Risedronate Reduces the Risk of First Vertebral Fracture in Osteoporotic Women

Risedronate treatment reduces the risk of vertebral fracture in women with existing vertebral fractures, but its efficacy in prevention of the first vertebral fracture in women with osteoporosis but without vertebral fractures has not been determined. We examined the risk of first vertebral fracture in postmenopausal women who were enrolled in four placebo-controlled clinical trials of risedronate and who had low lumbar spine bone mineral density (BMD) (mean T-score =–3.3) and no vertebral fractures at baseline. Subjects received risedronate 5 mg (n= 328) or placebo (n= 312) daily for up to 3 years; all subjects were given calcium (1000 mg daily), as well as vitamin D supplementation (up to 500 IU daily) if baseline serum 25-hydroxyvitamin D levels were low. The incidence of first vertebral fracture was 9.4% in the women treated with placebo and 2.6% in those treated with risedronate 5 mg (risk reduction of 75%, 95% confidence interval 37% to 90%; P= 0.002). The number of patients who would need to be treated to prevent one new vertebral fracture is 15. When subjects were stratified by age, similar significant reductions were observed in patients with a mean age of 64 years (risk reduction of 70%, 95% CI 8% to 90%; P= 0.030) and in those with a mean age of 76 years (risk reduction of 80%, 95% CI 7% to 96%; P= 0.024). Risedronate treatment therefore significantly reduces the risk of first vertebral fracture in postmenopausal women with osteoporosis, with a similar magnitude of effect early and late after the menopause. Received: 12 September 2001 / Accepted: 11 December 2001     

The significance of incomplete excision in patients with basal cell carcinoma

Sixty-seven patients with incompletely excised basal cell carcinomas are reviewed. No recurrences were seen in seven patients who had immediate supplementary treatment; 23 of 60 patients submitted to a "wait and see" regimen developed recurrent disease, Recurrence was commoner in those in whom both the lateral and deep margins were involved, and when the incomplete excision was for recurrent disease. The latter recurrences were more difficult to control in patients who had previously had radiotherapy, when the deep margin was involved and when a flap had been used to close the resulting defect. A case is made for immediate re-excision for all patients with incompletely excised basal cell carcinomas.     

The use of natural interferon alpha conjugated to a monoclonal antibody anti mammary epithelial mucin (Mc5) for the treatment of human breast cancer xenografts

Summary An immunoconjugate composed of natural interferon (nIFN) bound in a noncleavable fashion to a monoclonal antibody (MoAb) recognizing a breast epithelial membrane mucin (Mc5) was used to treat xenografts of a human mammary carcinoma cell line (MCF-7) growing in nude mice. The immunoconjugate (nIFN/Mc5) was administered as 20 intralesional (i.l.) injections to 1 of 2 xenografts in each animal. It was found that nIFN/Mc5 produced a significant enhancement of the growth inhibitory actions of nIFN on the injected tumors. Further enhancement was obtained when nIFN or nIFN together with Mc5 (at a dose 10 times larger than that present in nIFN/Mc5) were added to the immunoconjugate. Biodistribution experiments showed that the uptake of¹²⁵I-nIFN/Mc5 by the tumors was greater and its elimination slower than for¹²⁵I-nIFN alone or conjugated to irrelevant mouse IgG₁. In addition, the immunoconjugate up-regulated the antigenic expression of a breast epithelial membrane mucin by the carcinoma cells, an up-regulation which was not significantly different from that produced by nIFN alone. The contralateral noninjected tumors exposed to systemic levels of the immunoconjugate showed an enhancement of antitumor effects, but to a lesser extent than the injected tumors. These findings suggest that the enhancement of the growth inhibitory action of the immunoconjugate was related to the specific binding of Mc5 which targeted the IFN to the carcinoma cells and impeded its elimination. It is likely that the targeting was favored by the IFN-mediated up-regulation of antigenic expression by the carcinoma cells, thereby producing a cascade of interrelated effects. The results of this study point out the feasibility and potential usefulness of IFN treatment by means of immunoconjugates as well as the worth of pursuing and improving this form of therapy.     

Ultrasound Densitometry of the Os Calcis in Patients with Hemiparesis Following a Cerebrovascular Accident

Ultrasound densitometry has been measured in the os calcis of 31 stroke patients (14 women, 17 men), ages 46–87 years, to determine whether bone density is lower than expected for normal subjects at this site, and to investigate whether or not the stroke side has lower values than the nonstroke side. We have also measured a large control group of 268(39 men, 228 women) subjects who showed similar values to other published data. Immobility is a known precursor to bone loss and so we also compared ultrasound Stiffness Index with an index of mobility in 22 of the stroke patients. In healthy subjects, ultrasound densitometry (measured as Stiffness) fell by 25% in females from 48–52 to 68–72 years. Stiffness (expressed as z-score) in patients with stroke was low in females (P < 0.02) but not in males, but both stroke side and nonstroke side were equally low. Stiffness did not decline with time since stroke, but did correlate with mobility after stroke, on the stroke (r = 0.73) and nonstroke (r = 0.62) side. The data suggest that stroke patients, particularly females, have low bone density before the stroke event. The greater ultrasound Stiffness with increasing mobility after stroke may suggest that active rehabilitation after stroke may produce denser bone. Received: 30 July 1997 / Accepted: 10 June 1999     

Effect of vitamin C on glycosylation of proteins.

Twelve nondiabetic subjects consumed 1 g/day vitamin C for 3 mo. A fasting blood sample was taken at the start of the study and at the end of each month for the measurement of plasma and intraerythrocyte glucose, vitamin C, glycosylated hemoglobin (affinity chromatography and electrophoresis), and glycosylated albumin (affinity chromatography). Although there were no significant changes in fasting glycemia, glycosylated hemoglobin (affinity chromatography) decreased 18%, from 6.18 +/- 0.48% (mean +/- SD) at the start to 5.05 +/- 0.50% (P less than 0.0001) after 3 mo, whereas, HbA1 measured by electrophoresis increased 16%, from 6.17 +/- 0.61 to 7.16 +/- 0.59% (P less than 0.0001) in this period. Glycosylated albumin decreased 33%, from 1.56 +/- 0.24 to 1.04 +/- 1.01% (P less than 0.0001) after 3 mo. This discrepancy between glycosylated hemoglobin measured by electrophoresis and affinity chromatography was due to methodological differences between the two techniques, with affinity chromatography measuring "true" glycosylated hemoglobin. The greater decrease found with glycosylated albumin was probably due to the different distribution of vitamin C between plasma and within the erythrocyte, levels after 1 mo of supplementation being 109 +/- 19 and 59 +/- 9 microM, respectively (P less than 0.001). This indicates that administration of oral vitamin C may inhibit the glycosylation of proteins in vivo by a competitive mechanism.     

Effect of Paget's disease of bone on areal lumbar spine bone mineral density measured by DXA, and density of cortical and trabecular bone measured by quantitative CT

Although bone density may be increased in bone that is affected by Paget's disease, density changes in cortical and trabecular bone and the effect on bone that is apparently unaffected by Paget's disease are relatively unexplored. We have investigated 81 vertebrae (28 affected, 53 unaffected) in 27 patients with Paget's disease, by dual X-ray absorptiometry (DXA) and by quantitative CT (QCT) bone density measurements of trabecular and cortical bone. DXA bone density was high (mean z-score = 1.62, p < 0.001) in vertebrae affected by Paget's disease, but not significantly different from normal in unaffected vertebrae (mean z-score = 0.07, ns). Mean QCT z-score in Paget's vertebrae was 2.07 (p = 0.009) for cortical bone and 1.37 (p = 0.008) for trabecular bone. DXA correlated with QCT cortical values in affected and unaffected bone (r = 0.8 and 0.56, respectively), and with QCT trabecular values (r = 0.72 and 0.48, respectively). There was no significant difference in the slopes for the correlations in affected or unaffected bone. Cortical QCT values are underestimated in Paget's disease compared with physical measurements of density, owing to the computer algorithm used. High DXA values may alert to the possibility of Paget's disease, especially if the value deviates from the expected normal sequence in lumbar vertebrae. Osteoporotic vertebrae may be overlooked if the average value of bone mineral density is taken in the lumbar spine without reviewing each vertebra.     

Informed consent, parental awareness, and reasons for participating in a randomised controlled study

BACKGROUND: The informed consent procedure plays a central role in randomised controlled trials but has only been explored in a few studies on children. AIM: To assess the quality of the informed consent process in a paediatric setting. METHODS: A questionnaire was sent to parents who volunteered their child (230 children) for a randomised, double blind, placebo controlled trial of ibuprofen syrup to prevent recurrent febrile seizures. RESULTS: 181 (79%) parents responded. On average, 73% of parents were aware of the major study characteristics. A few had difficulty understanding the information provided. Major factors in parents granting approval were the contribution to clinical science (51%) and benefit to the child (32%). Sociodemographic status did not influence initial participation but west European origin of the father was associated with willingness to participate in future trials. 89% of participants felt positive about the informed consent procedure; however, 25% stated that they felt obliged to participate. Although their reasons for granting approval and their evaluation of the informed consent procedure did not differ, relatively more were hesitant about participating in future. Parents appreciated the investigator being on call 24 hours a day (38%) and the extra medical care and information provided (37%) as advantages of participation. Disadvantages were mainly the time consuming aspects and the work involved (23%). CONCLUSIONS: Parents' understanding of trial characteristics might be improved by designing less difficult informed consent forms and by the investigator giving extra attention and information to non-west European parents. Adequate measures should be taken to avoid parents feeling obliged to participate, rather than giving true informed consent.     

Lesion heterogeneity in multiple sclerosis: a study of the relations between appearances on T1 weighted images, T1 relaxation times, and metabolite concentrations

OBJECTIVES: Multiple sclerosis lesions appear as areas of high signal on T2 weighted MRI. A proportion of these lesions, when viewed on T1 weighted MRI, appear hypointense compared with surrounding white matter. These hypointense T1 lesions are thought to represent areas of greater tissue damage compared with the more non-specific, total T2 lesion load. This study aimed to better characterise the properties of high signal T2 lesions with differing appearances on T1 weighted MRI using quantitative MR techniques. METHODS: Eleven patients with secondary progressive multiple sclerosis were studied. Two high signal T2 lesions were selected from each patient-one of which appeared hypointense and one isointense on a T1 weighted image. A voxel was positioned around each lesion and for this volume of brain the metabolite concentrations were estimated using proton MR spectroscopy ((1)H-MRS) and the T1 relaxation time within each voxel calculated from a T1 map generated using a multislice technique. RESULTS: Compared with isointense T1 lesions, hypointense T1 lesions exhibited a significantly lower absolute concentration of N-acetyl derived metabolites (tNAA) and a significantly higher absolute concentration of myo-inositol (Ins). T1 relaxation time correlated significantly with both tNAA (r=-0.8, p < 0.001) and Ins (r=0.5, p=0. 012). There was no correlation between T1 relaxation times and creatine/phosphocreatine or choline containing compounds. CONCLUSIONS: Prolonged T1 relaxation times seem to reflect the severity of axonal damage or dysfunction (inferred by a low tNAA) and possibly also gliosis (inferred by a high Ins) in chronic multiple sclerosis lesions.