Secreted Wnt antagonists during eradication of cytomegalovirus infection in solid organ transplant recipients.

We evaluated secreted wingless (Wnt) modulators during cytomegalovirus (CMV) infection in solid organ transplant recipients (SOTr). The major findings were: (i) Plasma levels of Dickkopf-1 (DKK-1) were significantly lower in patients with CMV DNAemia above lower level of quantification at baseline. (ii) Receiver operating characteristic analysis indicated that low DKK-1 and increased secreted frizzled related protein-3 levels were predictors of poor virological outcomes during follow-up. Our findings demonstrate an imbalanced pattern of circulating secreted Wnt modulators in SOTr with poor virological outcomes following treatment for CMV disease, and may suggest a role for dysregulated Wnt signaling on viral pathogenesis during CMV infection.

Effects of the intensity of immunosuppressive therapy on outcome of treatment for CMV disease in organ transplant recipients.

An effective host immune response, critical for successful control of Cytomegalovirus (CMV) disease in solid organ transplant recipients, is affected by intensity and type of immunosuppressive therapy. We used information prospectively captured in the VICTOR-trial to investigate the impact of immunosuppressive therapy on short- and long-term outcomes of CMV treatment in organ transplant recipients. Dual, as compared to triple, immunosuppressive therapy ([odds ratios] OR of 2.55; 95% CI: 1.51-4.60; p = 0.002), lower blood concentrations of calcineurin inhibitors (OR of 5.53; CI: 1.04-29.35; p = 0.045), and longer time since transplantation (OR of 1.70; CI: 1.01-2.87; p = 0.047) all showed better early (Day 21) CMV DNAemia eradication. We observed no effect of the intensity of the immunosuppressive therapy on overall rates of viral eradication or recurrence. The type of calcineurin inhibitor (tacrolimus/cyclosporine) or use of mycophenolate did not affect treatment efficacy, although both tacrolimus and mycophenolate treated patients showed a lower rate of virological recurrence OR 0.51 (95% CI: 0.26-0.98; p = 0.044) and OR 0.45 (95% CI: 0.22-0.93; p = 0.031), respectively. Lower total intensity of immunosuppressive therapy was associated with more effective early, but not overall, CMV DNAemia eradication by valganciclovir/ganciclovir therapy. Both mycophenolate and tacrolimus (rather than cyclosporine) therapy seem to be associated with reduced risk of recurrence.

The Stroke in Italy and Related Impact on Outcome (SIRIO) study: design and baseline data.

The SIRIO study collected detailed information on the stroke care of patients treated in neurological departments in Italy. This report refers to the baseline profile of patients. Each centre recorded the incident cases of ischaemic and haemorrhagic stroke, excluding SAH, for 1-4 months. Baseline data include demographics, risk factors, comorbidities, pre-event medications, social conditions, NIHSS and Rankin scale on entry, Barthel Index pre-event, diagnostic tests and treatments applied on entry. Overall, 3018 patients (56.7% men; mean age 72.1+/-12.2 years) with ischaemic (85.3%) or haemorrhagic stroke were hospitalised in 103 centres; 51% arrived by ambulance. Median time to hospital was 140 min (RIQ: 60-615). TOAST classification of the 2573 ischaemic strokes was: 29.4% large-artery atherosclerosis, 24.6% cardioembolic, 26.2% small vessels occlusion, 6.5% other determined causes and 13.3% undetermined. CT and/or MR were performed in all patients. Total Greenfield's comorbidity score was 5.4+/-3.5. Mean Barthel Index pre-event was 93+/-17; Rankin score on entry was 4-5 in 48% of the patients and 0-1 in 25%. Mean NIHSS on entry was 7.1+/-5.4; 52% of the patients had a NHISS <6 and 1% >22. SIRIO began giving the expected insights on the in-hospital management of stroke in Italy. Further information will be provided by the longitudinal phase of the study, which is in progress. Pre-event patient management and mode of reporting call for additional educational actions.

Age and origin of the FCMD 3'-untranslated-region retrotransposal insertion mutation causing Fukuyama-type congenital muscular dystrophy in the Japanese population.

Fukuyama-type congenital muscular dystrophy (FCMD), an autosomal recessive disorder with a high prevalence in the Japanese population, is characterised by severe muscular dystrophy associated with brain malformation (cortical dysgenesis) and mental retardation. In Japan, 87% of FCMD-bearing chromosomes carry a 3-kb retrotransposal insertion of tandemly repeated sequences within the disease gene recently identified on chromosome 9q31, and most of them share a common founder haplotype. FCMD is the first human disease known to be caused primarily by an ancient retrotransposal integration. By applying two methods for the study of linkage disequilibrium between flanking polymorphic markers and the disease locus, and of its decay over time, the age of the insertion mutation causing FCMD in Japanese patients is calculated to be approximately 102 generations (95% confidence interval: 86-117 g), or slightly less. The estimated age dates the most recent common ancestor of the mutation-bearing chromosomes back to the time (or a few centuries before) the Yayoi people started migrating to Japan from the Korean peninsula. This finding makes the molecular population genetics of FCMD understandable in the context of Japan's history and the founder effect consistent with the prevalent theory on the origins of the modern Japanese population.

Low-dosage ibopamine treatment in progressive renal failure: a long-term multicentre trial.

A multicentre trial (11 nephrology centres) was carried out to test the effects of ibopamine, an orally active dopamine-like drug, on the progression of chronic renal failure. For a 2-year period 189 chronic renal failure patients (serum creatinine level 1.5-4.0 mg/dl) were observed. They were homogeneous for basic nephropathy, degree of residual renal function, blood pressure, and proteinuria. The patients were randomly divided into two groups: 96 took ibopamine at a dosage of 100 mg/day (group A) and 93 served as controls (group B). All were on a low-protein diet (mean 0.8 g/kg body weight). By the end of the observation period, the rate of decrease of the renal function indexes in time proved significantly slower (1.8 times) in group A than in group B. The survival curves for renal function (pre-established end points were creatinine level increases equal to or > 20% and equal to or > 40% of the basal values) proved significantly better (p < 0.02 and p < 0.002 respectively) in group A than in group B. The mean plasma creatinine values rose by 17% in group A and by 36% in group B. The creatinine clearance decreased by 5% in treated patients and by 14% in the controls. Statistical analysis ruled out any possible centre effect. The trial suggests that low-dosage ibopamine administration may be used as a valid and safe pharmacological adjunct for retarding the progression of renal failure in patients with mild or moderate chronic renal impairment.

The use of antisera ('Serocytol') in the management of gastritis: a double-blind clinical assessment versus placebo.

A double-blind, placebo-controlled study was carried out in 40 out-patients with endoscopically confirmed hypertrophic or erosive gastritis, without ulcer, to assess the effectiveness and tolerance of treatment with equine antisera (antidiencephalon and anti-stomach tissue). Patients were assigned at random to receive a single dose in suppository form on 2 days a week for 6 weeks of both antisera (anti-diencephalon on Days 1 and 4, anti-stomach tissue on Days 2 and 5) or placebo (saline solution). No other anti-ulcer treatment was allowed except standard antacid tablets, the consumption of which was recorded and used as an evaluation parameter. Endoscopy, haematology and haematochemistry were performed before and after treatment; symptoms (daytime and night-time pain, heartburn and dyspepsia) and possible adverse reactions were scored 0 to 4 in order of increasing severity before treatment and after 1, 2, 4 and 6 weeks. Five patients in the placebo group had to be withdrawn from the trial at the second week because of therapeutic failure. This proportion was significantly in favour of the antisera group, as was the proportion of patients endoscopically healed and the extent and rate of symptomatic improvement. Concomitant antacid consumption rapidly and significantly decreased in the antisera but not in the placebo group. Signs of intolerance were not observed with either treatment, nor were there any significant alterations in haematology or haematochemistry. In particular, the immune titre of patients did not increase after treatment, thus indicating that the administered heterologous proteins did not elicit an immunization of the patients against horse protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral glucosamine sulphate in the management of arthrosis: report on a multi-centre open investigation in Portugal.

An open study was carried out by 252 doctors throughout Portugal to assess the effectiveness and tolerability of oral glucosamine sulphate in the treatment of arthrosis. Patients received 1.5 g daily in 3 divided doses over a mean period of 50 +/- 14 days. The results from 1208 patients were analyzed and showed that the symptoms of pain at rest, on standing and on exercise and limited active and passive movements improved steadily through the treatment period. The improvement obtained lasted for a period of 6 to 12 weeks after the end of treatment. Objective therapeutic efficacy was rated by the doctors as 'good' in 59% of patients, and 'sufficient' in a further 36%. These results were significantly better than those obtained with previous treatments (except for injectable glucosamine) in the same patients. Sex, age, localization of arthrosis, concomitant illnesses or concomitant treatments did not influence the frequency of responders to treatment. Oral glucosamine was fully tolerated by 86% of patients, a significantly larger proportion than that reported with other previous treatments and approached only by injectable glucosamine. The onset of possible side-effects was significantly related to pre-existing gastro-intestinal disorders and related treatments, and to concomitant diuretic treatment.

Double-blind clinical trial of protacine versus oxyphenbutazone in rheumatic disorders.

A double-blind trial wa carried out in 30 in-patients, mainly with rheumatoid disorders, to compare the efficacy and tolerance of protacine with those of oxyphenbutazone. Patients were given oral doses either of 150 mg protacine or 200 mg oxyphenbutazone 3-times daily for 21 days. Clinical symptoms were assessed by semiquantitative scoring at 5-days' intervals. The same was done for side-effects. Protacine globally reduced the symptom scores by 55% and oxyphenbutazone by 34% (p < 0.001). Frequency and severity of side-effects were significantly less and less severe during protacine than during oxyphenbutazone treatment (p < 0.01). Physiological parameters did not vary during either treatment. Good efficacy, good tolerance and a convenient dose schedule suggest that protacine may well be suited also for long-term treatment.

Preliminary bioavailability study on protacine: a new, non-steroidal anti-inflammatory agent.

Time versus concentration curves of unchanged protacine were measured in the blood of 5 healthy volunteers by high pressure liquid chromatography after a single oral dose of 4 capsules (600 mg). These curves showed a maximum at 8 hours after administration, with an absorption half-life of 3.4 hours, and were interpreted according to the two-compartment open model with invasion. The elimination half-life was found to be 10 hours. This may allow a maintenance treatment, where necessary, with 1 capsule (150 mg) of protacine twice daily and strongly suggests that, apart from acute cases, protacine would be particularly well suited for long-term treatment.

Double-blind clinical evaluation of a new anti-inflammatory drug, protacine, versus indomethacin.

A double-blind clinical trial was carried out in 69 rheumatic in-patients to compare the efficacy and tolerance of a new, non-steroidal anti-inflammatory agent, protacine, with that of indomethacin. Patients received either 150 mg protacine or 50 mg indomethacin 3-times daily for 21 days. The time course of symptoms was recorded by semiquantitative scoring, as were side-effects. Uropepsinogen excretion, occult blood in faeces and standard physiological parameters were also monitored. Protacine globally decreased symptom scores by 58.5% and indomethacin by 24.3% (p less than 0.001). The computed time to reduce symptom scores by 50% was 17.2 days with protacine as compared to 39.2 days with indomethacin (p less than 0.001). Physiological parameters did not change, except white blood cells which decreased after protacine (each subject however, remaining well within the physiological range) and erythrocyte sedimentation rate, which decreased in both groups. Uropepsinogen excretion increased by 70% after protacine, and threefold after indomethacin (p less than 0.001). Occult blood search was positive in 1 patient receiving protacine, while 2 who were already positive before receiving protacine became negative during the treatment. Four patients taking indomethacin were found to be positive, 1 showing melaena. The one who was already positive before treatment showed increasing severity of occult bleeding during indomethacin administration. Frequency and severity of side-effects were significantly less with protacine (p = 0.004). In conclusion, protacine showed analgesic and anti-inflammatory actions significantly more potent and rapid than those of indomethacin, with significantly fewer and less severe side-effects.

Pharmacokinetic approach to proglumide long-term activity.

In order to explain the long-term therapeutic activity of (+/-)-4-benzamide-N,-di-n-propylglutaramic acid (proglumide, Milid) a pharmacokinetic study was carried out in rats by three administration routes. As a result, experimental data could have been fitted to a tri- or tetra-exponential equation, with terminal half-life of about 24 h. Since human pharmacokinetics was found to be rather similar to that in rats, it can be extrapolated that steady state plasma level of drug during therapeutic dosage regimen should range around 60% of peak level of single administration.

Double-blind clinical comparison between a gastrin-receptor antagonist, proglumide, and a histamine H2-blocker, cimetidine.

A double-blind trial was carried out in 30 patients with peptic ulcers to assess the effects of treatment with a gastrin-receptor antagonist, proglumide, compared with a histamine H2-blocker, cimetidine. Patients received either 1200 mg proglumide or 1200 mg cimetidine per day for 28 days. The results showed that both drugs significantly reduced clinical symptoms and gastric secretion. In patients treated with cimetidine there was a significant increase in blood gastrin levels and marked hypertrophy and hyperplasia of the antral mucosa was observed in almost all patients. No such changes were found in the patients treated with proglumide.