Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: A report of the International Brachial Artery Reactivity Task Force

Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). They all utilize l-arginine and molecular oxygen as substrates and require the cofactors reduced nicotinamide-adenine-dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and (6R-)5,6,7,8-tetrahydrobiopterin (BH(4)). All NOS bind calmodulin and contain haem. Neuronal NOS (nNOS, NOS I) is constitutively expressed in central and peripheral neurons and some other cell types. Its functions include synaptic plasticity in the central nervous system (CNS), central regulation of blood pressure, smooth muscle relaxation, and vasodilatation via peripheral nitrergic nerves. Nitrergic nerves are of particular importance in the relaxation of corpus cavernosum and penile erection. Phosphodiesterase 5 inhibitors (sildenafil, vardenafil, and tadalafil) require at least a residual nNOS activity for their action. Inducible NOS (NOS II) can be expressed in many cell types in response to lipopolysaccharide, cytokines, or other agents. Inducible NOS generates large amounts of NO that have cytostatic effects on parasitic target cells. Inducible NOS contributes to the pathophysiology of inflammatory diseases and septic shock. Endothelial NOS (eNOS, NOS III) is mostly expressed in endothelial cells. It keeps blood vessels dilated, controls blood pressure, and has numerous other vasoprotective and anti-atherosclerotic effects. Many cardiovascular risk factors lead to oxidative stress, eNOS uncoupling, and endothelial dysfunction in the vasculature. Pharmacologically, vascular oxidative stress can be reduced and eNOS functionality restored with renin- and angiotensin-converting enzyme-inhibitors, with angiotensin receptor blockers, and with statins.

/pdf/nitric-oxide-synthases-regulation-and-function-50kgzzd2xv.pdf

Nitric oxide synthases: regulation and function.

Mechanical forces associated with blood flow play important roles in the acute control of vascular tone, the regulation of arterial structure and remodeling, and the localization of atherosclerotic lesions. Major regulation of the blood vessel responses occurs by the action of hemodynamic shear stresses on the endothelium. The transmission of hemodynamic forces throughout the endothelium and the mechanotransduction mechanisms that lead to biophysical, biochemical, and gene regulatory responses of endothelial cells to hemodynamic shear stresses are reviewed.

/pdf/flow-mediated-endothelial-mechanotransduction-281f54bq52.pdf

Flow-mediated endothelial mechanotransduction

Nitric oxide (NO·) is an important protective molecule in the vasculature, and endothelial NO· synthase (eNOS) is responsible for most of the vascular NO· produced. A functional eNOS oxidizes its substrate l-arginine to l-citrulline and NO·. This normal function of eNOS requires dimerization of the enzyme, the presence of the substrate l-arginine, and the essential cofactor (6R)-5,6,7,8-tetrahydro-l-biopterin (BH4), one of the most potent naturally occurring reducing agents. Cardiovascular risk factors such as hypertension, hypercholesterolemia, diabetes mellitus, or chronic smoking stimulate the production of reactive oxygen species in the vascular wall. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases represent major sources of this reactive oxygen species and have been found upregulated and activated in animal models of hypertension, diabetes, and sedentary lifestyle and in patients with cardiovascular risk factors. Superoxide (O2·−) reacts avidly with vascular NO· to form peroxynitrite (ON...

Endothelial Nitric Oxide Synthase in Vascular Disease From Marvel to Menace

The vessel wall is an active, integrated organ composed of endothelial, smooth-muscle, and fibroblast cells coupled to each other in a complex autocrine-paracrine set of interactions The vasculature is capable of sensing changes within its milieu, integrating these signals by intercellular communication, and changing itself through the local production of mediators that influence structure as well as function Vascular remodeling is an active process of structural alteration that involves changes in at least four cellular processes -- cell growth, cell death, cell migration, and production or degradation of extracellular matrix -- and is dependent on a dynamic interaction between locally   

The Emerging Concept of Vascular Remodeling

Cervical spine fractures in the elderly

Twelve children with pathologically confirmed, well-differentiated spinal cord astrocytomas were studied, and correlations among the degree of resection, pathological characteristics, and time of recurrence were examined. Eight tumors were sampled for biopsy or subtotally resected, and 4 were thought to have been totally removed. Clinical recurrence was seen in 4 of 12 patients, 2 of whom died of their disease. The time to recurrence was 1, 2, 2, and 35 years, respectively. The other 8 children remain free of symptoms, with follow-up ranging from 6 months to 35 years (mean, 8.8 years). In 3 of 8 patients who underwent biopsy or subtotal resection, the tumor recurred, and 2 patients died, whereas there was one recurrence in the patients in whom a "total" resection had been obtained. The histologically well-differentiated nature of the lesions correlated well with the relatively prolonged clinical course seen in this series during the period of observation. The relatively long clinical courses seen in our limited series should be considered before high-risk therapy for spinal cord astrocytomas in children is implemented. The presence of four pilocytic astrocytomas in this group was of special interest, and it seems likely that these discrete neoplasms can be distinguished from the more infiltrating fibrillary astrocytic neoplasms by magnetic resonance imaging with enhancement with gadopentetate dimeglumine.

Clinical and pathological analysis of spinal cord astrocytomas in children.

tonic seizures associated with contralateral paraesthesia, they postulated transversely spreading activation between axons in the spinal cord as the mechanism. Similarly, Matthews7 proposed that the underlying pathophysiology in paroxysmal attacks in multiple sclerosis is abnormal lateral axonal spread of excitation in plaques. A normally transmitted impulse, on reaching a plaque of demyelination, depolarises a neighbouring demyelinated axon. This ephaptic conduction leads to the attack, the nature ofwhich is dependent on the afferent or efferent axon involved. Osterman and Westerberg' explain how transversely spreading activation of axons within a partially demyelinated plaque accounts for various paroxysmal phenomena by describing in detail the relevant anatomy of the spinal cord and brain stem. Thus, paroxysmal attacks in multiple sclerosis are considered to be due to axonal discharge rather than neuronal discharge through usual anatomical and physiological connections. Although the beneficial effect of the anticonvulsant drug carbamazepine seems to suggest that paroxysmal attacks in multiple sclerosis might be due to focal epilepsy, carbamezapine has effects on the axonal membrane thereby blockii:g ephaptic conduction9 as well as its better known effects on neuronal discharge.

https://jnnp.bmj.com/content/jnnp/52/12/1445.2.full.pdf

Parkinsonian symptoms in a patient with AIDS and cerebral toxoplasmosis.

An isolated oculomotor nerve palsy is very rarely the presenting sign of a pituitary adenoma. It may occur slowly due to mechanical compression or rapidly, secondary to pituitary apoplexy. Magnetic resonance imaging (MRI) with and without gadolinium DTPA enhancement provides excellent anatomical detail and is useful in the planning of the operative procedure. When correctly diagnosed and treated, the third nerve dysfunction appears to be reversible. We report a case of a pituitary adenoma presenting with an isolated, partial oculomotor nerve palsy in the setting of apoplexy. The pathophysiology, prognostic factors and MRI findings of this entity are discussed.

Isolated oculomotor nerve palsy following apoplexy of a pituitary adenoma.

The term “akathisia” was introduced by Haskovecl in 1903 and, translated from the Greek, means “not to sit.” The dieorder is characterized by motor restlessness and usually involvee pacing and the inability to sit still, with foot-tapping and other nervous gestures being prominent. Aknthisia is a well described extrapyramidal side effect of neuroleptic medication2 and ale0 occurs with Parkinson’s diseaee.3 The presentation her, always been bilateral. We report a patient with AIDS and a toxoplasmosis subthalamic abscess who developed unilateral akathisia. Case report. A.W. was a 54-year-old man with a history of IV drug abuse who was HIV positive, confirmed by ELISA titer and weetern blot. He first came to medical attention in 1987, when he presented with a right upper lobe infiltrate that resolved with a c o r n of broad spectrum antibiotics. Four months later, the patient was admitted to the hospital with complaints of jitterin-, reatleaaness, and intermittent frontal headaches that began 2 weeks before admimion. He was literally unable to sit or stand still and complained of feeling extremely anxious. Physical examination was significant for cachexia, old needle tract marks on the arms, generalized lymphadenopathy, and oral thrush. Neurologic examination revealed an anxious patient with dysrhythmic speech and no obvious language deficit. He was noted to be restleee, changing body position at least six t h e e per minute. Abnormal upper extremity movements included stroking the face and hair repeatedly with the right hand, and almost constant fidgety motions involving his right fingers, hand, and wrist. Abnormal movements were also present in the right lower extremity and included rapid tapping movements of the foot and sliding the foot back and forth on the floor. In addition, the patient would repeatedly cross and uncross his right leg over hie left. He was embarraeeed by these movementa and frequently eat on his right hand and acknowledged his lack of voluntary control of these movements. There was no limb weakness, sensory deficits, or choreiform movements of the mouth, tongue, or lips. He did have a mild right-sided hyperreflexia with a right Babinski sign. Gait was moderately wide based. He waked quickly with exaggerated swinging of the right arm, but without hemiballismus. CTs of the brain, with and without contrast, showed on the nonenhanced scan an area of hypodensity adjacent to the third ventricle on the left, locatedpredominantly in the lentiform nucleus, causing a left to right shift. The contrasted scan showed a nodular area of enhancement in the region of the left subthalamic nucleus with surrounding edema involving the lentiform nucleus (figure). In addition, there was a ring enhancing lesion in the left posterior parietal lobe, adjacent to the inner table of the skull, ale0 aeeociated with some edema. Thew finding were consistent with CNS toxoplmmosis, and the patient was started empirically on pyrethamine and sulfadiazine. Two weeks later, A.W. returned to the hospital because of naueea and vomiting. Laboratory data revealed a BUN of 58 and crentinine of 8.2. He continued to exhibit the unilateral akathisia and when given haloperidol for agitation, the movement dieorder became worse. The patient and family refused dialysis or further heroic measures. He continuedto have progressive renal deterioration and expired 1 month after onset of the neurologic illnees. A t autopsy, the brain was edematous, weighing 1,680 grama. On cut sections there was an area of necroeis (1.2 cm in diameter) involving the left subthalamic structures, with surrounding edema spreading throughout the left baeal ganglia and slight deviation of the third ventricle toward the right. A second, slightly larger area of necroeis (1.5 cm in diameter) was in the left parieto-occipital area. Microscopically, these areas revealed necrotizing Toxoplasma gondii encephalitis. Numerous intracellular cysts and extracellular trophozoites were present a t the margins of the necrotic foci, along with thrombosis and fibrinoid necrosis of vBBcular walls. Discussion. Neurologic eequelae of AIDS are relatively common. However, few extrapyramidal movement dieorders have been noted. Nath et a l 4 reported seven AIDS patients who had movement dieorders. Three had hemiballismus, two had segmental myoclonue, one had postural tremor with dyetonia, and one had paroxysmal dyetonia. Of relevance was a case with hemiballismus secondary to a toxoplmmoeis subthalamic abscess. Unlike our patient, however, this patient had a normal CT without edema or shift, the diagnosis was made at autopy and not radiographically. Although toxoplasmosis is the most common infection in AIDS patients with neurologic complications, movement disorders attributable to Toroplasma gondii were not reported until Nath et d4 The association of akathisia with postencephalitic Parkinson’s syndrome, idiopathic Parkinson’s dieeaee, and antipsychotic drug therapy suggeats that it ie an extrapyramidal movement dieorder. Although the pathogenesis is unknown, a current hypothesis implicates a competitive blockade of meeocortical poetsynaptic dopamine receptors? a notion not u n i v e d y accepted, however. Our case is of interest for several reasons. There is a paucity of documented movement dieorders secondary to AIDS, only one previous report of toxoplasmosis as the etiology,4 no previous report of akathisia in AIDS, and, finally, this is the first report of unilateral akathisia. Why our patient had akathisia and that of Nath et al4 had hemi-

Unilateral "akathisia" in a patient with AIDS and a toxoplasmosis subthalamic abscess.

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