The molecular cloning of the gene that causes the fragile X syndrome, and the demonstration that the causative mutation is an expansion of an unstable trinucleotide repeat, suggests that cytogenetic testing could be replaced by a molecular test. We compared the two methods in 525 routine referrals. 12 cases were positive in both tests. 1 case that had a negative DNA test for the fragile site at Xq27.3 (FRAXA), but a positive cytogenetic result, was shown to be caused by a mutation at the FRAXE locus on chromosome Xq28. DNA analysis is a sensitive, reliable, and cost-effective diagnostic alternative.

Corticosteroids are usually given for management of Graves' ophthalmopathy, but they have many and serious side-effects. By comparison, retrobulbar irradiation is well tolerated, although its efficacy has been evaluated only in uncontrolled studies. Therefore, we did a double-blind randomised trial, in which 28 patients with moderately severe Graves' ophthalmopathy were treated with a 3-month course of oral prednisone and sham irradiation, and 28 received retrobulbar irradiation (20 Gy) and placebo capsules. Therapeutic outcome, assessed twenty-four weeks after the start of treatment, was determined by the change in the highest NOSPECS class. A successful outcome was observed in 14 prednisone-treated and in 13 irradiated patients. Responders to treatment (but not nonresponders) in both groups showed improvements in total and subjective eye score and a decrease in eye-muscle volume. Response to either treatment was due largely to changes in soft-tissue involvement and eye-muscle motility. Mean elevation in responders to radiotherapy increased from 18.5 degrees (95% CI 14.8-22.2) at baseline to 21.8 degrees (18.6-25.0) at week twenty-four (p = 0.003), but did not change in prednisone responders. Side-effects were more frequent and severe during prednisone than during radiotherapy. Radiotherapy and oral prednisone appear to be equally effective as initial treatment in patients with moderately severe Graves' ophthalmopathy. In view of its better tolerability, radiotherapy should be considered the treatment of first choice.

Despite widespread application of ultrasound imaging and Doppler blood flow studies, the effects of their frequent and repeated use in pregnancy have not been evaluated in controlled trials. From 2834 women with single pregnancies at 16-20 weeks gestation, 1415 were selected at random to receive ultrasound imaging and continuous-wave Doppler flow studies at 18, 24, 28, 34, and 38 weeks gestation (the intensive group) and 1419 to receive single ultrasound imaging at 18 weeks (the regular group). Outcome data was obtained from 99% of women who entered the study. The only difference between the two groups was significantly higher intrauterine growth restriction in the intensive group, when expressed both as birthweight < 10th centile (relative risk 1.35; 95% confidence interval 1.09 to 1.67; p = 0.006) and birthweight < 3rd centile (relative risk 1.65; 95% confidence intervals 1.09 to 2.49; p = 0.020). While it is possible that this finding was a chance effect, it is also plausible that frequent exposure to ultrasound may have influenced fetal growth. Repeated prenatal ultrasound imaging and Doppler flow examinations should be restricted to those women to whom the information is likely to be of clinical benefit.

Post-stroke pathological crying is a distressing condition in which episodes occur in response to minor stimuli without associated mood changes. There is preliminary evidence of disturbed serotoninergic neurotransmission in such cases. We investigated the effect of the selective serotonin reuptake inhibitor citalopram on uncontrolled crying in stroke patients in a double-blind placebo-controlled crossover study. 16 consecutive patients (median age 58.5 years, range 40-83) entered the 9-week study a median of 168 days (range 6-913) post stroke and were treated with citalopram 10-20 mg daily for 3 weeks. Crying history was determined from semistructured interviews and from diaries kept by the patients. Psychiatric assessment was made with the Hamilton depression scale (HDS), and unwanted effects were measured with the UKU side-effect scale. In 13 patients in whom frequency of crying could be assessed, the number of daily crying episodes decreased by at least 50% in all cases during citalopram treatment vs 2 patients during placebo treatment (p < 0.005, McNemar's test), the effect being rapid (1-3 days) and pronounced in 11 (73%). There was a concomitant significant decrease in depression rating from HDS 8.9 to 5.3 (p < 0.005, Wilcoxon's test). Citalopram was well tolerated, the few side-effects being mild and transient. We conclude that serotoninergic neurotransmission plays an important part in post-stroke pathological crying and that citalopram is an effective and well-tolerated treatment.

Regular inhaled beta 2 agonist causes tolerance to the acute protective effect of beta 2 agonist against bronchoconstriction induced by chemical stimuli such as AMP, histamine, and methacholine. We examined a more clinically relevant stimulus, inhaled allergen, in a double-blind, cross-over, random-order trial in 13 mild atopic asthmatics, who had not used beta 2 agonist for at least 4 weeks. We compared regular inhaled salbutamol (200 micrograms four times daily for 2 weeks) with placebo (2 weeks) for effects on bronchodilator response, baseline methacholine, and allergen airway responsiveness, and on the acute protective effect of salbutamol against both stimuli. Baseline forced expiratory volume in 1 s (FEV1), bronchodilator response, and methacholine responsiveness were the same during both treatment periods. After regular salbutamol, the allergen PC20 (provocation concentration producing a 20% FEV1 decrease) fell by 0.91 (SD 0.66) (p = 0.0009) doubling doses, and the protective effects of salbutamol on methacholine and allergen were both significantly reduced (p = 0.026 and 0.025, respectively). Taking into account the reduced baseline allergen PC20, the post-salbutamol allergen PC20 was almost 2 doubling doses (1.94 [1.43], p < 0.01) lower during salbutamol treatment. Thus, 2 weeks of regular inhaled salbutamol increased airway responsiveness to allergen but not to methacholine, and caused tolerance to the protective effect of salbutamol on bronchoconstriction induced by both stimuli. These effects of inhaled beta 2 agonist provide further evidence to support detrimental effects of their regular use.

Survival after acute myocardial infarction has been enhanced by treatment with thrombolytic agents, aspirin, and beta-adrenoceptor blockade. However there remains a substantial subgroup of patients who manifest clinical evidence of heart failure despite the first two of these treatments, and for whom beta-adrenoceptor antagonists are relatively or absolutely contraindicated. These patients have a greatly increased risk of fatal and non-fatal ischaemic, arrhythmic, and haemodynamic events. In this selected high-risk subset of patients we investigated the effect of therapy with the angiotensin converting enzyme (ACE) inhibitor rampiril, postulating that it would lengthen survival. 2006 patients who had shown clinical evidence of heart failure at any time after an acute myocardial infarction (AMI) were recruited from 144 centres in 14 countries. Patients were randomly allocated to double-blind treatment with either placebo (992 patients) or ramipril (1014 patients) on day 3 to day 10 after AMI (day 1). Patients with severe heart failure resistant to conventional therapy, in whom the attending physician considered the use of an ACE inhibitor to be mandatory, were excluded. Follow-up was continued for a minimum of 6 months and an average of 15 months. On intention-to-treat analysis mortality from all causes was significantly lower for patients randomised to receive ramipril (170 deaths; 17%) than for those randomised to receive placebo (222 deaths; 23%). The observed risk reduction was 27% (95 % Cl 11% to 40%; p = 0.002). Analysis of prespecified secondary outcomes revealed a risk reduction of 19% for the first validated outcome (i.e., first event in an individual patient)--namely, death, severe/resistent heart failure, myocardial infarction, or stroke (95% Cl 5% to 31%; p = 0.008). Oral administration of rampiril to patients with clinical evidence of either transient or ongoing heart failure, initiated between the second and ninth day after myocardial infarction, resulted in a substantial reduction in premature death from all causes. This benefit was apparent as early as 30 days and was consistent across a range of subgroups.

The prevalence of posterior subcapsular cataracts in young patients receiving inhaled glucocorticoids for treatment of chronic asthma is unknown. In a cross-sectional study, slit-lamp examinations were done on 95 consecutive young patients who were taking inhaled beclomethasone or budesonide. No posterior subcapsular cataracts were found. The median age of the patients was 13.8 (range 5.8-24.8). The median dose of inhaled beclomethasone or budesonide was 750 micrograms/day (range 300-2000), or 12.9 micrograms/kg per day (range 7.5-34.2). The median duration of treatment was 5 years (range 1-15). 77% of the patients had not used oral glucocorticoids in the year preceding the examination. This study suggests that routine screening for posterior subcapsular cataracts in this patient population is not warranted.

The use of oral rehydration salts (ORS) to restore fluid balance in children with diarrhoea is universally accepted. However, there is uncertainty about whether glucose-based ORS or ORS based on precooked rice powder is more effective. In a randomised trial we compared the two types of ORS in children who were given food immediately after completion of rehydration. 460 boys aged 3-18 months, admitted to hospital with acute diarrhoea and signs of dehydration, were randomly assigned to groups receiving rice-based and glucose-based ORS solution (230 to each group). After full rehydration (4-12 h), a weaning food consisting of rice and mixed vegetables was given until the diarrhoea stopped. Continuing losses of liquid stool and vomitus were replaced with the assigned ORS solution. There were no differences between the groups during the rehydration phase in stool volume, volume of ORS solution taken, duration of rehydration phase, or weight gain. However, after initiation of feeding, the glucose-based ORS group had significantly lower stool volumes than the rice-based ORS group (142 [95% CI 117-173] vs 96 [77-120] g/kg); they also took a smaller amount of ORS solution (153 [127-185] vs 111 [90-136] mL/kg) and had a shorter duration of diarrhoea (55 [SD 35] vs 44 [35] h). Glucose-based ORS solution was more effective than rice-based ORS solution for the treatment of diarrhoea in children when feeding with a rice-based diet was started soon after correction of dehydration. These results support the continued recommendation of glucose-based ORS solution as standard therapy for treatment of children with acute diarrhoea and emphasize the importance of resuming feeding as soon as dehydration has been corrected.

In 1985 an overview of clinical trials confirmed that patients treated within 6 h of the onset of symptoms of myocardial infarction benefited from thrombolytic therapy. Doubt remained about treatment later than this and this uncertainty prompted further randomised studies. The South American multicentre trial EMERAS is one of these. 4534 patients entering hospital up to 24 h after the onset of suspected acute myocardial infarction were randomised between intravenous streptokinase (SK) 1.5 MU and placebo, during the period January, 1988, to January, 1991. Once the results of ISIS-2 were known, only patients presenting more than 6 h after symptom onset were randomised. There was no significant difference in mortality during the hospital stay (269/2257 [11.9%] deaths among SK patients vs 282/2277 [12.4%] in controls). Among the 2080 patients presenting 7-12 h from symptom onset there was a non-significant trend towards fewer deaths with SK (11.7% SK vs 13.2% control; 14% [SD 12] reduction with 95% confidence interval [CI] of 33% reduction to 12% increase), whereas there was little difference among the 1791 patients presenting after 13-24 h (11.4% vs 10.7%; 8% [16] increase with a 95% CI of 20% reduction to 45% increase). These 95% CIs are wide and are consistent with the results of previous studies among patients presenting late after symptom onset. The EMERAS results, though not conclusive on their own, do contribute substantially to accumulating evidence on the question of whether fibrinolytic therapy really does produce any worthwhile improvement in survival among such patients.

The effect of late thrombolysis in acute myocardial infarction (AMI)--ie, treatment beginning more than 6 h after the onset of symptoms--remains controversial. The Late Assessment of Thrombolytic Efficacy (LATE) study is a large randomised trial designed to resolve this question. 5711 patients with symptoms and electrocardiographic criteria consistent with AMI were randomised double-blind to intravenous alteplase (100 mg over 3 h) or matching placebo, between 6 and 24 h from symptom onset. Both groups received immediate oral aspirin and for later recruits intravenous heparin for 48 h was recommended. All patients were followed up for at least 6 months and 73% were followed up for 1 year. Intention-to-treat analysis of survival revealed a non-significant reduction in the alteplase group (397/2836 deaths) compared with placebo (444/2875). 35-day mortality was 8.86% and 10.31%, respectively, a relative reduction of 14.1% (95% CI 0-28.1%). Pre-specified survival analysis according to treatment within 12 h of symptom onset, however, showed a significant reduction in mortality in favour of alteplase: 35-day mortality was 8.90% versus 11.97% for placebo, a relative reduction of 25.6% (p = 0.0229, 95% CI 6.3-45.0%). Rates were 8.7% and 9.2%, respectively, for those treated at 12-24 h but subgroup analysis suggests that some patients may benefit even when treated after 12 h. Although treatment with alteplase resulted in an excess of haemorrhagic strokes, by 6 months the number of disabled survivors was the same in both treatment groups and other clinical events were observed with similar frequency in the two groups. We conclude that the time window for thrombolysis with alteplase should be extended to at least 12 h from symptom onset in patients with AMI.

Hepatic venous outflow obstruction (HVOO) is a rare cause of portal hypertension and conservative treatment is usually ineffective. A large series of patients gave us an opportunity to devise a management protocol for this disorder. Between 1978 and 1992, we prospectively studied 75 patients with HVOO. The obstruction was in the hepatic vein in 24, in the inferior vena cava (IVC) in 44, and in both in 7. For hepatic vein obstruction proximal splenorenal shunts were done in 7 (2 died postoperatively); 4 shunts blocked and only 1 patient became completely symptom free. In 2 patients with partial obstruction we performed balloon dilatation of the right hepatic veins but within 6 months the obstruction recurred. In the next 6 patients we constructed a side-to-side portocaval shunt; 2 died of encephalopathy after discharge and 4 are alive and well. For IVC obstruction, after surgical procedures had yielded poor results in 14 patients, we changed to balloon angioplasty which was successful in 28 of the 30 other patients; restenosis occurred in 4. Of the 7 patients with a combined block, 3 have had balloon angioplasty followed by a side-to-side portocaval shunt; 1 died, 2 are well, and the remainder have not completed treatment. Of our 75 patients, 22 have died (5 in hospital and 17 after discharge), 7 have not completed treatment, and 2 have been lost to follow-up. However, 44 are symptom free. We did not encounter any case of hepatocellular carcinoma. We suggest that patients with HVOO should be actively managed with a side-to-side portocaval shunt for hepatic vein obstruction, balloon angioplasty for inferior vena caval obstruction, and perhaps both procedures for those with combined obstructions.

The availability of monoclonal-antibody-purified factor VIII (FVIII) concentrates allows us to test the hypothesis, based on in vitro observations, that their use in HIV seropositive haemophiliacs would result in a difference in the rate of deterioration of immune function. We designed a multicentre, prospective, randomised, controlled study of symptom-free HIV-infected patients with haemophilia A who were assigned to receive either an intermediate-purity or monoclonal-antibody-purified product. All had CD4 lymphocyte counts of 100-600/microL, were negative for hepatitis B surface antigen, had not received any antiretroviral or immunomodulating drugs before study entry, and had previously received replacement therapy with intermediate purity FVIII concentrates. Use of antiretroviral therapy was permitted. 60 patients were recruited and 30 were assigned to each group. 35 completed the 3 year study, 20 in the monoclonal arm and 15 in the intermediate-purity arm. Among those completing the study, there were no differences between the two groups in the occurrence of AIDS-defining diagnoses (1 in each group). There were, however, striking and significant differences in terms of changes in absolute CD4 counts. The group receiving monoclonal-antibody-purified concentrates had essentially stable counts while a significant drop was observed in the group receiving intermediate-purity FVIII. These differences were independent of the use of antiretroviral therapy. These observations support the use of high-purity concentrates in the treatment of symptom-free HIV-positive patients with haemophilia A, and they should be taken into account along with cost, by doctors making therapeutic decisions.