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Sequence-specific polymers are proving to be a powerful approach to assembly and manipulation of matter on the nanometer scale. This has been most impressive in the case of DNA, and progress has been made toward templating inorganic nanoparticles using DNA nanostructures. One obstacle to this progress is that inorganic nanomaterials are often incompatible with DNA assembly conditions, which involve aqueous solutions high in either or both monovalent and divalent salt. Synthetic oligopeptide ligands have been shown by others to improve nanoparticle stability in high concentrations of monovalent salt. Ligands that are peptoids, or sequence-specific N-functional glycine oligomers, allow precise and flexible control over the arrangement of binding groups, steric spacers, charge, and other functionality. We have synthesized short peptoids that can prevent the aggregation of gold nanoparticles in high-salt environments including divalent salt, and allow coadsorption of a single DNA molecule. This degree of precision and versatility is likely to prove essential in bottom-up assembly of nanostructures and in biomedical applications of nanomaterials.

The differential light sensitivity (DLS) in healthy, but not glaucomatous eyes, is stable and unaffected by substantial loss of the ocular perfusion pressure resulting either from increased intraocular pressure (IOP) or from moderate to severe stenosis of the internal carotid arteries. Results of pulsatile ocular blood flow measurements provide evidence that this stability of vision in healthy eyes is dependent on autoregulation of blood flow to the retinal ganglion cell axons. The onset and progression of glaucoma is shown to be associated with instability of the DLS at discrete retinal points, which develops prior to visual loss, and with an abnormal sensitivity of the DLS to increased IOP. The abnormal fluctuation of the DLS in glaucomatous eyes and the loss of DLS induced by increased IOP and decreased ocular blood flow provides evidence of a microvascular impairment to discrete areas of the optic nerve.

The ocular hemodynamics in diabetic patients with increasingly severe retinopathy have been evaluated using a non-invasive computerized methodology. In a group of 19 healthy volunteers the mean ophthalmic arterial pressure and the ocular pulsatile blood flow were 83 +/- 2.4 mmHg and 648 +/- 42 microliters min-1 respectively. Nine diabetics with no apparent retinopathy had ophthalmic pressures and pulsatile blood flows similar to those in the control subjects. In 11 diabetic patients with background retinopathy the mean pulsatile blood flow was 471 +/- 70 microliters min-1. Thirteen diabetics with proliferative retinopathy had a pulsatile blood flow of 210 +/- 37 microliters min-1 and abnormally low ophthalmic arterial pressures. The results provide evidence that the choroidal blood flow decreases with the severity of the retinopathy in diabetes due to increased vascular resistance and a decreased ocular perfusion pressure.

The intraocular pressure pulse has been measured and used to evaluate the ophthalmic arterial pressure and the ocular pulsatile blood flow in 13 retinitis pigmentosa patients and ten similar aged healthy volunteers. The light sensitivity thresholds of the central fields of all persons were recorded using the Heijl-Krakau automated perimeter. The mean pulse amplitudes of 1.2 +/- 0.2 (26) and 2.3 +/- 0.25 (20) mmHg in the affected and in the control groups respectively differed significantly (p less than 0.001). The corresponding pulsatile blood flows were 310 +/- 24 (26) and 628 +/- 40 (20) microliters min-1. The mean ophthalmic arterial pressures in the two groups were equal. The light sensitivities in pairs of eyes of four of the patients differed substantially and in all cases the eye with the better visual performance had the higher ocular pulsatile blood flow. It is concluded that relative choroidal ischaemia is closely associated with visual loss and pigment cell degeneration in patients with retinitis pigmentosa.

A study has been made of the pupillary and intraocular pressure responses of conscious rabbits to daily topical applications of submaximal doses of epinephrine. On the first day, epinephrine caused rapid pupil dilation which preceded a prolonged -ecrease of intraocular pressure. On the second and subsequent days, the application of the same dose of epinephrine increased the duration of the pupillary response and caused a biphasic pressure response in all treated eyes; an initial increase of intraocular pressure lasting two to four hours followed by decrease of intraocular pressure below the initial value which lasted for more than twenty-four hours. The beta-receptor antagonist, propranolol, and the alpha-receptor antagonist, phenoxybenzamine, caused small and large reductions, respectively, in the hypertensive response to epinephrine. Phenoxybenzamine, but not propranolol, also inhibited the pupil dilation and the hypotensive response to epinephrine. Topical administration of phenoxybenzamine strongly inhibited the hypertensive response to epinephrine but left unaffected the pupillary response.

In a double-blind controlled clinical trial comparing the safety and efficacy of oral diethylcarbamazine citrate (DEC) with topical DEC for the treatment of onchocerciasis twenty men with moderate skin-snip microfilarial counts received daily therapy for 1 week, then weekly therapy for the rest of 6 months. The number of microfilariae per skin snip dropped quickly to 2% of initial levels and remained at low levels in those receiving oral DEC, and to 20% of initial levels in patients treated with DEC lotion. Side-effects in both groups included lymphadenopathy, fever, pruritus, rash, proteinuria, and chorioretinitis; they were commoner with topical DEC.

The response of 45 severely infected onchocerciasis patients to relatively high doses of diethylcarbamazine citrate (DEC-C) has been determined. The treatment comprised two sequential phases; the first phase comprised the topical applications of a DEC-C lotion and of the anti-inflammatory steroid betamethasone. The second phase comprised the daily oral administration of high doses of DEC-C (30 mg/kg body wt) for seven days. Onchocerca volvulus microfilarial (o.v.mf.) counts in skin snips of the 45 patients decreased by 96 +/- 1.5% after 5 days of treatment with topical DEC-C lotion. Following the administration of oral DEC, the average O.v.mf. counts in the skin snips at days 51, 97, and 143 remained decreased by 85 to 93%. The mean O.v.mf. counts in 10 nodules excised from 5 treated patients at day 77 had decreased by 93% compared to the mean O.v.mf. counts in 11 nodules taken from 5 untreated patients with similar initial O.v.mf. infection. No visual loss resulted from the treatment.

The intraocular pressure (IOP), the intraocular pulse to pressure (pulse/pressure) relationship, and the ophthalmic arterial pressure have been measured in 20 patients with either unilateral or bilateral hemodynamically significant lesions of the internal carotid arteries (ICA) as determined from arteriography. Studies were repeated in 5 of hte patients after surgical endarterectomy on the obstructed ICA. In age matched normal subjects the pulse/pressure relations were symmetrical in pairs of eyes, and the ophthalmic arterial systolic pressure was 89.0 +/- 2.1 mm Hg; this was 66 +/- 1% of the brachial arterial systolic pressure. In 19 of 20 patients with carotid occlusive disease in this study the IOP, pulse amplitudes and the pulse/pressure relationships differed in pairs of eyes. The ophthalmic arterial systolic pressure on the sides with 95 to 100% ICA stenosis was 49.9 +/- 4.05 mm Hg, which was 33 +/- 3% of the brachial arterial systolic pressure. In the remaining eyes the degree of stenosis of the ipsilateral ICA was 36.5 +/- 7.9%; the corresponding eyes had an ophthalmic arterial systolic pressure of 70.f1 +/- 51.18 mm Hg, which was 45 +/- 4% of the brachial arterial systolic pressure. Endarterectromy of the occluded arteries caused a significant increase in the ophthalmic arterial pressure on the ipsilateral side and a smaller increase in the contralateral eye; these changes were associated with a statistically significant increase in the intraocular pulse and improvement in the pulse/pressure relation.

Comparative intraocular pressure measurements made with the pneumatonograph and the Goldmann tonometer showed close agreement with a statistically higher mean pressure when using the pneumatonograph. Significant changes in mean pressure differences between the two instruments were seen upon changing the pneumatonograph calibration and with change in the order of testing (which instrument was used initially). However, transient biologic changes in an individual eye producing minute-to-minute fluctuations in intraocular pressure may be equal to or larger than differences in measurement between instruments.

A relationship has been derived between intraocular pressure and pulsatile blood flow in the eye. Measurements of intraocular pressure show a time variation that is associated with the pulsatile component of arterial pressure. Experimental results provide a means of transforming intraocular pressure changes into ocular volume changes. The eye is represented by a chamber with elastic walls, a pulsatile incoming flow of incompressible fluid (blood), and a steady outgoing flow of blood. Under these conditions, the rate of pulsatile blood flow through the eye can be approximated from the instantaneous intraocular pressure measurements. Data from a healthy human eye are used to illustrate the analysis.

A clinical study compared compression ophthalmodynamometry, suction ophthalmodynamometry, oculoplethysmography, modified oculopneumoplethysmography, and Doppler flow studies with graded arteriography for the detection of carotid artery stenosis. Compression ophthalmodynamometry and suction ophthalmodynamometry were the most accurate tests in this series with the results of both types of ophthalmodynanometry almost identical. A new, noninvasive procedure, oculocerebrovasculometry, was also performed in a slightly different group of patients. This procedure has theoretic advantages over the others tested because it measures directly the intraocular pressure as the end point of the test.

Counts of microfilariae in the skin, and histological and electronmicroscopic procedures have been used to analyze the response of onchocerciasis patients to diethylcarbamazine citrate (DEC) given either orally or topically. Oral administration of DRC failed to eliminate all microfilariae. Transepidermal DEC resulted in rapid degeneration of microfilariae, and daily single applications of the drug greatly reduced or apparently eliminated microfilariae from the skin. Following weekly topical applications of a DEC emulsion, effective suppression of O. volvulus microfilariae in patients living in a hyperendemic area was maintained for many months; and the dermal pathology resolved.

A study has been made of the time courses of the pupillary and intraocular pressure responses of conscious rabbits to clonidine administered either topically or intravenously. Topical unilateral application of clonidine caused transient pupil dilatation and a biphasic intraocular pressure response; an initial hypertensive response preceded a hypotensive phase lasting several hours. Pupillary and hypertensive responses were absent in the untreated eye, but there was a rapid decrease of intraocular pressure. Intravenous administration of clonidine caused an immediate and large decrease of intraocular pressure in both eyes. Phenoxybenzamine given intravenously inhibited the pupillary dilatation and the hypertensive responses to clonidine. The role of efferent adrenergic neuronal activity in mediating the local biphasic pressure response was studied in rabbits with unilateral precervical and postcervical sympathotomy. The results showed the hypotensive response to be dependent on an intact adrenergic innervation of the ocular tissues.

A report on a patient with pathological cupping of the disc and visual field defects similar to those found in glaucoma. In the sitting position the IOP was 18 and 21 mm Hg and in lying over 30 mm Hg. This abnormal positional effect was measured with the pneumotonograph which is based on a new principle of applanation independent of position. The classification of glaucoma simplex and low tension glaucoma as well as the differentiation from pseudoglaucoma are discussed.

In 77 normal and 65 glaucomatous eyes the influence of body position on the intraocular pressure was studied, using the pneumatonograph. The pressure increment when changing from the seated to the supine position averaged 2.9 mm Hg in normal eyes and 3.9 mm Hg in glaucomatous eyes. The pressure increase occurred immediately upon lying down and was reversible after returning to the seated position. Comparative measurements with the Goldman tonometer in the seated position showed good agreement with the results obtained by the pneumatonograph. The Schiotz tonometer did not reliably reveal the true supine intraocular pressure. The postural response (seated to supine) showed considerable variation in individual normal and glaucomatous eyes, and it did not correlate consistently with the intraocular pressure in the seated position. It should be taken into account that the results in the glaucomatous eyes were obtained while the patients were on glaucoma medication. In a series of six lowtension glaucomatous eyes the postural response was significant as a probable pathogenetic factor in that disease, because the intraocular pressure could rise from a normal to a glaucomatous level upon changing from the seated to the supine position.

The intraocular pressure and the pupillary responses in conscious rabbits to racemic erythro-alpha-methylnorepinephrine (alpha MeNE) have been investigated and its activity compared to L-norepinephrine (NE). Aqueous solutions of alpha MeNE applied topically caused dose-dependent decreases of intraocular pressure and of pupil dilatation. The maximal intraocular pressure response to alpha MeNE exceeded that to NE, and the sensitivity of the intraocular pressure response exceeded that to NE by 10-20 times. The onset of the decrease in intraocular pressure to alpha MeNE was rapid and contrasted to the slow onset of the intraocular hypotensive response to NE. Preganglionic cervical sympathotomy did not effect the intraocular pressure and the pupillary responses to either alpha MeNE or NE. Superior cervical ganglionectomy induced supersensitivity to NE but not to alpha MeNE. Studies using alpha 1, alpha 2, and beta adrenoceptor antagonists indicated that the intraocular pressure responses to alpha MeNE were mediated primarily by alpha 2 and beta adrenoceptors whereas the responses to NE were mediated primarily by alpha 1 adrenoceptors. The observations are discussed in the light of recent data of the affinities of alpha MeNE and NE to alpha 1, alpha 2, and beta adrenoceptors. The high potency of alpha MeNE compared to NE in decreasing intraocular pressure and in dilating the pupil does not correlate with their binding affinities to alpha and beta adrenoceptors. The observations support an alternative explanation that the differences in the potencies of alpha MeNE and NE are due to differences in rates of inactivation of the two compounds in the adrenergic neurone.

Two methods have been used to verify the diagnosis of patients living in the onchocerciasis hyperendemic region of Liberia found to have O.v. negative skin snips. The first was based on a histological and an electronmicroscopic examination of the skin to determine whether the characteristic onchocerciasis dermatitis was absent, and to compare the results with age matched subjects having minimal to densely O.v. mf infested skin. The second method involved the skin response of patients with O.v. mf negative skin snips to topically applied DEC. No O.v. mf were found in skin snips serially sectioned and examined histologically from patients in which the results of incubation studies were completely negative. Skin snips from these seemingly O.v. mf negative patients had a dermatitis, whereas no dermatitis was found in skin snips taken from subjects living in nearby nonendemic areas. Patients with O.v. mf positive skin snips responded to DEC applied topically with increased pruritus and a papular rash whose severity was proportionate to the intensity of infestation. Patients with O.v. mf negative skin snips responded to DEC applied topically with increased pruritus and developed either a localized papular rash or widely dispersed papules; confirmation of onchocerciasis in these patients was found in the identification of O.v. mf in histological sections of the papules.

A new procedure for measuring the outflow facility in conscious rabbits is described. The Langham pneumatic tonometer is applied horizontally against the eye; the intraocular pressure (IOP) is recorded before, during and immediately following 2 min of a pre-determined increased ocular pressure that is maintained at a fixed value by digital pressure applied through the eyelids. An increased volume of aqueous humor outflow resulting from the IOP increase is evaluated from the initial and final IOP values and the pressure volume relation for eyes of living rabbits. Close agreement in values of the outflow facilities in pairs of eyes of individual rabbits and excellent reproducibility of the procedure were found in repeated measurements made over a 24-hr period. The mean values of the IOP and the total outflow facility in 60 eyes of 30 rabbits were 20.5 +/- 0.2 mmHg and 0.17 +/- 0.01 microliter min-1 mmHg-1 respectively. Thirty minutes after an intravenous injection of acetazolamide, the IOP had decreased in both eyes of individual rabbits. This was associated with a decrease in the outflow facility and with a decrease of more than 50% in the rate of aqueous humor formation. One hour after the unilateral application of epinephrine the IOP had decreased in the treated eyes while the outflow facility remained unchanged.

A prospective masked study of the Langham Ocular Pressure Pulse Amplitude Procedure was made on 20 patients with arteriographically-confirmed completely patent carotid arteries (Group 1) and on 20 patients with either unilateral or bilateral stenoses of the internal carotid arteries (Group 2). The results are compared to similar studies previously reported on 20 patients with radiographically confirmed unilateral or bilateral occlusions of the internal carotid arteries (Group 3). The intraocular pressures, the pulse/intraocular pressure relations, and the ophthalmic arterial pressures were equal in pairs of eyes of Group 1 patients, and similar to those found in normal healthy subjects. The mean ophthalmic/brachial arterial pressure ratio in Group 1 patients was significantly higher than in normal subjects. In the Group 2 patients, the intraocular pressures were normal and all the measured parameters were similar in pairs of eyes, whereas, the ophthalmic/brachial arterial pressure ratios were significantly less than in the eyes of the Group 1 patients. The degree of stenoses of the internal carotid arteries (0 to 100%) as evaluated from arteriography varied inversely with the ophthalmic/brachial arterial pressure ratios (correlation coefficient 0.85). The coefficients of the sensitivity, the specificity, and the accuracy of the ophthalmic/brachial arterial pressure ratios in identifying the presence of stenotic lesions of the internal carotid artery defined by arteriography in the 120 eyes of the three groups were 89, 80, and 86% respectively. The ability of the Procedure to identify hemodynamic lesions of less than 50% is in keeping with published results of theoretical and experimental studies of the pressure gradient across stenoses in arteries with high rates of blood flow.

The pneumotonograph was evaluated for its capability to record and measure intraocular pressure through soft contact lenses. In a series of patients with chronic corneal diseases treated with soft contact lenses, good pressure and intraocular pulsations were recorded both with and without the soft lenses. Areas of scarred cornea give incorrect values, whereas areas of corneal edema give values similar to those obtained in the presence of a soft lens and are believed to reflect accurate and reliable pressure readings. In normal eyes, it has been found that the presence of a plain soft lens does not modify the accuracy of pressure measurement. High values do occur, however, when the refraction of the lens exceeds eight diopters.

The technique of pneumatic tonometry has been used to study new aspects of the response of the intraocular pressure to change of body position. The pneumatonographic procedure permits the intraocular pressure to be recoorded independent of body position. A modification of the procedure is described for the measurement of the ophthalmic arterial pressure and for the analysis of the change in intraocular pulse with increased intraocular pressure. The magnitude and symmetry of the postural response in normal healthy individuals have been found to contrast with the magnitude, stability, and asymmetry of the postural response in patients with ocular and arterial occlusive diseases. The abnormality of the postural response in a patient with severe occlusive disease is shown to parallel asymmetric and low ophthalmic arterial pressures.

Timolol maleate, a potent beta-adrenergic antagonist, reduces intraocular pressure in rabbits. With topical application in one eye, a significant reduction in pressure is seen in the contralateral, untreated eye also. When used in conjunction with timolol, other adrenergic amines, such as norepinephrine and epinephrine, produce an additional hypotensive response. On the other hand, pretreatment with timolol does inhibit the ocular hypotensive response to topically applied albuterol. No further reduction in pressure is seen after application of this beta-adrenergic agonist to eyes pretreated with timolol. In a double-blind study with patients who had previously been receiving various medications for control of elevated intraocular pressures, timolol was as effective as pilocarpine in reducing intraocular tension. Many common complaints associated with pilocarpine therapy, including miosis, ocular irritation, and blurred vision, were not encountered with timolol therapy.

1. A study has been made of the cause of the temporal disparity between the pupillary and intraocular pressure responses to noradrenaline applied topically. 2. Over a 5-day experimental period, the quantitative characteristics of the pupillary response to noradrenaline applied either once or several times daily remained essentially unchanged. In the same rabbits the delay in pressure response to noradrenaline on the first day was increased by a second application and, on subsequent days, multiple applications of noradrenaline induced a biphasic pressure response. 3. Intravenous phenoxybenzamine inhibited both the pupillary and the biphasic pressure responses to noradrenaline. Phenoxybenzamine applied topically inhibited the ocular hypertensive but not the hypotensive and pupillary responses. 4. Analysis of aqueous humour dynamics by manometric procedures showed that the hyper- and hypotensive responses were associated with increase and decrease, respectively, of the resistance to outflow of the aqueous humour.

A new methodological approach, embodied in the pneumatonograph, has been used to study the intraocular pressure, intraocular pulse and aqueous humor dynamics of normal and glaucomatous eyes. Comparative measurements of intraocular pressure in seated subjects by the Goldmann instrument and the pneumatonograph indicate close agreement over a wide range of pressures. On changing from the sitting to the supine position, it has been found by pneumatonometry that there is a significant increase of intraocular pressure in all eyes. In glaucomatous eyes, this postural response ranged up to as high as 12 mm Hg. Comparison of Schiotz and pneumatonometric pressure measurements on supine patients showed that the Schoitz values are significantly lower. This discrepancy of the values is in keeping with recent studies indicative that the Schiotz calibration is in error by 3-6 mm Hg. The coefficient of outflow facility was measured by a procedure of applanation tonography employing pressure-volume relations for the living human eye. The range of values found for normal eyes was significantly different from those of glaucoma eyes. It is concluded that pneumatonography is a useful method for improving the effectiveness of glaucoma diagnosis and clinical management.

The peripheral and central neural actions of clonidine on normal and glaucomatous eyes have been investigated. Threshold doses of clonidine applied topically induced a monotonic decrease of intraocular pressure in the treated eye and had no effect on the contralateral eye. With increased clonidine dose, a decrease of intraocular pressure occurred in the untreated eye, and there was a concomitant decrease of systemic arterial blood pressure. Analysis of aqueous humor dynamics showed that the ocular response to the peripheral and the central neural actions of clonidine were without effect on the tonographic coefficient of outflow facility. The episcleral venous pressure decreased in both the treated and the untreated eyes, but the changes were too small to account for the observed decrease of intraocular pressure. The results are consistent with the concept that both the peripheral and central ocular hypotensive actions of clonidine are mediated by an inhibition of adrenergic neurogenic vasoconstriction in the eye.

A double-masked, controlled clinical trial was conducted in Guatemala to assess the safety and efficacy of diethylcarbamazine (DEC) lotion as compared to placebo lotion in the treatment of onchocerciasis. One hundred eighty-seven people were enrolled in this study and were followed for two months. Lotion was applied daily for seven days, then weekly for seven weeks. The decrease in mean microfilarial counts per skin snip was significantly greater in those receiving DEC lotion than for those receiving placebo lotion. The proportionate reduction in microfilarial counts was similar for people with light, moderate, or heavy microfilarial loads. Side effects were mainly related to skin changes, fever, and malaise, and occurred in nearly one-third of the people receiving DEC lotion. These reactions occurred almost as commonly in those people who were lightly infected as in those who had moderate or heavy infections.

The effect of single and repeated topical application of adrenaline on the intraocular pressure and pupil in the rabbit eye was studied using a 2% adrenaline borate and a commercial preparation of 2% adrenaline hydrochloride. On the first day, the hydrochloride gave a more pronounced pressure reduction and pupil diladation than the borate. This was found to be due to the benzalkonium chloride in the chloride preparation causing a better permeability of the adrenaline into the eye. From the second to the fifth day of adrenaline treatment a marked pressure decrease was found from the previous application of the day before. The following adrenaline application gave a hypertensive phase of intraocular pressure lasting two or three hours and a subsequent hypotensive phase lasting more than 24 hrs. The pupil diladation on the second and following days of treatment was not essentially different from the first day considering the observation period of two hours. The hypertensive phase could not be influenced by intravenous or intramuscular propranolol, however, the topical application of propranolol inhibited it completely. Some aspects of adrenergic regulation of the intraocular pressure are discussed.