Impaired vision in children prenatally exposed to methadone: an observational cohort study.

BACKGROUND/OBJECTIVES: To examine prevalence of failed visual assessment at 8-10 years in children born to methadone-maintained opioid dependent (MMOD) mothers and relate this to known in utero substance exposure. SUBJECTS/METHODS: Follow up of observational cohort study of methadone-exposed and comparison children matched for birthweight, gestation and postcode of residence at birth. Participants were 144 children (98 exposed, 46 comparison). Prenatal drug exposure was previously established via comprehensive maternal and neonatal toxicology. Children were invited to attend for visual assessment and casenotes were reviewed. Presence of acuity poorer than 0.2 logMAR, strabismus, nystagmus and/or impaired stereovision constituted a 'fail'. Fail rates were compared between methadone-exposed and comparison children after adjusting for known confounding variables. RESULTS: 33 children attended in person: data were also derived from casenote review for all children. After controlling for maternal reported tobacco use, methadone-exposed children were more likely to have a visual 'fail' outcome, adjusted odds ratio 2.6, 95% CI 1.1-6.2; adjusted relative risk 1.8 (95% CI 1.1-3.4). Visual 'fail' outcome rates did not differ between methadone-exposed children who had (n = 47) or had not (n = 51) received pharmacological treatment for neonatal abstinence/opioid withdrawal syndrome (NAS/NOWS); fail rate 62% vs 53% (95% CI of difference-11-27%). CONCLUSIONS: Children born to MMOD mothers are almost twice as likely as unexposed peers to have significant visual abnormalities at primary school age. Prenatal methadone exposure should be considered in the differential diagnosis of nystagmus. Findings support visual assessment prior to school entry for children with any history of prenatal opioid exposure. TRIAL REGISTRATION: The study was prospectively registered on ClinicalTrials.gov (NCT03603301), https://clinicaltrials.gov/ct2/show/NCT03603301 .

Effects of postmenopausal hormone replacement therapy on lipoproteins including lipoprotein(a) and LDL subfractions.

The purpose of this study was to examine the effects on lipoprotein risk markers for CHD of oestradiol given alone and in combination with the androgenic progestogen, norethisterone. Eighty postmenopausal women were randomly allocated to receive oestradiol (2 mg/day) alone or with continuous norethisterone (1 mg/day). Serum lipoprotein levels, including lipoprotein(a), were monitored during 12 months on treatment in all the women, and in a sub-set of 32 patients cholesterol was measured in the two major density subfractions of LDL. Oestradiol caused a transient rise in triglycerides, a small decrease in LDL cholesterol (significant only at 3 and 6 months, P < 0.05) and a consistent significant increase in HDL cholesterol (16%, P < 0.01). There was a downward trend in lipoprotein(a) levels which did not achieve statistical significance. The combined preparation caused significant, sustained decreases in triglycerides (31%, P < 0.01), total cholesterol (15%, P < 0.001), VLDL (42%, P < 0.01), LDL (9%, P < 0.05) and HDL (11%, P < 0.001). Lipoprotein(a) was also reduced (39%, P < 0.05). In the sub-set of patients in which LDL subfractions were measured, the reduction in LDL induced by oestradiol monotherapy was significant only at the 3-month visit (6%, P < 0.05). This was due to a decrease in the 'light' (1.025 < d < 1.044 g/ml) subfraction (10%, P < 0.05) and resulted in an apparent shift in subfraction distribution towards the 'heavy' (1.044 < d < 1.060 g/ml) subfraction, although there was no absolute increase in the latter. None of these changes was statistically significant at 12 months. Oestradiol/norethisterone caused sustained decreases in both 'light' (15%, P < 0.05) and 'heavy' (29%, P < 0.05) subfractions, with no significant change in the relative amounts. The changes in 'light' and 'heavy' LDL in this group were highly correlated with changes in triglyceride levels (r = -0.57, P < 0.05 and r = 0.82, P < 0.01 respectively). Therefore, at the end of 1 year's treatment with unopposed oestradiol the only statistically significant change was an increase in HDL cholesterol. Addition of norethisterone to the preparation reversed this potentially beneficial change, but favourably influenced triglycerides, VLDL, LDL subfraction profile and lipoprotein(a), which may counteract the adverse effect on HDL.

Red blood cells mediate spontaneous aggregation of platelets in whole blood.

The influence of red blood cells on spontaneous platelet aggregation (SPA) has been studied ex vivo. Platelet aggregation was quantified by measuring the fall in single platelet count using a new whole blood platelet counter. When aliquots of whole blood and autologous platelet rich plasma (PRP) were roller-mixed at 37 degrees C, a marked fall in platelet count occurred in whole blood due to SPA but platelet count remained almost unchanged in PRP. When blood from healthy young controls, aged 20-35 years, was compared with healthy old controls, aged 48-80 years, and patients with thrombotic complications, the extent of SPA was in the order: thrombotic patients greater than old controls greater than young controls. Prostacyclin and the new stable prostacyclin analogue Iloprost, at 8 nM effectively inhibited SPA. 2-Chloroadenosine (10 microM) which is an inhibitor of ADP-induced platelet aggregation was also an effective inhibitor of SPA. Acetylsalicylic acid (56 microM) and the thromboxane A2 receptor blocker BM13.177 (0.5 microM) only partially inhibited SPA. ADP from red blood cells is suspected to mediate red cell-induced SPA. However, the possibility that the red cells have an important physical role in SPA cannot be ruled out.

Haemostatic effects of ketorolac with and without concomitant heparin in normal volunteers.

Ketorolac is a potent cyclo-oxygenase inhibitor used for the treatment of postoperative pain. It is known to have anti-platelet properties. The aim of this study was to determine the effect of ketorolac on haemostasis both alone and in combination with low dose heparin in 12 healthy male volunteers. Each volunteer received the following drug combinations in a double blind, placebo controlled, cross over manner: ketorolac placebo/heparin placebo, ketorolac active/heparin placebo, ketorolac active/heparin active and ketorolac placebo/heparin active. Ketorolac significantly prolonged bleeding time, inhibited platelet aggregation to arachidonic acid and collagen and platelet thromboxane production. Heparin had no effect on bleeding time or platelet function, but significantly prolonged the kaolin cephalin clotting time and increased anti-Xa levels. Ketorolac had no effect on the kaolin cephalin clotting time or anti-Xa levels and no interaction was found between ketorolac and heparin in any of the investigations. The prolongation of bleeding time seen with ketorolac is unlikely, to be of any major clinical significance as almost all subjects remained within the normal range; however, it should be used with caution in subjects with haemostatic problems.

A critical investigation into the existence of circulating platelet aggregates.

By a method of counting single platelets in diluted whole blood, platelet aggregates were quantified ex-vivo. Four groups: 20 thrombotic patients, 10 non-thrombotic patients, 10 healthy old controls and 10 healthy young controls were included in the study. Using a 19 gauge needle, with and without tubing, venous blood was taken into buffered EDTA, as a disaggregating agent and buffered EDTA-formalin, as the fixative. The amount of platelet aggregates quantified was affected by the quality of venepuncture or the rate of blood flow through the needle, but was unaffected by the presence of the tubing. There was no statistically significant difference between the four groups, in terms of the platelet aggregates quantified, but scanning electron microscopy revealed the presence of irreversible aggregates, composed of platelet red and white blood cells, in the blood of a greater number of thrombotic patients than non-thrombotic or healthy controls. Platelet aggregates were also quantified in aliquots of platelet rich plasma, and were found to be significantly greater than the corresponding values in whole blood. The difference appeared to be due to increased viscosity of the plasma, induced by the fixative which reduces platelet mobility during centrifugation. It is concluded that the platelet aggregates which disaggregate in buffered EDTA may represent an artifact of blood collection; the irreversible aggregates are suspected to represent the in vivo circulating aggregates.

Screening for amblyopia: a comparison of paediatric letter tests.

AIMS/BACKGROUND: The measurement of visual acuity is the most widely accepted indicator of amblyopia and is thought by some to be the only effective screening test. The aim of this study was to investigate the effectiveness of the traditional single optotype Sheridan-Gardiner test (SGT) in the measurement of visual acuity and the detection of amblyopia, compared with the log based linear format Glasgow acuity cards (GAC). METHODS: In the present study visual acuity was measured monocularly in 702 primary 1 schoolchildren using both acuity tests. RESULTS: A significant difference was found in the mean (SD) visual acuity measured with GAC (0.9 (0.08) modified logMAR) and SGT (1.13 (0.09) modified logMAR), df = 632, t = -59.08, p = 0.0001. The majority of children (89.3%) achieved visual acuities better than 6/6 in either eye when using the single optotype test. If the 95% confidence limits for a significant interocular difference in acuity are used as-criteria for the detection of unilateral amblyopia, GAC were found to be the most sensitive, correctly identifying 100%, while SGT identified 55% of the children with unilateral amblyopia. CONCLUSION: The results of this study highlight several problems with both the test format and testing procedure in the present school screening system.

Vision testing in schools: an evaluation of personnel, tests, and premises.

This study compared the results of vision screening of 5 year olds in schools by school nurses and an orthoptist, compared two tests, and examined testing conditions. The specificity of nurse testing was 95% and the sensitivity 83%. No conclusions about the tests could be made owing to the small numbers in this part of the study, but some children, after nearly one year at school, could not match a line of four letters required for the more accurate test. Only 13 of 22 schools had suitable testing conditions.

Effects of tibolone on lipoprotein(a) and HDL subfractions.

OBJECTIVE: To determine the effects of tibolone, a synthetic steroid used to alleviate climacteric symptoms and prevent osteoporosis, on lipoprotein metabolism, with particular reference to lipoprotein(a) levels and HDL subfraction profiles. DESIGN: Thirty nine postmenopausal women were treated with tibolone (Livial) 2.5 mg/day for 6 months and fasting serum lipoprotein levels were estimated at 0, 2, 4 and 6 months. RESULTS: Lipoprotein(a) levels were reduced significantly over the 6 months from a median level of 245 (range < 60-780) mg/l to 152 (range < 60-530) mg/l, a reduction of 39% in the median level. A decrease was observed in approximately two thirds of the women. Reductions were noted in all 6 subjects whose pretreatment levels were high, although concentrations remained at a level associated with increased risk in all but one. There were significant decreases in triglycerides and VLDL cholesterol and no significant change in LDL cholesterol. There was a significant reduction of 18% in HDL cholesterol and a 26% reduction in the HDL2-HDL3 ratio. CONCLUSION: The reduction in lipoprotein(a) levels may have a beneficial effect on cardiovascular risk, which could go some way towards balancing the potentially adverse effect on the cardiovascular system caused by the reduction in HDL cholesterol.

A review of school vision screening in Glasgow.

OBJECTIVES: To assess to what extent the primary school vision screening programme was being carried out in the years 1993-94 and 1994-95, what the prevalence of eye defects was in the primary schools and how many children had a positive screening test. DESIGN: Summary sheets of the results of screening were returned by each school nurse. SETTING: All 315 mainstream primary schools served by Greater Glasgow Health Board. SUBJECTS: All school nurses working in these schools. RESULTS: Large numbers of tests were being performed but the screening programme was not fully carried out in 10% of schools in 1993-94 and in 68% in 1994-95, although the number of schools where some screening was performed did increase. The years were not directly comparable due to a change in the age groups screened. When a class was screened 94-96% of children were tested. The rate of positive screening varied from 4% to 15.6% and varied with age and locality. Fewer abnormalities were found at five years than in the older age groups (Primary 1-7.6%, Primary 4-11.4%, and Primary 7-9.7%) and fewer abnormalities were detected in the North-West area where a pre-school orthoptic screening programme was operating (4% in the North-West compared with 11% in the South where no pre-school screening was carried out). CONCLUSION: If the recommended programme is carried out, then 95% of children at age five years could be tested at a stage when amblyopia is still potentially treatable. The reasons for the programme not being completed require to be addressed. Variations between areas need to be confirmed and the reasons for them identified. Further evaluation of the programme is required, exploring the accuracy of it and the long-term outcomes.

A dose-ranging study of the use of cyclical dydrogesterone with continuous 17 beta oestradiol.

OBJECTIVE: To establish the lowest dose of cyclical dydrogesterone that protects against endometrial hyperplasia induced by continuous 2 mg 17 beta oestradiol, and to study the dose effect on vaginal bleeding and side effects. DESIGN: Double-blind, prospectively randomised dose-ranging study. SETTING: Menopause clinics in the UK and The Netherlands. SUBJECTS: Three hundred and seventy-one postmenopausal women with intact uteri, aged 40 to 60. INTERVENTIONS: Administration of six 28-day treatment cycles of continuous daily micronised 17 beta oestradiol with a randomly allocated dose of 5 to 20 mg of dydrogesterone added for the last 14 days of each. MAIN OUTCOME MEASURES: Histological assessment of adequate progestational endometrial response, bleeding patterns and adverse effects. RESULTS: The study was completed by 320 subjects (86%). Endometrial transformation occurred in over 94% of those taking 5 mg of dydrogesterone, and in over 97% of those on higher doses, without significant differences between the 10, 15 and 20 mg groups. Acceptable bleeding patterns were found at all doses, with the incidence of withdrawal bleeding rising with increasing dose. The day of onset of bleeding was predictable from cycle to cycle, and occurred later in the 20 mg group than in the others. The incidence of noncyclic bleeding was about 6% at all doses. Withdrawal occurred in 3.3% due to unacceptable bleeding and in 5.4% due to side effects. There was no relation with dose. CONCLUSIONS: A dydrogesterone-17 beta oestradiol combination hormone replacement therapy confers endometrial protection with an acceptable bleeding pattern and few side effects At least 10 mg of dydrogesterone for 14 days is required for acceptable endometrial protection.

Long-term effects of continuous combined HRT on bone turnover and lipid metabolism in postmenopausal women.

This study was undertaken to investigate the effect of 10 years of hormone replacement therapy (HRT) on bone turnover and lipid metabolism in postmenopausal women. The single-centre trial was initiated as a 1-year, double-masked, randomized, parallel-group study of continuous combined HRT with 2 mg 17 beta-estradiol and 1 mg norethisterone acetate administered once daily with or without 1 mg estriol. Following preliminary results which showed no difference between the addition and omission of estriol, patients continued on an open-label extension phase of continuous combined HRT without estriol for a further 9 years. Of the 52 women who entered the original double-masked study, 32 entered the open-label extension phase. The 10-year analysis was based on 27 patients. Major increases in bone mineral density (BMD) of the lumbar spine were seen during the first 3 years of treatment, remaining statistically significant compared with baseline at all visits throughout the 10-year follow-up (p < or = 0.025). Statistical modelling confirmed that there were no decreases in BMD after these initial increases. BMD remained 5.5% higher than baseline values after 10 years of continuous combined HRT. Mean total cholesterol levels were significantly reduced after 10 years of therapy (p = 0.012), with no significant changes in serum triglyceride and low-density lipoprotein (LDL)-cholesterol levels from baseline values at this time. High-density lipoprotein (HDL)-cholesterol levels, however, were reduced by 15.4% (p < 0.001). In conclusion, 10 years of continuous combined HRT resulted in a significant and sustained increase in BMD. This treatment regimen therefore appears to be well suited for the long-term prevention of osteoporosis in postmenopausal women.

A comparison of morning and bed-time ultralente administration when using multiple injections in adolescence.

Ten adolescents took part in a randomized sequential crossover study comparing two insulin regimes: (1) three preprandial injections of soluble insulin from a pen injector plus ultralente given before bed; (2) morning soluble insulin with ultralente, plus two preprandial injections of soluble. Nine patients completed the study. Metabolic profiles were performed at the end of each 3-month treatment period. Glycosylated haemoglobin levels did not fall significantly on either regimen, and there were no differences between the changes in HbA1 concentration on the two regimens. However, blood glucose concentrations tended to be lower with bedtime than with morning ultralente, and were significantly different at 0800 h (13.1 +/- 2.3 mmol/l vs 17.9 +/- 1.9 mmol/l, p less than 0.02) and 1000 h (14.5 +/- 1.4 mmol/l vs 18.6 +/- 0.7 mmol/l, p less than 0.03). Plasma free insulin concentrations were not different. Total daily insulin dose and the proportion of ultralente given in each regimen did not differ. Results indicate that the rise in early morning fasting blood glucose concentrations was less when ultralente was given at bedtime rather than in the morning.

Association of binocular lower visual field impairment, impaired simultaneous perception, disordered visually guided motion and inaccurate saccades in children with cerebral visual dysfunction-a retrospective observational study.

The principal pathways serving higher visual function comprise the dorsal stream and the ventral stream. The dorsal stream runs between the occipital lobes and the parietal lobes and subserves the ability to process the whole visual scene and carry out visually guided movement. The ventral stream runs between the occipital lobes and temporal lobe tissue and primarily subserves visual recognition and memory. These tissues are susceptible to dysfunction in children with brain damage. We report a series of 40 children in whom damage to the brain has led to a common symptom complex affecting vision. Lower visual field loss was frequently elicited. This was associated with impaired ability to make accurate visually guided movement (particularly of the lower limbs) accompanied by impaired simultaneous perception, and in some cases, with inaccurate saccades and in others, impaired perception of movement. These features are consistent with parietal/dorsal stream dysfunction. Difficulty recognising faces and problems with route finding (which are ventral stream functions) were also present in a number of the children. These visual difficulties can be manifest in the presence of normal visual acuity. Recognition of these problems leads to understanding of the child's visual difficulties and facilitates adaptation of curriculum delivery at school.

Lipoprotein(a) and postmenopausal oestrogen.

Epidemiological studies have shown that postmenopausal oestrogen therapy substantially reduces the risk of cardiovascular and cerebrovascular disease and this is partly mediated by oestrogen-associated changes in lipoproteins, particularly high-density lipoprotein. In this study, we investigated whether changes in lipoprotein(a) might help to account for the reduction in coronary heart disease and stroke associated with postmenopausal oestrogen therapy. The study group consisted of 18 women who had hysterectomy and bilateral oophorectomy at least 2 months prior to recruitment and had received no previous hormonal therapy. Serum samples were collected for measurement of lipoprotein(a) before and after 4 months of treatment with oestradiol valerate (2 mg/day). Lipoprotein(a) levels ranged from 35 to 720 mg/l (median 180 mg/l) before treatment and from 55 to 780 mg/l (median 130 mg/l) after oestradiol treatment and showed no consistent pattern of change. It would appear, therefore, that treatment with unopposed oestrogen in relatively low doses not have a marked effect on lipoprotein(a), at least in the short term.