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Biomedical subjects

M Squires

Publications and source records attributed to M Squires.

8 recordsLinked to original sources
PubMed2003

Stable rAAV-mediated transduction of rod and cone photoreceptors in the canine retina.

Recombinant adeno-associated virus (rAAV) vectors are attractive candidates for the treatment of inherited and acquired retinal disease. Although rAAV vectors are well characterized in rodent models, a prerequisite to their clinical application in human patients is the thorough evaluation of their efficacy and safety in intermediate animal models. In this study, we describe rAAV-2-mediated expression of GFP reporter gene in retinal cells following local vector delivery in dogs. Subretinal delivery of rAAV.CMV.GFP was performed unilaterally in eight normal dogs from 6 weeks of age. The area of retinal transduction was maximized by the optimization of surgical techniques for subretinal vector delivery by pars-plana vitrectomy and the use of fine-gauge subretinal cannulae to create multiple retinotomies. rAAV-2 vectors mediated efficient stable reporter gene expression in photoreceptors and retinal pigment epithelial cells. We found efficient transduction of cone photoreceptors in addition to rods in both the canine retina and after subretinal vector delivery in another intermediate animal model, the feline retina. GFP expression in dogs was confined to the area of the retinal bleb and was sustained in cells at this site for at least 18 months. Electroretinography demonstrated a modest reduction in global rod-mediated retinal function following subretinal delivery of rAAV.CMV.GFP. Three of the eight animals developed delayed-onset intraocular inflammation, in two cases associated with a serum antibody response to GFP protein. We conclude that rAAV-2 vectors mediate efficient sustained transgene expression in rod and cone photoreceptors following subretinal delivery in this intermediate animal model. The possibility of adverse effects including intraocular immune responses and reduced retinal function requires further investigation prior to clinical applications in patients.

Animals↗
PubMed1982

Evidence that some mechanism other than the renin system causes sodium retention in nephrotic syndrome.

8 of 16 patients with nephrotic syndrome had normal or low plasma renin activity while spontaneously retaining sodium. The other 8 patients had a high plasma renin activity which may have caused the sodium retention. Oral captopril and albumin infusion given separately both suppressed the renin system in these patients. Despite this, urinary sodium excretion remained less than sodium intake and patients continued to retain sodium and gain weight. These results suggest that, even in patients with nephrotic syndrome who do have stimulation of the renin angiotensin system, some other overriding mechanism is responsible for sodium retention. Therefore it seems unlikely that angiotensin-converting enzyme inhibitors will be useful in the treatment of sodium retention in nephrotic syndrome.

Adolescent↗
PubMed1982

Double-blind randomised crossover trial of moderate sodium restriction in essential hypertension.

Nineteen unselected patients with mild to moderate essential hypertension, whose average supine blood pressure after two months' observation on no treatment was 156/98 mm Hg, were advised not to add salt to food and to avoid sodium-laden foods. After 2 weeks of sodium restriction patients were entered into an 8-week double-blind randomised crossover study of 'Slow Sodium' (Ciba) versus slow sodium placebo. The mean supine blood pressure was 7.1 mm Hg (6.1%) lower in the fourth week of placebo than that in the fourth week of slow sodium (p less than 0.001). Urinary sodium excretion in the fourth week of slow sodium was 162 +/- 9 mmol/24 h and that in the fourth week of placebo was 86 mmol +/- 9 mmol/24 h (p less than 0.001). There was no difference in potassium excretion. These results suggest that moderate sodium restriction achieved by not adding salt and avoiding sodium-laden foods should, if not already, become part of the management of essential hypertension.

Adult↗
PubMed1982

Is the renin-angiotensin-aldosterone system involved in the sodium retention in the nephrotic syndrome?

12 patients with the nephrotic syndrome during a phase of spontaneous sodium retention were studied on a sodium balance. When retaining sodium and gaining weight for more than 3 days, 6 patients had an elevated plasma renin activity; plasma aldosterone was elevated or at the upper range of normal, and blood volume was less than predicted in 5. The other 6 patients had a low or normal plasma renin activity and plasma aldosterone; blood volume was greater than predicted in 5 of these patients. There was a significant inverse correlation between plasma albumin and plasma renin activity (r = -0.70, p less than 0.02). Thus the renin-angiotensin-aldosterone system is not stimulated in many patients with the nephrotic syndrome when spontaneously retaining sodium. In these patients, sodium retention is probably due to some other mechanism, possibly intrarenal. Stimulation of the renin-angiotensin-aldosterone system in other patients may be a compensatory mechanism to the lower plasma albumin and reduced blood volume, and may not be the underlying mechanism for sodium retention.

Adolescent↗
PubMed1981

Non-sulfhydryl-containing angiotensin-converting enzyme inhibitor (MK421): evidence for role of renin system in normotensive subjects.

A non-sulfhydryl-containing inhibitor of angiotensin-converting enzyme (MK421) was given as a single dose in a randomised double-blind cross-over trial using 20 mg and 5 mg of MK-421 or matched placebo to nine normotensive volunteers receiving a sodium intake of 150 mmol (mEq) daily. The two dosages of MK-421 caused similar, significant falls in supine and standing blood pressure, which were maximum four to six hours after dosing (9.5-11.0% fall). With this fall in blood pressure there was a significant fall in activity of angiotensin-converting enzyme and in concentrations of plasma angiotensin II and aldosterone and a rise in plasma renin activity. Placebo caused no significant change in blood pressure or blood measurements. The study showed that MK-421 inhibits angiotensin-converting enzyme activity and lowers blood pressure in normotensive subjects. It strongly suggested that the renin system plays an important part in maintaining blood pressure in normotensive subjects receiving normal sodium intake. The results also suggest that this non-sulfhydryl-containing converting-enzyme inhibitor will be an effective blood-pressure-lowering drug in patients with blood pressure. A single dose of 5 mg was as effective at lowering blood pressure as a single dose of 20 mg.

Adult↗
PubMed1979

Sensitive radioimmunoassays using partially purified gamma globulins coupled to enzacryl (acrylamide polymer) solid support.

Enzacryl polythiolactone is a cross-linked acrylamide polymer with an active thiolactone group, capable of coupling to lysine, serine and tyrosine residues. Gamma globulins from antisera specific to human chorionic gonadotropin, carcinoembryonic antigen, alpha-foetoprotein or casein were isolated using Protein A Sepharose and were subsequently coupled to enzacryl. The resulting coupled antibodies were found to provide greater sensitivity and convenience in radioimmunoassay studies than conventional double antibody precipitation methods using the same antisera.

Acrylic Resins↗