A 6-month open-label study of the effectiveness and tolerability of galantamine in patients with Alzheimer's disease

The objective of this study was to assess the effectiveness and tolerability of galantamine in patients with mild-to-moderate Alzheimer's disease (AD) in everyday clinical practice. Patient selection was made on 36 sequential patients attending Belfast City Hospital Memory Clinic between December 2000 and June 2001. Patients were treated with galantamine for 6 months, starting from 4 mg twice daily increasing to 8 mg twice daily and then to 12 mg twice daily at 4-weekly intervals. Patients (25 females, 11 males), mean age 78 years (59-90), were diagnosed with probable AD and had a mini-mental state examination (MMSE) score of 10-26. Efficacy was assessed using the MMSE, neuropsychiatric inventory (NPI), neuropsychiatric inventory caregiver distress (NPI-D) scale and the Bristol activities of daily living (B-ADL) scale at baseline and after 3 and 6 months of treatment. Mean improvements were noted on all four measures of efficacy at 3 and 6 months; improvements were significant on the MMSE, NPI and NPI-D at 3 months and on the NPI-D at 6 months. Galantamine was overall well tolerated. The most common adverse events were gastrointestinal, particularly nausea. Four patients stopped treatment due to adverse events, and seven were stabilised on 8 mg twice daily as they were unable to tolerate the target dose. This naturalistic study confirms clinical trial data, which shows galantamine improves cognition and behavioural symptoms and is overall well tolerated. © 2004 Blackwell Publishing Ltd.

A Multicenter, Randomised Open Study of Early Corticosteroid Treatment (OSECT) in Preterm Infants With Respiratory Illness: Comparison of Early and Late Treatment and of Dexamethasone and Inhaled Budesonide

AIM: To compare early (15 days) steroid therapy and dexamethasone with inhaled budesonide in very preterm infants at risk of developing chronic lung disease. METHODS: Five hundred seventy infants from 47 neonatal intensive care units were enrolled. Criteria for enrollment included gestational age 30%. Infants were randomly allocated to 1 of 4 treatment groups in a factorial design: early (15 days) dexamethasone, and delayed selective budesonide. Dexamethasone was given in a tapering course beginning with 0.50 mg/kg/day in 2 divided doses for 3 days reducing by half until 12 days of therapy had elapsed. Budesonide was administered by metered dose inhaler and a spacing chamber in a dose of 400 microg/kg twice daily for 12 days. Delayed selective treatment was started if infants needed mechanical ventilation and >30% oxygen for >15 days. The factorial design allowed 2 major comparisons: early versus late treatment and systemic dexamethasone versus inhaled budesonide. The primary outcome was death or oxygen dependency at 36 weeks and analysis was on an intention-to-treat basis. Secondary outcome measures included death or major cerebral abnormality, duration of oxygen treatment, and complications of prematurity. Adverse effects were also monitored daily. RESULTS: There were no significant differences among the groups for the primary outcome. Early steroid treatment was associated with a lower primary outcome rate (odds ratio [OR]: 0.85; 95% confidence interval [CI]: 0.61,1.18) but even after adjustment for confounding variables the difference remained nonsignificant. Dexamethasone-treated infants also had a lower primary outcome rate (OR: 0.86; 95% CI: 0.62,1.20) but again this difference remained not significant after adjustment. For death before discharge, dexamethasone and early treatment had worse outcomes than budesonide and delayed selective treatment (OR: 1.42; 95% CI: 0.93,2.16; OR: 1.51; 95% CI: 0.99,2.30 after adjustment, respectively) with the results not quite reaching significance. Duration of supplementary oxygen was shorter in the early dexamethasone group (median: 31 days vs 40-44 days). Early dexamethasone was also associated with increased weight loss during the first 12 days of treatment (52 g vs 3 g) compared with early budesonide, but over 30 days there was no difference. In the early dexamethasone group, there was a reduced incidence of persistent ductus arteriosus (34% vs 52%-59%) and an increased risk of hyperglycemia (55% vs 29%-34%) compared with the other 3 groups. Dexamethasone was associated with an increased risk of hypertension and gastrointestinal problems compared with budesonide but only the former attained significance. CONCLUSIONS: Infants given early treatment and dexamethasone therapy had improved survival without chronic lung disease at 36 weeks compared with those given delayed selective treatment and inhaled budesonide, respectively, but results for survival to discharge were in the opposite direction; however, none of these findings attained statistical significance. Early dexamethasone treatment reduced the risk of persistent ductus arteriosus. Inhaled budesonide may be safer than dexamethasone, but there is no clear evidence that it is more or less effective

Glucocorticoid induced muscle atrophy is associated with upregulation of myostatin gene expression

The mechanisms by which excessive glucocorticoids cause muscular atrophy remain unclear. We previously demonstrated that dexamethasone increases the expression of myostatin, a negative regulator of skeletal muscle mass, in vitro. In the present study, we tested the hypothesis that dexamethasone-induced muscle loss is associated with increased myostatin expression in vivo. Daily administration (60, 600, 1,200 micro g/kg body wt) of dexamethasone for 5 days resulted in rapid, dose-dependent loss of body weight (-4.0, -13.4, -17.2%, respectively, P <0.05 for each comparison), and muscle atrophy (6.3, 15.0, 16.6% below controls, respectively). These changes were associated with dose-dependent, marked induction of intramuscular myostatin mRNA (66.3, 450, 527.6% increase above controls, P <0.05 for each comparison) and protein expression (0.0, 260.5, 318.4% increase above controls, P <0.05). We found that the effect of dexamethasone on body weight and muscle loss and upregulation of intramuscular myostatin expression was time dependent. When dexamethasone treatment (600 micro g. kg-1. day-1) was extended from 5 to 10 days, the rate of body weight loss was markedly reduced to approximately 2% within this extended period. The concentrations of intramuscular myosin heavy chain type II in dexamethasone-treated rats were significantly lower (-43% after 5-day treatment, -14% after 10-day treatment) than their respective corresponding controls. The intramuscular myostatin concentration in rats treated with dexamethasone for 10 days returned to basal level. Concurrent treatment with RU-486 blocked dexamethasone-induced myostatin expression and significantly attenuated body loss and muscle atrophy. We propose that dexamethasone-induced muscle loss is mediated, at least in part, by the upregulation of myostatin expression through a glucocorticoid receptor-mediated pathway.

Chemical ablation of gastric inhibitory polypeptide receptor action by daily (Pro3) GIP administration improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure in obesity-diabetes.

Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide [GIP]) is an important incretin hormone secreted by endocrine K-cells in response to nutrient ingestion. In this study, we investigated the effects of chemical ablation of GIP receptor (GIP-R) action on aspects of obesity-related diabetes using a stable and specific GIP-R antagonist, (Pro3)GIP. Young adult ob/ob mice received once-daily intraperitoneal injections of saline vehicle or (Pro3)GIP over an 11-day period. Nonfasting plasma glucose levels and the overall glycemic excursion (area under the curve) to a glucose load were significantly reduced (1.6-fold; P <0.05) in (Pro3)GIP-treated mice compared with controls. GIP-R ablation also significantly lowered overall plasma glucose (1.4-fold; P <0.05) and insulin (1.5-fold; P <0.05) responses to feeding. These changes were associated with significantly enhanced (1.6-fold; P <0.05) insulin sensitivity in the (Pro3)GIP-treated group. Daily injection of (Pro3)GIP reduced pancreatic insulin content (1.3-fold; P <0.05) and partially corrected the obesity-related islet hypertrophy and ß-cell hyperplasia of ob/ob mice. These comprehensive beneficial effects of (Pro3)GIP were reversed 9 days after cessation of treatment and were independent of food intake and body weight, which were unchanged. These studies highlight a role for GIP in obesity-related glucose intolerance and emphasize the potential of specific GIP-R antagonists as a new class of drugs for the alleviation of insulin resistance and treatment of type 2 diabetes.

Prediction of Scattered Dose to the Testes in Abdominopelvic Radiotherapy.

Radical abdominal radiotherapy in men runs the risk of impairing their fertility owing to scattered dose to the testes, outside of the treated volume. In patients for whom this is a concern it is important to be able to predict the dose to the testes before treatment in order to determine whether semen cryopreservation should be undertaken and testicular shielding performed during treatment. Measurements have been made on an anthropomorphic phantom to determine the magnitude of these doses for a four-field treatment consisting of an anterior-posterior parallel pair and a lateral parallel pair. A dataset is presented, which, together with a correction for patients size, allows an estimate of testicular dose to be made given only the photon energy, interfield distances and the distance from the testes to the nearest beam edge. Thermoluminescent dosimetry has been carried out in 17 patients to validate the use of the data tables. The results indicate that testicular doses may be estimated with a standard deviation corresponding to 1%-2% of the tumour dose, which is sufficient for the purpose of determining whether fertility is threatened by a planned treatment.

Potential improvements in the therapeutic ratio of prostate cancer irradiation: dose escalation of pathologically identified tumour nodules using intensity modulated radiotherapy.

The potential of intensity modulated radiotherapy (IMRT) to improve the therapeutic ratio in prostate cancer by dose escalation of intraprostatic tumour nodules (IPTNs) was investigated using a simultaneous integrated boost technique. The prostate and organs-at-risk were outlined on CT images from six prostate cancer patients. Positions of IPTNs were transferred onto the CT images from prostate maps derived from sequential large block sections of whole prostatectomy specimens. Inverse planned IMRT dose distributions were created to irradiate the prostate to 70 Gy and all the IPTNs to 90 Gy. A second plan was produced to escalate only the dominant IPTN (DIPTN) to 90 Gy, mimicking current imaging techniques. These plans were compared with homogeneous prostate irradiation to 70 Gy using dose–volume histograms, tumour control probability (TCP) and normal tissue complication probability (NTCP) for the rectum. The mean dose to IPTNs was increased from 69.8 Gy to 89.1 Gy if all the IPTNs were dose escalated (p=0.0003). This corresponded to a mean increase in TCP of 8.7–31.2% depending on the /ß ratio of prostate cancer (p

The visual processing of motion-defined transparency

Our understanding of how the visual system processes motion transparency, the phenomenon by which multiple directions of motion are perceived to co-exist in the same spatial region, has grown considerably in the past decade. There is compelling evidence that the process is driven by global-motion mechanisms. Consequently, although transparently moving surfaces are readily segmented over an extended space, the visual system cannot separate two motion signals that co-exist in the same local region. A related issue is whether the visual system can detect transparently moving surfaces simultaneously, or whether the component signals encounter a serial â??bottleneckâ?? during their processing? Our initial results show that, at sufficiently short stimulus durations, observers cannot accurately detect two superimposed directions; yet they have no difficulty in detecting one pattern direction in noise, supporting the serial-bottleneck scenario. However, in a second experiment, the difference in performance between the two tasks disappears when the component patterns are segregated. This discrepancy between the processing of transparent and non-overlapping patterns may be a consequence of suppressed activity of global-motion mechanisms when the transparent surfaces are presented in the same depth plane. To test this explanation, we repeated our initial experiment while separating the motion components in depth. The marked improvement in performance leads us to conclude that transparent motion signals are represented simultaneously.

Heterogeneity in the granulomatous response to mycobacterial infection in patients with defined genetic mutations in the interleukin 12-dependent interferon-gamma production pathway

Granulomatous Diseases Review Heterogeneity in the granulomatous response to mycobacterial infection in patients with defined genetic mutations in the interleukin 12-dependent interferon-gamma production pathway