Clinico-radiological correlation of magnetic resonance imaging findings in patients with idiopathic intracranial hypertension.

PURPOSE: Although several studies have reported imaging findings associated with idiopathic intracranial hypertension (IIH), less is known about the correlation between imaging findings and IIH-related symptoms or signs. Our study aimed to determine if clinical features of IIH are correlated with magnetic resonance imaging (MRI) features. METHODS: A retrospective chart review was conducted on consecutive patients presenting at the neuro-ophthalmology department over the last 15 years. All patients diagnosed with IIH were identified and those with available MRI were included in the final analysis. All MRI images were reviewed by a neuroradiologist blinded to the presenting symptoms and signs. Statistical analysis was performed to determine the correlation between the MRI findings with each clinical symptom or sign. RESULTS: Thirty-one out of 88 patients with the initial diagnosis of IIH had MRI available and were included in the study. Significant correlations were observed between colour vision and amount of perineural fluid around the optic nerve on MRI (r = - 0.382; p = 0.004), disc assessment and intraocular optic nerve protrusion (r = 0.364; p = 0.004), disc assessment and perineural fluid around the optic nerve (r = 0.276; p = 0.033) and disc assessment and venous sinus stenosis (r = 0.351; p = 0.009). CONCLUSION: Our study highlights correlations between imaging and clinical findings of IIH. MRI findings in IIH may be useful in ruling out ominous causes of intracranial pressure and risk stratifying ophthalmologic intervention and management of patients with headaches possibly due to IIH.

Comparison of blind and electrically guided tracheal needle insertion in human cadavers.

The purpose of this study was to investigate whether an electrically guided needle insertion technique would enable greater success at intratracheal needle tip insertion than the traditional, aspiration-of-air technique. Twenty-seven anaesthesiology residents were assessed in their ability to place a needle tip in the trachea of cadavers using the two methods. Success of needle placement, time to placement and confidence in placement were recorded. Correct intratracheal needle placement was achieved by 22% of residents (6/27) using the aspiration-of-air method vs 82% (22/27) using the electrically guided method (p<0.001). For the instances of success, there was no significant difference between the two methods in the median (IQR [range]) time taken (28 (24-49 [18-63]) s aspiration vs 32 (19-49 [15-84]) s electrical; p=0.93). The electrically guided method provides an acceptably quick and accurate way of placing a needle tip into the tracheal lumen and can be learnt easily by anaesthesiology residents.

Quantum-classical modeling of photoisomerization of polyatomic molecules.

A new method, non-Markovian quantum-classical approximation (NQCA), is suggested to model the photoisomerization of polyatomic molecules. The NQCA method can be successfully applied to follow the photoisomerization process for a wide class of reacting systems, namely, those for which the time scale required for the equilibration in the phase space of the potential energy surface (PESs) is short compared to the time scale of the transitions between them. Such a situation is quite typical for the nonadiabatic transitions between the different electronic states in polyatomic molecules, where a high density of vibronic states facilitates the intramolecular vibrational energy redistribution, thus providing an efficient relaxation for the phase space distribution. The NQCA can easily be combined with molecular dynamics and quantum-chemical methods to describe the evolution of the classical degrees of freedom and the quantum part of the problem.

On the structure of hot absorption spectra of polyatomic molecules: solvent effect on the transition energy gap.

Hot absorption spectra of polyatomic molecules may exhibit a characteristic shoulder. Its origin and connection to the 0-0 transition energy gap has been established on the basis of a recently developed quantum-classical approach. We demonstrate that an accurate estimate of the transition energy can be obtained directly from experimental data. The method can be used to study the solvent influence on the energetics of electronic transitions.

Immigrant women family caregivers in Canada: implications for policies and programmes in health and social sectors.

Migration has become a profound global phenomenon in this century. In Canada, uncoordinated policies, including those related to immigration, resettlement, employment, and government funding for health and social services, present barriers to immigrant women caregivers. The purpose of this paper is to share relevant insights from individual and group interviews with immigrant women family caregivers, service providers and policy influencers, and discuss these in relation to immigration, health and social policy, and programme trends in Canada. The present authors conducted individual interviews with immigrant women family caregivers (n = 29) in phase 1, followed by two group interviews with women family caregivers (n = 7), and two group interviews with service providers and policy-makers (n = 15) in phase 2. Using an inductive approach, the authors employed thematic content data analysis. Immigrant women experienced barriers to health and social services similar to Canadian-born family caregivers, particularly those who have low incomes, jobs with limited flexibility and heavy caregiving demands. These immigrant women family caregivers avoided certain formal services for a variety of reasons, including lack of cultural sensitivity. However, their challenges were compounded by language, immigration and separation from family in the home country. The identified barriers to support reinforce the importance of modifying and expanding policies and programmes affecting immigrant women's ability to care for family members with illnesses or disabilities within the context of Canadian society. Participants recommended changes to policies and programmes to deal with information, transportation, language, attitudinal and network barriers. The various barriers to services and programmes which were experienced by immigrant women caregivers underscore the importance of reviewing policies affecting immigration, caregiving, and access to health and social services. Intersectoral collaboration among agencies is essential to reduce the barriers identified in the present study, and to establish services which are linguistically and culturally appropriate.

Topical epinephrine causes a decrease in density of beta-adrenergic receptors and cathecholamine-stimulated chloride transport in the rabbit cornea.

A single administration, or twice daily administration for 4.5 days, of topical 2% epinephrine to the rabbit eye in vivo causes a 30-40% decrease in the density of beta-adrenergic receptors on membranes prepared from the cornea. Such treatment also causes complete loss of the ability of excised corneas to respond to epinephrine in vitro with enhanced active chloride transport. These findings indicate that stimulation with a high concentration of catecholamine depresses the entire pathway from receptor to physiological response.

Service system finance: implications for children with depression and manic depression.

An estimated 6.2% of children in the United States satisfy the criteria for a depression diagnosis, but approximately half of this group do not receive necessary treatment. Thus it is important to consider potential barriers to use through service system finance. This article reviews three major types of changes affecting access: parity legislation, managed care, and public contracting. How these developments will affect children with depression and manic depression (DMD) is unclear. To better understand the potential effects on children with DMD, this review uses new data from the Medical Expenditure Panel Survey to describe the service use patterns of this population. These children have higher levels of expenditures, higher rates of inpatient use, and higher rates of Medicaid payment than do other children with mental health diagnoses; they also are overrepresented among the costliest cases of mental illness in children. Children with DMD pay a relatively low out-of-pocket share, suggesting that parity efforts focusing only on copayments and deductibles will have little effect on the absolute out-of-pocket burden for these children. Because children with DMD are overrepresented among high utilizers of health services, health care rationing arrangements or techniques, such as utilization review and capitation, may place this population at particular risk.

Cellular localization of neuronal nitric oxide synthase (NOS-1) in the human and rat retina.

The neuronal form of nitric oxide synthase (NOS-1) has been localized to several cell types in the retinas of experimental animals; however, localization in the human retina has not been definitive. By using in situ hybridization and immunohistochemistry, we have compared the cellular expression and localization of NOS-1 in the rat and human retinas. In both rat and human retinas, NOS-1 is expressed in the inner segments of photoreceptors, cells in the inner nuclear layer, particularly amacrine cells, and retinal ganglion cells. In human cones, NOS-1 is abundantly present in the outer segments. In the rat, optic nerve transection caused a loss of cells that were positive for NOS-1 in the ganglion cell layer. Although a retinal ganglion cell localization has not been reported consistently in the literature, our data clearly localize NOS-1 to the retinal ganglion cells of the rat and human retinas.

A tissue culture assay of corneal epithelial wound closure.

Experimental assays have been developed using cultured tissue derived from rabbit corneal epithelium to study migration of epithelial sheets during wound closure and cell-substrate adhesion. To study wound closure, epithelial defects, 6 mm in diameter, were produced in vitro in 24 well multiplates by a local freezing technique, and the size of the remaining defect was quantitated over time by staining. To study adhesion, cultured cells were labeled with 3H-leucine, suspended, and added to fresh culture plates. At various times, adherent cells were lysed and the radioactivity of the lysate was determined. Serum enhances the closure of experimental defects, but laminin and fibronectin have no effect. Agents which alter mitotic rate, such as epidermal growth factor and 5-fluorouracil, do not influence the rate of wound closure in this assay. Compounds which elevate intracellular levels of cyclic AMP inhibit wound closure but promote cell-substrate adhesion. Thus, cultured corneal epithelial cells may be used to assay for influences on the migratory events governing closure of superficial epithelial wounds.

The rabbit cornea lacks cholinergic receptors.

Cholinergic receptors were studied in membranes prepared from rabbit cornea, iris-ciliary body, and retina, using 3H-quinuclidinyl benzilate (3H-QNB) to identify muscarinic receptors and 125I-alpha-bungarotoxin (125I-BGT) to identify nicotinic receptors. Muscarinic cholinergic receptors were not found in the cornea. As a positive control, muscarinic cholinergic receptors were characterized in preparations of the iris-ciliary body. Specific binding of 3H-QNB to iris-ciliary body membrane preparations was saturable, with a Kd of 1.3 nM QNB. Specificity of the assay for muscarinic receptors was confirmed by the relative abilities of the following compounds to displace 3H-QNB: atropine greater than pilocarpine greater than hexamethonium. Nicotinic cholinergic receptors were not found in the cornea. As a positive control, nicotinic cholinergic receptors were characterized in preparations of the retina. Specific binding of 1252-BGT to retinal membrane preparations was saturable with both high and low affinity receptors (Kd values of 1.0 nM and 93 nM BGT, respectively). Specificity of the assay for nicotinic receptors was confirmed by the relative abilities of the following compounds to prevent 125I-BGT binding: curare greater than or equal to nicotine greater than hexamethonium greater than atropine. The lack of cholinergic receptors in the cornea, which has high levels of acetylcholine and related enzymes, suggests either an extraordinary use or a lack of function for acetylcholine in this tissue.

Beta-adrenergic and serotonergic responsiveness of rabbit corneal epithelial cells in culture.

Rabbit corneal epithelial cell cultures were established from Dispase-treated anterior corneas. In culture medium containing cholera toxin, insulin and epidermal growth factor, these cells proliferated in vitro in the absence of any contaminating cells. Following subculture, cells retained epithelial morphology and the ability to synthesize cAMP in response to beta-adrenergic stimulation, but lacked the ability to respond to serotonergic stimulation. Retention of the beta-adrenergic system in culture serves as a functional epithelial cell marker; whereas expression of serotonergic responsiveness may be regulated by developmental or extrapithelial systems that are absent in these cell cultures.

In vitro determination of the ability of drugs to bind to adrenergic receptors.

Alpha- and beta-adrenergic receptors were studied by measuring the binding of 3H-dihydroergocryptine and 3H-dihydroalprenolol, respectively, to membranes prepared from homogenized rabbit iris--ciliary bodies. The binding of 3H-dihydroergocryptine appears to be specific for alpha-adrenergic receptors, since adrenergic agents displace this radioligand with the following order of potency: phentolamine greater than epinephrine greater than or equal to norepinephrine greater than or equal to isoproterenol = propranolol. The binding of 3H-dihydroalprenolol appears to be specific for beta-adrenergic receptors, since adrenergic agents displace this radioligand with the following order of potency: propranolol greater than or equal to isoproterenol greater than or equal to epinephrine greater than norepinephrine greater than or equal to phentolamine. Clonidine and dopamine bind to the alpha-adrenergic receptor but have little activity at the beta-adrenergic receptor. Timolol, d-isoproterenol, and dipivalyl epinephrine bind to the beta-adrenergic receptor but have little activity at the alpha-adrenergic receptor. The results demonstrate that in vitro binding assays for alpha- and beta-adrenergic receptors are useful for studying the mechanism of drug action.

Study of central regulation of intraocular pressure using ventriculocisternal perfusion.

The ability of hypoosmotic solution, prostaglandin E1 (PGE1) and clonidine to influence intraocular pressure (IOP) by a central mechanism was studied using the technique of ventriculocisternal perfusion in conscious rabbits. IOP remained unchanged during the perfusion of 150 mOsm artificial cerebrospinal fluid. IOP rapidly increased by 15 mmHg during the perfusion of PGE1 at the dose of 1 or 3 micrograms/min. However, when PGE1 was perfused intravenously at the dose of 1 microgram/min, a similar IOP response was observed. Furthermore, during the ventriculocisternal perfusion of PGE1 a significant systemic absorption occurred. These observations indicate that the ocular hypertension during the ventriculocisternal perfusion of PGE1 is primarily due to the peripheral action of systematically absorbed PGE1. IOP gradually decreased by 3 mmHg during the ventriculocisternal perfusion of clonidine at the dose of 0.1 or 0.33 micrograms/min. Intravenous perfusion of clonidine at the same doses did not change the IOP. These results indicate that clonidine can lower IOP by a centrally mediated mechanism. Ventriculocisternal perfusion of clonidine (0.1 micrograms/min) in rabbits with unilateral superior cervical ganglionectomy lowered IOP in both eyes, indicating that ocular adrenergic innervation does not participate in this centrally mediated IOP response. However, the cardiovascular parameters of anesthetized rabbits were altered by the ventriculocisternal perfusion of clonidine (0.1 micrograms/min), suggesting that a change in systemic hemodynamics is involved in the central IOP effect of clonidine.

Cell culture of the human lamina cribrosa.

The extracellular matrix of the lamina cribrosa may be important in the changes in the optic nerve head associated with glaucoma. To investigate the cell biology of this tissue, human lamina cribrosa was explanted in tissue culture and two cell types grown from this tissue were characterized. The most common cell type obtained was a large, flat, polygonal cell which was negative for glial fibrillar acidic protein (GFAP) and could be serially subcultured. This cell type synthesized collagens type III and type IV, fibronectin and elastin. Much less commonly grown was a cell type with conspicuous long processes and which was positive for GFAP. This presumed astrocyte synthesized collagen type IV and fibronectin. Fibroblastic cells were not obtained from this tissue but were easily grown from sclera. The cells that we have cultured from the human lamina cribrosa may produce the extracellular matrix present in the cribriform plates of this tissue and be important in the glaucomatous process.

Isoforms of nitric oxide synthase in the optic nerves of rat eyes with chronic moderately elevated intraocular pressure.

PURPOSE: To investigate the hypothesis that nitric oxide (NO) in the optic nerve heads of rats with chronic moderately elevated intraocular pressure (IOP) contributes to neurotoxicity of the retinal ganglion cells, the presence of the three isoforms of nitric oxide synthase (NOS) was determined in the tissue. METHODS: Unilateral chronic moderately elevated IOP was produced in rats by cautery of three episcleral vessels. Histologic sections of optic nerves from eyes with normal IOP and with chronic moderately elevated IOP were studied by immunohistochemistry and by immunoblot analysis. Polyclonal antibodies to NOS-1, NOS-2, NOS-3, and glial fibrillary acidic protein (GFAP) were localized with immunoperoxidase. RESULTS: In the optic nerve of rat eyes with normal IOP, NOS-1 was constitutively present in astrocytes, pericytes and nerve terminals in the walls of the central artery. NOS-2 was not present in eyes with normal IOP. In these eyes, NOS-3 was constitutively present in the vascular endothelia of large and small vessels. Rat eyes treated with three-vessel cautery had sustained elevated IOP (1.6 fold) for at least 3 months. In these eyes, no obvious changes in NOS-1 or NOS-3 were noted. However, at time points as early as 4 days of chronic moderately elevated IOP, NOS-2 appeared in astrocytes in the optic nerve heads of these eyes and persisted for up to 3 months. Immunoblot analysis did not detect differences in NOS isoforms. CONCLUSION: The cellular distributions of constitutive NOS isoforms in the rat optic nerve suggest physiological roles for NO in this tissue. NOS-1 in astrocytes may produce NO as a mediator between neighboring cells. NO, produced by NOS-1 in pericytes and nitrergic nerve terminals and by NOS-3 in vascular endothelia, is probably a physiological vasodilator in this tissue. In eyes with chronic moderately elevated IOP, NOS-2 is apparently induced in astrocytes. The excessive NO production that is associated with this isoform may contribute to the neurotoxicity of the retinal ganglion cells in eyes with chronic moderately elevated IOP.

In vitro pharmacologic separation of corneal endothelial migration and spreading responses.

Repair of corneal endothelial wounds involves two forms of cell translocation: (1) "migration," in which individual cells at the wound edge break contacts with neighboring cells and move as individuals into the wound defect, and (2) "spreading," in which cells within the confluent monolayer adjacent to the wound move as a group into the wound area. The authors combined morphometric analysis of Giemsa-stained cultures, phase-contrast video microscopy, and Rh-phalloidin staining of actin filaments to study the effects of epidermal growth factor (EGF) and indomethacin on the migratory and spreading responses to wounding using an in vitro wound-closure model which mimics the amitotic state and general behavior of human corneal endothelium. They found that EGF stimulated the migration of individual cells from the wound edge, induced cellular elongation, and promoted a diffuse distribution of actin filaments. Indomethacin promoted spreading of the confluent monolayer into the wound defect, induced enlargement and flattening of cells, and promoted the formation of long, thick actin stress fibers. These results provide evidence that the migration and spreading responses of corneal endothelial cells to wounding can be pharmacologically separated. The findings suggest that migration of individual cells during wound repair may result from an endogenous form of EGF-like stimulation and that the elongated shape associated with this form of translocation results, at least in part, from an EGF-like alteration in actin-filament organization. Spreading of the confluent monolayer to cover the wound defect may result from a decrease in cyclic adenosine monophosphate induced by a transient reduction in prostaglandin E2 synthesis. This form of translocation may result, in part, from enlargement and flattening of corneal endothelial cells secondary to an enhancement of actin stress-fiber formation.

Localization of collagen types I and IV mRNAs in human optic nerve head by in situ hybridization.

Using in situ hybridization, individual cells expressing mRNAs for collagen types I and IV were localized in fixed-tissue sections of adult and fetal human optic nerve heads. Astroglial cells lining the cribriform plates and cells inside the cribriform plates of the lamina cribrosa had mRNA for collagen type IV. Cells in the glial columns, pial septa, and vascular wall also contained mRNA collagen type IV. Collagen type I mRNA was expressed by cells of the cribriform plates of the lamina cribrosa of adults. Few cells in the glial columns, pial septa, and blood vessels had mRNA for collagen type I. Scleral fibroblasts contained mRNA for collagen type I. These results indicated that the expression of mRNA for both collagen types I and IV paralleled the localization of these extracellular matrix proteins in the optic nerve head and suggested that both collagen types were synthesized in this tissue throughout life.

Adrenergic stimulation of ciliary process epithelium causes surface membrane internalization.

An ultrastructural change induced in the nonpigmented epithelium (NPE) of the ciliary processes by adrenergic stimulation in the albino rabbit was studied. Thirty min after topical treatment with 2% isoproterenol, an extensive intracellular membranous network, previously reported to be smooth endoplasmic reticulum, was revealed by electron microscopy. It was postulated that this network originated from the plasma membrane. Using cationized ferritin (CF) as an ultrastructural tracer, freshly isolated anterior segments were incubated in buffer containing 10(-5) M isoproterenol and 0.2% CF. As early as 10 min, and for at least 30 min, the isoproterenol-treated NPE cells contained a membranous network that was morphologically similar to that which occurs in vivo. CF particles were present within the network, indicating that the membranous network had originated at the cell surface. This labeling was prevented by pretreatment with the beta-adrenergic antagonist timolol maleate. In both treated and control ciliary processes, CF was present in the ciliary canals between the NPE and the underlying pigmented epithelium after 10 min incubation. This suggests that the NPE is able to transport CF from its basilar to apical surface. These experiments imply that the NPE is able to internalize rapidly large amounts of plasma membrane in response to adrenergic stimulation. This response may be part of the mechanism of adrenergic receptor desensitization, alteration of aqueous humor production, or another adrenergic response.

Effects of stimulation of the ocular sympathetic nerves on IOP and aqueous humor flow.

Ocular sympathetic nerves were stimulated chronically in awake rabbits using electrodes unilaterally implanted on the cervical sympathetic trunk. IOP was measured by pneumatonometry and aqueous inflow was measured by fluorophotometry. In each animal, continuous trains of 1 msec pulses were delivered by means of a portable electrical stimulator. Experiments were spaced by 1 week recovery periods. Stimulation was varied over a range of amplitudes (5-15 V) and frequencies (3-12 Hz). Continuous sympathetic stimulation produced an immediate sharp decrease in IOP followed by a gradual rise to pre-stimulation values which were attained 60-90 min after onset. A rebound increase in IOP occurred when stimulation was terminated. The magnitude of the initial IOP drop, the delay in the return to pre-stimulation IOP, and the rebound rise in IOP subsequent to termination of electrical stimulation were proportional to the stimulation frequency. Maximal effects were observed at 12 Hz, and stimulation with 8-10 Hz for 180 min caused a sustained reduction in anterior chamber aqueous humor flow. Topical 2% phentolamine 1 hr before stimulation markedly reduced IOP and abolished the acute IOP changes observed in untreated stimulated animals. Topical 1% timolol did not affect either the initial IOP drop or the rebound; however, the IOP recovered during stimulation to values greater than pre-stimulation IOP. We conclude that in rabbits the beta-adrenergic effect of prolonged sympathetic nerve stimulation is to decrease aqueous flow. Chronic electrical stimulation in awake animals provides an experimental model for studying the role of the ocular sympathetic nerves.

Pharmacological regulation of morphology and mitosis in cultured rabbit corneal endothelium.

Cultured rabbit corneal endothelial cells elongate when grown in the presence of epidermal growth factor (EGF) and indomethacin (INDO); whereas maintenance of the differentiated polygonal cell shape is apparently dependent upon endogenous synthesis of prostaglandin E2 (PGE2). In the current study, the authors demonstrate morphological changes in phenotypically altered cells and identify two intracellular pathways which interdependently regulate endothelial cells. Morphometric and mitotic analyses of cultures treated with a variety of pharmacological agents indicate that both protein kinases A- and C-dependent pathways regulate cell shape and cell division in corneal endothelial cells. Marked intracellular reorganization is associated with the morphological changes in the endothelial cells. When stained with rhodamine conjugated phallicidin, polygonal endothelial cells have circumferential bands of f-actin at their borders. EGF and/or INDO induce elongation and redistribution of f-actin into a diffuse cytoplasmic reticulum. Transmission electron microscopy demonstrates loss of several characteristic morphological markers for endothelial cells in response to pharmacologically induced elongation. The elongated cells lose intracellular junctions, apical/basal polarity and rough endoplasmic reticulum. These ultrastructural markers and circumferential f-actin bands are restored in cultures supplemented with exogenous PGE2. Modulation of these pathways in vivo may regulate cellular migration and mitosis during wound closure, stress, trauma and with age.