The dynamics of the oesophageal squamous epithelium 'normalisation' process in patients with gastro-oesophageal reflux disease treated with long-term acid suppression or anti-reflux surgery.

BACKGROUND: Proton pump inhibitors and laparoscopic anti-reflux surgery (LARS) offer long-term symptom control to patients with gastro-oesophageal reflux disease (GERD). AIM: To evaluate the process of 'normalisation' of the squamous epithelium morphology of the distal oesophagus on these therapies. METHODS: In the LOTUS trial, 554 patients with chronic GERD were randomised to receive either esomeprazole (20-40 mg daily) or LARS. After 5 years, 372 patients remained in the study (esomeprazole, 192; LARS, 180). Biopsies were taken at the Z-line and 2 cm above, at baseline, 1, 3 and 5 years. A severity score was calculated based on: papillae elongation, basal cell hyperplasia, intercellular space dilatations and eosinophilic infiltration. The epithelial proliferative activity was assessed by Ki-67 immunohistochemistry. RESULTS: A gradual improvement in all variables over 5 years was noted in both groups, at both the Z-line and 2 cm above. The severity score decreased from baseline at each subsequent time point in both groups (P < 0.001, all comparisons), attaining a normal level by 5 years. Corresponding decreases in Ki-67 expression were observed (P < 0.001, all comparisons). No significant differences were found between esomeprazole treatment and LARS. Neither baseline severity score nor Ki-67 expression predicted the risk of treatment failure. CONCLUSIONS: Five years of treatment is generally required before squamous epithelial cell morphology and proliferation are 'normalised' in patients with chronic GERD, despite endoscopic and symptomatic disease control. Control of the acid component of the refluxate seems to play the predominant role in restoring tissue morphology.

Long-term safety of proton pump inhibitor therapy assessed under controlled, randomised clinical trial conditions: data from the SOPRAN and LOTUS studies.

BACKGROUND: Control of chronic gastro-oesophageal reflux disease may be achieved either by anti-reflux surgery (ARS) or by long-term medical therapy with proton pump inhibitors (PPIs). The primary efficacy results of the SOPRAN study, comparing long-term omeprazole use with open ARS, and the LOTUS study, comparing long-term esomeprazole use with laparoscopic ARS, have been reported. A secondary objective of these studies was to address the long-term safety of these respective therapeutic strategies and thereby provide a valid scientific platform for assessing long-term PPI safety. AIM: To assess the safety of long-term PPI therapy with omeprazole and esomeprazole through analyses of data from the randomised SOPRAN and LOTUS studies. METHODS: Safety data were collected from patients during the 12-year period of the SOPRAN study (n = 298) and the 5-year period of the LOTUS study (n = 514). Reported serious adverse events (SAEs) and changes in laboratory variables were analysed. RESULTS: Across both studies, SAEs were reported at a similar frequency in the PPI and ARS treatment groups. Taking the time frames into consideration, the number of fatal SAEs in the two studies was low in both treatment groups. Laboratory results, including routine haematology and tests for liver enzymes, electrolytes, vitamin D, vitamin B12 , folate and homocysteine, showed no clinically relevant changes over time. As expected, gastrin and chromogranin A were elevated in the PPI groups, with the greatest increases observed in the first year. CONCLUSION: No major safety concerns arose during 5-12 years of continuous PPI therapy. (ClinicalTrials.gov: NCT00251927 and NCT00256737).

Gastric exocrine and endocrine cell morphology under prolonged acid inhibition therapy: results of a 5-year follow-up in the LOTUS trial.

BACKGROUND: Sustained acid inhibition with PPI stimulates gastrin secretion, exerting a proliferative drive on enterochromaffin-like cells (ECL cells) of the oxyntic mucosa. It may also accelerate development of gastric gland atrophy in Helicobacter pylori-infected individuals. AIMS: To evaluate gastric exocrine and endocrine cell changes in GERD patients randomised to laparoscopic antireflux surgery (LARS, n = 288) or long-term (5 years) esomeprazole (ESO) treatment (n = 266). METHODS: Antral and corpus biopsies were taken at endoscopy and serum gastrin and chromogranin A levels were assayed, at baseline and after 1, 3 and 5 years' therapy. RESULTS: Biopsies were available at each time point for 158 LARS patients and 180 ESO patients. In H. pylori-infected subjects, antral mucosal inflammation and activity improved significantly (P < 0.001) and stabilised after 3 years on esomeprazole while no change in inflammation was observed after LARS. Oxyntic mucosal inflammation and activity remained stable on esomeprazole but decreased slightly over time after LARS. Neither intestinal metaplasia nor atrophy developed in the oxyntic mucosa. ECL cell density increased significantly after ESO (P < 0.001), corresponding with an increase in circulating gastrin and chromogranin A. After LARS, there was a significant decrease in ECL cell density (P < 0.05), accompanied by a marginal decrease in gastrin and chromogranin. CONCLUSIONS: Antral gastritis improved in H. pylori-infected GERD patients after 5 years on esomeprazole, with little change in laparoscopic antireflux surgery patients, who acted as a control. Despite a continued proliferative drive on enterochromaffin-like cells during esomeprazole treatment, no dysplastic or neoplastic lesions were found and no safety concerns were raised. NCT 00251927.

Quality of life following liposuction and conservative treatment of arm lymphedema.

Arm lymphedema can produce an additional burden from a psychosocial point of view. Although edema reduction through treatment can be an advantage in terms of reduced weight of the arm and simplified clothing needs, the purpose of the present study was to register changes in psychosocial parameters during one year after treatment. Thirty-five patients underwent liposuction combined with postoperative CCT (Controlled Compression Therapy), while 14 received CCT alone. Edema volume and range of motion in the shoulder joint were measured and effects on quality of life were assessed with various questionnaires. Liposuction+CCT removed the arm lymphedema completely, whereas CCT alone reduced it by half. The treatments improved range of motion in the shoulder joint and patients' quality of life in relationship to the volume reduction. Liposuction+CCT improves patients' quality of life, particularly qualities related to the volume reduction and hence qualities associated with everyday activities. CCT is beneficial too, but the effect is less obvious than when combined with surgery, probably because the edema reduction is less. The consequences of arm lymphedema for more psychologically oriented qualities and social life in general seem to be less serious and we found few notable effects of treatment in these domains.

Prevalence and incidence of gastroduodenal ulcers during treatment with vascular protective doses of aspirin.

BACKGROUND: Aspirin is valuable for preventing vascular events, but information about ulcer frequency is necessary to inform risk-benefit decisions in individual patients. AIM: To determine ulcer prevalence and incidence in a population representative of those given aspirin therapy and evaluate risk predictors. METHODS: Patients taking aspirin 75-325 mg daily were recruited from four countries. Exclusions included use of gastroprotectant drugs or other non-steroidal anti-inflammatory drugs. We measured point prevalence of endoscopic ulcers, after quantitating dyspeptic symptoms. Incidence was assessed 3 months later in those eligible to continue (no baseline ulcer or reason for gastroprotectants). RESULTS: In 187 patients, ulcer prevalence was 11% [95% confidence interval (CI) 6.3-15.1%]. Only 20% had dyspeptic symptoms, not significantly different from patients without ulcer. Ulcer incidence in 113 patients followed for 3 months was 7% (95% CI 2.4-11.8%). Helicobacter pylori infection increased the risk of a duodenal ulcer [odds ratio (OR) 18.5, 95% CI 2.3-149.4], as did age >70 for ulcers in stomach and duodenum combined (OR 3.3, 95% CI 1.3-8.7). CONCLUSIONS: Gastroduodenal ulcers are found in one in 10 patients taking low-dose aspirin, and most are asymptomatic; this needs considering when discussing risks/benefits with patients. Risk factors include older age and H. pylori (for duodenal ulcer).

Lack of Pharmacokinetic Interaction between Esomeprazole and the Nonsteroidal Anti-Inflammatory Drugs Naproxen and Rofecoxib in Healthy Subjects.

BACKGROUND: We investigated the potential interactions between esomeprazole and a non-selective nonsteroidal anti-inflammatory drug (NSAID; naproxen) or a cyclo-oxygenase (COX)-2-selective NSAID (rofecoxib) in healthy subjects. METHODS: Two studies of identical randomised, open, three-way crossover design were conducted. Subjects (n = 32 for both studies) were to receive 1 week's treatment with esomeprazole 40mg once daily (studies A and B), naproxen 250mg twice daily (study A), rofecoxib 12.5mg once daily (study B), and esomeprazole in combination with naproxen (study A) or rofecoxib (study B). Study periods were separated by a 2-week washout period. RESULTS: On day 7 of dosing, the ratios (and 95% CIs) for the area under the plasma concentration-time curve during the dosing interval (AUC(tau)) and observed maximum plasma concentration (C(max)) of esomeprazole and NSAID combination/NSAID alone were 0.98 (0.94, 1.01) and 1.00 (0.97, 1.04), respectively, for study A, and 1.15 (1.06, 1.24) and 1.14 (1.02, 1.28), respectively, for study B. The ratios (and 95% CIs) for AUC(tau) and C(max) of esomeprazole and NSAID combination/esomeprazole alone were 0.96 (0.89, 1.03) and 0.92 (0.85, 1.00), respectively, for study A, and 1.05 (0.96, 1.15) and 1.05 (0.94, 1.18), respectively, for study B. All treatments were well tolerated during the study period. CONCLUSION: Naproxen and rofecoxib do not interact with esomeprazole, and esomeprazole does not affect the pharmacokinetics of naproxen or rofecoxib. These findings indicate that esomeprazole can be used in combination with NSAIDs without the risk of a pharmacokinetic interaction.

Relative contribution of mucosal injury and Helicobacter pylori in the development of gastroduodenal lesions in patients taking non-steroidal anti-inflammatory drugs.

BACKGROUND AND AIMS: A past history of peptic ulceration increases the risk of an ulcer developing during non-steroidal anti-inflammatory drug (NSAID) use. Whether this is due to Helicobacter pylori infection or to reactivation of the original lesion is unclear. METHODS: We used multivariate regression analyses of three large similar trials to identify factors that placed patients at high risk of ulcer development or relapse. We compared the efficacy of omeprazole 20 mg daily, misoprostol 200 micro g twice daily, and ranitidine 150 mg twice daily in preventing ulcers and erosions at different sites and in patients who were H pylori positive and negative. RESULTS: Patients with endoscopic lesions (which healed) initially were significantly more likely than those without to develop further erosions or ulcers during treatment (rate ratio 2.12, 1.07-4.17). Risk mounted further with ulcers versus erosions, particularly those that had been slow to heal. There was a highly significant tendency for the relapse lesion to replicate the site and type of the original lesion (mean odds ratios ranging from 3 to 14). Treatment failure was significantly less likely with omeprazole than with placebo, misoprostol, or ranitidine. This advantage was especially evident in H pylori positive patients receiving acid suppression (5.7% v 16.6% for gastric ulcer with omeprazole). CONCLUSIONS: Relapse of lesions in patients taking NSAIDs was highly site and type specific and not adversely affected by H pylori status. This strongly implies that local mucosal factors predispose to ulcer development in patients taking NSAIDs. Identification of the responsible mucosal changes would aid understanding and could promote better treatment.

Influence of sex and Helicobacter pylori on development and healing of gastroduodenal lesions in non-steroidal anti-inflammatory drug users.

BACKGROUND AND AIMS: Factors predisposing to endoscopic ulcer formation or healing with non-steroidal anti-inflammatory drugs (NSAIDs) have not been well defined. METHODS: We used multivariate analysis of data from three large similar trials to identify factors associated with endoscopic lesions and healing. We compared the effectiveness of omeprazole 20 mg and 40 mg daily, misoprostol 200 micro g four times daily, and ranitidine 150 mg twice daily in healing ulcers and erosions at different sites and in patients who were Helicobacter pylori positive and negative. RESULTS: Older age, past ulcer history, rheumatoid arthritis, and H pylori infection were significantly associated with ulcers. Duodenal ulcer was significantly more likely than gastric ulcer with a past ulcer history (odds ratio 1.59, 1.16-2.17), H pylori infection (1.4, 1.04-1.92), and male sex (2.35, 1.75-3.16) while female sex, older age (> or = 60 years: 1.39, 1.03-1.88), and higher NSAID dose (>1 defined daily dose: 1.57, 1.16-2.14) were associated with gastric ulceration. Sex differences were seen in both H pylori positive and negative patients. Gastric and duodenal ulcer healing was significantly faster with omeprazole 20 mg than with misoprostol 200 micro g four times daily or ranitidine 150 mg twice daily although misoprostol was more effective at healing erosions. Gastric ulcer healing was slower with large ulcers (0.37, 0.25-0.54 for >10 mm v 5-10 mm) or a past ulcer history (0.51, 0.34-0.76), and faster with H pylori infection (1.55, 1.06-2.29), especially with acid suppression (72% v 37% at four weeks with ranitidine). CONCLUSIONS: Among NSAID users, H pylori and male sex independently increase the likelihood of duodenal ulceration. H pylori infection does not affect duodenal ulcer healing and enhances gastric ulcer healing by ranitidine and possibly other acid suppressing treatments.

Acupuncture and transcutaneous nerve stimulation in stroke rehabilitation: a randomized, controlled trial.

BACKGROUND AND PURPOSE: In small trials with control groups that receive no intervention, acupuncture has been reported to improve functional outcome after stroke. We studied effects of acupuncture and transcutaneous electrical nerve stimulation on functional outcome and quality of life after stroke versus a control group that received subliminal electrostimulation. METHODS: In a multicenter randomized controlled trial involving 7 university and district hospitals in Sweden, 150 patients with moderate or severe functional impairment were included. At days 5 to 10 after acute stroke, patients were randomized to 1 of 3 intervention groups: (a) acupuncture, including electroacupuncture; (b) sensory stimulation with high-intensity, low-frequency transcutaneous electrical nerve stimulation that induces muscle contractions; and (c) low-intensity (subliminal) high-frequency electrostimulation (control group). A total of 20 treatment sessions were performed over a 10-week period. Outcome variables included motor function, activities of daily living function, walking ability, social activities, and life satisfaction at 3-month and 1-year follow-up. RESULTS: At baseline, patients in each group were closely similar in all important prognostic variables. At 3-month and 1-year follow-ups, no clinically important or statistically significant differences were observed between groups for any of the outcome variables. The 3 treatment modalities were all conducted without major adverse effects. CONCLUSIONS: When compared with a control group that received subliminal electrostimulation, treatment during the subacute phase of stroke with acupuncture or transcutaneous electrical nerve stimulation with muscle contractions had no beneficial effects on functional outcome or life satisfaction.

Quality of life in chronic NSAID users: a comparison of the effect of omeprazole and misoprostol.

OBJECTIVE: To compare the impact on quality of life (QoL) of omeprazole and misoprostol during healing, and omeprazole, misoprostol, and placebo during maintenance treatment in chronic NSAID users with NSAID-associated gastroduodenal lesions. METHODS: Validated baseline and follow-up QoL questionnaires were completed by 610 patients (healing: after 4/8 weeks; maintenance: after 6 months). RESULTS: Patients with arthritis being treated with NSAIDs have a poor QoL. Rheumatoid arthritis causes more joint problems and physical mobility limitations than osteoarthritis. Chronic NSAID use causes heartburn and dyspepsia. QoL improved on both treatments (about equally on two general QOL scales), but omeprazole relieved gastrointestinal symptoms more than misoprostol, particularly reflux, abdominal pain and indigestion symptoms. During maintenance, both treatments maintained QoL, but misoprostol induced diarrhoea. CONCLUSION: QoL in arthritis patients on chronic NSAID treatment is destroyed. Omeprazole is superior to misoprostol for relief and prevention of NSAID-associated gastrointestinal symptoms allowing continued NSAID treatment without compromising the patients' QoL.

Omeprazole and H2-receptor antagonists in the acute treatment of duodenal ulcer, gastric ulcer and reflux oesophagitis: a meta-analysis.

This paper is a meta-analysis of 30 published, double-blind clinical trials comparing omeprazole with ranitidine or cimetidine for the treatment of duodenal ulcer, gastric ulcer and reflux oesophagitis. These studies compare the recommended doses of omeprazole with those for ranitidine and cimetidine, and the confidence intervals for the therapeutic gain show that the findings are highly reliable. The difference in healing rates favoured omeprazole over ranitidine in patients with duodenal ulcer after 2 weeks of treatment (15.2 percentage units; P < 0.001), and after 4 weeks of treatment in patients with gastric ulcer (9.9 percentage units; P = 0.005), or reflux oesophagitis (23 percentage units; P < 0.001). Similarly, omeprazole gave a 20.6 percentage units higher average healing rate than cimetidine in patients with duodenal ulcer after 2 weeks of treatment (P < 0.0001). Significantly more patients treated with omeprazole were free of symptoms at their first follow-up visit than patients treated with ranitidine or cimetidine.

The closure of a mental hospital in Sweden. 5 years of transition to district-based long-term care.

A political decision to decentralize psychiatric care in a county of Sweden was made in October 1984. This will lead to the closure of the county's only large psychiatric hospital. Short-term psychiatric care will be provided by three smaller hospitals in the county, while long-term care in hospital will cease completely and be replaced by district-based psychiatric services. All patients (n = 199) in the large hospital's long-term unit were studied over 5 years of the transition period. The results showed that 42% of patients were discharged during the period, mainly to other institutions. Only 8 patients were provided with alternative types of care, such as group homes. Sixty-eight per cent of all patients died, most of them before being discharged (80% of the organically demented patients and 51% of the others). The mortality rate for patients with severely impaired activities of daily living (ADL functioning) was 92% for those who were also organically demented and 84% for the others. The patients who survived the 5-year period were mainly (80%) nondemented patients with relatively well-preserved ADL functioning, but with behavioural disturbances.

Protein analyses in cerebrospinal fluid. I. Influence of concentration gradients for proteins on cerebrospinal fluid/serum albumin ratio.

Concentration gradients in lumbar cerebrospinal fluid (CSF) for albumin and IgG were studied in 8 healthy individuals and 44 neuropsychiatric patients by serial sampling of 6 successive portions of CSF, each containing 4 ml, in all 24 ml. Significant and identical decreases between the first (0-4th ml) and the last (21st-24th ml) portions were found for CSF-albumin (21% decrease, p < 0.0001) and CSF-IgG (21% decrease, p < 0.0001). Therefore, the CSF/serum albumin ratio also showed a significant gradient with a 21% decrease (p < 0.0001), while no gradients were found to the IgG index. These results imply that analyses of proteins in the CSF should be performed on a standardized volume of CSF, preferably the first 12 ml, to allow comparisons of scientific results between various patient groups and controls and between different laboratories and to increase the validity of protein analyses in clinical practice.

Protein analysis in cerebrospinal fluid. II. Reference values derived from healthy individuals 18-88 years of age.

Analyses of the cerebrospinal fluid (CSF) to determine the blood-CSF barrier function and to detect intrathecal IgG production are used in the diagnosis of neurological and psychiatric diseases. Therefore, accurate reference values for these parameters are of utmost importance. However, current reference values are based on 'reference groups' consisting of patients with psychiatric and/or neurological symptoms but without positive clinical findings and on groups of young students. The present study presents reference values for CSF proteins in a large sample (n = 105) of healthy individuals, with a large age-span (18-88 years of age). The parameter for the determination of the blood CSF barrier function, the CSF/serum (CSF/S) albumin ratio, was found to show an increasing variability in individuals over 45 years of age, suggesting a less stable blood-CSF barrier function than in younger individuals. The upper reference limit for the CSF/S albumin ratio was 6.8 for individuals under 45 years of age and 10.2 for individuals over 45 years of age. The IgG index, a dimensionless quotient for the determination of intrathecal IgG production, showed only a minor correlation with age and had an upper reference limit of 0.63.

Individual mood profiles in alcohol withdrawal.

Daily self-reports of moods, using a Swedish Mood Adjective Check List with six bipolar dimensions, were performed in patients with alcohol dependence. One group (n = 13), consisting of inpatients in late withdrawal at a home for addicts, was studied for 6 weeks; another group (n = 12), consisting of outpatients in full remission, was studied for 1 week. The results of the ratings on the check-list were used to test a statistical model for its capacity to describe the individual courses of mood states during the recovery process. Time Series Analysis revealed that the individual courses of moods fitted an autoregressive statistical model and could thereby be summarized in numerical measures for individual baselines, amplitudes, and lengths of recovery. Such individual profiles of the alcohol recovery process, may be useful for both clinical and research purposes, making it possible, for instance, to predict points in time for an individual's recovery with respect to his total well-being, as well as the various dimensions of his mood states.

White matter low attenuation on computed tomography in Alzheimer's disease and vascular dementia--diagnostic and pathogenetic aspects.

Demented patients with early-onset Alzheimer's disease (AD) (n = 17), late-onset Alzheimer's disease (n = 30) and vascular dementia (VD) (n = 20) were studied with computed tomography of the brain. Semiquantitative evaluation of white matter low attenuation (WMLA) and central and cortical atrophy was performed without knowledge of the clinical diagnosis. In early onset AD there was almost complete absence of WMLA and central atrophy compared with the other groups, which showed moderate to severe changes. This suggests that early-onset AD should be separated from the late-onset form. The increased systolic blood pressure found in the WMLA group supports the opinion that WMLA has a vascular origin. The high percentage of WMLA in VD and late-onset AD indicates that subcortical factors have to be considered in the pathogenesis of these disorders.

Alcohol withdrawal and mood.

The usefulness of a self-report technique for description of mood was tested at various stages of alcohol withdrawal. The Mood Adjective Check List (MACL), consisting of 71 mood-associated adjectives and measuring 6 bipolar aspects of mood, was used. Three groups of alcohol-dependent patients (DSM-III-R) reported on their momentary mood states twice a day, respectively, during early withdrawal (n = 78), during late withdrawal (n = 13), and after full remission (n = 12). Significant improvement was found in all 6 mood dimensions during early withdrawal. Improvement in 3 basic mood dimensions was also found during late withdrawal, thus indicating a prolonged time of recovery. The reports given by patients in full remission showed no changes in mood over time. Relative to norm group values, significant differences were found in 4 of the 6 mood dimensions for patients in very early withdrawal. The present study shows that mood changes attributable to after-effects of alcohol intake can be assessed and described during various stages of withdrawal.

Monoamines and their metabolites in cerebrospinal fluid of patients with senile dementia of Alzheimer type using high performance liquid chromatography and gas chromatography-mass spectrometry.

Monoamines and their main metabolites were measured using HPLC-EC in the cerebrospinal fluid from age-matched elderly in-patients affected with senile dementia of Alzheimer type and chronic schizophrenia. Determination of the monoamine metabolites MHPG, HVA and 5-HIAA was also performed by means of gas chromatography-mass spectrometry. Significant differences were obtained with the two methods, the largest deviation being found for HVA, which was 15% higher in the HPLC method than in the GC-MS method, despite the correlation between the results of two measurements being consistent for all the three metabolites. The degrees of motor, intellectual and emotional deterioration were assessed using GBS rating scale. The results show a clear psychobehavioral and neurochemical differentiation of the two patient groups. HVA and 5-HIAA levels were significantly lower in SDAT patients, and showed a trend toward negative correlation with the degree of dementia.

Changes in dopamine receptor sensitivity in humans after heavy alcohol intake.

Dopamine (DA) sensitivity, assessed through maximal growth hormone (GH) response to stimulation by apomorphine (APO) (0.18-0.24 mg iv) was studied in 16 chronic alcoholics newly admitted after a period of heavy alcohol intake. Repeated hormonal tests were thereafter performed during a 2-month period under strictly controlled conditions to avoid relapse into alcohol consumption. Eight healthy volunteers with alcohol consumption slightly less than that of the general population were used as controls. It was found that DA sensitivity in the early abstinence phase was higher than later in the 2-month recovery period but not significantly different from control values. The relatively higher DA sensitivity in the early abstinence phase might be responsible for a lower threshold for psychotic symptoms and neuroleptic-induced extrapyramidal side effects. The results of this study give further evidence of a prolonged recovery phase after heavy alcohol intake.