Discrepancies between self- and adult-perceptions of social competence in children with neuropsychiatric disorders.

BACKGROUND: The present study examines discrepancies between self- and adult-perceptions of social competence in children with attention deficit-hyperactivity disorder (ADHD), autism spectrum disorders (ASD) and possible co-morbid disruptive behaviour disorders (DBD). METHOD: Self-reported questionnaires were collected from multiple informants at the baseline of a multi-systemic family intervention programme for children (aged 5-12) with ADHD, ASD and possible co-morbid DBD. In total, out of the 154 families eligible for the study, information was received concerning children from 124 families (children n = 121; mothers n = 117; fathers n = 86; teachers n = 97). In addition to this, a comparison community sample of 318 school-aged children (approximately 10 years old) was utilized to examine the perceptions of children's social competence across intervention and population groups in more detail. RESULTS: Children's self-perceptions in the prosocial dimension of social competence (i.e. cooperating skills, empathy) did not differ between the intervention and comparison groups. Interestingly, the children in the intervention sample expressed more impulsivity and disruptiveness - the antisocial dimension of social competence - when compared with the children in the comparison sample. Adult ratings demonstrated that mothers, fathers and teachers reported decreased prosocial behaviour and increased antisocial behaviour across overall dimensions and sub-dimensions when compared with adults' ratings of elementary school children. Informant discrepancies between self-ratings and adult ratings across intervention groups yielded significant effect sizes (eta-squared) across all domains of social competence ranging from .09 to .25. CONCLUSION: Children's positive self-ratings of social competence relative to adult ratings increased within intervention sample when compared with population sample. The intervention sample children appeared to acknowledge their social competence deficits, yet self-perceptions were inflated relative to adult ratings when focusing on peer relationship difficulties, particularly, aggression to peers.

Endosomal cholesterol traffic: vesicular and non-vesicular mechanisms meet.

The endoplasmic reticulum is traditionally perceived as the key compartment for regulating intracellular cholesterol metabolism. Increasing evidence suggests that the endocytic pathway provides an additional regulatory level governing intracellular cholesterol trafficking and homoeostasis. Sterols can enter, and apparently also exit, endosomal compartments via both vesicular and non-vesicular mechanisms. A number of studies have focused on endosomal sterol removal as its defects lead to cholesterol storage diseases. So far, the bulk of evidence on endosomal sterol egress describes the involvement of membrane trafficking machineries. Interestingly, two late endosomal sterol-binding proteins were recently shown to regulate the movement of late endosomes along cytoskeletal tracks. These studies provide the first indications of how non-vesicular and vesicular mechanisms may co-operate in endosomal sterol trafficking.

Prevention of flower development in birch and other plants using a BpFULL1::BARNASE construct.

The prevention of flower formation is important for avoiding the spread of transgenes from genetically modified plants into wild populations. Moreover, the resources not expended for the generation of flowers and fruits might be allocated to increased vegetative growth. We have been developing methods for preventing flower formation in silver birch (Betula pendula), a tree species of considerable economical importance in the boreal region. Here we study the suitability of the promoter of BpFRUITFULL-LIKE1 (BpFULL1, formerly BpMADS5) for tissue-specific ablation of inflorescences in Arabidopsis, tobacco and birch. With all these species, the development of inflorescences was successfully prevented. The results show that the BpFULL1::BARNASE construct has potential biotechnological applications in different plant species.

The Finnish evidence-based guideline for open-angle glaucoma.

In most patients, chronic open-angle glaucoma is a slowly progressive disease. Eyes with very high intraocular pressure (IOP > 30 mmHg) represent an exception to this and should be treated and followed extremely intensively. As lowering IOP is, so far, the only means of treating glaucoma, the majority of research reports deal with the IOP-lowering effect of the treatment. The primary goal of treatment, however, is to prevent glaucomatous damage to the structures and function of the eye. The effectiveness of treatment is monitored with optic disc and retinal nerve fibre layer imaging and with visual field examinations. If the glaucomatous changes are progressing, more effective treatment should be given. In the course of follow-up, it should be noted that the changes in the optic nerve structure and function appear and progress at different time-points with delays of up to several years. The assessment of abnormalities is dependent on the examination method and requires a great deal of experience on the part of the examiner. The important risk factors in glaucoma are elevated IOP (even if IOP is within normal range in half of patients ), age, positive family history, exfoliation, race and myopia.

Localised changes in glaucomatous visual fields after trabeculectomy.

BACKGROUND AND OBJECTIVE: Modern techniques of automated perimetry have shown that surgical reduction of intraocular pressure (IOP) may have a beneficial effect on the glaucomatous visual field. The purpose of the present study was to analyse and quantify the changes in the visual fields of glaucoma patients after trabeculectomy. MATERIALS AND METHODS: Octopus visual fields of twenty-seven glaucoma patients were analysed. Change in visual field mean sensitivity (MS) was calculated to detect total field changes. A clinical and a statistical analysis of small clusters of test points were used to define whether local changes had occurred. RESULTS: MS in the operated eyes improved significantly from 16.4+/-5.6 to 18.2+/-5.5 dB. The patients had on average 3.9+/-6.2 clusters where the retinal sensitivity had improved at least 5 dB and only 0.4+/-0.9 clusters where sensitivity had deteriorated at least 5 dB after trabeculectomy. 17 patients had more improved than deteriorated clusters postoperatively. CONCLUSION: Statistically significant improvement was seen in the MS, but improvement was also found in small local areas of the visual fields after trabeculectomy.

Plasma concentration of topically applied betaxolol in elderly glaucoma patients.

Our aim was to study the concentration of betaxolol in plasma after its topical ocular use during the normal 12 hr dosing interval. Twenty microliters of betaxolol 0.5% solution were applied into both eyes of nine glaucoma patients, and the plasma concentrations of the drug were measured 12 hr thereafter using a radioreceptor assay. The same amount of betaxolol was then applied ocularly, and its concentration in plasma was measured at 5, 10, 15, 30 min and 1, 2, 4 and 8 hr thereafter. The mean (SD) concentration of betaxolol in plasma twelve hr after the first dose was 0.4 (0.2) ng/ml. After the second dose, the patients showed a biphasic concentration vs. time curve, the first peak occurring at 8 (4) min, and the second peak at 210 (132) min; the mean (SD) peak concentrations being 1.1 (0.3) and 2.0 (1.1) ng/ml, respectively. The area under the concentration vs. time curve showed a 4-fold variation among our patients. Topically applied betaxolol was rapidly absorbed into systemic circulation, and concentrations were detectable even at 12 hr. The interindividual variation in the systemic absorption of betaxolol was large.

"Scleral tunnel incision"-trabeculectomy with one releasable suture.

PURPOSE: To describe a modified surgical technique, a scleral tunnel incision- trabeculectomy (STIT) and evaluate its safety and efficacy in lowering IOP in glaucoma patients. METHODS: One hundred and three patients were included in a retrospective, nonrandomized clinical study. Fifty-three patients were operated conventionally and 40 patients underwent STIT. In the modified technique the sides of the scleral flap are opened only half-way to the limbus and the flap is closed with a single releasable "slipknot"-suture. RESULTS: The mean IOP on the first postoperative day was 4.5 +/- 6.8 mmHg in the conventional group and 7.4 +/- 7.1 mmHg in the tunnel incision group (p = 0.012). On the second postoperative day the mean IOP was 4.5 +/- 7.3 mmHg and 6.3 +/- 6.5 mmHg in the conventional group and tunnel incision group, respectively (p = 0.065). There was no statistically significant difference in the mean postoperative IOP between the groups at one month and at 6-12 months. Shallow anterior chamber and iridocorneal touch occurred statistically significantly less in the tunnel incision group than in the conventional group. CONCLUSION: STIT appears to be equivalent to conventional trabeculectomy (CT) in lowering IOP during the first 6-12 months postoperatively. It is also relatively safe and has fewer early complications related to excessive aqueous outflow than CT.

Mobilization of late-endosomal cholesterol is inhibited by Rab guanine nucleotide dissociation inhibitor.

Cholesterol entering cells in low-density lipoproteins (LDL) via receptor-mediated endocytosis is transported to organelles of the late endocytic pathway for degradation of the lipoprotein particles. The fate of the free cholesterol released remains poorly understood, however. Recent observations suggest that late-endosomal cholesterol sequestration is regulated by the dynamics of lysobisphosphatidic acid (LBPA)-rich membranes [1]. Genetic studies have pinpointed a protein, Niemann-Pick C-1 (NPC-1), that is required for the mobilization of late-endosomal/lysosomal cholesterol by an unknown mechanism [2]. Here, we report the removal of accumulated cholesterol by overexpression of the NPC-1 protein in NPC-1-deficient fibroblasts from patients with Niemann-Pick disease, and in normal fibroblasts upon release of a progesterone-induced block of cholesterol transport. We show that late-endosomal/lysosomal cholesterol mobilization is specifically inhibited by microinjection of Rab GDP-dissociation inhibitor (Rab-GDI). Moreover, clearance of the cholesterol deposits by NPC-1 in patients' fibroblasts is accompanied by the redistribution of LBPA and of a lysosomal hydrolase that utilizes the mannose-6-phosphate receptor. Our results reveal, for the first time, the involvement of a specific molecular component of the membrane-trafficking machinery in cholesterol transport and the coupling of late-endosomal cholesterol egress to the trafficking of other lipid and protein cargo.

The favorable effect of topical betaxolol and timolol on glaucomatous visual fields: a 2-year follow-up study.

BACKGROUND: It has been suggested that beta-adrenergic antagonists might have mechanisms of action other than ocular hypotensive effects affecting the visual function in glaucoma patients and that betaxolol might protect the visual field better than others. A randomized, double-blind study was conducted to compare the effects of betaxolol and timolol on visual fields of glaucoma patients. METHODS: Sixty-four glaucoma patients were treated with either 0.5% betaxolol or 0.25% timolol eyedrops twice daily. The Octopus visual field performance was followed up for 2 years and analyzed to find diffuse and localized changes. We analyzed the change in the mean sensitivity (MS) and performed a cluster analysis and clinical assessment of the visual fields in both treatment groups. RESULTS: The mean sensitivity (MS) improved significantly and equally in both treatment groups. There was a tendency towards more improved clusters in the betaxolol group than in the timolol group and more worsened cluster in the timolol group than in the betaxolol group, but the difference was not statistically significant. The clinical assessment also showed no statistically significant difference between the two groups. CONCLUSION: In the present study both betaxolol and timolol had a favorable effect on the visual fields of glaucoma patients. There was no statistically significant difference between betaxolol- and timolol-treated patients either in the change in mean retinal sensitivity or in the change in localized scotomatous areas.

Aqueous humour concentration and the intraocular pressure-lowering effect of topical betaxolol before cataract surgery.

OBJECTIVE: The aim was to study the relationship between aqueous humour betaxolol concentration and intraocular pressure (IOP). METHODS: In this double-blind, randomized study, we administered betaxolol (a) or placebo (b) ocularly to 131 patients scheduled for cataract surgery. The patients were randomly divided into ten groups. In groups 1a and 1b, the drug was scheduled to be instilled 1-2 h, in groups 2a and 2b 12 h, in groups 3a and 3b 24 h, and in groups 4a and 4b 48 h before surgery. The pupil was dilated in all eyes prior to surgery. The IOP was measured with Perkins' applanation tonometer before the instillation of the drug and just before the peribulbar block. Twenty microlitres of 0.5% betaxolol or placebo solution was instilled into the eye. IOP was also measured before instillation of the drug and after 1 2 h in undilated eyes of 20 patients, whose contralateral eye was to be operated on, to rule out the effect of pupil dilation on IOP (groups 5a and 5b). Aqueous humour betaxolol concentrations were analysed using a radioreceptor assay. RESULTS: Betaxolol did not decrease IOP significantly in eyes with pupillary dilation. Both betaxolol and placebo decreased IOP significantly in patients without pupillary dilation, the effect of betaxolol being slightly more pronounced. The betaxolol concentration in aqueous humour was 731 ng m-1 in group la, 2.4 h after drug instillation. Measurable concentrations of betaxolol were also detected in aqueous humour in group 4a 47.7 h after drug administration. CONCLUSION: No correlation between aqueous humour concentration of betaxolol and the effect on IOP was found in eyes where the pupil was dilated before surgery. A single betaxolol dose did not decrease IOP significantly in patients undergoing cataract surgery, but the IOP decreasing effect was, however, clearly seen in patients who did not receive mydriatic drugs. The routine use of topical betaxolol prior to cataract surgery to decrease IOP is not recommended.

Mutation analysis of the glial cell line-derived neurotrophic factor gene in Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for nigrostriatal dopaminergic, central cholinergic, and motoneurons. GDNF also prevents the neuronal loss in experimental animal models for Parkinson's disease (PD). We have now investigated the GDNF gene for possible mutations in a group of nonfamilial PD and other patients. By cleavase fragment length polymorphism (CFLP) analysis and direct sequencing of the full coding region of GDNF gene we found a novel GDNF sequence variant in 1 of 30 PD patients. The alteration does not change the predicted amino acid sequence and it was also found in 1 of 20 patients without PD, suggesting that it represents a polymorphism in the gene. No other sequence variations were found. We conclude therefore that mutations in the GDNF coding region are not commonly contributing to the pathogenesis of PD.

Recurrent severe hypotony after cataract surgery in an eye with previous trabeculectomy.

This report describes a patient who developed severe recurrent hypotony after uneventful phacoemulsification and intraocular lens (IOL) implantation 4 years after trabeculectomy. Hypotony was first noticed 1 month postoperatively and treated successfully with topical steroids. However, it reappeared 2 months later and slowly subsided only with steroid and cycloplegic treatment. There was no anterior chamber shallowing, leakage, or signs of inflammation. The cause of hypotony in this patient remains unknown. One possible explanation is subclinical postoperative inflammation as a foreign-body reaction to the IOL.

Evaluation of glaucoma patients referred to a university clinic during one year.

PURPOSE: In the spring of 1994, the post-referral waiting time for glaucoma patients at our institution was approximately 7 months. In an attempt to evaluate and possibly reduce this waiting time we compared the referral criteria to the actual treatment requirements of 472 patients admitted for glaucoma in 1995. RESULTS: 175 patients were referred as glaucoma suspects, 134 as chronic simple glaucoma, and 123 as capsular glaucoma. In addition, 40 patients were referred as other types of glaucoma. Elevated IOP was the main criterion for referral in 133 (76%) of glaucoma suspects. The diagnosis of glaucoma could not, however, be confirmed in 54 (31%) glaucoma suspects. 93 (69%) patients with simple open angle glaucoma and 103 (84%) patients with capsular glaucoma were also referred because of IOP > or = 22 mmHg. Maximally tolerated medication was not used by 44% of open angle glaucoma patients at time of referral. CONCLUSION: The clinical follow-up of glaucoma patients and glaucoma suspects should primarily take place at an ophthalmologist's office and the new effective glaucoma drugs and laser treatments should also be more actively in use. The cooperation between the referring ophthalmologists and the university clinic should be improved. Hospitalisation turned out to be unnecessary because, with a few exceptions, all procedures could have been performed on an out-patient basis, which is a general practice in most glaucoma clinics today. The university clinic should focus only on those patients who need special evaluation or surgical treatment.

Plasma kinetics and antagonist activity of topical ocular timolol in elderly patients.

BACKGROUND: Systemic adverse effects of ocular timolol therapy are due to absorption of the drug from the eye into the systemic circulation. Elderly patients are frequently more susceptible to side effects than younger patients. This study was conducted to evaluate the plasma kinetics and antagonist activity of ocular timolol in elderly patients. METHODS: Plasma kinetics and antagonist activity of timolol were studied in 12 patients scheduled for extracapsular cataract extraction and intraocular lens implantation. The patients received 40 microliters of 0.25% timolol into the lower cul-de-sacs of each eye. Blood samples were collected over a period of 12 h and plasma concentrations of timolol were analyzed using a radioreceptor assay. The corresponding ex vivo beta 1- and beta 2-receptor occupancies were calculated using radioligand binding techniques. RESULTS: Timolol was absorbed rapidly into the systemic circulation and occupied on average up to 68% of beta 1-receptors and up to 87% of beta 2-receptors. The beta 1- and beta 2-receptor occupancy decreased slowly and was on average 38% and 64%, respectively, 12 h after the single dose. The calculated mean area under concentration-time curve of timolol in plasma was 10.28 ng/ml per hour and the mean half-life was 4.8 h. Both values were about twice as high as those found in healthy young volunteers following an intravenous 0.25-mg dose of timolol. CONCLUSIONS: In elderly patients the beta-receptor antagonist effect of ocular timolol after a single dose is strong and long-lasting. This finding may explain the frequent reported systemic side effects of ophthalmic timolol.

Systemic absorption and anticholinergic activity of topically applied tropicamide.

We studied the plasma levels and systemic anticholinergic activity of tropicamide after ocular administration in eight women. Two 40 microliters drops of 0.5% tropicamide were instilled into the lower cul-de-sac of one eye of the subjects and concentrations and respective muscarinic receptor occupancy of tropicamide in plasma were monitored using radioligand binding techniques. Tropicamide was rapidly absorbed systemically with the mean peak concentration in plasma being 2.8 +/- 1.7 ng/ml (mean +/- SD) at five minutes after instillation. Tropicamide disappeared rapidly from the systemic circulation: drug concentration in plasma was 0.46 +/- 0.51 ng/ml (mean +/- SD) at 60 minutes and below 240 pg/ml at 120 minutes after instillation. Tropicamide bound to muscarinic receptors of rat brain with an apparent equilibrium binding constant (Ki-value in plasma) 220 +/- 25 nM (mean +/- SD, n = 3). Tropicamide occupied maximally 8% of muscarinic receptors in plasma after ocular application. The low affinity of tropicamide for muscarinic receptors and its negligible receptor occupancy in plasma can explain the low incidence of systemic side-effects of tropicamide eyedrops.

Absorption of ocular timolol: drug concentrations and beta-receptor binding activity in the aqueous humour of the treated and contralateral eye.

We studied the ocular and systemic absorption of 40 microliters of topical 0.5% timolol in 57 patients using radioligand binding techniques. The mean concentration of timolol in aqueous humour of the treated eye was 1.9 +/- 0.8 micrograms/ml 74 minutes after instillation of the drug. About 18 h after drug instillation the aqueous humour concentration of timolol was 105.5 +/- 60.9 ng/ml. Timolol was found in 15 (42%) contralateral eyes. Concentration of timolol in the contralateral eye increased from 0.04 +/- 0.08 ng/ml at 50 min to 0.3 +/- 0.2 ng/ml at 134 min and was 0.2 +/- 0.4 ng/ml at 18 h after instillation. Timolol concentrations in the aqueous humour of the treated eye appeared to be high enough to occupy beta 1- and beta 2-receptors completely (100%) at 74 min and at 18 h after drug instillation. Timolol concentrations in the contralateral eye were high enough to occupy up to 33.0 +/- 24.7% of the beta 2-receptors and up to 51.7 +/- 35.1% of beta 2-receptors. High drug concentrations and complete beta-receptor occupancy in the aqueous humour of the treated eye after topical timolol are in agreement with the long-lasting ocular hypotensive effects. The low drug concentrations and partial receptor occupancy in the contralateral eye may also be of some clinical significance.

Concentrations and antagonist activity of topically applied betaxolol in aqueous humour.

Aqueous humour concentrations and antagonist activity of betaxolol were studied after ocular administration in forty-five patients scheduled for cataract surgery. The patients were randomly divided into five groups and received 40 microliters of 0.5% betaxolol into the lower cul-de-sac of one eye. In groups I, II, III and IV the drug was instilled 5-6, 12, 24 and 48 h, respectively, before surgery, into the eye to be operated, and in group V 4 h before surgery into the contralateral eye. Aqueous humour samples were aspirated at the beginning of the operation. Aqueous humour concentrations of betaxolol were analyzed using a radioreceptor assay, and the ex-vivo-beta 1- and beta 2-receptor occupancies of betaxolol were calculated. The highest concentration of betaxolol in aqueous humour was found 5-6 hours after instillation of the drug. Topical betaxolol was found to stay in aqueous humour for 48 h, a much longer time than the recommended interval of dosage. Betaxolol beta 1-receptor occupancy was 99-95% during the study, but also beta 2-receptor occupancy was significant (52%) 24 h after instillation of the drug. Because receptor occupancy is the basis of antagonist activity, the role of beta 2-receptor blocking effect of betaxolol in lowering intraocular pressure cannot be excluded.

Beta 1- and beta 2-antagonist activity of topically applied betaxolol and timolol in the systemic circulation.

The beta 1- and beta 2-antagonist activity of betaxolol and timolol in the systemic circulation was studied ex-vivo after their ocular administration in thirty patients during cataract surgery. The patients received 40 microliters of 0.5% betaxolol or 0.25% timolol into the lower cul-de-sacs of both eyes. Blood samples were collected up to four h after instillation of the doses. Plasma concentrations of betaxolol and timolol were analyzed using a radioreceptor assay. The ex-vivo-beta 1-and beta 2-receptor occupancies corresponding drug plasma levels were calculated using radioligand binding techniques. The extent of beta 1-receptor occupancy of betaxolol in the systemic circulation was less than 20% and its beta 2-receptor occupancy was negligible. The extent of beta 1-receptor occupancy of timolol was about 65% and its beta 2-receptor occupancy about 80%. Because receptor occupancy is the basis of antagonist activity of beta-blocking agents, this study shows that the beta 1-antagonist activity of betaxolol in the systemic circulation is much less than that of timolol, and that its beta 2-antagonist activity is negligible. The study suggests that the reported side effects of betaxolol in patients with obstructive pulmonary diseases are not mediated via its beta 2-receptor blocking properties.

The effect of betaxolol and timolol on postoperative intraocular pressure.

Postoperative intraocular pressure (IOP) elevation is a well documented phenomenon after cataract surgery. Many pharmacological agents have been used to prevent this complication. We conducted a randomized double-blind, placebo-controlled study to evaluate the effect of topical betaxolol and timolol on postoperative IOP after extracapsular cataract extraction and intraocular lens implantation. One hundred and twenty patients were randomly divided into three groups. At the end of the operation, the patients were given one drop of 0.5% betaxolol, 0.5% timolol or placebo solution into the lower cul-de-sac of the operated eye. IOP was measured preoperatively and five and twenty-four h postoperatively. There was a significant rise in IOP in the placebo and betaxolol groups but not in the timolol group five h postoperatively. IOP was significantly higher in all groups twenty-four h after the operation than preoperatively. Betaxolol did not have any significant effect on the postoperative IOP, but timolol was effective in preventing the early IOP rise. The differences in the antagonist effects of these drugs and the possible role of beta 2-receptors in mediating the aqueous humour flow are discussed.

Plasma and aqueous humour concentrations and systemic effects of topical betaxolol and timolol in man.

Plasma and aqueous humour concentrations and systemic effects of timolol and betaxolol were studied after ocular administration in 45 patients scheduled for extracapsular cataract extraction and intraocular lens implantation. The patients were divided randomly into three groups and received 40 microliters of either 0.5% betaxolol, 0.25% timolol or placebo into the lower cul-de-sacs of both eyes. Blood samples were collected over a period of 4 h and blood pressure and heart rate were monitored during the study. Aqueous humour samples were aspirated at the beginning of the operation. Plasma and aqueous humour concentrations of timolol and betaxolol were analyzed using a sensitive radioreceptor assay. The mean plasma concentrations of betaxolol were lower than those of timolol. The concentration of betaxolol in the aqueous humour was twice as high as the concentration of timolol. Both drugs produced a significant decrease in heart rate. In the timolol group a decrease in heart rate was found 15 min after drug administration, and in the betaxolol group after one hour.