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Background: Lifestyle changes soon after diagnosis might improve outcomes in patients with type 2 diabetes mellitus, but no large trials have compared interventions. We investigated the effects of diet and physical activity on blood pressure and glucose concentrations., Methods: We did a randomised, controlled trial in southwest England in adults aged 30-80 years in whom type 2 diabetes had been diagnosed 5-8 months previously. Participants were assigned usual care (initial dietary consultation and follow-up every 6 months; control group), an intensive diet intervention (dietary consultation every 3 months with monthly nurse support), or the latter plus a pedometer-based activity programme, in a 2:5:5 ratio. The primary endpoint was improvement in glycated haemoglobin A(1c)(HbA(1c)) concentration and blood pressure at 6 months. Analysis was done by intention to treat. This study is registered, number ISRCTN92162869., Findings: Of 593 eligible individuals, 99 were assigned usual care, 248 the diet regimen, and 246 diet plus activity. Outcome data were available for 587 (99%) and 579 (98%) participants at 6 and 12 months, respectively. At 6 months, glycaemic control had worsened in the control group (mean baseline HbA(1c) percentage 6·72, SD 1·02, and at 6 months 6·86, 1·02) but improved in the diet group (baseline-adjusted difference in percentage of HbA(1c) -0·28%, 95% CI -0·46 to -0·10; p=0·005) and diet plus activity group (-0·33%, -0·51 to -0·14; p<0·001). These differences persisted to 12 months, despite less use of diabetes drugs. Improvements were also seen in bodyweight and insulin resistance between the intervention and control groups. Blood pressure was similar in all groups., Interpretation: An intensive diet intervention soon after diagnosis can improve glycaemic control. The addition of an activity intervention conferred no additional benefit., Funding: Diabetes UK and the UK Department of Health., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Despite strong evidence for its effectiveness, cognitive-behavioural therapy (CBT) remains difficult to access. Computerised programs have been developed to improve accessibility, but whether these interventions are responsive to individual needs is unknown. We investigated the effectiveness of CBT delivered online in real time by a therapist for patients with depression in primary care., Methods: In this multicentre, randomised controlled trial, 297 individuals with a score of 14 or more on the Beck depression inventory (BDI) and a confirmed diagnosis of depression were recruited from 55 general practices in Bristol, London, and Warwickshire, UK. Participants were randomly assigned, by a computer-generated code, to online CBT in addition to usual care (intervention; n=149) or to usual care from their general practitioner while on an 8-month waiting list for online CBT (control; n=148). Participants, researchers involved in recruitment, and therapists were masked in advance to allocation. The primary outcome was recovery from depression (BDI score <10) at 4 months. Analysis was by intention to treat. This trial is registered, number ISRCTN 45444578., Findings: 113 participants in the intervention group and 97 in the control group completed 4-month follow-up. 43 (38%) patients recovered from depression (BDI score <10) in the intervention group versus 23 (24%) in the control group at 4 months (odds ratio 2.39, 95% CI 1.23-4.67; p=0.011), and 46 (42%) versus 26 (26%) at 8 months (2.07, 1.11-3.87; p=0.023)., Interpretation: CBT seems to be effective when delivered online in real time by a therapist, with benefits maintained over 8 months. This method of delivery could broaden access to CBT., Funding: BUPA Foundation.

Background: The optimum way to improve the recognition and treatment of postnatal depression in developing countries is uncertain. We compared the effectiveness of a multicomponent intervention with usual care to treat postnatal depression in low-income mothers in primary-care clinics in Santiago, Chile., Methods: 230 mothers with major depression attending postnatal clinics were randomly allocated to either a multicomponent intervention (n=114) or usual care (n=116). The multicomponent intervention involved a psychoeducational group, treatment adherence support, and pharmacotherapy if needed. Usual care included all services normally available in the clinics, including antidepressant drugs, brief psychotherapeutic interventions, medical consultations, or external referral for specialty treatment. The primary outcome measure was the Edinburgh postnatal depression scale (EPDS) score at 3 and 6 months after randomisation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00518830., Findings: 208 (90%) of women randomly assigned to treatment groups completed assessments. The crude mean EPDS score was lower for the multicomponent intervention group than for the usual care group at 3 months (8.5 [95% CI 7.2-9.7] vs 12.8 [11.3-14.1]). Although these differences between groups decreased by 6 months, EPDS score remained better in multicomponent intervention group than in usual care group (10.9 [9.6-12.2] vs 12.5 [11.1-13.8]). The adjusted difference in mean EPDS between the two groups at 3 months was -4.5 (95% CI -6.3 to -2.7; p<0.0001). The decrease in the number of women taking antidepressants after 3 months was greater in the intervention group than in the usual care group (multicomponent intervention from 60/101 [59%; 95% CI 49-69%] to 38/106 [36%; 27-46%]; usual care from 18/108 [17%; 10-25%] to 11/102 [11%; 6-19%])., Interpretation: Our findings suggest that low-income mothers with depression and who have newly born children could be effectively helped, even in low-income settings, through multicomponent interventions. Further refinements to this intervention are needed to ensure treatment compliance after the acute phase.

Background: Depression in women is one of the commonest problems encountered in primary care. We aimed to compare the effectiveness of a stepped-care programme with usual care in primary-care management of depression in low-income women in Santiago, Chile., Methods: In a randomised controlled trial, in three primary-care clinics in Chile, 240 adult female primary-care patients with major depression were allocated stepped care or usual care. Stepped care was a 3-month, multicomponent intervention led by a non-medical health worker, which included a psychoeducational group intervention, structured and systematic follow-up, and drug treatment for patients with severe depression. Data were analysed on an intention-to-treat basis. The primary outcome measure was the Hamilton depression rating scale (HDRS) administered at baseline and at 3 and 6 months after randomisation., Findings: About 90% of randomised patients completed outcome assessments. There was a substantial between-group difference in all outcome measures in favour of the stepped-care programme. The adjusted difference in mean HDRS score between the groups was -8.89 (95% CI -11.15 to -6.76; p<0.0001). At 6-months' follow-up, 70% (60-79) of the stepped-care compared with 30% (21-40) of the usual-care group had recovered (HDRS score <8)., Interpretation: Despite few resources and marked deprivation, women with major depression responded well to a structured, stepped-care treatment programme, which is being introduced across Chile. Socially disadvantaged patients might gain the most from systematic improvements in treatment of depression.

Background: There has been a long-standing failure in many countries to satisfy the demand for several elective surgical treatments, including total hip replacement. We set out to estimate the population requirement for primary total hip replacement in England., Methods: We undertook a cross-sectional study of a stratified random sample of 28,080 individuals aged 35 and over from 40 general practices in inner-city, urban, and rural areas of Avon and Somerset, UK. Prevalent disease was identified through a two-stage process: a self-report screening questionnaire (22,978 of 26,046 responded) and subsequent clinical examination. Incident disease was estimated from the point prevalence by statistical modelling. The requirement for total hip replacement surgery was estimated on the basis of pain and loss of functional ability, with adjustment for evidence of comorbidity and patients' treatment preferences., Findings: 3169 people reported hip pain on the screening questionnaire. 2018 were invited for clinical examination, and 1405 attended. The prevalence of self-reported hip pain was 107 per 1000 (95% CI 101-113) for men and 173 per 1000 (166-180) for women. The prevalence of hip disease severe enough to require surgery was 15.2 (12.7-17.8) per 1000 aged 35-85 years. The corresponding annual incidence of hip disease requiring surgery was estimated as 2.23 (1.56-2.90), which suggests an overall requirement in England of 46,600 operations per year for patients who expressed a preference for, and were suitable for, surgery; the recent actual provision in England was about 43,500., Interpretation: This research suggests that the satisfaction of demand for total hip replacement, given agreed criteria for surgery, is a realistic objective.

Background: Otitis media with effusion (OME) is the most common cause of hearing loss in children and is generally treated by elective surgery. We compared in children with persistent OME the effect on speech and language development of immediate surgery (ventilation-tube insertion) and watchful waiting before surgery., Methods: We did a randomised controlled trial with masked outcome assessment in Bristol Children's Hospital, Bristol, UK. We included 186 children born between April 1, 1991, and Dec 31, 1992, who had confirmed bilateral OME and bilateral hearing impairment of 25-70 dB of at least 3 months' duration. Children were randomly assigned surgery within 6 weeks (n=92), or 9 months of watchful waiting (n=90), after which bilateral tube insertion was done if required. We assessed hearing loss, expressive language, and verbal comprehension at 9 months and 18 months., Findings: At 9 months, standardised scores for expressive language and verbal comprehension differed between groups with marginal significance after adjustment for baseline differences (p=0.04 and p=0.028, respectively). At 9 months, verbal comprehension and expressive language skills in the watchful-waiting group were 3.24 months behind those in the early-surgery group. The watchful-waiting group was delayed on these two measures compared with their age-expected levels. 18 months after randomisation, 85% of children in the watchful-waiting group had received surgery and groups did not differ significantly., Interpretation: There is some benefit from ventilation-tube insertion for expressive language and verbal comprehension but the timing of surgery is not critical.

Background: The effectiveness of cataract surgery on one eye is well established, but concerns over health-care expenditure have called into question the value of cataract surgery on the second eye. We examined the effects of second eye surgery in terms of patient perceptions as well as through visual acuity, contrast sensitivity, and stereoacuity tests., Methods: 208 otherwise healthy patients awaiting second eye cataract surgery were recruited into our randomised trial. At randomisation participants were allocated expedited surgery (planned to take place within 6 weeks) or routine surgery (routine waiting time, 7-12 months). Assessments were made at randomisation and again at review after about 6 months. Eight primary trial outcomes consisted of four questionnaire items and four visual function tests, done with both eyes open., Findings: Traditional clinical tests of success in cataract surgery (visual acuity and contrast sensitivity) showed only slight differences in binocular vision in favour of the expedited-surgery group. There were major benefits for the expedited-surgery group in terms of reported visual symptoms and effects on quality of life. At review, differences in self-reported vision related difficulties between the two groups ranged from 11% (95% CI 4.4-17%, activities) to 30% (19-41%, reading). Stereoacuity was better in the expedited surgery group, the difference between the groups for the proportions with stereoacuity of 3000 s of arc or worse was 58% (47-69%)., Interpretation: This trial has shown that there is a clear benefit from second eye cataract surgery.

In early hepatic fibrosis, increased amounts of type III collagen are deposited. Persistently high serum concentrations of aminoterminal type III procollagen propeptide (PIIIP) correlate with the activity of the fibrogenic process. Another index for the detection of fibrosis, the PGA index, combines the prothrombin time, gamma-glutamyl transpeptidase activity, and serum apolipoprotein A1 concentration (the latter falls with progressive fibrosis). We compared PIIIP measurements and PGA index in patients with various histological forms of alcoholic liver disease (104), primary biliary cirrhosis (38), and chronic B virus hepatitis (27), and in healthy age-matched controls (30). The ability of each test to identify correctly patients with fibrosis or cirrhosis was assessed with receiver operating curves. The PGA index was much higher in all groups of patients with alcoholic liver disease than in controls (p < 0.0001). PIIIP concentrations were also substantially higher than in controls (p < 0.05 for fatty liver, p < 0.0001 for all other groups), especially in the group with alcoholic hepatitis and cirrhosis. For the detection of cirrhosis the PGA was 91% sensitive and 81% specific and the PIIIP concentration was 94% sensitive and 81% specific. The two tests combined had 85% sensitivity, but 93% specificity. Among patients with primary biliary cirrhosis, both PGA index and PIIIP concentration correlated well with the severity of the disease, determined by the Mayo score (r = 0.72 and 0.66 respectively). The combined tests were 96% sensitive for the detection of fibrosis. All patients with chronic B virus hepatitis had raised PGA and PIIIP values in comparison with controls (p < 0.0001) but there were no differences between subgroups. Substantially raised PIIIP concentrations thus identify the subgroup of alcoholic patients with both hepatitis and cirrhosis. The combination of PGA index and PIIIP concentration may be useful for targeting treatment with antifibrotic drugs and to reduce the need for liver biopsy.

Acetaldehyde dehydrogenase activity in liver biopsy specimens was considerably lower in 12 non-cirrhotic alcoholics than in 11 control subjects. It is suggested that reduced enzyme activity may cause the impaired metabolism of acetaldehyde reported in alcoholics and may play a part in the pathophysiology of alcoholism. Subcellular fractionation studies showed that acetaldehyde dehydrogenase was localised in the mitochondrial and cytosolic fractions of the liver cell, but in alcoholics the cytosolic component was selectively depleted. This deficiency may be a primary defect in alcoholics, reflecting the genetic aspect of alcoholism.

Iron uptake by human duodenal mucosa in vitro was considerably higher in iron-deficient patients than in controls. In biopsy specimens taken after treatment with iron, uptake fell to normal levels, although total iron in the mucosa remained low. In iron-overloaded patients with primary haemochromatosis, there was inappropriately high uptake of iron by the biopsy specimens. Kinetic analysis suggested that this was the result of affinity for iron being increased in a carrier in the enterocyte.

Breath hydrogen (H2), collected by end-expiratory sampling, was measured in twenty-five patients with abdominal symptoms or diarrhoea after ingesting 50 g. of lactose. This was compared with established tests of hypolactasia. Fifteen patients with a blood-glucose rise of more than 20 mg. per 100 ml. had less than 4 parts per million (p.p.m.) rise in breath H2 at 2 hours. In contrast, ten patients with blood-glucose rises of less than 20 mg. per 100 ml. had more than a 20 p.p.m. H2 rise (mean 85.8 p.p.m. plus or minus s.d. 44.3) at 2 hours. Similarly, two patients with normal jejunal lactase activity had no significant H2 production, whereas six patients with hypolactasia had more than a 20 p.p.m. rise in H2. Symptoms related to milk or lactose ingestion were found to be unreliable. End-expiratory sampling of breath H2 would seem to be a simple, non-invasive, and accurate method of diagnosing hypolactasia, which is also very acceptable to patients. This should make it a valuable tool both in diagnostic gastroenterology and in epidemiological surveys.

The suggestion that the intestinal mucosa may be abnormally permeable and a site of absorption of antigens in rheumatoid arthritis was tested by the use of a 51Cr-EDTA (edetic acid) absorption test. 24 patients with rheumatoid arthritis excreted significantly more 51Cr-EDTA than did 34 controls. Intestinal permeability was normal in untreated patients but almost invariably abnormal in patients treated with non-steroidal anti-inflammatory drugs. Studies in patients with osteoarthritis showed that the permeability abnormalities were due to an effect of NSAIDs on both the proximal and the distal intestine and that the effect was systemically mediated. Indium-111-labelled leucocyte scans showed ileocaecal inflammation in 6 of 9 patients on or recently on NSAIDs. Although increased intestinal permeability does not seem to be important in the pathogenesis of rheumatoid arthritis, the administration of NSAIDs may lead to loss of intestinal integrity, thus facilitating antigenic absorption and perhaps contributing to persistence of the disease.

Cardiac tissue obtained by left-ventricular endomyocardial biopsy from patients with valvular heart-disease was assayed for marker enzyme activities of subcellular organelles and these were correlated with left ventricular function as assessed by haemodynamic studies. In patients with poor left ventricular function, calcium-dependent adenosine-triphosphatase (A.T.P.ase) activity, predominantly localised to the myofibrils, was strikingly reduced. Activity of lactate dehydrongenase, a cytosol enzyme, was significantly increased in tissue from patients with poor left ventricular function. The activity of enzymes associated with sarcolemma (5'-nucleotidase), mitochondria (glutamate dehydrogenase and monoamine oxidase), microsomes (neutral alpha-glucosidase), and lysosomes (acid phosphatase, N-acetyl-beta-glucosaminidase) was no different in patients with good or poor left ventricular function. It is suggested that reduced myofibrillary A.T.P.ase concentration is the biochemical basis for the impaired ventricular function.

In the 24 h after ingestion of 100 microCi of 51Cr-labelled EDTA (edetic acid), controls (22) excreted less than 2.5% of the dose, whereas patients with coeliac disease in relapse (6) excreted between 4.7% and 14.7%. In 10 patients with coeliac disease in complete clinical and histological remission, excretion of 51Cr-labelled EDTA was between 3.0% and 12.7% of the dose. This indicates a persistent or primary defect of intestinal permeability in these patients and confirms previous in vitro results. The reproducibility, safety, simplicity, and accuracy of the procedure suggest that it may be suitable as a routine screening test for coeliac disease.

Strikingly reduced activity of an enzyme, normally located in the plasma membrane of human neutrophils, has been demonstrated in a male patient with chronic granulomatous disease (C.G.D.). The subcellular distribution of N.A.D.H.-dependent reduction of nitroblue tetrazolium (N.B.T.) was determined in neutrophils because reduction of this dye by these patients is grossly impaired. Assayed at high concentrations of N.A.D.H. (1 mmol/1), N.B.T. is reduced by enzymes in the cytosol and mitochondria in addition to the plasma membrane by both normal and C.G.D. cells--properties which previously obscured the identity and location of this enzyme. At a more physiological concentration of N.A.D.H. (25 mumol/1), reduction of the dye by the plasma membrane, the principal site of N.B.T. reduction by normal neutrophils, was absent in the patient with C.G.D. It is suggested that absence or imperfect function of this reductase enzyme is the primary lesion in this disease.

Intestinal permeability was investigated with a chromium-51-EDTA (edetic acid) absorption test in 36 non-intoxicated alcoholic patients without liver cirrhosis or overt clinical evidence of malabsorption or malnutrition. Patients abstaining from alcohol for less than 4 days almost invariably had higher intestinal permeability than controls, and in many the abnormality persisted for up to 2 weeks after cessation of drinking. The presence of gastritis did not correlate with the presence of increased permeability. The site of altered intestinal permeability was shown by an in-vitro permeability test to be the small bowel. The increased intestinal permeability to toxic "non-absorbable" compounds of less than 5000 molecular weight may account for some of the extraintestinal tissue damage common in alcoholic patients.

151 problem drinkers (105 men and 46 women) were recruited from the general medical and psychiatric services of a district general hospital and were allocated randomly to a community-based day centre (ACCEPT) or standard hospital inpatient and outpatient services. 115 patients (79%) were followed up at 12 months. The group as a whole showed improvement in all outcome indices at the 3-month follow-up, and this was maintained at 6 and 12 months. Patients assigned to ACCEPT services claimed to have reduced their alcohol intake (55%) more than their hospital counterparts (37%), and this was confirmed by their informants. Patients referred from the psychiatric services reduced their alcohol intake more than those from general medical services. It is concluded that treatment at a community day centre is at least as cost effective as hospital treatment of alcohol abuse.

In alcoholic patients with fatty liver the activity of cytosolic, but not of mitochondrial, acetaldehyde dehydrogenase was lower than in controls. Sequential studies in abstaining alcoholics showed that the cytosolic acetaldehyde dehydrogenase activity remained low, although the previously low activity of alcohol dehydrogenase returned to normal values. It is suggested that reduced cytosolic acetaldehyde dehydrogenase activity may represent a primary defect in alcoholism and is, in part, the cause of the abnormal acetaldehyde metabolism in alcoholic patients. Isoelectric focusing showed distinct isoenzymes of acetaldehyde dehydrogenase in the liver cytosolic and mitochondrial fractions. A survey of eight control subjects and twenty alcoholic patients showed no evidence of a missing or abnormal enzyme in the alcoholic group.

A membrane-bound enzyme that is capable of inhibiting adenosine-diphosphate (A.D.P.)-induced platelet aggregation has been found in rabbit aorta. This inhibition is caused by degradation of A.D.P. to products (adenosine monophosphate and adenosine) which can also inhibit aggregation. The enzyme could be important in regulating haemostasis and thrombosis.

In-vitro calcium influx was measured in jejunal biopsy specimens from 10 men with idiopathic hypercalciuria. Calcium uptake in these adults was a passive process which was not sensitive to inhibition by 2,4 dinitrophenol and sodium fluoride, and showed no evidence of carrier saturation. In 7 of 10 patients with idiopathic hypercalciuria calcium uptake was above the normal range, and the mean uptake for all patients was significantly higher than in 10 control subjects (p < 0.01). The kinetic features suggest that this increased influx was the result of increased brush border permeability to calcium ions.