Value of internal limiting membrane peeling in surgery for idiopathic macular hole stage 2 and 3: a randomised clinical trial.

AIM: To determine the effect of internal limiting membrane (ILM) peeling on anatomical and functional success rates in stage 2 and 3 idiopathic macular hole surgery (MHS). METHODS: Randomised clinical trial of stage 2 and 3 idiopathic macular hole without visible epiretinal fibrosis and with less than 1 year's duration of symptoms. Eyes were randomised to (1) vitrectomy alone without retinal surface manipulation, (2) vitrectomy plus 0.05% isotonic Indocyanine Green (ICG)-assisted ILM peeling or (3) vitrectomy plus 0.15% Trypan Blue (TB)-assisted ILM peeling. Main outcomes were hole closure after 3 and 12 months and best-corrected visual acuity after 12 months. RESULTS: 78 eyes were enrolled. Primary closure rates were significantly higher with ILM peeling than without peeling for both stage 2 holes (ICG peeling 100%, non-peeling 55%, p = 0.014) and for stage 3 holes (ICG peeling 91%, TB peeling 89%, non-peeling 36%, p<0.001). Visual outcomes in eyes with primary hole closure were not significantly different between the groups. CONCLUSIONS: Dye-assisted ILM peeling was associated with significantly higher closure rates than non-peeling in both stage 2 and 3 MHS. Intraoperative ILM staining with 0.05% isotonic ICG was not associated with a significantly different visual outcome than non-peeling or TB peeling in eyes with primary hole closure. TRIAL REGISTRATION NUMBER: NCT00302328.

Pain induced by photodynamic therapy of warts.

BACKGROUND: Photodynamic therapy with topical 5-aminolevulinic acid (ALA), followed by irradiation with red light (ALA-PDT), is used for non-melanoma skin cancer and other dermatological diseases. Pain during and after light exposure is a well-known adverse advent that may be a limiting factor for treatment, particularly, in viral warts. METHODS: To assess the pain induced by ALA-PDT, we asked 45 patients enrolled in a randomized, placebo-controlled trial with six consecutive ALA- and placebo-PDT treatments for recalcitrant foot and hand warts to fill in questionnaires about pain immediately and 24 h after each treatment. RESULTS: Immediately and 24 h after each of the six treatments, pain intensity was significantly higher in warts treated with ALA-PDT than in warts treated with placebo-PDT (P<0.028). Severe or unbearable pain was reported from a median of 17% (6-31%) of the ALA -treated warts and from a median of 2% (0-15%) from the placebo-treated warts immediately after the treatments. With increasing treatments, no significant change in pain intensity was observed and no significant relation was found between the pain intensity and the relative change in wart area. The pain was primarily characterized as burning and shooting. The pain lasted about 30 h (range: 1-96 h). CONCLUSION: We conclude that pain induced by ALA-PDT is of such intensity in about one-fifth of the warts that pain relief is indicated.

Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses.

PURPOSE: To explore whether reported methodologic quality affects estimated intervention effects in randomized trials and contributes to discrepancies between the results of large randomized trials and small randomized trials in meta-analyses. DATA SOURCES: Meta-analyses of randomized trials that included at least one large trial (>/=1000 participants) were included, regardless of the therapeutic area. Eligible meta-analyses were identified through electronic searches and bibliographies of relevant articles. STUDY SELECTION: Full-length randomized trials. DATA EXTRACTION: Methodologic quality was assessed according to reported randomization, double blinding, and follow-up as separate components and by using the Jadad composite scale. DATA SYNTHESIS: Fourteen meta-analyses involving 190 randomized trials from eight therapeutic areas were included. Compared with large trials, intervention effects were exaggerated in small trials with inadequate allocation sequence generation (ratio of odds ratios, 0.46 [95% CI, 0.25 to 0.83]; P = 0.011), inadequate allocation concealment (ratio of odds ratios, 0.49 [CI, 0.27 to 0.86]; P = 0.014), and no double blinding (ratio of odds ratios, 0.52 [CI, 0.28 to 0.96]; P = 0.01). Large trials did not differ significantly from small trials with adequate generation of the allocation sequence, adequate allocation concealment, or adequate double blinding. No association was seen between reported follow-up and intervention effects. The Jadad scale provided no additional information because the scale and the quality components overlapped substantially. CONCLUSIONS: Inadequate generation of the allocation sequence, allocation concealment, and double blinding lead to exaggerated estimates of intervention benefit and may contribute to discrepancies between the results of large randomized trials and small randomized trials in meta-analyses.

Magnesium therapy in type 1 diabetes. A double blind study concerning the effects on kidney function and serum lipid levels.

To test the hypothesis that magnesium depletion might be of importance for the development of vascular complications in diabetes mellitus we performed a randomized, double-blind, placebo-controlled study during 12 months with 20-30 mmol/day of oral magnesium hydroxide in 28 type 1 diabetic patients. Urinary albumin excretion, Cr-EDTA-clearance and certain blood cardiovascular risk factors were measured. At the end of the study there were no significant differences of these parameters between the two groups, except that serum triglyceride values increased in three magnesium treated patients who either showed an increase in blood glycosylated hemoglobin values or body weight during the study.

Interferon alfa-2a modifies the course of subfoveal and juxtafoveal choroidal neovascularisation.

The first double masked placebo controlled trial of interferon alfa-2a for the treatment of overt choroidal neovascular membranes is presented. A total of 43 consecutive patients were randomised to double masked treatment with either interferon alfa-2a, 3 million IU subcutaneously three times a week or matching placebo, for a period of 8 weeks. End of study changes from baseline in distance and near visual acuity, macular visual field, contrast sensitivity, and macular morphology (fluorescein angiography) were assessed. The between group difference in distance visual acuity, the primary efficacy variable, was significant in favour of interferon alfa-2a (p = 0.023). Fluorescein angiograms, macular visual fields, and near vision all showed a trend in favour of interferon alfa-2a. It was concluded that, at the dosage used in this study, interferon alfa-2a is a reasonably well tolerated and apparently effective short term treatment of subfoveal and juxtafoveal choroidal neovascularisations.

Intraocular pressure-reducing effect of PhXA41 in patients with increased eye pressure. A one-month study.

PURPOSE: To establish the dose-response relationship for the effect on intraocular pressure (IOP) and side effects during long-term treatment of patients with ocular hypertension with the prostaglandin F2 alpha (PGF2 alpha) analog PhXA41. METHODS: A three-center, randomized, double-masked study where IOP, conjunctival hyperemia, and ocular irritation were followed during a 1-month twice-daily treatment with placebo or 35, 60, or 115 micrograms/ml PhXA41 in 60 patients with ocular hypertension, primary open-angle glaucoma, or capsular glaucoma. RESULTS: The three concentrations of PhXA41 reduced the average IOP between 31% and 38% during the second day of treatment, with only a weak dose-response relationship. The initial effect declined somewhat during the first 2 weeks of treatment but then remained at the same level for the rest of the study, with a pressure reduction of approximately 20% for all three concentrations. On the second day of treatment, mild conjunctival hyperemia could be observed in most treated patients. Nineteen of 45 PhXA41-treated patients, compared with 2 of 15 placebo-treated patients, reported to have mild to moderate ocular irritation. These side effects became less pronounced during the study, and at the end there was little difference in the degree of conjunctival hyperemia between placebo- and drug-treated eyes, and no drug-related ocular irritation was reported with the two lowest concentrations of PhXA41. CONCLUSIONS: It is confirmed that the PGF2 alpha analog PhXA41 is a major improvement with respect to the effect-side effect relationship and that it may become a valuable new agent for the treatment of glaucoma.

Relationship between insulin injection regimen and metabolic control in young Danish type 1 diabetic patients. The Danish Study Group of Diabetes in Childhood.

In 1987 and 1989 nationwide screening for HbA1c was carried out in Denmark. Twenty-one paediatric departments treating children with diabetes participated in the first study and twenty-two in the second. During this 2-year period metabolic control deteriorated despite the fact that the use of multiple injection regimens increased from 39% to 54%. The possible reasons for the deterioration in metabolic control were examined in the 429 children (> or = 9 years, 1987) and adolescents (< 18.8 years, 1989) who participated in both studies. All had diabetes duration of greater than one year (1987) and all were treated by the same departments during the study period. The children were divided into three subgroups according to injection regimen. Group A (n = 128) received twice-daily insulin injections; group B (n = 171) were on multiple injections (three or more) while group C (n = 130) shifted from twice-daily insulin to multiple injections during the 2-year period. A deterioration of blood glucose control as assessed by HbA1c was observed in all three treatment groups. For group C the 2-year increase in daily insulin dose was more pronounced for males (19%) than for females (6%). Body mass index increased significantly in all treatment groups during the study period. The 1989 mean levels were higher in group B (males 20.6 kg m-2, females 22.0 kg m-2) than group A (males 19.3 kg m-2, p = 0.002; females 20.7 kg m-2, p = 0.000003) and group C (males 19.4 kg m-2, p = 0.0005; females 20.7 kg m-2, p = 0.008).(ABSTRACT TRUNCATED AT 250 WORDS)

PhXA34--a prostaglandin F2 alpha analogue. Effect on intraocular pressure in patients with ocular hypertension.

PhXA34, a prostaglandin analogue, was given topically to 40 patients with untreated ocular hypertension in a double masked randomised study. One single dose of 0.3, 1, 3, 10 micrograms, or placebo (vehicle) was given to one eye of each patient. A dose related IOP reduction ranging from 11 to 35% was observed with a maximal effect with 3 and 10 micrograms PhXA34. No hyperaemia was seen except after 10 micrograms PhXA34, where a mild to moderate hyperaemia was seen from 8 hours with a duration of up to 24 hours. Mild foreign body sensation in the PhXA34-treated eye was noted by three patients. No cells or flare were seen.

PhXA34, a new potent ocular hypotensive drug. A study on dose-response relationship and on aqueous humor dynamics in healthy volunteers.

The prostaglandin analogue PhXA34 was tested in two studies in normal human eyes; 1, 3, and 10 micrograms of PhXA34 reduced the intraocular pressure by about 2, 3, and 4 mm Hg, respectively, 6 to 10 hours after a single topical dose. The only side effect observed was a slight conjunctival hyperemia after 10 micrograms of PhXA34. In a second study we determined the effect of 10 micrograms of PhXA34 once daily for 7 days on intraocular pressure, outflow facility, aqueous flow, blood-aqueous barrier permeability, ocular discomfort, and hyperemia. The mean intraocular pressure was below 9 mm Hg 12 hours post dose. About one third of the intraocular pressure reduction could be explained by increased outflow facility. Aqueous flow was unaffected. Treatment caused a 21% increase in aqueous fluorescence 1 hour after an oral dose of fluorescein. Mild ocular discomfort and some hyperemia were initially observed in half of the subjects, but frequency and magnitude of these side effects declined during the study.

Image analysis of conjunctival hyperemia. A personal computer based system.

An image analysis system that estimates conjunctival hyperemia is described. The system gives a good estimate of minor to moderate hyperemia in the conjunctiva, and is easy and fast to operate.

A nation-wide cross-sectional study of urinary albumin excretion rate, arterial blood pressure and blood glucose control in Danish children with type 1 diabetes mellitus. Danish Study Group of Diabetes in Childhood.

Nation-wide screening for microalbuminuria in Denmark was performed in 22 paediatric departments treating children with Type 1 diabetes. Over a period of 6 months 1020 children (less than or equal to 12 years) and adolescents (greater than 12 to 19 years) were screened (81% of total). Of these, 957 (94%) performed at least two timed overnight urine collections. In 209 non-diabetic subjects the upper 95% limit for normal albumin excretion rate (AER) was 20 micrograms min-1. Mean overnight AER was significantly (p less than 0.001) elevated in diabetic (3.0 x/divided by 2.3 (SD tolerance factor) micrograms min-1) and in non-diabetic (2.5 x/divided by 2.2 micrograms min-1) adolescents compared with diabetic (1.7 x/divided by 2.1 micrograms min-1) and non-diabetic (1.3 x/divided by 2.2 micrograms min-1) children. In the diabetic patients AER was positively correlated with the body surface area and age. Among the patients with Type 1 diabetes, 4.3% (18 males and 23 females) had AER greater than 20 to 150 micrograms min-1 (persistent microalbuminuria). A further 7 adolescents (0.7%) had overt proteinuria (greater than 150 micrograms min-1). Clinical data for the 41 diabetic patients with AER greater than 20 to 150 micrograms min-1 were compared with those for 569 diabetic adolescents with AER less than or equal to 20 micrograms min-1 and duration of diabetes more than 2 years. The group with AER greater than 20 to 150 micrograms min-1 had significantly higher mean age (16.5 years) than the group with AER less than or equal to 20 micrograms min-1 (15.0 years; p less than 0.001). Females with AER greater than 20 to 150 micrograms min-1 had significantly higher mean HbA1c level (10.8 +/- 1.9%) than those with AER less than or equal to 20 micrograms min-1 (9.8 +/- 1.9%, p less than 0.003); they also had impaired linear growth (standard deviation score -0.25 vs + 0.16; p = 0.003). These associations were not found in males. Mean body mass index (BMI) was significantly increased in both females (22.2 +/- 2.9 kg m-2) and males (20.8 +/- 2.7 kg m-2) with AER greater than 20 to 150 micrograms min-1, compared with diabetic patients with AER less than or equal to 20 micrograms min-1 (females 20.8 +/- 3.0 kg m-2, p = 0.02; males 19.7 +/- 2.4 kg m-2, p less than 0.006).(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of adding prostaglandin F2 alpha-isopropylester to timolol in patients with open angle glaucoma.

Prostaglandin F2 alpha-isopropylester (PGF2 alpha-IE) (0.5 microgram) or placebo was added twice daily for 1 week to one eye in each of 30 patients with open angle glaucoma not adequately controlled with timolol treatment. Compared with placebo, PGF2 alpha-IE reduced the intraocular pressure of these timolol-treated eyes significantly. The absolute difference in mean change between PGF2 alpha-IE and placebo groups was 4.5 mm Hg with a 95% confidence interval of 3.1 to 6.6 mm Hg, corresponding to a mean reduction of initial intraocular pressure of 17.4% in eyes treated with PGF2 alpha-IE. Conjunctival or episcleral hyperemia was seen in all eyes treated with PGF2 alpha-IE for up to 4 hours but not in eyes treated with timolol and placebo, and aqueous flare was not observed in any eye. Thirteen of 15 patients treated with PGF2 alpha-IE, compared with only 3 of 15 who received placebo, reported mild to moderate subjective discomfort in the treated eye in the form of a foreign-body sensation that lasted for up to 2 hours. These results demonstrate that PGF2 alpha-IE, in a dose that has previously been shown to reduce intraocular pressure in normotensive volunteers or in patients with glaucoma who are taking no other medications, also significantly reduces the intraocular pressure of patients with glaucoma whose pressures are not adequately controlled on a twice-daily regimen of timolol.

Ocular effects of two different prostaglandin F2 alpha esters. A doublemasked cross-over study on normotensive eyes.

Ocular hypotensive effects and side effects of two different topically applied prostaglandin (PG) esters were evaluated in a double masked study in 12 healthy males. Three doses of 15-propionat-PGF2 alpha-isopropylester (15-prop-PGF2 alpha-IE), two doses of PGF2 alpha-isopropylester (PGF2 alpha-IE), and placebo were compared. At equipotent doses 15-prop-PGF2 alpha-IE caused similar ocular side effects as PGF2 alpha-IE. It is concluded that both PGF2 alpha-IE and 15-prop-PGF2 alpha-IE reduce the IOP in normal eyes, but the use of a diester such as 15-prop-PGF2 alpha-IE does not provide a better separation between effect on IOP and side effects than PGF2 alpha-IE.

Prostaglandin F2 alpha-isopropylester eye drops: effect on intraocular pressure in open-angle glaucoma.

In 30 patients with previously untreated open-angle glaucoma an intraocular pressure (IOP) curve was taken before and during treatment with PGF2 alpha-isopropylester (PGF2 alpha-IE) eye drops in one eye. Compared with the pretreatment IOP, the PGF2 alpha-IE induced a slowly increasing reduction in IOP. Just before the first dose the IOP was 31.4 (SEM 1.6) mm Hg. When corrected for the fall in pressure observed in the fellow eye the largest reduction, 5.8 (SEM 0.7) mm Hg (p less than 0.001), was obtained 24 hours later, that is, 12 hours after the second dose. In a subgroup of 10 patients the treatment was continued for one week. In this group the final pretreatment IOP was 25.9 (SEM 1.3) mm Hg. The reduction 24 hours later was 4.5 (SEM 0.6) mm Hg (p less than 0.001). The effect was maintained and even slightly increased during the week, and on the seventh day of treatment the IOP reduction ranged between 4.8 and 7.6 mm Hg compared with the pretreatment IOP. No serious subjective or objective side effects were observed.

Prostaglandin F2 alpha-isopropylester eye drops: effects in normal human eyes.

The effects of PGF2 alpha-isopropylester eye drops on intraocular pressure (IOP) and aqueous humour dynamics were investigated in healthy male volunteers. The other eye was treated with vehicle and used as a control. Special attention was also paid to adverse effects. Single and repeated doses were tested. There was a dose related effect on IOP. Significant reductions were observed 4, 8, and 12 hours after application of 1.0, 2.5, or 10 micrograms PGF2 alpha equivalents of the drug. With 10 micrograms the effect lasted 24 hours. An initial tendency towards an increase in IOP was observed for these doses. Repeated doses of 1.0 microgram daily or 0.5 microgram twice daily produced a significant and lasting IOP reduction of about 2 mmHg for 1-2 weeks. Aqueous humour production was not altered, and outflow facility was not significantly changed. There was a dose dependent hyperaemia with a maximum within 2 hours after application. A foreign body sensation, some pain, and photophobia were noted with increasing doses. A slight miosis of 1 mm was seen in three of six eyes treated with 10 micrograms. No signs of intraocular inflammation were recorded, but a slight increase in penetration of fluorescein into the anterior chamber was observed after 16 days of treatment.

Effects of topically applied PGF2 alpha and its isopropylester on normal and glaucomatous human eyes.

A lipid-soluble PG ester such as PGF2 alpha-IE reduces IOP in the human eye when given in considerably lower doses than are needed for the tromethamine salt of this PG to do so. However, with the pharmaceutical composition now used, the concomitant and dose-related side effects, both objective and subjective, are clearly clinically unacceptable at doses corresponding to the upper part of the dose-response curve for IOP reductions. Moderate side effects were observed after twice-daily treatment with the 0.5 microgram dose for up to two weeks. The pressure reduction obtained in healthy eyes with this dose of PGF2 alpha-IE was less than one would expect with conventional glaucoma drugs. However, the pressure reduction in response to this dose of PGF2 alpha-IE among glaucoma patients who had moderately increased IOP was adequate for clinical use. A useful approach to the development of PGs as potential drugs for the treatment of glaucoma would clearly be the identification of an alternative PG or PG formulation that will permit the use of doses at the upper portion of the IOP dose-response curve without unacceptable side effects. Long-term studies on glaucoma patients, using an appropriate PG formulation, remain to be done before we can evaluate the true clinical usefulness of this new class of ocular hypotensive drugs.

Development of insulin antibodies, metabolic control and B-cell function in newly diagnosed insulin dependent diabetic children treated with monocomponent human insulin or monocomponent porcine insulin.

One hundred and thirty eight patients participated in a two-year randomized, double-blind multicentre trial to compare monocomponent human insulin and porcine insulin in the treatment of newly diagnosed insulin dependent diabetic children with respect to development of insulin antibodies, metabolic control and B-cell function. There was no difference between the two patient groups throughout treatment either in the level of IgG insulin binding or the percentage of patients with insulin antibodies (IgG-insulin greater than 0.012 U/l). However, the estimated mean of log insulin binding values in the antibody positive patients alone was significantly lower (p less than 0.05) in the human insulin treated group at all times apart from 1 and 18 months (e.g., human insulin group at one and two years: 0.104 and 0.152 U/l, porcine insulin group at one and two years: 0.162 and 0.212 U/l). The insulin antibodies in both patient groups bound equivalent amounts of human and porcine insulin tracer. Metabolic control, insulin dosage and B-cell function in the two treatment groups were similar throughout the treatment period. It is concluded that in newly diagnosed insulin dependent diabetic children monocomponent human insulin is slightly less immunogenic than monocomponent porcine insulin, and equally effective in overall metabolic control.

Insulin compatibility with polymer materials used in external pump infusion systems.

In a study designed to mimic actual user conditions for external insulin pump infusion, the insulin quality after passage through the infusion set was assessed by various analytical methods, including high performance liquid chromatography. The two infusion sets tested consisted of, firstly, a polyvinylchloride/rubber syringe and a polyvinylchloride catheter sterilized by gamma irradiation and, secondly, a polyethylene/polypropylene syringe connected to a polyethylene catheter and sterilized by ethylene oxide. The insulin solution delivered through the PVC infusion set showed a reduction of preservative to less than 30% of the initial content and increased formation of chemical transformation products of insulin varying from twice the reference level during the first day to more than three times on the third day. By contrast, the polyethylene/polypropylene infusion system showed only a minor decrease in preservative content and no increase in chemical transformation. These effects were observed irrespective of the brand of insulin and were not affected by increase of the zinc content of the insulin solution. Investigation of the influence of the sterilization methods performed on polyvinylchloride and polyethylene catheters revealed that gamma irradiated polyvinylchloride catheters were markedly harmful to the insulin solution, whereas ethylene oxide sterilization did not influence the chemical stability of insulin.

Clinical experience with a new device that will simplify insulin injections.

In order to test clinically a newly developed, simple, and convenient device for giving multiple injections of short-acting insulin (Actrapid HM, Novo, Bagsvaerd, Denmark), 16 type I diabetic patients previously stabilized on intensified conventional therapy regimens participated in a randomized crossover study for a period of 6 wk. The patients used conventional syringes for injections of short-acting insulin during one period and the new device during the other. Conventional syringes were used for injections of basal insulin during both periods. Metabolic control was assessed by twice-weekly blood glucose profiles, HbA1c, and the frequency of hypoglycemic reactions; no significant differences were found during the two treatment periods. No infections at the injection sites were seen. Patients' evaluation of the new device was very positive.