequently contaminated with bacteria carried into the wound and lodged in the devitalized traumatized tissues. Depending on the virulence of the bacteria and immediateness and extent of surgical attention and cleansing of the wound, the infection may be limited to the skin or soft tissue or extend to the bone (osteomyelitis). A combination of aerobic and anaerobic organisms may cause gangrene of the lower extremity, a terminal hemolytic anemia, hemoglobinuric neph- rosis, uremia, and septicemia. Crush syndrome: crushing injuries of the extremities — In this entity, there is traumatic or ischemic muscle necrosis in persons pinned by beams and falling debris. Effects of injury on preexisting natural disease — There may be delir- ium tremens in alcoholics, uremia in patients with chronic renal disease, cardiac decompensation in patients with heart disease, cerebral damage dur- ing shock, etc. Injury to upper extremities occurs in association with motor vehicle accidents, falls, and assaults. In the case of homicide, the upper extremities should be closely scrutinized for defensive and offensive injuries. The finger- nails, fingers, hands, and forearms should be carefully examined for abra- sions, contusions, and lacerations. Broken or avulsed fingernails in a rape victim may indicate that the victim tried to protect herself. Fractured fingers and forearms are sustained by victims when they attempt to ward off a blunt instrument. Contusions, abrasions, and superficial lacerations over the knuckles may corroborate a perpetrator’s contention of self-defense. Absence of injuries to the hand, however, does not exclude the possibility that blows were struck with the fists. Injuries to the back of the arms may indicate the victim was attempting to ward off blows. Suzuki I, Sato M, Hoshi N, and Manjo H, Coronary arterial laceration after blunt chest trauma. Ono M, Yagyu K, Furuse A, Kotsuka Y and Kubota H, A case of Stanford Type A acute aortic dissection caused by blunt chest trauma. Winter B and Baum R, Complete traumatic rupture of the bronchus with minimal trauma. Trauma to the Skull and Brain: Craniocerebral 6 Injuries Injuries to the head can be grouped into two broad categories based on the mechanism by which the injury is produced: Impact injuries and accelera- tion or deceleration injuries.

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Supraventricular Tachyarrhythmias (See Chapters 37 and 38) Sinus Tachycardia Sinus tachycardia is typically associated with augmented sympathetic activity and may provoke transient hypertension or hypotension purchase clozaril online from canada. Treating sinus tachycardia caused by pain purchase clozaril now, anxiety buy cheap clozaril 50mg on-line, or fever with beta blockers is reasonable, but these agents are contraindicated in patients who are tachycardic because of pump failure. Clinicians face the critical task of distinguishing recurrent angina or infarction from nonischemic causes of discomfort that might result from infarct expansion, pericarditis, pulmonary embolism, and non–cardiac-related conditions. Diagnosis Extension of the original zone of necrosis or reinfarction into a separate myocardial zone can be a difficult diagnosis, especially within the first 24 hours after the index event. The presence of a rub and lack of responsiveness to nitroglycerin may be useful in distinguishing pericardial discomfort, but doing so on clinical grounds is frequently challenging, and diagnostic coronary angiography may be necessary to exclude acute native vessel or stent thrombosis. Prognosis Regardless of whether postinfarction angina is persistent or limited, its presence is important because of the associated higher short-term morbidity rate. Stent thrombosis can occur acutely (hours to days after stent deployment) or late (many months after stent deployment) (see Chapter 62). Pericardial Effusion and Pericarditis (See Chapter 83) Pericardial Effusion Effusions are generally detected echocardiographically, and their incidence varies with imaging modality and technique, criteria, and laboratory expertise. The reabsorption rate of a postinfarction pericardial effusion is slow, with resolution often taking several months. An effusion does not necessarily indicate pericarditis; although they may coexist, most effusions develop without other evidence of pericarditis. When tamponade does occur, it is usually 150 caused by ventricular rupture or hemorrhagic pericarditis. The pain of pericarditis may be confused with that resulting from postinfarction angina, recurrent infarction, or both. An important distinguishing feature is radiation of the pain to either trapezius ridge, a finding that is almost pathognomonic of pericarditis and rarely seen with ischemic discomfort. Additionally, the discomfort of pericarditis usually worsens during a deep inspiration but can be relieved or diminished by sitting up and leaning forward. An acute fibrinous pericarditis, pericarditis epistenocardica, occurs frequently after transmural infarction, but most patients do not report any symptoms from this process. Although transient pericardial friction rubs are relatively common within the first 48 hours in patients with transmural infarction, pain or electrocardiographic changes occur much less often. The development of a pericardial rub, however, appears to correlate with a larger infarct and greater hemodynamic compromise. Nevertheless, detection of a significant (≥1 cm) or enlarging pericardial effusion usually should indicate discontinuation of anticoagulation. Patients in whom continuation or initiation of anticoagulant therapy is strongly indicated (e. Late pericardial constriction caused by anticoagulant-induced hemopericardium has been reported. Treatment of pericardial discomfort consists of aspirin, but usually in doses higher than prescribed routinely following infarction—doses of 650 mg orally as often as every 4 hours may be necessary. Dressler Syndrome Also known as post–myocardial infarction syndrome, Dressler syndrome usually occurs 1 to 8 weeks after infarction. The wall of a true aneurysm is thinner than that of the rest of the left ventricle (eFig. Pathogenesis Aneurysm formation presumably occurs when intraventricular tension stretches the noncontracting infarcted heart muscle and thus produces expansion of the infarct, a relatively weak, thin layer of necrotic muscle, and fibrous tissue that bulges with each cardiac contraction. Aneurysms occur approximately four times more often at the apex and in the anterior wall than in the inferoposterior wall. The overlying pericardium generally adheres densely to the wall of the aneurysm, which may even become partially calcified after several years. Death in these patients is frequently sudden and presumably related to the relatively high incidence 152 of ventricular tachyarrhythmias that occur with aneurysms. With loss of shortening from the area of the aneurysm, the remainder of the ventricle may become hyperkinetic to compensate, but with relatively large aneurysms, complete compensation is impossible. Stroke volume falls, or if maintained, it is at the expense of an increase in end-diastolic volume, which in turn leads to increased wall tension and myocardial oxygen demand. Surgical aneurysmectomy generally succeeds only if contractile performance in the nonaneurysmal portion of the left ventricle is relatively preserved. A transcatheter approach for aneurysm exclusion is currently under investigation; to date, device implantation has been generally 154,155 successful, but outcome data are limited. Left Ventricular Thrombus and Arterial Embolism Endocardial inflammation and the relative stasis of blood during the acute phase of infarction probably provide a thrombogenic surface for clots to form in the left ventricle. With extensive transmural infarction of the septum, however, mural thrombi may overlie infarcted myocardium in both ventricles. Even though a mural thrombus adheres to the endocardium overlying the infarcted myocardium, superficial portions can become detached and embolize systemically. Although estimates vary because of 156 patient selection, approximately 10% of mural thrombi result in systemic embolization. Echocardiographic risk factors for thrombus embolization include increased mobility and protrusion into the ventricular chamber, visualization on multiple views, and contiguous zones of akinesis and hyperkinesis. However, because of a low event rate, 156 precluded demonstrating reduced systemic embolism. However, antithrombotic therapy with heparin cloud the interpretation of data from fibrinolytic trials. Recommendations for anticoagulation vary considerably, and fibrinolysis has precipitated fatal embolization. Nevertheless, anticoagulation for 3 to 6 months with warfarin is reasonable for many patients with demonstrable mural thrombi. Such patients appear to be suitable candidates for hospital discharge less than 5 days from the onset of symptoms; current practice in U. Most complications that would preclude early discharge occur within the first 3 days of admission, permitting identification of patients suitable for expedited discharge early during the hospitalization. In patients who have experienced a complication, discharge is deferred until their condition has been stable for several days and they clearly have responded appropriately to any interventions. Counseling Before discharge from the hospital, all patients should receive detailed instruction concerning physical activity. Initially, this should consist of walking at home but avoidance of isometric exercise such as lifting. The patient should be given fresh nitroglycerin tablets and instructed in their use (see Chapter 61). Graded resumption of activity should be encouraged, ideally as part of a monitored cardiac rehabilitation program (see Chapter 54). Many approaches have been used, ranging from formal rigid guidelines to general advice advocating moderation and avoidance of any activity that evokes symptoms.

W. Nemrok. San Jose State University.

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