John Ferguson, MB ChB, MD

• Assistant Professor of Internal Medicine, Department of Medicine,
• Division of Cardiovascular Medicine, University of Virginia,
• Charlottesville, VA, USA

One of the most feared complications in the anterior cervical approach is injury to the vertebral artery medicine 6469 purchase arava 10mg overnight delivery. It can initially manifest as dysphagia or pain but may result in stridor and airway obstruction symptoms 5dpiui buy arava uk. Immediate surgical evacuation and reestablishment of hemostasis must be instituted if there is any chance of significant size of the hematoma medications you cant drink alcohol purchase arava 20mg with amex. It may be able to be prevented with the use of a drain leading from the vertebral surface (bone edges are often the source of the bleeding) medicine wheel images 10 mg arava mastercard, although removal of the drain sometimes promotes bleeding symptoms 24 hour flu cheap arava 10 mg without prescription. The longer a fusion segment denivit intensive treatment 10mg arava otc, the greater impact collapse or telescoping has on alignment of the spine. With graft settling, loss of lordosis and frank kyphosis can lead to pain, instability, and compromise of the canal. This problem can be prevented by not overdrilling the end plates above or below and by choosing a graft that is as wide as possible to decrease the pressure. The approach for placing an odontoid screw is similar to that for anterior cervical diskectomy and fusion. This method has all the risks of complication as the other anterior cervical approaches, with additional risks related to capture of the odontoid tip. Risks include failure to maintain the correct lateral angle and missing the tip of the dens and the potential for spinal cord injury from migration of the dens or a poorly placed drill or screw. Patients should be selected in whom the dens is aligned with the C2 body and not significantly displaced. Screw fracture, because of the long moment arm and high torque on the odontoid screw, can be prevented by using a tapered thread. Dens capture is easier with threaded lag screws because they reduce the likelihood of the screw pushing the fragment instead of threading into it. PosteriorCervicalApproach Posterior cervical surgical procedures carry risks different from those of anterior procedures. The prototypical procedure is cervical laminectomy, which is performed for numerous indications, from Chiari decompression to cervical stenosis to intramedullary tumor exposure. The primary risks associated with cervical laminectomy are similar to those of laminectomy at other levels and include cord injury, dural injury, and nerve root injury. Even with no evidence of direct trauma to the roots, transient C5 palsy can be seen in approximately 5% to 15% of patients undergoing posterior cervical decompression, with or without instrumentation. Although some authors recommend intraoperative monitoring with motor evoked potentials and deltoid electromyographic recording, C5 root injury may occur in the absence of intraoperative findings. At this point, the artery becomes most vulnerable to injury because the vessel turns from a lateral course and moves dorsally before entering the dura adjacent to the C1 lamina. Frequently, injury to the venous plexus is initially confused with injury to the vertebral artery, but the consequences are not nearly as significant. As with most venous bleeding, it can be controlled easily by tamponade with Gelfoam or Surgicel and a neurosurgical cotton patty. Injury to the vertebral artery may require opening the dura and ligating or performing a bypass or end-to-end anastomosis, depending on the nature of the injury and its location. Injury to the vertebral artery during posterior cervical procedures occurs more frequently than during anterior procedures, with a rate of up to 1. Risks related to the decompression procedures laminotomy and laminectomy are similar, regardless of location, and consist primarily of injury to surrounding neural elements, injury to bony elements, and excessive bleeding. Additional care should be taken with placement of a Kerrison rongeur to exclude dura within the teeth of the instrument. A small neurosurgical cotton patty can be gently passed underneath the bony edge and used to bluntly dissect the dura away while protecting it from the rongeur. Lateral mass screws require precise localization of the entry point and angle with respect to the lateral and rostrocaudal planes. The orientation of the facet joints is an angle oblique to the coronal plane, and to avoid injury to the vertebral artery when anteromedial to the entry point, the screws need to be aimed significantly laterally. One rule of thumb is that if the drill guide is not leaning on the spinous process of the caudal vertebra, the surgeon is not aiming laterally enough. As with the use of anterior plates, overtightening a screw results in fracture of the threads and loss of pullout integrity. If this complication occurs, a rescue screw should be used, or methyl methacrylate should be injected into the screw hole and the screw replaced. Use of a screw that is a little too long (1 to 2 mm), if in the correct orientation, is not likely to cause significant morbidity and can achieve bicortical purchase. Screws that are too long and in the inappropriate orientation are potentially dangerous. ThoracicSpinalProcedures Thoracic spinal procedures, because of the surrounding organs, carry risks different from those of cervical spine procedures. Anterior approaches, such as the transthoracic, endoscopic, and retropleural approaches, put major arteries, veins, and organs such as the heart, lungs, and diaphragm at risk for injury. Some complications are related to the exposure, whereas others are related to the procedure being performed. Thoracic laminectomy has long been performed for many procedures, including repair of intramedullary, intradural, and epidural lesions. Risks are similar to those for the subaxial cervical spine, and it is important to keep the lateral exposure to the minimum that can provide the necessary exposure. Too wide an exposure risks taking down the costotransverse ligaments and even risks pneumothorax. For tumor patients in whom the wound has been or will be irradiated, a curvilinear incision with a myocutaneous flap should be used to maintain vascular supply to the skin and reduce the risk for infection and tissue breakdown. Thoracoscopic procedures need smaller incisions to approach the spine and thus reduce the likelihood of significant wound breakdown and postoperative incisional pain, but because of the multiple ports used and the limited sight angles, the potential for injury to structures such as vessels and organs remains significant. AnteriorLumbarProcedures Anterior lumbar procedures can be subdivided into three main categories: transperitoneal open, endoscopic transperitoneal, and retroperitoneal approaches. Potential morbidities are associated more with the approach than with the individual procedure, and when the spinal procedures differ, they are discussed separately. Anterior procedures are performed to augment spinal stability by bone fusion or instrumentation or to perform arthroplasty. The choice of approach depends on the exposure needs of the procedure, the type of instrumentation being performed, and preferences of the surgeon and patient. The transperitoneal open procedure is performed through a laparotomy, usually through a midline incision, although a Pfannenstiel bathing suit line incision can also be performed. The procedure calls for mobilization of the abdominal viscera with a midline anterior approach to the spine after mobilization of the various branches of the aorta, inferior vena cava, or iliac vessels. This approach has a higher risk than the retroperitoneal approach for postoperative complications such as injury to the major vessels, adhesions, and adynamic ileus. Anterior endoscopic procedures are performed through multiple small incisions and with the use of multiple ports. The approach is essentially the same as an anterior transperitoneal approach in terms of mobilization of the abdominal viscera and major vessels, although because of the port size and the use of endoscopic techniques, mobilization is more difficult. The assistance of a general surgeon with significant endoscopic experience in performing the exposures is recommended for neurosurgeons who are not comfortable with the management of injury to the structures being mobilized. Other possible complications include hypercapnia if carbon dioxide insufflation is used and delay in converting to an open procedure if bleeding or another major complication occurs. Lost time in gaining control of a difficult situation can lead to greater morbidity from blood loss. It can be performed with a wide exposure to allow extensive instrumentation,421,425,426 or it can be used with a short incision for placement of an interbody fusion construct. The main risks are vascular, although entry into the peritoneum or sigmoid colon is possible. The primary risk with this approach is tearing segmental arteries and veins that may be under tension and difficult to visualize as retraction for the exposure proceeds. This exposure may be extended up to the diaphragm, with further mobilization of the kidney and, if necessary, the spleen and liver. The approach is usually done from the left side because of the smaller size of the liver on the left. Because of the retroperitoneal exposure, the ureter is less subject to injury in the lower levels than with a transperitoneal approach. Anterior interbody fusions can be performed with the use of interbody threaded cages, interbody square cages, interbody threaded bone dowels, femoral ring allografts, and autograft bone. Fusion can be performed from a straight anterior transperitoneal or a lateral retroperitoneal approach, depending on the technique and device used. Whether an endoscopic or open procedure is used depends on the body habitus of the patient, the preference of the surgeon and patient, and the availability of equipment and assistance. One significant risk related to the anterior approach is retrograde ejaculation in male patients undergoing L5-S1 fusion. There is a 10-fold higher incidence of retrograde ejaculation with a transperitoneal approach than with a retroperitoneal approach to L4-L5 and L5-S1. When approaching from a retroperitoneal trajectory, the plexus is mobilized off the disk spaces along with the posterior peritoneum to protect it from injury. When the approach is via a midline transperitoneal route, the plexus itself is directly injured. If a transperitoneal approach is required, dissecting the plexus off the rightsided iliac vessels and mobilizing the fascia toward the left may protect the plexus and prevent this complication. The best way to reduce the chance of neurological injury is to remove the disk under fluoroscopic guidance. If the surgeon can visualize just how deep each pass of the pituitary rongeur goes, there is less chance of going too deep, passing the annulus, and biting the dura or nerve roots. Continuous use of fluoroscopy allows evaluation of each step of the reaming and tapping, thereby allowing the surgeon to correct any misalignment before it becomes irreversible and leads to instability of the construct. One way to reduce the chance that the cage or bone graft will push disk fragments posteriorly is to ensure that the diskectomy is adequately performed and that no residual disk remains in the path of the construct. Vertebrectomies are best performed through the retroperitoneal approach because the screws can be placed along the long axis of the bodies and achieve better purchase. The exposure can be carried up or down multiple levels without significant risk to structures that cross the midline and only minimal risk to structures that cross the exposure (primarily the radicular arteries and veins). The chance of causing a significant injury to the artery of Adamkiewicz and resulting in ischemia of the lower cord can be reduced by avoiding sacrificing the radicular artery too far distal from the aorta. The location of the radicular vessels in the middle of the bodies makes it nearly impossible to save them at the level above or below if a plate or other instrumentation is applied. To prevent unnecessary blood loss, it is best to isolate the vessels, sacrifice them cleanly with ties or hemoclips, and then cut them under direct vision. This technique prevents avulsion and retraction of the vessels into surrounding soft tissue or, worse, avulsion at their insertion into the aorta or vena cava. PosteriorLumbarProcedures Dorsal lumbar procedures are primarily used for laminectomy, laminotomy, and fusions, with or without instrumentation, and they are the oldest and most commonly performed procedures for spine surgery. Hemilaminotomies can be performed for small exposure of intraspinal epidural lesions such as disk herniations, synovial cyst herniations, and ligamentous or bony hypertrophy as a result of degenerative disk disease. If retraction is performed too aggressively or in the wrong location, a facet fracture can occur. This risk can be minimized with the use of a retractor that spreads the tissue without digging lateral to the facet joint. Use of such a retractor, however, carries with it the risk of spinous process fracture, so careful use of any retractor is recommended. Fracture of the facet can also occur if the medial facetectomy is carried too far laterally. The usual landmark for completion of bone removal laterally is the medial border of the pedicle below, which is located right under the root of the ascending facet. Going beyond this point confers a greater chance of fracture of the ascending or descending facet and, consequently, pain on movement postoperatively. At least half the width of the pars interarticularis should be preserved to prevent postoperative pars fracture and spondylolisthesis. Prevention of postoperative epidural scarring after dorsal procedures is a challenge that does not have a simple answer. Several techniques are available, such as placement of a fat graft, Gelfoam sponge, or artificial adhesion barrier. The nerve root can be unintentionally cut during opening of the annulus if the root has not been adequately identified and retracted. Frequently, overly aggressive retraction can result in transient weakness or sensory changes in a root that has not been cut. This injury tends to respond to steroids and physical therapy, although it is better avoided by careful dissection. Failure to recognize a redundant nerve root may lead to injury to the root, even after presumed protection of one of the branches. Cauda equina syndrome as an immediate or delayed result of lumbar diskectomy is a catastrophic neurological complication. It can occur as a result of injury to the nerve roots from epidural hematoma after closure, from infection of the arachnoid or epidural space, from retraction of neural elements against a calcified herniated fragment, or from extrusion of disk or end-plate fragments postoperatively. Catastrophic injury to the organs or vessels of the abdomen and pelvis can result from diskectomy. Bleeding, which may or may not well up into the surgical field, is not responsive to attempts to arrest it. The onset of symptoms may be more insidious and not appear until the patient is in recovery, or in the case of bowel injury, symptoms can develop after discharge. Management of life-threatening vascular injury requires termination of the neurosurgical procedure, turning the patient over, and performing an exploratory laparotomy and vascular repair of some kind. Ignoring the problem, failing to obtain a vascular surgical consultation, or simply transfusing the patient can result in catastrophic blood loss and perhaps death. Minimally invasive techniques for the treatment of lumbar disease include chemonucleosis, thermal or laser coagulation, and automated percutaneous diskectomy. One benefit of the absence of regional or global anesthesia is that any irritation or compression of the nerve root can be felt, and the surgeon is able to change whatever it was that triggered the response. The entry point is from the side of the disk, and it may be difficult to enter the L5-S1 space directly because of the position of the iliac crest relative to the disk space.

Premature attempts at extubation can result in hypoxia and may necessitate emergency tracheotomy medications hard on liver cheap arava 20mg with mastercard. Surgeons should immediately seal the portals of entry with bone wax medicine vs dentistry generic 10mg arava with visa, electrocautery treatment xanthelasma eyelid purchase cheapest arava and arava, and full-field irrigation medications for ptsd cheap arava line. Repositioning the patient in the left lateral decubitus position may facilitate removal of air from the right atrium medications hyperkalemia order arava without a prescription. Pulmonary embolism symptoms depression purchase arava online pills, however, is thought to subsequently occur in 15% of such patients. Doppler ultrasonography and impedance plethysmography are useful in detecting proximal venous thrombosis and are the mainstay of diagnosis, with sensitivities exceeding 90%. Early mobilization of postoperative patients is important in preventing thrombus formation. In general, those with hemorrhagic tumors as well as multiple metastasis from known hemorrhagic primary tumors (thyroid, renal cell, choriocarcinoma, and melanoma) should not receive pharmacologic prophylaxis. In addition, enoxaparin and heparin have been shown to be equally safe and effective. Air travels from the head down the venous system to the heart and eventually to the lungs, where pulmonary constriction and pulmonary hypertension ensue, or in patients with a right-to-left heart shunt, paradoxical air embolism may occur. Peripheral resistance decreases, and cardiac output initially increases to compensate and maintain blood pressure. Later, as the volume of air infused increases, cardiac output drops, as does blood pressure. Monitoring methods and devices used to detect emboli include precordial Doppler ultrasonography, capnography or mass spectrometry, transesophageal echocardiography, transcutaneous oxygen, esophageal stethoscope, and right heart catheter. Because no single monitor is completely reliable, two or more should be used simultaneously. In subarachnoid hemorrhage patients, aneurysms should be secured before initiation of pharmacologic prophylaxis. Management options include full-dose heparinization or inferior vena cava interruption. Treatment with intravenous heparin (target partial thromboplastin time of 45 to 60 seconds) is followed by oral warfarin sulfate (target international normalized ratio of 2) when not contraindicated. Anticoagulation should be continued for 6 weeks to 3 months in uncomplicated cases. Patients experiencing pulmonary embolism complain of pleuritic chest pain, hemoptysis, and dyspnea. Jugular venous distention, fever, rales, tachypnea, hypotension, and altered mental status may be found on physical examination. Arterial blood gas determination reveals a Po2 of less than 80 mm Hg in 85% of patients, accompanied by a widened alveolar-arterial gradient. In patients with massive embolism, right axis deviation, right ventricular strain, or right bundle branch block may be identified on electrocardiography. A nuclear medicine ventilationperfusion scan is sensitive in detecting pulmonary embolism but is not specific. The entire clinical scenario, including patient examination, laboratory results, and radiographic evaluation, leads to the diagnosis. Patients with a massive, life-threatening embolus, however, should be fully anticoagulated despite the risk for intracranial hemorrhage. This subset of patients usually requires ventilatory support and vasopressor therapy to ensure adequate oxygenation and blood pressure. Because thrombolytic therapy with urokinase or streptokinase has a higher risk for complications than does treatment with heparin, with no significant improvement in outcome, these modes of therapy have largely been abandoned. When all else fails, pulmonary embolectomy may be performed as a lifesaving measure. Patients about to undergo neurosurgery should, when medically suitable, avoid the use of aspirin products in the week before surgery and other nonsteroidal anti-inflammatory agents on the day before surgery. Wound Complications Because of the vascularity of the scalp, most cranial wounds heal well. Several potential problems related to the wound area and wound closure can be anticipated and prevented. Ideally, postoperative hematomas can be prevented by meticulous hemostasis during the procedure, but such is not always the case. Postoperative drainage may also be advantageous in patients in whom postoperative anticoagulation may be required because some of these patients have slightly delayed hematoma formation. It is best to keep a drain in the submuscular space during this time to prevent a postoperative seroma that can become infected. Recent guidelines for infection prevention recommend prophylactic antibiotics 1 hour before incision and 24 hours postoperatively. However, there is no consensus as to whether antibiotics should be continued until a wound drain is removed. For ventriculostomy drains, antibioticcoated catheters have been shown to be more effective than prophylactic antibiotic use in preventing infection. Prolonged steroid use, irradiation or chemotherapy, reoperations, and malnutrition can predispose patients to poor wound healing. Known or unknown intraoperative violations of sterility may lead to subcutaneous infection and resultant loss of wound integrity. Failure to use perioperative antibiotics can also lead to local infection and failure of the incision line. Maintenance of a dry, sterile wound area results in better wound healing, and if a dressing becomes significantly stained or wet, it must be changed immediately. One way to prevent wound breakdown in a compromised host is the use of an incision that avoids the impaired area. Craniotomies may require a larger incision, such as a bicoronal or larger curvilinear incision that avoids a focused radiation area. Through removal of the incision from the avascular midline plane and creation of a vascularized myocutaneous flap, patients with cancer or severe malnutrition can have wound-healing rates that are the same as or better than those in healthy patients. If the incision is made off the midline, the pressure is also not directly on the wound and the instrumentation. Other modalities being investigated include the use of cultured keratinocytes or fibroblasts injected back into the wound area, supplemental or hyperbaric oxygen therapy for several days after surgery, and injection of various growth factors into the wounds. Hemorrhagic and Transfusion-Related Issues Two significant and somewhat similar complications related to bleeding are diffuse intravascular coagulation and transfusion reactions. The other is a reaction to incompatible blood and can result in fever, rash, or shock. When bone is bleeding in an area where the need for fusion precludes the use of bone wax, thrombin-soaked Gelfoam can be rubbed on the bleeding bone surfaces and acts in much the same way as bone wax. When hemostasis alone is not enough to minimize transfusion requirements, as with some long spinal procedures, autologous blood salvage. Manipulation of brain tissue, postoperative edema, and hematoma formation are common causes of surgically induced seizures. The overall incidence of immediate and early seizures after craniotomy is 4% to 19%. It is important to identify any risk factors that may contribute to the development of seizures postoperatively. Lesions of the supratentorial intracranial compartment are responsible for seizures after craniotomy in most situations; seizures after infratentorial procedures are attributed to the resultant retraction or movement of supratentorial structures. Patients with subtherapeutic levels of prophylactic agents are also at a higher risk for immediate and early postoperative seizures. Multiple episodes are more common than single episodes, but status epilepticus is relatively uncommon. Seizures can occur in unconscious, comatose patients and may manifest as nonconvulsive status epilepticus. Metabolic acidosis, hyperazotemia, hyperkalemia, hypoglycemia, hyperthermia, and hypoxia may develop and exacerbate the situation, thereby leading to further seizure activity. Adequate preoperative loading of parenteral or oral phenytoin has definitively been shown to decrease the incidence of postoperative seizures. It follows that therapeutic preoperative levels should be measured in patients undergoing supratentorial procedures whenever possible. Administration of the anticonvulsant should continue through the acute and early postoperative period. Electrolyte abnormalities should be corrected immediately in the postoperative period to further reduce the chance for a seizure. Blood levels of antiseizure medications should also be verified and brought into the therapeutic range. Multiple seizures or any seizure lasting longer than 5 minutes should be aggressively treated rather than waiting 30 minutes to fulfill the criteria for status epilepticus. Treatment may entail the administration of lorazepam, diazepam, or midazolam, followed by fosphenytoin. For refractory cases, reintubation followed by phenobarbital coma or general anesthesia may be necessary. In most cases, it is probably best to image the patient postoperatively after the seizure episode has been treated. The possibility of intracranial hemorrhage, edema, infarction, or pneumocephalus must be entertained and the appropriate surgical or medical management initiated as soon as possible. Reports have called into question the routine practice of phenytoin prophylaxis for patients without a history of seizures. In patients who have a history of seizures preoperatively, antiepileptics are continued for 3 to 6 months after surgery. The duration and force of tissue retraction on central nervous system tissue are directly related to the amount of postoperative swelling in the supratentorial and infratentorial compartments. Bipolar coagulation can further contribute to this edema when cortical bleeding is caused by retraction. The edema may be worsened if venous drainage is impaired and results in local congestion. Sustained venous hypertension may cause infarction and petechial hemorrhage, often with disastrous consequences. For lengthy procedures or when significant brain retraction is necessary, the use of a rigid, self-retaining retractor system combined with rigid head fixation can help limit the damage caused by tissue manipulation. Preservation of the cerebral vasculature during surgery, with limited coagulation and careful tissue handling, can reduce the occurrence of severe edema postoperatively. The neurological deficits caused by brain swelling may be permanent or transient, and the severity of the deficit depends on the patient. Edema usually begins within 5 hours after the procedure and reaches its maximum approximately 48 to 72 hours later. Cerebral hypodensity, sulcal effacement, midline shift, loss of the graywhite matter interface, and small lateral ventricles are the hallmarks of postoperative edema. If impaired venous drainage secondary to the incompetence of venous sinuses is suspected, conventional venous-phase angiography or magnetic resonance venography may be helpful in diagnosing the location and severity of the occlusion. High-dose dexamethasone should be given to patients with vasogenic edema to alleviate tumor-related swelling. When using diuretics, it is important that serum chemistries and osmolalities be monitored to ensure that the patient does not become severely dehydrated. Hypertonic saline solutions are now increasingly being used with success for the treatment of vasogenic edema. Because high-grade gliomas are not curable by surgery, surgery represents a palliative treatment aimed at reducing tumor bulk and maximizing quality of life. Patients with metastatic brain lesions can have a significant improvement in their survival by removal of brain metastases. It is therefore incumbent on neurosurgeons to minimize complications when patients are in the early stages of their disease and their clinical condition is best. The decision about whether surgery is warranted involves carefully weighing the possible surgical complications against the potential benefits. Studies have shown that craniotomies for intraparenchymal lesions typically result in mortality rates of 2. Surgery on gliomas typically results in more morbidity and mortality than does surgery on brain metastases. Neurological compromise may result from resection or retraction of normal functional brain tissue or compromise of the vascular supply. Neurological morbidities usually consist of motor or sensory deficits or aphasias (Table 6-2). The result is a tradeoff between radical tumor resection and risk for resection of functional brain tissue and subsequent neurological deterioration. Avoidance of vascular compromise involves meticulous attention to detail and preservation of all significant vasculature seen to supply normal brain tissue. Computer-assisted stereotactic systems enhance the ability of the surgeon to delineate between normal brain and tumor. Intraoperative functional mapping helps identify and avoid injury to eloquent cortex. Craniotomy performed while the patient is awake is particularly helpful in resecting lesions surrounding the speech centers. Using an awake craniotomy technique, Taylor and Bernstein reported an overall complication rate of 16. Increasingly, functional imaging is being applied intraoperatively, with evidence suggesting that it allows more complete resection while minimizing the risk for deficits. By using these modalities, they were able to improve extent of resection by 15% without incurring postoperative neurological deficit. Prevention begins with checking preoperative coagulation studies and ensuring that the patient has not been taking an aspirin-containing product. Intraoperatively, meticulous hemostasis must be achieved with a variety of hemostatic agents and bipolar electrocautery. Tight blood pressure control during extubation and in the postoperative period is important. Rarely, distal intracerebral or intracerebellar hemorrhages can occur, although their cause is unexplained.

The attitudes of the early 1990s medicine 4h2 pill purchase arava online, when treatment was less effective and restrictions of practice loomed in the background medicine youth lyrics buy arava 20 mg with visa, have passed medications with weight loss side effect generic 20mg arava fast delivery. A total of 119 cases came from France treatment episode data set purchase arava 10mg without prescription, 65 cases from the United Kingdom medicine hat arava 20 mg otc, and 29 cases from the United States medicine 377 discount 20 mg arava amex. West Nile virus infection has been transmitted by transfusion and must be considered a potential occupational pathogen during the viremic phase of the disease. Perhaps the most intriguing of future issues in blood-borne transmissible disease is prion disease, or "infectious proteins. It is thought to transmit disease by the abnormally folded pathogen protein serving as a template, which results in the normally occurring prion protein assuming the abnormal configuration. This near elimination of transmissions is likely due to the identification of patients with suspected disease, the use of disposable instruments, quarantine of nondisposable instruments when disease is suspected, and rigorous sterilization procedures of instruments used when disease is confirmed. Occupational transmission is a potential consideration either from handling infected tissues or from blood exposure from patients with clinical or asymptomatic disease. In the final analysis, human blood contains many known and unknown transmissible hazards that pose a potential risk to neurosurgeons. It can only be concluded that blood is a potentially toxic substance and that the clinical surgeon must exercise due diligence in the avoidance of blood contact or percutaneous injury in the course of providing surgical care. The Influence of Double-Gloving on Manual Dexterity and Tactile Sensation of Surgeons. Use of hepatitis-B vaccine and infection with hepatitis B and C among orthopaedic surgeons. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: Evidence of a new acquired cellular immunodeficiency. Molecular cloning and disease association of hepatitis G virus: a transfusion-transmissible agent. The incidence of transfusion-associated hepatitis G virus infection and its relation to liver disease. Evolving concepts of the clinical and serologic consequences of hepatitis B virus infection. Use of Hepatitis-B vaccine and infection with hepatitis B and C among orthopaedic surgeons. Guidelines for prevention of transmission of human immunodeficiency virus and hepatitis B virus to health-care and public-safety workers-a response to P. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Reduction of maternalinfant transmission of human immunodeficiency virus type 1 with zidovudine treatment. A survey of occupational blood contact and human immunodeficiency virus infection among orthopedic surgeons. Frequency of glove perforations and subsequent blood contact in association with selected obstetric surgical procedures. Gloves, extragloves or special types of gloves for preventing percutaneous exposure injuries in healthcare personnel. The influence of doublegloving on manual dexterity and tactile sensation of surgeons. Evaluation of blunt suture needles in preventing percutaneous injuries among healthcare workers during gynecologic surgical procedures-New York City, March 1993-June 1994. Blunt versus sharp suture needles for preventing percutaneous exposure incidents in surgical staff. Sharpless surgery: a prospective study of the feasibility of performing operations using non-sharp techniques in an urban, university-based surgical practice. Use of safety scalpels and other safety practices to reduce sharps injury in the operating room: what is the evidence Prevention and control of infections with hepatitis viruses in correctional settings: Centers for Disease Control and Prevention. Transmission of hepatitis B virus to multiple patients from a surgeon without evidence of inadequate infection control. Transmission of hepatitis B virus from a surgeon to his patients during high-risk and low-risk surgical procedures during 4 years. Patient-to-patient transmission of hepatitis B virus associated with oral surgery. Transmission of hepatitis B virus from an orthopedic surgeon with a high viral load. Risk of hepatitis C virus transmission from an infected gynecologist to patients: results of a 7-year retrospective investigation. Phylogenetic analysis indicates transmission of hepatitis C virus from an infected orthopaedic surgeon to a patient. Patient-to-patient transmission of hepatitis C virus through the use of multidose vials during general anesthesia. Nosocomial transmission of hepatitis C virus associated with the use of multidose saline vials. Hepatitis C virus infections from a contaminated radiopharmaceutical used in myocardial perfusion studies. Acute hepatitis C virus infections attributed to unsafe injection practices at an endoscopy clinic-Nevada 2007. A large nosocomial outbreak of hepatitis C and hepatitis B among patients receiving pain remediation treatments. A large nosocomial outbreak of hepatitis C virus infections at a hemodialysis center. Recommendations for preventing transmission of human immunodeficiency virus and hepatitis B virus to patients during exposure-prone invasive procedures. Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: a national heart, lung, and blood institute collaborative study. West Nile virus: epidemiology and clinical features of an emerging epidemic in the United States. Variant Creutzfeldt-Jakob disease: risk of transmission by blood transfusion and blood therapies. As illustrated in this 7th edition of Youmans and Winn Neurological Surgery, the techniques are changing much faster than the questions posed. Although the anatomy of the human brain has not changed since physicians acquired the ability to study it, the ability to visualize pathways, at both gross and microscopic levels, has changed dramatically, as has the ability to probe its depths and treat its pathology. Chapter 1 also shows how attempts to treat its maladies have been refined over time, from chiseling away at the cranium with crude chisels to using the microscope in combination with navigation systems. In Chapters 2 and 3, the authors discuss how the frontiers of gross and three-dimensional anatomy have been expanded. As important as neuroanatomy is to the neurosurgeon, the same can be said of the basic and clinical sciences to the neurosurgeon who aspires to be a clinician scientist. In this "Basic and Clinical Sciences" section, Chapters 44 through 57 cover a gamut of topics ranging from molecular biology to neurosurgical epidemiology. Chapter 45 ("Optogenetics and Clarity") highlights two new and exciting techniques that are revolutionizing research in the neurosciences. Through the selective introduction of light-activated receptors into the membranes of neurons, optogenetics has made it possible to activate specific populations of neurons in a manner that allows scientists to both create and correct abnormalities that mediate important functions and behaviors. Through the selective removal of lipids from the brain, clarity is allowing scientists to peer into the threedimensional depths of the brain and create panoramic maps with selective stains and molecular probes. In Chapter 46 ("Neuroembyology"), the authors describe some of the molecular pathways that underlie the amazingly complex unfolding of the development of the nervous system. Chapter 47 ("Stem Cell Biology") is an exploration of the persistence of embryonic cells in the adult nervous system and their potential role in diseases, such as brain tumors, as well as recovery after injury. Chapter 48 ("Neurons and Neuroglia") is a description of the important roles that neurons and glia play in creating and maintaining the complex circuitry and physiologic functions in the nervous system. In Chapter 49 ("Cellular Mechanisms of Brain Energy Metabolism"), the authors describe the molecular pathways that provide necessary energy for the brain and how imbalances result in impaired function and in extreme cases cell death. In Chapter 50 ("Cellular and Molecular Responses in the Peripheral and Central Nervous Systems: Similarities and Differences"), the authors compare and contrast the responses of the adult central and peripheral nervous systems to injury and how these differences lead to different outcomes. Chapters 51 ("The Blood-Brain Barrier"), 52 ("Physiology of the Cerebrospinal Fluid and Intracranial Pressure"), 53 ("Cerebral Edema"), and 54 ("Extracellular Fluid Movement and Clearance in the Brain: the Glymphatic System") deal with different aspects of the very important homeostatic mechanisms that maintain and regulate the flow of fluid in the brain and contribute to such important parameters as cerebral blood flow, perfusion pressure, and intracranial pressure. Chapter 55 ("Altered Consciousness") makes the transition from brain anatomy and physiology to human behavior by discussing the different levels of consciousness ranging from being comatose to being alert. Chapter 56 ("Neuropsychological Testing") is a description of the battery of tests that are available both to evaluate patients and to determine the efficacy of treatments. In Chapter 57 ("Neurosurgical Epidemiology and Outcomes Assessment"), the authors describe the tools that neurosurgeons can use to determine the prevalence and incidence of the disorders that they treat, as well as the success or failure of treatments and interventions. Other relevant basic and clinical science topics can be found in portions of some of the more clinical chapters in other sections of this book. Currently, neurosurgeons are at a stage analogous to trying to understand light emanating from a light bulb before the discovery of electromagnetic waves. Scientists could study the electricity running through the filament that gives rise to the light that passes through the glass. But it was possible to study light itself only after scientists had an understanding of electromagnetic waves and photons that allowed them to measure and quantify directly light itself. It is hoped that breakthroughs and paradigm shifts in the future will help neurosurgeons understand the mind from the brain at both conceptual and physical levels. The role of basic and clinical research is vital not only in the education of neurosurgery residents but also in developing and fostering an expectation within them that they can and should contribute to the evolution and advancement of their chosen field and profession. The very fact that questions always far outnumber answers keeps neurosurgeons humble and expectant, as well as being a wonderful antidote to boredom and preventing their work from becoming stale and lackadaisical. In addition to providing the very best care available to patients now, research provides hope, both to patient and to physician, that one day currently intractable medical problems will become more manageable and treatable. Research should nourish the intellect and spirit of neurosurgeons, irrespective of the status of their training or their site of practice, while simultaneously motivating self-improvement. It also provides hope to counteract the devastating consequences when disease overcomes the best therapeutic efforts. Understanding the concerted action of combinatorial gene sets expressed by discrete sets of cells and, increasingly, by single cells continues to be one of the most enduring fundamental challenges in contemporary neuroscience. The length of these sequences, as well as the probes, is not drawn to scale, and they would contain many more base pairs than depicted. Eberwine knowledge of their etiologic role in a disease state enabled molecular geneticists to narrow the number of candidate causative genes. Before the completion of the Human Genome Project, identifying these loci was an incredibly arduous and timeconsuming task, in large part because of the lack of high-resolution genetic and physical chromosomal maps. Expanding on the sequence of methods conceptualized first by Sol Spiegelman3 and most effectively by Edwin Southern,4 molecular biologists have exploited the now well-worn principle of molecular hybridization in which a single-stranded nucleic acid probe (or primer) forms a stable hybrid molecule, as a result of nucleotide complementarity, with a single-stranded target sequence immobilized on a solid support. Under the appropriate experimental conditions the stability and biochemical kinetics of the hybrid are directly proportional to the length and the degree of nucleotide complementarity. Indeed, Southern blot analysis of the dystrophin gene has identified duplications as well as mapped various exon deletion mutants. Recently, variation in the copy number of genes has received new consideration as several new genomic disorders have been shown to manifest in a gene dosage-dependent manner. By reducing the stringency of hybridization conditions, however, differences in hybridization patterns may reveal the existence of certain fragments that are not able to hybridize to the probe under the most stringent hybridization conditions. These data are often the first clues that the gene is part of a larger multigene family that shares significant but not complete nucleotide sequence identity. It is confirmed also that those more or less intimate contacts are always established, not between the nerve arborizations alone, but between these ramifications on the one hand, and the body and protoplasmic processes on the other. These arrays of neural networks codify our perceptions and other cognitive functions. To do so, synapses bring together in apposition specialized morphologic structures of the presynaptic, usually axonal, and postsynaptic, typically dendritic, subcellular neuronal domains often ensheathed by the end feet of astrocytes. The precision and strength of these connections rely on the pinpoint placement of gene products in each of these cellular compartments. Our understanding of neuroscience in these molecular terms has been one of the fundamental challenges in the last several decades but has been complicated by the varying intrinsic properties of neurons-including morphology, types of neurotransmitter release, projection targets, and basic input and output characteristics-that exist along a wide spectrum of neuronal phenotypes even within the same neuroanatomic region. Over the last several decades, neuroscientists have embraced a rapidly evolving set of molecular biologic techniques to gain insight into understanding these dynamics of gene expression. These findings have been critical in understanding not only the mechanistic underpinnings of normal development but also the role that some genes play in neurological diseases from the developmental to the degenerative. We do so in the broader context of the traditional candidate gene approach and the more recent rise of functional genomics. Using linkage analysis to look at differences in chromosome structure in diseased versus nondiseased individuals often in tandem with linkage disequilibrium mapping to define broad. A probe, labeled here with biotin, that has nucleotide complementarity to genomic sequence will bind with specificity. Using this principle in some form, a table of the basic tools of molecular biology is given to provide a cursory overview of the methods and their uses. Furthermore, differences in the size of the transcript within or among samples suggest any number of biologic causes, including but not limited to alterative splicing, alternate start sites, or differences in polyadenylation. Typically, medium- and highabundance messages are readily visualized with labeled probes. Although gene-specific primers can be used for the reverse transcription, a polythymidine oligonucleotide (oligo-dT), random hexamers, or combination of them are most frequently used. Before quantitation, it is essential that the primers be exhaustively tested with the target template to ensure that the gene of interest is amplified and is the expected size. Detection and quantitation occurs only as signal is emitted because the fluorescent reporter is physically cleaved from the quencher by the 5-3 exonuclease activity of the thermostable polymerase during the elongation step. In addition, de novo expression, induction, and repression are rarely observed in the mature nervous system, so the dynamic range of expression is often modest. To determine the cellular resolution of gene expression, in situ hybridization is most often used. Many times, it is present at higher levels of abundance in specific subpopulations of neurons than one would detect within the whole tissue.

The numbers refer to normal oxygen tensions in millimeters of mercury (mm Hg) units calculated from the equations for capillary and venous oxygen tensions and for mitochondrial oxygen tension symptoms 24 order arava 20mg online. The oxygen tension of the average tissue compartment or capillary-mitochondrial diffusion interface is a simple linear average treatment efficacy best order for arava. Note that the term capillary bed is used for the entire portion of the vascular bed that interacts with the tissue symptoms rheumatoid arthritis discount arava 20mg on line. Longitudinal gradients in periarteriolar oxygen tension: a possible mechanism for the participation of oxygen in local regulation of blood flow treatment bursitis cheap arava 20 mg visa. Other factors treatment 21 hydroxylase deficiency buy cheap arava 20 mg on line, such as specific resistance at the endothelium of brain capillaries treatment ibs 10mg arava for sale,76 may also influence oxygen delivery. A significant fraction of the oxygen transported to brain tissue is extracted during the passage of blood in microvessels in the brain. On average, 40% of the oxygen in blood is extracted, but it may increase to as much as 60%. It appears that oxygen is delivered to the tissue entirely by diffusion and that the large extraction lowers the pressure gradient responsible for diffusion of oxygen. It is possible to calculate the loss of oxygen from the blood that flows through capillaries and hence the decline in oxygen partial pressure, which depends on the extraction fraction. Elevation of blood flow that exceeds the increment in oxygen consumption counters the decline in the pressure gradient, as described by simple one-dimensional models of oxygen diffusion to brain tissue. Generally speaking, these processes are glycolysis, or the breakdown of glucose to pyruvate, and oxidative phosphorylation, or the breakdown of pyruvate to carbon dioxide and the reduction of oxygen to water. These relationships apply only to the steady state, in which there are no changes in substrate concentrations in the brain, and glucose and oxygen do not enter other pathways. The formulation of lactate efflux applies to the tissue as a whole, under the assumption that pyruvate and lactate as monocarboxylic acids are not subject to compartmentation. Thus, the accumulation of lactate is a simple function of the pyruvate concentration and lactate exchange across the blood-brain barrier. Enzymes and transporters are among the proteins that subserve the nonequilibrium and nearequilibrium reactions that could contribute to these mechanisms. Near-equilibrium reactions buffer minute changes in the relevant substrates, but flux-generating and flux-directing nonequilibrium reactions adjust the magnitude and direction of metabolism dictated by extrinsic regulators. The formation of lactate from pyruvate at normal oxygen tension sometimes is known as the Warburg effect when it occurs in tumor cells, and by extension in brain. As little as 15% is present in soluble form in the cytosol, but the distribution is variable and depends on numerous factors that are not fully understood. The functional significance of the soluble and bound forms of the enzyme is also uncertain. Because glucose is normally the preferred substrate for brain metabolism, control of glycolysis is integral to understanding how increased energy production and use are linked. This regulation also explains the circumstances in which brain metabolism in general or metabolism in a separate cellular compartment such as neurons or glial cells has a preference for ketone bodies, lactate, or acetate when these substrates are present in excess (lactation, starvation, physical exertion, and possibly neuronal excitation). The time constants dictate the half-times of change, that is, the times that it takes the system to reach the halfway point of a new steady state. It is apparent from Table 49-6 that glycolysis responds to change with time constants on the order of milliseconds, whereas oxidative metabolism responds with time constants of seconds or minutes. Hence, oxidative metabolism responds to any stimulus with a certain delay, compared with glycolysis. Glucose-6-phosphate occupies a pivotal position in glycolysis where it links a number of reactions, including the main glycolytic pathway itself, the pentose phosphate pathway, the glycogenesis pathway, and the important hexosamine and nucleotide Oxygen Glucose Glucose Glucose-6-P Glycogen Glycolysis Glycolysis is defined as the breakdown of glucose to pyruvate under normal aerobic conditions. An important step in glycolysis is the reaction catalyzed by the triose phosphate dehydrogenase step. In turn, this ratio determines the direction and net flux of the reaction between pyruvate and lactate and the competition between glucose and lactate as sources of pyruvate when lactate is available in excess. The ratio between the concentrations of lactate and pyruvate is also the apparent ratio between their affinities. At steady state, the ratio must be the same everywhere, given the near-equilibrium and facilitated diffusion nature of the proton symporters of lactate and pyruvate. Increases in calcium concentration often occur as repeated spikes with steep upslopes and shallower downslopes that reach baseline during sustained excitation. Extrusion of protons from the matrix establishes a gradient of hydrogen ion concentration across the inner membrane. When dissipated by escape of hydrogen ion back into the matrix through several different channels, this gradient drives specific molecular interactions that depend on its magnitude. Released into the matrix, hydrogen ions form water in a key interaction when they combine with oxide ions. The kinetics of this relationship shows that the rate of oxygen consumption depends critically on the average capillary oxygen tension and that it fails to rise above a certain threshold despite increases in cytochrome oxidase activity unless the affinity or diffusibility of oxygen is simultaneously adjusted. The threshold is dictated by the mitochondrial oxygen tension and is reached when the tension declines below the level associated with sufficient oxygen saturation of cytochrome oxidase. Oxidative Phosphorylation At steady state, brain metabolism has a respiratory quotient of unity, consistent with the oxidation of glucose96-98 and with the integration of glycolysis and oxidative metabolism. This subsection presents the primary regulatory steps for oxidative metabolism in mitochondria. PyruvateDehydrogenaseComplex andtheTricarboxylicAcidCycle Recent evidence suggests that mitochondria may import both pyruvate and lactate. In total, per mole of glucose, 20 hydrogen ion equivalents are extruded from the mitochondrial matrix and join four hydrogen ion equivalents generated in the cytosol. Despite the importance of this process to the entire understanding of brain function, regulation of oxidative phosphorylation in the brain in vivo is still poorly understood. Cytochrome c oxidase has been estimated to be 95% saturated at the oxygen tension prevailing in mitochondria in human brain in vivo,108 but its sensitivity to variations in oxygen tension is much greater than implied by this occupancy because lower mitochondrial oxygen tensions imply impaired diffusion of oxygen from microvessels. There is a theoretical limit to the efficacy of this adjustment, particularly when the cytosolic energy charge is unchanged. In reality, it appears that the near-equilibrium hypothesis assigns the ultimate maintenance of oxygen consumption to the regulation of oxygen delivery, particularly in situations in which mitochondrial oxygen tension threatens to fall below a minimum threshold. As a result of the imbalance between oxygen delivery and cytochrome oxidase activity in these states, cytochrome c oxidase does not remain saturated when the mitochondrial oxygen tension declines relative to the average capillary oxygen tension. This section describes the properties of the separate metabolic compartments of neurons and astrocytes that confer important joint roles of these compartments in the regulation of metabolic responses to excitation. The two pools of glutamate are now largely believed to represent neurons and astrocytes, respectively. In mammalian cortex, transfer of glutamate between the two pools occurs through neuronal release of glutamate during excitation and subsequent import by neurons and glia. Astrocytes play a critical role in the synthesis of glutamate and import of glutamate and potassium from the interstitial space surrounding the intrasynaptic clefts. The importance of uncoupling has recently emerged as a potential but still elusive form of control of brain energy metabolism that is not reflected by changes in oxygen consumption. Uncoupling of mitochondria from energy metabolism takes place when protons escape to the matrix through permanent or inducible channels. The more active this channel, the greater the leak of hydrogen ions, such that an upper limit of 90% coupling is observed. The lower limit is actually 0% coupling (100% uncoupling) in isolated mitochondria, with a 75% average in the rat in vivo. In addition, there are important enzymatic differences that cause the two groups of cells to react differently to changes in metabolism. The proximal and distal parts of neurons are shown in green and the proximal and distal parts of astrocytes in blue. Metabolites linked by near-equilibrium transporter and enzyme reactions are shown with bidirectional arrows. The metabolic fates of pyruvate and lactate depend on relative preferences for each transporter or enzyme, which are regulated by affinities in relation to pyruvate and lactate concentrations. Several factors influence the exchange of metabolites between metabolic compartments: the distribution of glycolytic and hexokinase activities among the compartments, the distribution of oxidative capacity among the compartments, and the volumes of the different compartments. These factors, in turn, determine the number of compartments that must be considered. When these factors are taken into account, it is likely that at least four different compartments can be discerned. The answer is important because any local imbalance in glycolytic and oxidative capacities necessarily leads to exchanges of pyruvate and lactate among these localities, facilitated as they are by the more or less homogeneous pools of glucose, pyruvate, and lactate that exist in brain tissue. In these pools, glucose is consumed at the sites of phosphorylation in proportion to the hexokinase activity, wherever this is established, whereas pyruvate is consumed in proportion to the local oxidative capacity, with lactate acting as a buffering intermediate among these sites. In a study of both cell types in isolation, Itoh and colleagues found that both release lactate, albeit to different extents. Thus, neurons or astrocytes, or both, could in principle release pyruvate and lactate at low activity in vitro but still require net uptake of either at high activity in vivo. The significance of this point depends on the individual glycolytic and oxidative capacities of the two cell types and on the extent to which these capacities undergo change during functional activity in vivo. The notion that glial cells are considerably more glycolytic than neurons arises from different experiments. The latter represents the necessary cofactor in the scavenging of reactive oxygen species produced by the high oxidative activity of neurons. The estimation of volumes suggests that at least four metabolic compartments are present, including on one hand the cell bodies and proximal sites of neurons and the cell bodies and proximal sites of astrocytes that are not part of the neuropil, and on the other hand the distal sites of neurons and astrocytes that make up the neuropil, possibly with very gradual transitions among the four. This is possible only if these parts of the neurons import most of the necessary pyruvate in the form of lactate from sources other than the glucose imported directly by neurons. When other compartments, including the distal parts of neurons and the proximal and distal parts of astrocytes and extracerebral sources of lactate, supply pyruvate to a uniform tissue pool, the proximal elements of neurons draw a sizable portion of their glycolytic needs from this pool. Proximal neuronal sites have the highest oxidative metabolic rate, no less than 9. In comparison, distal astrocytic sites (processes) then have the second to highest oxidative metabolic rate of 1. The circumstances listed in Table 49-7 are consistent with a higher rate of production of lactate by astrocytic processes than by neuronal terminals, as demonstrated by Itoh and associates in vitro. Recent assessment has shown that the cell body volumes of neurons and astrocytes in human cerebral cortex average 10% and 2% of the total volumes of the cells, respectively. Estimated glycolytic and oxidative fluxes of glucose, pyruvate, and lactate, along with volumes of extracellular fluid and neuronal and astrocytic compartments in the mammalian cerebral cortex. Glucose, pyruvate, and lactate occupy single homogeneous pools encompassing all compartments. Glucose feeds into the pyruvate pool in proportion to the hexokinase capacity of the intracellular compartments, and pyruvate supplies the oxidative metabolism of the two cell types (green and blue) in proportion to their oxidative capacities. This analysis suggests that the functional ranges of the activities are very different in the two cell types, in keeping with the very different functional contingencies facing the two cell types in normally functioning brain tissue. It is evident that the issue of the rates of glycolysis and oxidative phosphorylation in neurons and glial cells hinges on the mechanisms underlying the estimates of the relative glycolytic and oxidative capacities of the respective cellular compartments, of which there appear to be at least four, including subdivisions of the neuronal and astrocytic populations of cells. The relative capacities arise from the differential activities of hexokinase, phosphofructokinase, and cytochrome oxidase in the compartments, which in turn appear to depend on the time constants of the metabolic fluctuations and on the average metabolic activity. Low time constants are likely to favor glycolysis and low average oxidative rates, whereas high time constants favor high oxidative rates, much as in muscle cells. Under resting normal physiologic conditions in vivo, a higher share of the glycolytic capacity resides in astrocytes and the neuropil, whereas a higher share of the oxidative capacity relative to volume resides in the proximal elements of neurons, with substantial differences between the proximal and distal parts in both cell types (factor of 5 in astrocytes, factor of 13 in neurons). Even though neurons and astrocytes differ with respect to metabolite enzyme and transporter distribution, there is no evidence that the pools of glucose, pyruvate, and lactate are compartmentalized inside and outside neurons and glia. Because transport in vivo is entirely passive, it is puzzling that glutamate in vitro inhibits glucose transport into neurons and triggers glucose transport into astrocytes. The effect of these differences and this change is not clear: Are the differences due to loss or gain of metabolites of glucose from brain tissue by mechanisms other than complete oxidation of glucose, or are the differences due to gain of tissue in childhood by incorporation of metabolites of glucose or loss of tissue components by breakdown of the aging brain According to this view, most of the phosphorylated glucose that is not fully oxidized is instead incorporated into the structural expansions of the brain, particularly during the development of the brain in childhood and youth. Top and middle, Steady-state neuronal membrane potential change as a function of altered sodium and potassium ion membrane permeability at 0. Ordinates, ion permeability (mL/g/min); abscissae, membrane potential (mV) calculated from the Goldman-Hodgkin-Katz constant field equation. Bottom, Steady-state metabolism permitting membrane depolarization of the magnitude dictated by the increased sodium and potassium permeability. Much empirical evidence could be cited in favor of the theory that the unitary experience of consciousness is related to the global level of energy turnover in the brain rather than to the activity in isolated regions of the brain. Among these findings is the correlation between reported magnitudes of global brain energy metabolism and levels of consciousness. Understanding brain function is the goal of neuroscientific explorations of brain activity, but it is not often clear which specific hypothesis the explorations actually test. Collectively, these measures can contribute to a comprehensive description of activity in brain tissue, but no single measure can be said to unequivocally represent activation-or even brain function-per se. The discipline of neuroenergetics focuses on measures of the energy turnover of brain tissue as keys to the functional integrity of brain tissue, including consciousness. The insights gleaned from the accomplishments of this discipline have been limited by the convention that changes in energy turnover are a consequence of, or response to , changes in brain function, rather than the opposite. The changes in membrane potential reflect changes in both sodium and potassium, or chloride, ion permeability. Brain Energy Metabolism during Activation During maximal excitation of brain tissue in vivo, such as with epileptic seizures, local increases in the metabolism of glucose or oxygen can reach 100% or more of the metabolism of the normal default state, depending on the intensity of the stimulus. The experimental evidence for increases in brain energy metabolism during excitation in vivo comes in three different forms: as global steady-state changes brought on by general reductions or increases in brain activity; as localized responses to specific stimulation, mostly the cerebral cortex; and as changes in substrates and metabolites in the circulation and in brain tissue. Focal activation responses in a number of stimulation studies of human brain (summarized in Table 49-8) fall into two fundamentally different categories of stimulation. It is important to note that the functional stages assigned to the global changes reflect major perturbations in consciousness that are not consistent with normal cognition.

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