Daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), for the treatment of moderately to severely active ulcerative colitis: a randomised, double blind, placebo controlled, dose ranging trial.

BACKGROUND: An uncontrolled pilot study demonstrated that daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), might be effective for the treatment of active ulcerative colitis. METHODS: A randomised, double blind, placebo controlled trial was conducted to evaluate the efficacy of daclizumab induction therapy in patients with active ulcerative colitis. A total of 159 patients with moderate ulcerative colitis were randomised to receive induction therapy with daclizumab 1 mg/kg intravenously at weeks 0 and 4, or 2 mg/kg intravenously at weeks 0, 2, 4, and 6, or placebo. The primary end point was induction of remission at week 8. Remission was defined as a Mayo score of 0 on both endoscopy and rectal bleeding components and a score of 0 or 1 on stool frequency and physician's global assessment components. Response was defined as a decrease from baseline in the Mayo score of at least 3 points. RESULTS: Two per cent of patients receiving daclizumab 1 mg/kg (p = 0.11 v placebo) and 7% of patients receiving 2 mg/kg (p = 0.73) were in remission at week 8, compared with 10% of those who received placebo. Response occurred at week 8 in 25% of patients receiving daclizumab 1 mg/kg (p = 0.04) and in 33% of patients receiving 2 mg/kg (p = 0.30) versus 44% of those receiving placebo. Daclizumab was well tolerated. The most frequently reported adverse events in daclizumab treated patients compared with placebo treated patients were nasopharyngitis (14.6%) and pyrexia (10.7%). CONCLUSION: Patients with moderate ulcerative colitis who are treated with daclizumab are not more likely to be in remission or response at eight weeks than patients treated with placebo.

Looking 'back to the future': alumni perceptions of a UK undergraduate medical programme.

The five year Bachelor of Medicine (BM5) programme of the University of Southampton commenced in 1971. In keeping with other medical schools, the Southampton BM5 programme has been involved in a number of incremental curriculum reforms over the years. Complementing the School's annual pre-registration house officer (PRHO) questionnaire, this study of alumni cohorts (2000-2003) sought to investigate further how past graduates view their medical education and whether there are emerging priorities in medical practice. Findings confirm that alumni rate the BM5 highly and generally value the BM5 aims. Considering the impact of the social context on individual well-being and patient care, increased emphasis may need to be placed on preventive medicine, including greater alignment of several curriculum areas with clinical practice.

Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.

BACKGROUND: Elderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures. METHODS: In a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures. FINDINGS: 698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups. INTERPRETATION: The findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.

Osteoporosis in men.

Osteoporosis in men is a common cause of morbidity, mortality and health care expenditure throughout the Western world. Most cases are secondary to disease or to drug therapy, but in 30-45% of affected individuals no cause can be identified. Research into the factors underlying 'idiopathic' male osteoporosis is limited, but is gradually moving more patients into the 'secondary' category. Recently, attention has focused on interactions between sex hormones and bone: there is evidence that male bone requires both androgens and oestrogens for normal health. Many conditions predispose to osteoporosis in men: hypogonadism, alcohol abuse and the use of corticosteroids are the most frequently identified factors. Osteoporosis following organ transplantation attracts interest despite its relative rarity. Treatment for osteoporotic men is poorly researched and remains largely unsupported by experimental evidence, although clinical experience suggests a useful role for bisphosphonates, testosterone and perhaps fluorides. Symptom control and explanation remain the most important therapeutic interventions.

Effect of intermittent cyclical disodium etidronate therapy on bone mineral density in men with vertebral fractures.

OBJECTIVES: to investigate the effects of oral intermittent cyclical etidronate therapy on bone mineral density (BMD) in men with idiopathic vertebral osteoporosis. DESIGN: consecutive case series. SETTING: regional specialist clinic for metabolic bone disease. SUBJECTS: 42 men aged 35-81 (median 60.5) with established vertebral crush fractures and back pain, in whom secondary causes of osteoporosis had been excluded. INTERVENTION: repeated cycles of treatment with oral disodium etidronate 400 mg daily for 14 days followed by oral calcium 500 mg as citrate daily for 76 days. OUTCOME MEASURES: BMD measurement of the lumbar spine and femoral neck by dual energy x-ray absorptiometry at 6-12-month intervals; bone biochemistry (serum calcium, phosphate, alkaline phosphatase and urine calcium/creatinine and hydroxyproline/creatinine ratios) at 6-month intervals. RESULTS: all 42 men have been treated for more than 18 months, and 35 of them for more than 24 months. Median follow-up for the group as a whole is 31 months (range 18-45). The treatment was well tolerated. BMD at the lumbar spine increased by a mean of 0.024 g/cm2 per year of follow-up (95% confidence interval 0.017-0.032 g/cm2). This is equivalent to an average annual rate of change of 3.2% of baseline values. There was a small, non-significant rise in mean BMD at the hip equivalent to 0.7% of baseline values per year. Serum alkaline phosphatase tended to fall in the first 6 months of treatment, returning to baseline values at 2 years. Serum calcium and phosphate were unchanged and no decrease in urinary calcium/creatinine ratio or hydroxyproline/creatinine ratio was seen. CONCLUSIONS: intermittent cyclical etidronate therapy increased lumbar spine BMD over a 2-year period in an unselected group of men with osteoporotic vertebral fractures. This treatment warrants further evaluation in a randomized controlled trial.

Alteration of the dismal natural history of fibrosing cholestatic hepatitis secondary to hepatitis B virus with the use of lamivudine.

BACKGROUND: Fibrosing cholestatic hepatitis (FCH) is a severe form of hepatitis B virus (HBV) infection occurring as either primary allograft reinfection after liver transplantation for HBV or as severe HBV reactivation induced by immunosuppression in patients with previously latent infection. Without treatment, FCH is universally fatal within a few months of diagnosis. Some improvement has been reported with long-term ganciclovir, with and without foscarnet, but an effective and easily available treatment has not yet been reported. METHODS: We report the prolonged survival of a renal transplant recipient who developed histologically confirmed FCH 6 months after transplantation and was treated with lamivudine. RESULTS: At the time of diagnosis, the patient had jaundice, ascites, and a serum HBV-DNA level of 3868 pg/ml. Lamivudine was instituted 2 months later, and after 6 months of treatment, the HBV-DNA level was undetectable with the serum bilirubin within the normal range. Twelve months after the diagnosis of FCH, the patient remains stable without progression of liver dysfunction. CONCLUSION: Our experience demonstrates that lamivudine therapy can improve the dismal natural history of FCH.

Failure of ketoprofen and interferon combination therapy to improve interferon-resistant chronic hepatitis C.

Preliminary reports suggest that patients with interferon (IFN)-resistant chronic hepatitis C respond better to a combination of IFN-alpha and nonsteroidal anti-inflammatory drugs than to IFN alone. The efficacy of IFN combined with ketoprofen in the treatment of patients with IFN-resistant chronic hepatitis C was evaluated. Seventeen patients, nonresponsive after at least six months of treatment with IFN-alpha 2b and subsequently treated with the combination of IFN-alpha 2b plus ketoprofen for four months, were studied. Serum aminotransferases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and serum hepatitis C virus (HCV) RNA were analyzed before and throughout treatment. No patient normalized serum aminotransferases after combination therapy. There were no significant differences in mean serum ALT and AST levels before and after ketoprofen intervention. Serum HCV RNA became undetectable after treatment in only one patient, but was detectable again three months after treatment cessation. These results provide no convincing evidence that the combination of IFN-alpha 2b with ketoprofen improves the response to IFN in patients nonresponsive to IFN alone.

Androgen supplementation in eugonadal men with osteoporosis: effects of six months' treatment on markers of bone formation and resorption.

There is no established treatment for osteoporosis in men, a common and disabling condition the incidence of which is increasing rapidly. We conducted an open study to investigate the efficacy and mode of action of testosterone therapy in eugonadal men with osteoporotic vertebral crush fracture. Twenty-one men, aged 34-73 (mean 58), were treated with intramuscular testosterone esters (Sustanon 250) every 2 weeks for 6 months. Bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry was performed at baseline and 6 months. We also measured biochemical markers of bone turnover, testosterone, estradiol, sex hormone binding globulin (SHBG), and gonadotrophins at baseline and after 3 and 6 months of treatment. Treatment was well tolerated, and side effects were uncommon. Lumbar spine BMD increased by 5% from 0.799 to 0.839 g/cm2 (p < 0.001). All bone markers decreased, indicating that treatment suppressed bone turnover. Although serum osteocalcin levels fell only slightly, there were large reductions in urinary deoxypyridinoline and N-telopeptide (p < 0.05), which were correlated with the increase in spinal BMD. Interpretation of the findings with other markers, such as bone-specific alkaline phosphatase and pyridinoline, was confounded by the wide scatter of values. Serum testosterone increased by 55%, while SHBG decreased by 20%, leading to a rise in free androgen of 90%. Serum estradiol also increased by 45%. The change in spine BMD was significantly correlated with a change in serum estradiol but not with a change in serum testosterone. We therefore conclude that testosterone is a promising treatment for men with idiopathic osteoporosis, acting to suppress bone resorption by a mechanism that may involve estrogen.

Androgen supplementation in eugonadal men with osteoporosis-effects of 6 months of treatment on bone mineral density and cardiovascular risk factors.

This open, prospective therapeutic trial studied the effects of regular moderate androgen supplementation on bone mineral density in eugonadal men with established osteoporosis, and collected data on the safety of androgen therapy used in this setting. 23 men, aged 34-73 years, with vertebral crush fractures and back pain, in whom secondary causes of osteoporosis had been excluded, were treated with fortnightly intramuscular injections of 250 mg testosterone esters (Sustanon 250(R)) for 6 months. Blood pressure was recorded monthly; fasting lipids, glucose, haematocrit, plasma viscosity, and testosterone levels were measured every 3 months. Psychological effects were assessed using the Hospital Anxiety and Depression Scale (HADS) and General Health Questionnaire (GHQ), together with questioning on libido changes. Principal outcomes measured were changes in bone mineral density at the hip and spine by dual-energy X-ray absorptiometry (DEXA) over the treatment period. 21 men completed the study period. Mean bone mineral density at the lumbar spine increased from 0.799 g/cm(2) to 0.839 g/cm(2) during treatment (p < 0. 001), a rise of 5% in 6 months. Bone mineral density at the hip did not change. There were significant, favorable changes in diastolic blood pressure (-4.7 mmHg, p < 0.01), serum triglyceride levels (-0.405 mmol/L,p < 0.01), and total cholesterol (-0.27 mmol/L, p < 0.05). Adverse changes included a fall in HDL cholesterol (-0.087 mmol/L, p < 0.05) and a rise in plasma viscosity which was significant at 3 months but not at 6 months. The expected rises in hematocrit (0.434 to 0.456) and FAI (0.504 to 0.887) occurred. We conclude that testosterone supplementation significantly increased bone mineral density in this heterogeneous group of men with idiopathic primary osteoporosis, without an overall adverse effect on cardiovascular risk factors. This treatment warrants further evaluation in a randomized, controlled trial.

Seasonal change in the exacerbations of Crohn's disease.

BACKGROUND: Ulcerative colitis (UC) has been reported to run a clinical course with seasonal exacerbations in both retrospective and prospective studies; such a seasonality was not been observed, however, in Crohn's disease (CD). METHODS: The monthly distribution in the relapse of CD was retrospectively studied to ascertain whether there is any seasonal variation in the exacerbations of the disease. During the period of 1972 to 1993, 139 patients who had been regularly followed up for at least 13 consecutive months were analyzed. RESULTS: In a total of 10,693 follow-up months for these patients 592 relapses occurred in the study period. The highest relapse rate was found in the autumn and winter, whereas the lowest was in the summer. CONCLUSION: This study shows that CD runs a clinical course with seasonal exacerbations, suggesting that seasonal or exogenous factors may be involved in the relapse of CD.

A comparison of the effectiveness and cost of treatment for vertebral fractures in women.

Of the treatments available for the management of established vertebral osteoporosis, hormone replacement therapy (HRT), intermittent cyclical etidronate therapy and salmon calcitonin have been shown in randomized, controlled trials to reduce the risk of further vertebral fractures. In order to compare the cost effectiveness of these different treatments we examined the cost and efficacy of each treatment using previously published data. HRT, cyclical etidronate and salmon calcitonin all decrease the incidence of further vertebral fracture by 50-60%. Estimation of the cost per vertebral fracture averted therefore reflects the underlying cost of medication, with HRT costing 138-680 pounds per fracture averted compared with 1880 pound for cyclical etidronate therapy and 9075-25 013 pounds for salmon calcitonin therapy. HRT is therefore the treatment of choice for post-menopausal women with osteoporosis, particularly as it may also decrease the risk of ischaemic heart disease. Although salmon calcitonin appears as effective as the other treatments, it is considerably more expensive, so should be reserved for situations where HRT and cyclical etidronate are inappropriate.

Lymphocytic gastritis and giant gastric folds associated with gastrointestinal protein loss.

Lymphocytic gastritis is a recently described lesion which occurs in a significant proportion of patients with celiac sprue. This paper describes two patients with lymphocytic gastritis and no evidence of celiac sprue. Both patients had markedly enlarged gastric folds and serum hypoproteinemia, which were clinically suggestive of Ménétrier's disease. These cases indicate that lymphocytic gastritis may cause a protein-losing gastropathy and should be considered in the differential diagnosis of Ménétrier's disease.

Hepatic hemangioblastoma. An unusual presentation in a patient with von Hippel-Lindau disease.

We report a case of multiple capillary hemangioblastomas of the liver occurring in a patient with von Hippel-Lindau disease and a history of previous cerebellar and spinal hemangioblastomas. Although rare examples of this tumor have previously been recorded in the pancreas, kidney, and urinary bladder, this appears to be the first recorded case with hepatic involvement. The histology and immunohistochemical appearance of this neoplasm are identical with those of the cerebellar tumor. We believe it represents a separate primary neoplasm rather than metastatic disease.

Progressive aphasia without dementia: further documentation.

Two patients with progressive aphasia without dementia had magnetic resonance imaging findings of focal left temporal lobe abnormality. Unlike most of the other documented cases of progressive aphasia, onset was not presenile, occurring at ages 68 and 69.

Acute liver failure: a possible consequence of severe hypophosphatemia.

A patient with acute liver failure, in whom no infectious, toxic, or other cause of hepatic damage could be found, developed severe hypophosphatemia along with hepatocellular necrosis. We propose that phosphate depletion may be responsible for the liver cell damage, as hypophosphatemia impairs tissue oxygenation and depletes cellular ATP.