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By: S. Urkrass, M.B. B.CH. B.A.O., Ph.D.

Clinical Director, Oregon Health & Science University School of Medicine

The spectrum of acceptable conformations is then energy minimized (using a quantum mechanics or molecular mechanics approach bacteria yeast and blood slide cheap panmycin 250 mg otc, as discussed above) virus 7g7 part 0 purchase panmycin paypal, and ranked by energy. Although it is necessary to generate a large number of conformations, in principle it is possible, within a user-defined timeframe, to achieve a representative sample from low-energy conformational space. A second, widely used method for searching conformational space is through molecular dynamics calculations. A simple definition of molecular dynamics is that it simulates the motions of a system of atoms with respect to the forces that are present and acting on the molecule. If one can calculate the next configuration of the collection of atoms, it is possible to follow the evolution of the atomic movements within the molecule over time. This is different from the Monte Carlo method, which requires outside intervention to produce change by a random move; in molecular dynamics, all changes result without external intervention and arise from within the system itself. In a molecular dynamics calculation, the molecule is "heated" by assigning velocities randomly to the atoms for a given temperature. Once the first velocities have been assigned, the molecular dynamics simulation is self perpetuating. As the simulation of the atomic movements progresses, the new atomic positions are calculated. By "heating" the molecule and permitting it to cool, it is possible to explore the conformational space of the molecule, thereby identifying low energy shapes. The genetic algorithm method is a technique that has very recently gained attention for searching conformational space. Genetic algorithms may be applied to the multiple minima problem of molecular conformational analysis via a variety of methods. In one such method, the torsional angles within a given molecule are designated as "genes. If this offspring has a lower energy than its parents (as determined using either molecular mechanics or quantum mechanics calculations), the conformation is said to have "fitness" and is permitted to survive. The "most fit" conformations are permitted to propagate by exchanging their genes with their sibling conformers. A mathematical procedure, termed a "mutation operator," is used to incorporate greater diversity amongst the genes as successive generations are created. Genetic algorithm calculations permit families of low energy conformers to be identified. Monte Carlo methods, molecular dynamics calculations, and genetic algorithm methods are all techniques for searching conformational space; each has strengths and weaknesses. The techniques are complementary rather than competitive, and may be used together in a concerted attempt to identify low energy conformers of drug molecules. Since these methods are simply techniques for skipping across the conformational space of a molecule, they must be used in conjunction with a mechanics method. One final issue, which confounds the use of these methods for identifying the elusive global energy minimum, concerns the biological relevance of this lowest energy conformation once it has been identified. Just because a detailed quantum mechanics calculation has identified a given conformation as the lowest energy shape for a drug molecule, this does not mean that this is the bioactive conformation. The interaction of a drug with its receptor is a dynamic process in which each molecule flexes to fit the other. It is entirely possible that the drug molecule may assume a higher energy conformation (by several kcal/mol) in order to achieve this fit, thereby rendering the search for a global energy minimum somewhat irrelevant. For someone who has never taken a course in quantum mechanics, this discussion of quantum pharmacology may have been somewhat confusing. However, understanding these basic principles is important because of the important and ever-increasing role of molecular modeling in drug design and discovery. Since a molecule may have an almost infinite variety of shapes, the infinite number of single energy values corresponding to these shapes define a surface (termed the potential energy hypersurface). The lowest point on this surface (global minimum) is assumed to represent the most probable shape of the molecule.

Two-thirds of patients present with lacunar syndromes such as pure motor antibiotic vitamin c cheap 250mg panmycin with amex, ataxic hemiparesis antimicrobial nanotechnology order 250 mg panmycin with mastercard, pure sensory or sensory motor stroke. With increasing load of subcortical white matter lesion, vascular dementia with deficits of executive functions, and attentional and memory deficits develops (mean age of 50 years). Twenty percent of patients have severe mood disorders, and focal or generalized seizures have been observed in about 8% of patients. Not infrequently, such a constellation may lead to a false suspicion of multiple sclerosis. Alpha-galactosidase deficiency leads to accumulation of glycolipids, mainly in endothelial and smooth muscle cells. A more recent study of 721 sufferers from acute cryptogenic stroke aged 18 to 55 years showed a rare but not negligible frequency of Fabry disease, which was 4. The patients are mainly young and present with a variety of symptoms and signs which are caused by deposition 147 Section 3: Diagnostics and syndromes Figure 9. In this patient, the two vascular territories, posterior cerebral artery and middle cerebral artery, of the left hemisphere are involved. The most specific abnormality, however, appears to be a hyperintense signal of the pulvinar thalami on T1-weighted images [33]. Up to one-quarter of patients with Fabry disease may show this abnormality, which could be a consequence of microvascular calcification. Clinically silent or manifest strokes, both cortical and subcortical, are caused by occlusion of small vessels or by extasia of larger vessels, embolism from the heart, and rarely by intracranial hemorrhage. Blood lactate levels are elevated, indicating dysfunction of the respiratory chain. Many different phenotypes, alone or in combinations, have been reported with this mutation (hearing impairment, cognitive decline, progressive external ophthalmoplegia, or epilepsy). The lesions may also subside without remaining signal changes, which would be quite unusual for infarction, and have a tendency to slowly progress or to reoccur at other sites, sometimes within relatively short intervals of days to weeks [35]. The most likely origin of strokelike episodes is a sudden metabolic failure with loss of function and transient or persistent cellular damage. Most patients with dissections are between 30 and 50 years of age, and the mean age is approximately 40 years. The annual incidence of cervical internal carotid artery dissection was found to be 3. The vertebral artery is most mobile and susceptible to mechanical injury at the C1/C2 level. Estimates of dissection risk after chiropractic manipulation vary widely with the study methodology but range from 1 in 5. One study found connective tissue disorders in one-fourth of patients with cervical artery dissections after chiropractic manipulations [40]. Arterial dissections usually arise from an intimal tear that allows the development of an intramural hematoma (false lumen). In some patients, no communication between the true and the false lumen can be demonstrated, suggesting that some dissections are the result of a primary intramedial hematoma. Mechanisms of ischemic stroke are either hemodynamic compromise secondary to luminal narrowing or occlusion or embolism from thrombus within the true lumen. The absence of an external elastic lamina and a thin adventitia makes intracranial arteries prone to subadventitial dissection and subsequent subarachnoid hemorrhage. A 60-year-old man noticed right-sided neck pain, ipsilateral headache, problems with swallowing and tongue movements and dysarthria (hoarseness). Some weeks later he was admitted to a neurological department and presented with rightsided glossopharyngeal and spinal accessory nerve lesions (moderate paresis of the upper portion of the trapezius and the sternocleidomastoid muscles), hypoglossus and recurrent nerve palsies. There was a prominent coiling of the internal carotid artery in the area of dissection. Aortic arch dissection can cause generalized brain hypoxemia and low-flow infarction as a result of systemic hypotension caused by cardiac tamponade, acute aortic regurgitation or myocardial infarction. Clues for the diagnosis of aortic dissection are [1]: sudden and severe anterior chest pain and/or interscapular pain which may move as the dissection extends syncope hypotension diminished, unequal or absent arterial pulses and blood pressure in the arms and sometimes legs acute aortic regurgitation and cardiac failure simultaneous or sequential ischemia in carotid, subclavian, vertebral, spinal, coronary and other aortic branches if the dissection extends over several centimeters. Small collaterals develop from the lenticulostriate, thalamoperforating and pial arteries at the base of the brain, from leptomeningeal collaterals of the posterior cerebral artery or from branches of the external cerebral artery (orbital, ethmoidal or transdural).

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Acute prostatitis Chronic bacterial prostatitis Granulomatous prostatitis Benign prostatic hyperplasia Prostatic adenocarcinoma 363 antibiotic resistance science project buy 250mg panmycin with mastercard. A 67-year-old male is found on rectal examination to have a single antibiotic resistance to gonorrhea cheap 500 mg panmycin overnight delivery, hard, irregular nodule within his prostate. A biopsy of this lesion reveals the presence of small glands lined by a single layer of cells with enlarged, prominent nucleoli. Anterior zone Central zone Peripheral zone Periurethral glands Transition zone 364. A newborn female is being worked up clinically for several congenital abnormalities. During this workup, it is discovered that normal development of the vagina and uterus in this female infant has not occurred. Failure of the uterus to develop (agenesis) is directly related to the failure of what embryonic structure to develop? Urogenital ridge Mesonephric duct Paramesonephric duct Metanephric duct Epoophoron Reproductive Systems 387 365. Multiple small mucinous cysts of the endocervix that result from blockage of endocervical glands by overlying squamous metaplastic epithelium are called a. If this area of leukoplakia is due to lichen sclerosis, then biopsies from this area will most likely reveal a. Atrophy of epidermis with dermal fibrosis Epidermal atypia with dysplasia Epithelial hyperplasia and hyperkeratosis Individual malignant cells invading the epidermis Loss of pigment in the epidermis 367. Condyloma acuminatum Cervical carcinoma Clear cell carcinoma Carcinoma of the endometrium Squamous carcinoma of the vagina 388 Pathology 369. The photomicrograph below depicts a biopsy of the uterine cervix that was done following an abnormal Pap smear report. A 29-year-old female presents with severe pain during menstruation (dysmenorrhea). The pathology report from this specimen makes the diagnosis of chronic endometritis. Based on this pathology report, which one of the following was present in the biopsy sample of the endometrium? Neutrophils Lymphocytes Lymphoid follicles Plasma cells Decidualized stromal cells Reproductive Systems 389 371. In giving a history she describes severe pain during menses, and she also tells you that in the past another doctor told her that she had "chocolate in her cysts. Metastatic ovarian cancer Endometriosis Acute pelvic inflammatory disease Adenomyosis A posteriorly located subserosal uterine leiomyoma 372. Abnormal menstrual bleeding characterized by excessive bleeding at irregular intervals is best referred to as a. An endometrial biopsy is obtained approximately 5 to 6 days after the predicted time of ovulation. This biopsy specimen reveals secretory endometrium, but there is a significant difference (asynchrony) between the estimated chronologic menstrual date and the estimated histologic menstrual date. Based on this information, what is the correct diagnosis for this biopsy specimen? Anovulatory cycle (no corpus luteum formed) Inadequate luteal phase (decreased functioning of the corpus luteum) Irregular shedding (prolonged functioning of the corpus luteum) Normal endometrium during the follicular phase of the cycle (no corpus luteum formed). Normal endometrium during the luteal phase of the cycle (normal corpus luteum) 390 Pathology 374. Which one of the listed endometrial abnormalities has the greatest risk of developing into endometrial cancer? Simple hyperplasia Complex hyperplasia Atypical hyperplasia Cystic hyperplasia Polyp 375. Prolonged unopposed estrogen stimulation in an adult female increases the risk of development of endometrial hyperplasia and subsequent carcinoma. Adenocarcinoma Clear cell carcinoma Small cell carcinoma Squamous cell carcinoma Transitional cell carcinoma 376.

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Because these fibers are concerned with conveying information to the central nervous system virus 63 cheap panmycin 250 mg amex, they are called sensory fibers antimicrobial liquid soap order discount panmycin on-line. The cell bodies of these nerve fibers are situated in a swelling on the posterior root called the posterior root ganglion. Some of these nerves are composed entirely of afferent nerve fibers bringing sensations to the brain (olfactory, optic, and vestibulocochlear), others are composed entirely of efferent fibers (oculomotor, trochlear, abducent, accessory, and hypoglossal), while the remainder possess both afferent and efferent fibers (trigeminal, facial, glossopharyngeal, and vagus). Sensory Ganglia the sensory ganglia of the posterior spinal nerve roots and of the trunks of the trigeminal, facial, glossopharyngeal, and vagal cranial nerves have the same structure. Each ganglion is surrounded by a layer of connective tissue that is continuous with the epineurium and perineurium of the peripheral nerve. The neurons are unipolar, possessing cell bodies that are rounded or oval in shape. A single nonmyelinated process leaves each cell body and, after a convoluted course, bifurcates at a T junction into peripheral and central branches. The former axon terminates in a series of dendrites in a peripheral sensory ending, and the latter axon enters the central nervous system. The nerve impulse, on reaching the T junction, passes directly from the peripheral axon to the central axon, thus bypassing the nerve cell body. Each nerve cell body is closely surrounded by a layer of flattened cells called capsular cells or satellite cells. The capsular cells are similar in structure to Schwann cells and are continuous with these cells as they envelop the peripheral and central processes of each neuron. B: Transverse section of the pons showing the sensory and motor roots of the trigeminal nerve. Autonomic Ganglia the autonomic ganglia (sympathetic and parasympathetic ganglia) are situated at a distance from the brain and spinal cord. The neurons are multipolar and possess cell bodies that are irregular in shape. The dendrites of the neurons make synaptic connections with the myelinated axons of preganglionic neurons. The axons of the neurons are of small diameter (C fibers) and unmyelinated, and they pass to viscera, blood vessels, and sweat glands. Each nerve cell body is closely surrounded by a layer of flattened cells called capsular cells or satellite cells. The capsular cells, like those of sensory ganglia, are similar in structure to Schwann cells and are continuous with them as they envelop the peripheral and central processes of each neuron. Peripheral Nerve Plexuses Peripheral nerves are composed of bundles of nerve fibers. In their course, peripheral nerves sometimes divide into branches that join neighboring peripheral nerves. It should be emphasized that the formation of a nerve plexus allows individual nerve fibers to pass from one peripheral nerve to another, and in most instances, branching of nerve fibers does not take place. A plexus thus permits a redistribution of the nerve fibers within the different peripheral nerves. At the root of the limbs, the anterior rami of the spinal nerves form complicated plexuses. Cutaneous nerves, as they approach their final destination, commonly form fine plexuses that again permit a rearrangement of nerve fibers before they reach their terminal sensory endings. The autonomic nervous system also possesses numerous nerve plexuses that consist of preganglionic and postganglionic nerve fibers and ganglia. Conduction in Peripheral Nerves In the resting unstimulated state, a nerve fiber is polarized so that the interior is negative to the exterior; the potential difference across the axolemma is about -80 mV and is called the resting membrane potential. Figure 3-17 Ionic and electrical changes that occur in a nerve fiber when it is conducting an impulse.

The normal pressure of cerebrospinal fluid with the patient lying quietly on his or her side and breathing through the mouth is between 60 mm and 150 mm of water antibiotics with anaerobic coverage cheapest panmycin. If the flow of cerebrospinal fluid in the subarachnoid space is blocked infection 2 app cheap panmycin 250 mg with amex, the normal variations in pressure corresponding to the pulse and respiration are reduced or absent. Compression of the internal jugular veins in the neck raises the cerebral venous pressure and inhibits the absorption of cerebrospinal fluid in the arachnoid villi and granulations, thus producing a rise in the manometric reading of the cerebrospinal fluid pressure. If this fails to occur, the subarachnoid space is blocked, and the patient is exhibiting a positive Queckenstedt sign. Should the tumor completely occupy the vertebral canal in the region of the cauda equina, no cerebrospinal fluid may flow out of the spinal tap needle. In the presence of a tumor, the cerebrospinal fluid may become yellow and clot spontaneously, owing to the rise in protein content. Tumors of the Fourth Ventricle Tumors may arise in the vermis of the cerebellum or in the pons and invade the fourth ventricle. Tumors in this region may invade the cerebellum and produce the symptoms and signs of cerebellar deficiency, or they may press on the vital nuclear centers situated beneath the floor of the ventricle; the hypoglossal and vagal nuclei, for example, control movements of the tongue, swallowing, respiration, heart rate, and blood pressure. Blood-Brain Barrier in the Fetus and Newborn In the fetus, newborn child, or premature infant, where these barriers are not fully developed, toxic substances such as bilirubin can readily enter the central nervous system and produce yellowing of the brain and kernicterus. Brain Trauma and the Blood-Brain Barrier Any injury to the brain, whether it be due to direct trauma or to inflammatory or chemical toxins, causes a breakdown of the blood-brain barrier, allowing the free diffusion of large molecules into the nervous tissue. It is believed that this is brought about by actual destruction of the vascular endothelial cells or disruption of their tight junctions. Drugs and the Blood-Brain Barrier the systemic administration of penicillin results in only a small amount entering the central nervous system. This is fortunate, because penicillin in high concentrations is toxic to nervous tissue. In the presence of meningitis, however, the meninges become more permeable locally, at the site of inflammation, thus permitting sufficient antibiotic to reach the infection. Chloramphenicol and the tetracyclines readily cross the blood-brain barrier and enter the nervous tissue. Lipid-soluble substances such as the anesthetic agent thiopental rapidly enter the brain after intravenous injection. On the other hand, water-soluble substances such as exogenous norepinephrine cannot cross the blood-brain barrier. Phenylbutazone is a drug that becomes bound to plasma protein, and the large drug protein molecule is unable to cross the barrier. Most tertiary amines such as atropine are lipid soluble and quickly enter the brain, whereas the quaternary compounds such as atropine methylnitrate do not. In Parkinson disease, there is a deficiency of the neurotransmitter dopamine in the corpus striatum. Unfortunately, dopamine cannot be used in the treatment, as it will not cross the blood-brain barrier. Tumors and the Blood-Brain Barrier Brain tumors frequently possess blood vessels that have no blood-brain barriers. Anaplastic malignant astrocytomas, glioblastomas, and secondary metastatic tumors lack the normal barriers. A 55-year-old man was being investigated for signs and symptoms that suggested the presence of a cerebral tumor. What other investigation might be carried out in this patient to display the ventricles of the brain? Using your knowledge of neuroanatomy, determine the location of the tumor in this patient. After a careful history had been taken and a detailed physical examination had been performed, a diagnosis of hydrocephalus was made. A 50-year-old man was found on ophthalmoscopic examination to have edema of both optic discs (bilateral papilledema) and congestion of the retinal veins. A 38-year-old man was admitted to the neurosurgery ward with symptoms of persistent headache and vomiting and some unsteadiness in walking. Using your knowledge of neuroanatomy, explain the symptoms and signs experienced by this patient, and try to make a diagnosis.

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