Validation of instruments for the assessment of dysphagia due to malignancy of the esophagus.

The aim of the study was to validate the Watson scale, the Ogilvie scale, and the Goldschmid scale for assessment of dysphagia due to malignancy of the esophagus. After translation of the scales to Swedish, 35 patients with dysphagia due to esophageal malignancy were asked to participate. On day 1, patients were asked to fill in the questionnaires. The patients also kept a food diary for 4 consecutive days, for assessment of actual swallowing ability. On day 10, the patients were asked to fill in the scales again, to control for individual variability. As an external control group, 29 healthy volunteers were asked to fill in the questionnaires once. External validation was done against actual swallowing ability, and against the European Organization for Research and Treatment of Cancer scales QLQ-C30 and QLQ-OG25, which are already validated quality of life scales for malignancy. Reliability in the categorical variables (Ogilvie and Goldschmid) showed weighted kappa values of 0.52 and 0.54, respectively. For the Watson scale and the Dysphagia module of QLQ-OG25, the intraclass correlation coefficients were 0.68 and 0.80, respectively. Correlations between all scales were good to excellent with values of correlation coefficients (rs) between 0.69 and 0.88, with the strongest correlations between the Ogilvie score and the dysphagia module in QLQ-OG25. These latter two scales had the strongest correlation to the food diary (rs = 0.72). Although the Ogilvie scale was superior, all the three scales showed good reliability and are thus judged to have good validity for assessment of dysphagia due to esophageal malignancy.

Comparison of the pharmacokinetics and pharmacodynamics of dapagliflozin in patients with type 1 versus type 2 diabetes mellitus.

AIMS: To compare the pharmacokinetics and pharmacodynamics of dapagliflozin in patients with type 1 diabetes mellitus (T1DM) versus type 2 diabetes mellitus (T2DM) in order to explore the potential of dapagliflozin as add-on therapy to insulin in patients with T1DM. METHODS: Steady-state pharmacokinetics and pharmacodynamics of dapagliflozin (1-100 mg) were evaluated in a meta-analysis of patients with T1DM or T2DM. A model was constructed of the relationship between dapagliflozin systemic exposure and urinary glucose excretion (UGE) in patients with T1DM versus those with T2DM. RESULTS: Data were analysed from 160 patients (T1DM, n = 70; T2DM, n = 90). Dapagliflozin systemic exposure (maximum concentration and area under the curve) increased similarly in a dose-related manner in both patient populations. Dose-dependent increases in 24-h UGE were observed with dapagliflozin in both populations. Unadjusted results showed that with regard to UGE response, dapagliflozin was more potent in patients with T1DM {mean half-maximum effective concentration [EC50 ] = 2.72 ng/ml [95% confidence interval (CI) 1.14, 5.08]} than in patients with T2DM [EC50 = 12.2 ng/ml (95% CI 4.91, 21.1)]. After normalization for baseline fasting plasma glucose, estimated glomerular filtration rate and UGE, however, the UGE potency of dapagliflozin was similar between the two populations [T1DM: mean EC50 , 8.12 ng/ml (95% CI 2.95, 14.6); T2DM: mean EC50 , 7.75 ng/ml (95% CI 1.35, 18.1)]. CONCLUSIONS: Dapagliflozin pharmacokinetics and the predicted UGE dose exposure response to dapagliflozin were similar in patients with T1DM and those with T2DM and suggest that the dapagliflozin dosages currently used for the treatment of T2DM may provide benefit as add-on therapy to insulin in patients with T1DM.

One-year efficacy and safety of saxagliptin add-on in patients receiving dapagliflozin and metformin.

AIMS: Greater reductions in glycated haemoglobin (HbA1c) with saxagliptin, a dipeptidyl peptidase-4 inhibitor, versus placebo add-on in patients with type 2 diabetes who had inadequate glycaemic control with dapagliflozin 10 mg/d plus metformin were demonstrated after 24 weeks of treatment. Results over 52 weeks of treatment were assessed in this analysis. MATERIALS AND METHODS: Patients (mean baseline HbA1c 7.9%) receiving open-label dapagliflozin 10 mg/d plus metformin were randomized to double-blind saxagliptin 5 mg/d or placebo add-on. RESULTS: The adjusted mean change from baseline to week 52 in HbA1c was greater with saxagliptin than with placebo add-on -0.38% vs 0.05%; difference -0.42% (95% confidence interval -0.64, -0.20)]. More patients achieved the HbA1c target of <7% with saxagliptin than with placebo add-on (29% vs 13%), and fewer patients were rescued or discontinued the study for lack of glycaemic control with saxagliptin than with placebo add-on (19% vs 28%). Reductions from baseline in body weight (≤1.5 kg) occurred in both groups. Similar proportions of patients reported ≥1 adverse event with saxagliptin (58.2%) and placebo add-on (58.0%); no new safety signals were detected. Hypoglycaemia was infrequent in both treatment groups (≤2.5%), with no major episodes. The rate of urinary tract infections was similar in the saxagliptin and placebo add-on groups (7.8% vs 7.4%). The incidence of genital infections was 3.3% with saxagliptin versus 6.2% with placebo add-on. CONCLUSIONS: Triple therapy with saxagliptin add-on to dapagliflozin plus metformin for 52 weeks resulted in sustained improvements in glycaemic control without an increase in body weight or increased risk of hypoglycaemia.

Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers.

AIMS: To characterize the effect of dapagliflozin on albuminuria and estimated glomerular filtration rate (eGFR) and to determine whether effects on albuminuria were mediated through changes in glycated haemoblogin (HbA1c), systolic blood pressure (SBP), body weight or eGFR. METHODS: We conducted a post hoc analysis of data pooled from two phase III clinical trials in hypertensive patients with type 2 diabetes (T2DM) on stable angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, randomly assigned to dapagliflozin 10 mg/day or matched placebo. This analysis included only patients with microalbuminuria or macroalbuminuria at baseline. RESULTS: Patients were randomized to receive dapagliflozin 10 mg (n = 167) or placebo (n = 189). Dapagliflozin resulted in greater 12-week reductions in albuminuria compared with placebo: -33.2% [95% confidence interval (CI) -45.4, -18.2]. The reduction in albuminuria was also present after adjusting for age, sex and changes in HbA1c, SBP, body weight and eGFR: -23.5% (95% CI -37.6, -6.3). There was a decrease in eGFR with dapagliflozin versus placebo that was readily reversed 1 week after last dose. No serious renal-related adverse events were observed in any group. CONCLUSIONS: Dapagliflozin was effective in lowering albuminuria in patients with T2DM and hypertension using renin-angiotensin system blockade therapy. Reductions in albuminuria were still present after adjusting for changes in HbA1c, SBP, body weight and eGFR. Dapagliflozin-induced improvements in glycaemic control and reductions in SBP, coupled with other potentially beneficial renal effects, may lead to a reduced long-term renal and cardiovascular risk.

Efficacy and safety of triple therapy with dapagliflozin add-on to saxagliptin plus metformin over 52 weeks in patients with type 2 diabetes.

We previously reported that dapagliflozin versus placebo as add-on to saxagliptin plus metformin resulted in greater reductions in glycated haemoglobin (A1C), fasting plasma glucose (FPG) and body weight (BW) after 24 weeks of treatment in patients with type 2 diabetes (T2D). Here we report results after 52 weeks of treatment. Patients stabilized on open-label metformin and saxagliptin 5 mg/day for 8-16 weeks were randomized to placebo or dapagliflozin 10 mg/day plus open-label saxagliptin plus metformin for 52 weeks. Changes from baseline to week 52 were greater with dapagliflozin versus placebo in A1C (-0.74% vs. 0.07%), FPG (-27 vs. 10 mg/dL) and BW (-2.1 vs. -0.4 kg). More patients achieved A1C <7% with dapagliflozin (29.4%) versus placebo (12.6%). Adverse events were similar with dapagliflozin (66%) and placebo (71%), and hypoglycaemia was rare (≤2%). Genital infections occurred more often with dapagliflozin (6%) than with placebo (1%); frequency of urinary tract infections was similar between the two groups (9% vs. 10%). Triple therapy with dapagliflozin add-on to saxagliptin plus metformin is a durable, effective and well-tolerated intervention for the treatment of T2D.

Long-term maintenance of efficacy of dapagliflozin in patients with type 2 diabetes mellitus and cardiovascular disease.

AIM: To evaluate the long-term efficacy, safety and tolerability of dapagliflozin versus placebo added to usual care in patients with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). METHODS: Data were pooled from two phase III studies (NCT01031680 and NCT01042977) in high-risk patients (N = 1887) with T2DM and CVD treated with dapagliflozin (10 mg/day) or placebo. Patients completing the double-blind treatment studies (24 weeks) entered one or two sequential double-blind, long-term (LT) extensions of 28 (LT1; n = 1649) and 52 (LT2; n = 568) weeks. RESULTS: Baseline and CVD characteristics were similar in the two groups. Patients entering LT1 and LT2 on dapagliflozin maintained a greater mean reduction in glycated haemoglobin (HbA1c) versus placebo at 52 weeks [LT1, -0.58% (95% confidence interval -0.68, -0.49)] and 104 weeks [LT2, -0.35% (95% confidence interval -0.59, -0.12)]. Mean body weight and systolic blood pressure (SBP) reductions versus placebo were maintained in patients entering LT1 (52 weeks; -2.23 kg and -3.25 mmHg, respectively) and LT2 (104 weeks; -3.16 kg and -2.03 mmHg, respectively). Patients on dapagliflozin had a better three-item composite endpoint of clinical benefit (glycaemia, weight and SBP) compared with placebo at week 24 (LT1, 10.1% vs. 1.1%) and week 104 (LT2, 6.7% vs. 1.4%). Genital and urinary tract infections were more frequent with dapagliflozin than with placebo. Events of hypoglycaemia, renal impairment/failure and volume depletion were similar between groups. CONCLUSIONS: The long-term efficacy of dapagliflozin to maintain reductions in HbA1c, SBP and body weight over 2 years, together with its tolerability profile, make dapagliflozin an appropriate option in high-risk patients with T2DM and CVD.

Dapagliflozin-induced weight loss affects 24-week glycated haemoglobin and blood pressure levels.

The aim of this study was to investigate the associations between dapagliflozin-mediated reductions in body weight and reductions in glycated haemoglobin (HbA1c) and blood pressure. Data were pooled from seven studies evaluating dapagliflozin 10 mg as monotherapy or combination therapy over 24 weeks. Using linear regression to estimate the contribution of weight loss to HbA1c and blood pressure reductions, the ß-value estimate for HbA1c (%)/kg was 0.028 (p < 0.0001). Weight loss of 2 kg with dapagliflozin contributed to 6% of the total HbA1c reduction. For systolic (SBP) and diastolic blood pressure (DBP), the ß-value (mmHg/kg) estimates were 0.606 (p < 0.0001) and 0.253 (p < 0.0001), respectively. Weight loss of 2 kg contributed to 28% of the overall SBP reduction, and 24% of the overall DBP reduction. In conclusion, dapagliflozin-mediated weight loss may contribute to overall reductions in HbA1c and blood pressure.

Durability and tolerability of dapagliflozin over 52 weeks as add-on to metformin and sulphonylurea in type 2 diabetes.

AIMS: To evaluate the safety and efficacy of dapagliflozin as add-on therapy to metformin plus sulphonylurea over 52 weeks. METHODS: Patients with type 2 diabetes mellitus (T2DM) using sulphonylurea and metformin received dapagliflozin 10 mg/day or placebo added to therapy for 52 weeks (24-week randomized, double-blind period plus 28-week double-blind extension). RESULTS: A total of 219 patients were randomized 1 : 1 to dapagliflozin or placebo. Over 52 weeks, glycated haemoglobin (HbA1c) and fasting plasma glucose levels showed greater improvement from baseline with dapagliflozin (-0.8% and -1.5 mmol/l) than with placebo (-0.1% and 0.6 mmol/l). More patients achieved HbA1c <7.0% with dapagliflozin (27.3%) than with placebo (11.3%) at 52 weeks. Dapagliflozin was associated with greater reductions in body weight and systolic blood pressure (-2.9 kg and -1.0 mmHg) compared with placebo (-1.0 kg and 1.1 mmHg). Greater increases in total, LDL and HDL cholesterol and decreases in triglycerides were observed with dapagliflozin (3.4, 4.8, 6.9 and -8.0%, respectively) versus placebo (1.4, 0.9, 0.6 and 2.9%, respectively). Fewer patients were rescued for failing to reach glycaemic targets with dapagliflozin (9.3%) than with placebo (44.4%). Adverse events and serious adverse events were similar between groups (dapagliflozin: 69.7 and 6.4%; placebo: 73.4 and 7.3%). More hypoglycaemic events were observed with dapagliflozin (15.6%) than with placebo (8.3%). Genital infections were reported in more patients in the dapagliflozin (10.1%) than in the placebo group (0.9%) and urinary tract infection frequency was similar in the two groups (10.1 and 11.0%). CONCLUSION: Dapagliflozin as add-on to metformin plus a sulphonylurea was well tolerated and improvement in glycaemic control was maintained over 52 weeks.

Dose-ranging study with the glucokinase activator AZD1656 as monotherapy in Japanese patients with type 2 diabetes mellitus.

AIM: To assess the glucose-lowering effects of monotherapy with the glucokinase activator AZD1656 in Japanese patients with type 2 diabetes mellitus. METHODS: This was a randomized, double-blind, placebo-controlled study performed in Japan (NCT01152385). Patients (n = 224) were randomized to AZD1656 (40-200, 20-140 or 10-80 mg titrated doses) or placebo. The primary variable was the placebo-corrected change from baseline to 4 months in glycated haemoglobin (HbA1c). Effects on fasting plasma glucose (FPG) and safety were also assessed. RESULTS: HbA1c was reduced numerically from baseline by 0.3-0.8% with AZD1656 and by 0.1% with placebo over the first 2 months of treatment, after which effects of AZD1656 started to decline. The changes from baseline to 4 months in HbA1c were not significant for the AZD1656 40-200 mg group versus placebo [mean (95% CI) placebo-corrected change: -0.22 (-0.65, 0.20)%; p = 0.30]. Formal significance testing was not carried out for the other two AZD1656 dose groups. A higher percentage of patients on AZD1656 achieved HbA1c ≤ 7% after 4 months versus placebo, but responder rates were low. Results for FPG reflected those for HbA1c. Cases of hypoglycaemia were rare with AZD1656 (one patient) and no safety concerns were raised. CONCLUSIONS: Although initially favourable plasma glucose reductions were observed, there was a loss of effect over time with sustained AZD1656 treatment. The study design did not allow an evaluation of the reasons for this lack of long-term efficacy.

Dose-ranging study with the glucokinase activator AZD1656 in patients with type 2 diabetes mellitus on metformin.

AIM: To investigate the effect of glucokinase activator AZD1656 on glycated haemoglobin (HbA1c) as an add-on to metformin in patients with type 2 diabetes. METHODS: This randomized, double-blind, placebo-controlled study (NCT01020123) was conducted over 4 months with an optional 2-month extension. Patients (n = 458) with HbA1c 7.5-10% were randomized to AZD1656 20 mg (n = 40) or 40 mg (n = 52) fixed doses or 10-140 mg (n = 91) or 20-200 mg (n = 93) titrated doses, placebo (n = 88) or glipizide 5-20 mg titrated (n = 94). Patients (n = 72) with HbA1c >10 and ≤12% received open-label AZD1656 (20-200 mg titrated). Primary outcome was placebo-corrected change in HbA1c from baseline to 4 months of treatment. RESULTS: Significant reductions in HbA1c from baseline to 4 months were observed with blinded AZD1656 10-140 and 20-200 mg versus placebo [mean (95% CI) changes: -0.80 (-1.14; -0.46) and -0.81 (-1.14; -0.47) %, respectively), with similar reductions observed with glipizide. A higher percentage of patients on AZD1656 than on placebo achieved HbA1c ≤7.0 or ≤6.5 % after 4 months. Mean (s.d.) change in HbA1c for open-label AZD1656 (20-200 mg) was -2.8 (1.19) % after 4 months. AZD1656 was well tolerated, with less hypoglycaemia than glipizide. In the extension population, HbA1c was still reduced with AZD1656 versus placebo after 6 months, but the effect of AZD1656 on glucose control was not sustained over time. CONCLUSION: Addition of AZD1656 (individually titrated) to metformin gave significant improvements in glycaemic control up to 4 months, although efficacy diminished over time.

Combined stent insertion and single high-dose brachytherapy in patients with advanced esophageal cancer--results of a prospective safety study.

Previous randomized studies comparing the two commonly used palliative treatments for incurable esophageal cancer, i.e. stent insertion and intraluminal brachytherapy, have revealed the pros and cons of each therapy. While stent treatment offers a more prompt effect, brachytherapy results in more long-lasting relief of dysphagia and a better health-related quality of life (HRQL) in those living longer. This prospective pilot study aimed to explore the feasibility and safety of combining these two regimes and incorporating a single high dose of internal radiation. Patients with newly diagnosed, incurable cancer of the esophagus and dysphagia were eligible for inclusion, and stent insertion followed by a single dose (12 Gy) of brachytherapy was performed as a two-stage procedure. Clinical parameters including HRQL and adverse events were registered at inclusion, and 1, 2, 3, 6, and 12 months later. Twelve patients (nine males) with a median age of 73 years (range 54-85) were included. Stent insertion followed by a single dose of brachytherapy was successfully performed in all but one patient who was treated with stent only. Relief of dysphagia was achieved in the majority of cases (10/11, P < 0.05), but HRQL did not improve except for dysphagia-related items. Only minor adverse events, including chest pain, reflux, and restenosis, were reported. The median survival time after inclusion was 6.6 months. Our conclusion is that the combination of stent insertion and single high-dose brachytherapy seems to be a feasible and safe palliative regime in patients with advanced esophageal cancer. Randomized trials comparing the efficacy of this strategy to stent insertion or brachytherapy alone are warranted.

Human complement regulators: a major target for pathogenic microorganisms.

The C3 convertases of the human complement system are controlled by fluid-phase and membrane proteins in the RCA (regulators of complement activation) family. Accumulated data show that many pathogenic microorganisms interact with these complement regulators. Recent advances in this field include determination of the crystal structure of the binding domains in the measles virus receptor CD46 and identification of a CD46 transgenic mouse line that is sensitive to measles virus. Moreover, recent findings support the hypothesis that pathogenic bacteria binding fluid-phase RCA proteins exploit these proteins to escape complement attack. These studies provide novel insight into the interplay between pathogens and the innate immune system and may have implications for the plans to use animals expressing an RCA protein for xenotransplantation.

Health economic evaluation of therapeutic strategies in patients with idiopathic achalasia: results of a randomized trial comparing pneumatic dilatation with laparoscopic cardiomyotomy.

BACKGROUND: We have prospectively collected information concerning the costs incurred during the management of patients allocated to either forceful dilatation or to an immediate laparoscopic operation because of newly diagnosed achalasia. METHODS: Fifty-one patients with newly diagnosed achalasia were randomized to either pneumatic dilatation to a diameter of 30-40 mm or to a laparoscopic myotomy to which was added a posterior partial fundoplication. Follow-ups were scheduled at 1, 3, 6, and 12 months after inclusion. At each follow-up visit a study nurse interviewed the patients regarding symptoms and their quality of life (QoL) and a health economic questionnaire was completed. In the latter questionnaire, patients were asked to report the presence and character of contacts with the healthcare system since the last visit. RESULTS: In the dilatation group six patients (23%), including the patient who was operated on because of perforation, were classified as failures during the first 12 months of follow-up compared to one (4%) in the myotomy group (p = 0.047). Five of those classified as failures in the dilatation group subsequently had a surgical myotomy and the sixth patient was treated with repeated dilatations. The patient classified as failure in the myotomy group was treated with endoscopic dilatation. The initial treatment cost and the total costs were significantly higher for laparoscopic myotomy compared to a pneumatic dilatation-based strategy (p = 0.0002 and p = 0.0019, respectively). When the total costs were subdivided into the different resources used, we found that the single largest cost item for pneumatic dilatation was that for hospital stay and that for laparoscopic myotomy was the actual operative treatment (operating room time). The cost-effectiveness analysis, relating to the actual treatment failures, revealed that the cost to avoid one treatment failure (incremental cost-effectiveness ratio) amounted to 9239 euros. CONCLUSION: The current prospective, controlled clinical trial shows that despite a higher level of clinical efficacy of laparoscopic myotomy to prevent treatment failure in newly diagnosed achalasia, the cost effectiveness of pneumatic dilatation is superior, at least when a reasonable time horizon is applied.

A neurologic syndrome in Golden Retrievers presenting as a sensory ataxic neuropathy.

BACKGROUND: A sensory ataxic neuropathy has been observed in Swedish Golden Retrievers recently. ANIMALS: Twenty-one affected Golden Retrievers. METHODS: Clinical and neurologic status, electrophysiologic, and pathologic status as well as pedigree analyses were evaluated. RESULTS: Clinical signs had an insidious onset between 2 and 8 months of age and a slowly progressive course. Affected dogs were ataxic and dysmetric. They had abnormal postural reactions and decreased spinal reflexes but no apparent muscle atrophy. Clinical pathology, radiography, and electrophysiology of motor systems were all within reference values. Sensory nerve conduction results of affected dogs were significantly different from those of a group of control dogs. Necropsy revealed a chronic progressive central and peripheral sensorimotor axonopathy; the proprioceptive pathways were most severely affected. CONCLUSIONS AND CLINICAL IMPORTANCE: This disease in these Golden Retrievers is distinct from other canine breed-related neurodegenerative diseases or hereditary neurodegenerative diseases described in humans. Pedigree analyses indicated a hereditary background, but the mode of inheritance could not be established.

An antireflux stent versus conventional stents for palliation of distal esophageal or cardia cancer: a randomized clinical study.

BACKGROUND: Self-expandable metal stents placed across the esophagogastric junction for palliative treatment of malignant strictures may lead to gastroesophageal reflux and pulmonary aspiration. This study compared the effects of a Dua antireflux stent with those of a conventional stent. METHODS: Patients with incurable cancer of the distal esophagus or gastric cardia were randomly assigned to receive an antireflux stent (n = 19) or a standard stent (n = 22) at nine Swedish hospitals during the period September 1, 2003 to July 31, 2005. Complications were recorded at clinical follow-up visits. Survival rates were assessed through linkage to the Population Register. Dysphagia, reflux symptoms, esophageal pain, dyspnea, and global quality of life were assessed as changes in mean scores between baseline and 1 month after stent insertion through validated questionnaires. RESULTS: No technical problems occurred during stent placement in the 41 enrolled patients. Fewer patients with complications were observed in the antireflux stent group (n = 3) than in the standard group (n = 8), but no statistically significant difference was shown (p = 0.14). The survival rates were similar in the two groups (p = 0.99; hazard ratio, 1.0; 95% confidence interval, 0.5-2.0). The groups did not differ significantly in terms of studied esophageal or respiratory symptoms or quality of life. Clinically relevant improvement in dysphagia occurred in both groups. Dyspnea decreased after antireflux stent insertion (mean score change, -11), and increased after insertion of standard stent (mean score change, +21). CONCLUSIONS: Antireflux stents may be used without increased risk of complications, mortality, esophageal symptoms, or reduced global quality of life. These results should encourage large-scale randomized trials that can establish potentially beneficial effects of antireflux stents.

p53-dependent and -independent differentiation of leukemic U-937 cells: relationship to cell cycle control.

Observations based on overexpression of the suppressor gene p53 or interference with endogenous p53 support a role for p53 in mediating not only growth inhibition and apoptosis but also differentiation. The aim of this study was to characterize the mechanisms of p53-dependent differentiation in the monoblastic leukemia cell line U-937. These cells were transfected with a mutant of the p53 gene expressing wild-type p53 at a permissive temperature. The results showed that wild-type p53 and interferon (IFN)-gamma were able to work synergistically to promote differentiation. This cooperative response was not associated with early G1 arrest of the cell cycle, indicating that p53 can mediate differentiation by mechanisms other than those used for mediating G1 arrest. The differentiation response to transfected p53 with or without INF-gamma was inhibited by cyclic adenosine monophosphate (cAMP)-inducing agents (dibutyryl cyclic adenosine 3':5'-monophosphate, forskolin, and 3-isobutyl-1-methylxanthine) in a dose-dependent manner. In contrast, the differentiation response of p53-negative U-937 cells to 1,25-dihydroxychole-calciferol or all-trans retinoic acid was enhanced by cAMP-inducing agents at optimal concentrations and inhibited at higher concentrations. In addition, 1,25-dihydroxycholecalciferol-mediated differentiation could be achieved in cells arrested in G1 by concomitant incubation with cAMP-inducing agents, indicating that differentiation can occur in the absence of proliferation. In conclusion, the results of this study indicate that p53-dependent and -independent differentiation can occur independently of cell cycle regulation.

Baclofen-mediated gastro-oesophageal acid reflux control in patients with established reflux disease.

AIM: To explore the effect of baclofen on oesophageal acid exposure in patients with gastro-oesophageal reflux disease. METHODS AND MATERIALS: Twenty patients with established reflux disease were included in this double-blind, randomized, crossover study. Baclofen, 40 mg, or placebo was given as a single dose with a washout period of 4 weeks. Symptoms were assessed by a visual analogue scale. Oesophageal pH was registered for 12 h and analysed for the whole period and for the 0-4-h, 4-8-h, 8-12-h and 2-h post-prandial periods. RESULTS: Baclofen significantly reduced the number of reflux episodes during the 0-4-h (7.9 vs. 16.5, P < 0.0001; post-prandially: 6.0 vs. 11.2, P < 0.0001) and 0-12-h (46.5 vs. 73, P=0.0001; post-prandially: 18.8 vs. 29.3, P < 0.0001) periods. The fraction of time with pH < 4 was significantly lowered during the 0-4-h period (9.3 vs. 15.6, P=0.0019; post-prandially: 16.1 vs. 23.5, P=0.0083). Similar results were also obtained in patients with a hiatus hernia (n=13). Belching was significantly reduced (32 vs. 69 episodes, P < 0.01). CONCLUSIONS: A single oral dose of 40 mg baclofen significantly reduced both the number of reflux episodes and the fraction of time with pH < 4, an effect primarily found during the first 4 h after dosing.

Dose-dependent reduction of bone inductive properties by ethylene oxide.

Sterilisation of demineralised bone matrix with ethylene oxide has been claimed to destroy the ability of bone matrix to induce new bone formation on intramuscular implantation. Other workers have routinely used ethylene oxide sterilised bone matrix for assays in rodents without detrimental effects. We studied the effects of various lengths of exposure to ethylene oxide gas, and found that bone induction properties are destroyed in a dose-dependent manner. After a short exposure, bone induction properties were moderately diminished. However, this short ethylene oxide treatment did not kill Bacillus subtilis spores. A sterilisation procedure that killed these spores rendered the implants incapable of bone-induction.