Prediction of response to Certolizumab-Pegol in rheumatoid arthritis (PreCePRA) by functional MRI of the brain - Study protocol for a randomized double-blind controlled study.

BACKGROUND: Tumor necrosis factor inhibitors (TNFi) signify a major advance in the treatment of rheumatoid arthritis (RA). However, treatment success initially remains uncertain as approximately half of the patients do not respond adequately to TNFi. Thus, an unmet need exists to better predict therapeutic outcome of biologicals. OBJECTIVES: We investigated whether brain activity associated with arthritis measured by functional magnetic resonance imaging (fMRI) of the brain can serve as a predictor of response to TNFi in RA patients. METHODS: PreCePRA is a multi-center, randomized, double-blind, placebo-controlled fMRI trial on patients with RA [1] [2]. Active RA patients failing csDMARDs therapy with a DAS28 > 3.2 and at least three tender and/or swollen joints underwent a brain BOLD (blood-oxygen-level dependent) fMRI scan upon joint compression at screening. Patients were then randomized into a 12-week double-blinded treatment phase with 200 mg Certolizumab Pegol (CZP) every two weeks (arm 1: fMRI BOLD signal activated volume > 2000 voxel, i.e. 2 cm3; arm 2: fMRI BOLD signal activated volume <2000 voxel) or placebo (arm 3). DAS28 low disease activity at 12 weeks was assigned as primary endpoint. A 12-week follow-up phase in which patients were switched from the placebo to the treatment arm followed the blinded phase. fMRI was carried out at screening as well as after 12 and 24 weeks of receiving CZP or placebo. CONCLUSION: We hypothesize that high-level central nervous representation of pain in patients with rheumatoid arthritis predicts response to the TNFi CZP which we further investigate in the PreCePRA trial.

[Current overview of cartilage regeneration procedures]. / Aktuelle Übersicht knorpelregenerativer Verfahren.

BACKGROUND: Cartilage is an avascular, alymphatic and non-innervated tissue with limited intrinsic repair potential. The high prevalence of cartilage defects and their tremendous clinical importance are a challenge for all treating physicians. AIM: This article provides the reader with an overview about current cartilage treatment options and their clinical outcome. METHODS: Microfracture is still considered the gold standard in the treatment of small cartilage lesions. Small osteochondral defects can be effectively treated with the autologous osteochondral transplantation system. Larger cartilage defects are successfully treated by autologous membrane-induced chondrogenesis (AMIC) or by membrane-assisted autologous chondrocyte implantation (MACI). CONCLUSION: Despite limitations of current cartilage repair strategies, such procedures can result in short- and mid-term clinical improvement of the patients. Further developments and clinical studies are necessary to improve the long-term outcome following cartilage repair.

[Fusion in adolescent idiopathic scoliosis : Anterior, posterior or combined? One-stage or two-stage?]. / Korrekturspondylodesen von adoleszenter idiopathischer Skoliose : Ventral, dorsal, ventrodorsal? Einzeitig oder zweizeitig?

Scoliosis is a complex, three-dimensional spinal deformity with various causes. Adolescent idiopathic scoliosis (AIS) is the most common form. Surgical treatment is indicated for curves greater than 45-50° meaured using the Cobb method. We can distinguish among posterior, anterior or combined surgical procedures. Today, the posterior, transpedicular approach has revolutionized scoliosis surgery. This review gives an overview of current surgical options in scoliosis treatment.

[Multidisciplinary Rehabilitation and Fast-track Rehabilitation after Knee Replacement: Faster, Better, Cheaper? A Survey and Systematic Review of Literature]. / Multidisziplinäre Rehabilitation und multimodale Fast-Track-Rehabilitation in der Knieendoprothetik: Schneller, besser, günstiger? Eine Umfrage und systematische Literaturrecherche.

INTRODUCTION: The aim of multidisciplinary rehabilitation after total knee replacement (TKA) is to reduce postoperative complications and costs and enable faster convalescence. The goals of fast-track rehabilitation, as a multidisciplinary concept, are to reduce the length of hospital stay and achieve early functional improvements by optimizing the perioperative setting. METHOD: A literature review was carried out for the years 1960-2013. The search terms were: "rehabilitation", "training", "physiotherapy", "physical therapy", "recovery", "exercise program", "knee surgery", "TKA", "total knee replacement", "arthroplasty", "intensive", "multidisciplinary", "accelerated", "rapid" or "fast track". Only randomized controlled trials and metaanalyses were included. A survey was also performed to assess care as actually offered in orthopaedic rehabilitation clinics in North Rhine-Westphalia. RESULTS: A total of 729 articles were identified of which 11 studies were included. Fast-track rehabilitation can significantly reduce both the duration of hospital stay and costs after TKA. Current studies showed that a better short-/middle-term clinical outcome might be achieved with multidisciplinary rehabilitation. However, a difference in the long-term outcome could not be observed. Our survey shows that most patients are admitted to a rehabilitation clinic in a state of poor general condition as well as decreased mobility and knee range of motion. CONCLUSIONS: Fast-track rehabilitation facilitates a shortened hospital stay as well as cost saving. It probably can be used to optimize the condition of the patient before admission to a rehabilitation facility.

[Pathophysiology of traumatic bone marrow edema]. / Pathophysiologie des traumatischen Knochenmarködems.

BACKGROUND: Morphologically, bone marrow edema (BME) is an accumulation of fluid in the bone marrow. The BME is per se non-specific but can be identified at an early stage with magnetic resonance imaging (MRI). The underlying pathomechanism remains unclear. The BME can occur as an individual entity and as an accompanying condition of many diseases. The BME can be divided into three groups, ischemic, reactive and mechanical BME. Mechanical BME occurs after trauma or repetitive strain. Typical histological changes are present and there is no clear boundary between edema and microfracture. Some forms of trauma show BME in typical localizations. Both the trauma and the possible accompanying injuries can be indirectly indicated in this way in cases with an unknown trauma mechanism. CONCLUSION: The BME can be present as an isolated entity or as a comorbidity. For initiation of therapy, a comprehensive medical history and targeted diagnostics are indispensable. In some cases BME is indicative of the trauma mechanism and possible further accompanying injuries.

Long-term intraocular pressure-lowering efficacy and safety of timolol maleate gel-forming solution 0.5% compared with Timoptic XE 0.5% in a 12-month study.

PURPOSE: To evaluate the long-term intraocular pressure-lowering efficacy and safety of timolol maleate gel-forming solution 0.5% (Timolol GFS 0.5%, Alcon Research Ltd, Fort Worth, Texas) compared with Timoptic XE 0.5% (Merck, Inc, West Point, Pennsylvania) in patients with open-angle glaucoma or ocular hypertension. METHODS: Two hundred forty-one patients with open-angle glaucoma or ocular hypertension, who had intraocular pressure between 22 and 36 mm Hg in at least one eye, were randomly assigned in a 2:1 ratio to receive either Timolol GFS 0.5% once daily or Timoptic XE 0.5% once daily, in a 12-month randomized, multicenter, double-masked, prospective study. The primary efficacy variable was mean trough intraocular pressure measured at 8:00 AM, approximately 24 hours after dosing. RESULTS: The Timolol GFS 0.5% group produced significant trough intraocular pressure reductions from a baseline of 4.5 to 5.2 mm Hg (P =.0001), compared with reductions of 4.1 to 5. 3 mm Hg (P =.0001) in the Timoptic XE 0.5% group. The difference in mean intraocular pressure between the two treatments was 0.9 mm Hg or less, and the upper 95% confidence limit between groups was 0.92 mm Hg or less at all time points, demonstrating both clinical and statistical equivalence. A similar percentage of patients in the Timolol GFS 0.5% group (71%) and Timoptic XE group (72%) had clinically relevant reductions in intraocular pressure. There was no significant difference in the safety profiles of the two treatments. CONCLUSION: Both treatments were clinically effective in lowering intraocular pressure and maintaining the reductions over long-term use. Timolol GFS 0.5% is a safe and effective therapy for open-angle glaucoma or ocular hypertension and is both clinically and statistically equivalent to Timoptic XE 0.5% in reducing intraocular pressure.

Patient preference, efficacy, and compliance with timolol maleate ophthalmic gel-forming solution versus timolol maleate ophthalmic solution in patients with ocular hypertension or open-angle glaucoma.

This study was designed to compare timolol maleate ophthalmic gel-forming solution 0.5% (timolol gel) once daily with timolol maleate ophthalmic solution 0.5% (timolol solution) twice daily with respect to patient preference, intraocular pressure (IOP)-lowering effect, and tolerability. A total of 202 patients with ocular hypertension or open-angle glaucoma and an IOP > or = 22 mm Hg were enrolled in this 12-week, randomized, observer-masked, two-period crossover study. Significantly more patients preferred timolol gel to timolol solution (P < 0.001). Ninety-two percent of patients preferring timolol gel strongly agreed or agreed that once-daily dosing was a reason for their preference. Those who preferred timolol solution did so because of fewer side effects. The mean IOP-lowering effects of the 2 treatments were similar at both morning trough and peak time points. The incidence of drug-related adverse experiences was similar (timolol gel 11.4% vs timolol solution 10.9%). Because both treatments were well tolerated and effective in lowering IOP, timolol gel, with its once-daily dosing regimen, should be considered in patients who are candidates for therapy with an ophthalmic beta-blocking agent.

Double-dummy comparison of suprofen and indometacin sustained release formulations.

In a randomized double-dummy study a new dosage form of alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol), i.e., suprofen sustained release 600 mg tablets, was compared with indometacin sustained release 75 mg capsules. The test population included 60 hospitalized subjects in severe chronic pain requiring analgesic treatment. The treatment groups were homogeneous as to their anamnestic data. Treatment was given for 3 weeks; the drugs were uniformly administered in the morning and in the evening. The intensity of pain was assessed using a visual analog scale (VAS) prior to administration of the first dose on day 1 of the therapy, and then for up to 10 h. Further assessments of pain intensity and pain relief were obtained after 1, 2, and 3 weeks of therapy. Comparison of the mean pain intensity (VAS) at the individual rating times revealed statistically significant better pain relief with suprofen than with indometacin already 1 h after the administration (p less than 0.05, multivariate analysis of variance). This statistically significant difference as compared with indometacin was confirmed at all subsequent time points. The weekly assessments of pain intensity showed that the results obtained with suprofen were superior to those with indometacin, although they were not statistically significant. However, pain relief after 2 weeks' treatment with suprofen was significantly superior (p = 0.0061, exact test) to the result observed with indometacin. The results obtained with suprofen in weeks 1 and 3 were superior to those with indometacin, but they were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

[Ginkgolip, a new geriatric drug. Results of a double-blind study]. / Ginkgolip, ein neues Geriatrikum. Ergebnisse einer Doppelblindstudie.

The results of a placebo controlled double blind study with Ginkgolip on 50 hospitalized patients are reported. All patients showed symptoms of cerebrovascular insufficiency. For evaluation psychometric and psychopathometric test methods were applied. Further evaluation of the patients symptoms was carried out by the investigator, by the attending staff, by the patients, using a special rating scale. The final symptoms showed significant improvements of perceptible ability, concentration, adaptability, social ability, depression and wakefulnes. The evaluation by the attending staff showed an improvement of social behaviour, time of reaction and perceptible ability. The patient's rating scale showed a lower rate of complaints of the Verumgroup than of the Placebo-group. The psychometric and psychopathometric test methods showed no showed no significant differences. The drug was well tolerated, there were no incompatibilities or side effects.

Fluorophotometric study of epinephrine and timolol in human subjects.

The action and interaction of topical 2% epinephrine hydrochloride and 0.5% timolol maleate therapy were studied in 12 normal and 16 ocular hypertensive subjects. Measurements of intraocular pressure, outflow facility, and aqueous secretion by fluorophotometry were made. Uveoscleral outflow values were calculated. Epinephrine, applied topically twice daily for one week, resulted in a decrease in IOP of 3.3 +/- 0.9 mm Hg and an increase in outflow facility of 0.05 +/- 0.01 microL/min/mm Hg, as well as an increase in the rate of aqueous production of 0.32 +/- 0.09 microL/min. Uveoscleral outflow showed an increase of 0.83 +/- 0.23 microL/min. Timolol, applied topically twice daily for one week, reduced the IOP 3.9 +/- 1.0 mm Hg and decreased aqueous flow 0.84 +/- 0.23 microL/min, but produced no change in outflow facility or uveoscleral flow. When epinephrine and timolol are given in combination, the effects in lowering IOP may not be completely additive.

Retinal vascular accidents in glaucoma and ocular hypertension.

The incidence of primary open angle glaucoma in patients with central retinal vein occlusion is reported to be between 5.7 and 66%, while that of primary angle closure glaucoma is from 0 to 9%. (Corrected for the relative incidence of these two types of glaucoma in the general population, these rates are comparable). There appears to be a causal relationship between elevated intraocular pressure and central retinal vein occlusion, which does not correlate with the height to which the pressure is elevated. Other etiologic factors may be important, particularly arteriosclerosis. The association between elevated pressure and branch vein occlusion is less clear. Central vein occlusions occur in 3.5 to 5% of patients with primary open angle glaucoma. Similarly, central vein occlusions occur in approximately 3% of patients with ocular hypertension. It is recommended that ocular hypertensive patients over the age of 65 be treated to lower their pressure below 25 mm Hg.

Exercise-induced increase of intraocular pressure in the pigmentary dispersion syndrome.

A 32-year-old man with pigmentary dispersion syndrome had blurred vision and halos after strenuous exercise, associated with a release of pigment into the anterior chamber and increased intraocular pressure (IOP). Additionally, he had typical symptoms after emotional stress or exposure to dim illumination, and had a high IOP without angle closure during a darkroom provocative test. The exercise-induced symptoms and the increase of IOP were prevented by the use of pilocarpine 0.5% drops immediately before exercise.

[Diphenoxinhydrochloride, a new anti-diarrhea agent]. / Difenoxinhydrochlorid, ein neues Antidiarrhoikum

The new antidiarrheal drug difenoxin hydrochloride is a preparation with a broad range of action; it is suitable for symptomatic treatment of acute and chronic diarrhea of varying etiology and may be administered as additional medication in cases of specific intestinal infections accompanied by diarrhea. Difenoxin hydrochloride was tested in two studies involving 220 patients with acute diarrhea and 41 patients with chronic diarrhea respectively. Side effects were extremely rare and stool frequency and consistency returned to normal at a daily dose of about 6 tablets. This dose could be reduced for the chronic cases after initial treatment with the higher dose. Positive results were obtained within a very short time in more than 80% of the acute cases and in more than 70% of the chronic cases.

[Activity of enzymes of galactose metabolism in so-called congenital cataract (author's transl)]. / Enzymaktivitätswerte des Galaktosestoffwechsels bei der sogenannten Cataracta congenita

Activity of galactokinase (69 subjects) and galactose-1-phosphate uridyl transferase (92 subjects) were measured in haemolysed blood from children (predominantly of school age) with congenital cataract. chi2 tests, gene-frequency determination and metabolic-kinetic studies indicated that the changes in the lens in congenital cataract are partly due to a manifest or latent disorder of galactose metabolism, in particular a glactose-1-phosphate uridyl transferase defect.