Biocompatibility and degradation of the open-pored magnesium scaffolds LAE442 and La2.

Porous magnesium implants are of particular interest for application as resorbable bone substitutes, due to their mechanical strength and a Young's modulus similar to bone. The objective of the present study was to compare the biocompatibility, bone and tissue ingrowth, and the degradation behaviour of scaffolds made from the magnesium alloys LAE442 (n= 40) and Mg-La2 (n= 40)in vivo. For this purpose, cylindrical magnesium scaffolds (diameter 4 mm, length 5 mm) with defined, interconnecting pores were produced by investment casting and coated with MgF2. The scaffolds were inserted into the cancellous part of the greater trochanter ossis femoris of rabbits. After implantation periods of 6, 12, 24 and 36 weeks, the bone-scaffold compounds were evaluated usingex vivo µCT80 images, histological examinations and energy dispersive x-ray spectroscopy analysis. The La2 scaffolds showed inhomogeneous and rapid degradation, with inferior osseointegration as compared to LAE442. For the early observation times, no bone and tissue could be observed in the pores of La2. Furthermore, the excessive amount of foreign body cells and fibrous capsule formation indicates insufficient biocompatibility of the La2 scaffolds. In contrast, the LAE442 scaffolds showed slow degradation and better osseointegration. Good vascularization, a moderate cellular response, bone and osteoid-like bone matrix at all implantation periods were observed in the pores of LAE442. In summary, porous LAE442 showed promise as a degradable scaffold for bone defect repair, based on its degradation behaviour and biocompatibility. However, further studies are needed to show it would have the necessary mechanical properties required over time for weight-bearing bone defects.

The German trial on Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE): a multicenter, randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Comprehensive treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major clinical challenge. The current therapy gold standard is aciclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains around 20% and a majority of survivors suffer from severe disability. Experimental research and recent retrospective clinical observations suggest a favourable therapy response to adjuvant dexamethasone. Currently there is no randomized clinical trial evidence, however, to support the routine use of adjuvant corticosteroid treatment in HSVE. METHODS: The German trial of Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE) studied the effect of adjuvant dexamethasone versus placebo on top of standard aciclovir treatment in adult patients aged 18 up to 85 years with proven HSVE in German academic centers of Neurology in a randomized and double blind fashion. The trial was open from November 2007 to December 2012. The initially planned sample size was 372 patients with the option to increase to up to 450 patients after the second interim analysis. The primary endpoint was a binary functional outcome after 6 months assessed using the modified Rankin scale (mRS 0-2 vs. 3-6). Secondary endpoints included mortality after 6 and 12 months, functional outcome after 6 months measured with the Glasgow outcome scale (GOS), functional outcome after 12 months measured with mRS and GOS, quality of life as measured with the EuroQol 5D instrument after 6 and 12 months, neuropsychological testing after 6 months, cranial magnetic resonance imaging findings after 6 months, seizures up to day of discharge or at the latest at day 30, and after 6 and 12 months. RESULTS: The trial was stopped prematurely for slow recruitment after 41 patients had been randomized, 21 of them treated with dexamethasone and 20 with placebo. No difference was observed in the primary endpoint. In the full analysis set (n = 19 in each group), 12 patients in each treatment arm achieved a mRS of 0-2. Similarly, we did not observe significant differences in the secondary endpoints (GOS, mRS, quality of life, neuropsychological testing). CONCLUSION: GACHE being prematurely terminated demonstrated challenges encountered performing randomized, placebo-controlled trials in rare life threatening neurological diseases. Based upon our trial results the use of adjuvant steroids in addition to antiviral treatment remains experimental and is at the decision of the individual treating physician. Unfortunately, the small number of study participants does not allow firm conclusions. TRIAL REGISTRATION: EudraCT-Nr. 2005-003201-81.

Precision and reproducibility of automated computer-guided Psoriasis Area and Severity Index measurements in comparison with trained physicians.

BACKGROUND: The Psoriasis Area and Severity Index (PASI) represents the gold standard for psoriasis severity assessments but is limited by its subjectivity and low intra- and inter-rater consistency. OBJECTIVES: To investigate the precision and reproducibility of automated, computer-guided PASI measurements (ACPMs) in comparison with three trained physicians. METHODS: This was a comparative observational study assessing ACPMs attained by automated total-body imaging and computerized digital image analysis in a cohort of 120 patients affected by plaque psoriasis of various severities. The level of agreement between ACPMs and physicians' PASI measurements was calculated by the intraclass correlation coefficient (ICC). The reproducibility of ACPMs in comparison with physicians' PASI measurements was investigated by performing two successive 'repeat PASI calculations' in the same patients. RESULTS: The agreement between ACPMs and physicians' PASI calculations in 120 fully evaluable patients was high (ICC 0·86, 95% confidence interval 0·80-0·90, mean absolute difference 2·5 PASI points). Repeat ACPMs to measure the reproducibility showed an excellent ICC of 0·99 (95% confidence interval 0·98-0·99) with a mean absolute difference of 0·5 PASI points. The ACPMs thus outperformed the three physicians for intrarater reliability (mean ICC 0·86). CONCLUSIONS: The results of this first clinical study investigating ACPMs in 120 patients with psoriasis indicate a similar precision and higher reproducibility in comparison with trained physicians. Limitations arise from poorly observable body sites and from patients unable to attain predefined postures during automated image acquisition.

Intra- and interobserver variability of image-based PASI assessments in 120 patients suffering from plaque-type psoriasis.

BACKGROUND: The Psoriasis Area and Severity Index (PASI) is the standard for psoriasis severity assessment. However, PASI measurement is complex and subjective, frequently leading to a high intra- and interobserver variability. To date, the precise extent of variability in PASI measurements and its underlying causes remain unknown. OBJECTIVE: To determine the inter- and intrarater variability of image-based PASI measurements by calculating Intra-Class-Correlation-Coefficients (ICCs) and to investigate the impact of the different PASI components and specific anatomic regions on the extent of variability. METHODS: First, the methodology of 'image-based' vs. commonly used 'live' PASI measurements was validated in a pilot study. Next, in an observational cohort study, PASI scores of 120 patients affected by plaque psoriasis were prospectively evaluated by three formally trained physicians by means of total body images (TBI). Each observer independently performed two rounds of image-based PASI calculations in all patients at two different time points. RESULTS: Overall, 720 image-based PASI scores were calculated with a mean PASI of 8.8 (range 0.7-34.8). An interrater variability with an ICC of 0.895 and mean absolute difference (MAD) of 3.3 PASI points were observed. Intrarater variability showed a mean ICC of 0.877 and a MAD of 2.2 points. When considering specific PASI components, the highest agreement was found for the assessment of the involved body surface area (BSA), while the lowest ICCs were calculated for severity scoring of 'scaling' and 'induration'. As BSA scores serve as a multiplier in the calculation of PASI, minor inaccuracies were capable of inducing a large share of variability. CONCLUSION: The overall inter- and intrarater reliability of image-based PASI measurements in this study was good. However, physicians were formally trained and experienced, which frequently is not the case in a real-life clinical setting. Therefore, new strategies for higher standardization and objectivity of PASI calculations are needed.

The Impact of Conscious Sedation versus General Anesthesia for Stroke Thrombectomy on the Predictive Value of Collateral Status: A Post Hoc Analysis of the SIESTA Trial.

BACKGROUND AND PURPOSE: Radiologic selection criteria to identify patients likely to benefit from endovascular stroke treatment are still controversial. In this post hoc analysis of the recent randomized Sedation versus Intubation for Endovascular Stroke TreAtment (SIESTA) trial, we aimed to investigate the impact of sedation mode (conscious sedation versus general anesthesia) on the predictive value of collateral status. MATERIALS AND METHODS: Using imaging data from SIESTA, we assessed collateral status with the collateral score of Tan et al and graded it from absent to good collaterals (0-3). We examined the association of collateral status with 24-hour improvement of the NIHSS score, infarct volume, and mRS at 3 months according to the sedation regimen. RESULTS: In a cohort of 104 patients, the NIHSS score improved significantly in patients with moderate or good collaterals (2-3) compared with patients with no or poor collaterals (0-1) (P = .011; mean, -5.8 ± 7.6 versus -1.1 ± 10.7). Tan 2-3 was also associated with significantly higher ASPECTS before endovascular stroke treatment (median, 9 versus 7; P < .001) and smaller mean infarct size after endovascular stroke treatment (median, 35.0 versus 107.4; P < .001). When we differentiated the population according to collateral status (0.1 versus 2.3), the sedation modes conscious sedation and general anesthesia were not associated with significant differences in the predictive value of collateral status regarding infarction size or functional outcome. CONCLUSIONS: The sedation mode, conscious sedation or general anesthesia, did not influence the predictive value of collaterals in patients with large-vessel occlusion anterior circulation stroke undergoing thrombectomy in the SIESTA trial.

A novel biodegradable frontal sinus stent (MgNd2): a long-term animal study.

The frontal sinus recess consists of anatomically narrow passages that are prone to stenosis in endonasal frontal sinus surgery for chronic sinus disease. Over the past 100 years, diverse frontal sinus stents have been developed and evaluated in clinical and animal studies. However, superinfection, formation of granulations tissue, stent dislocation and late stenosis of the duct have remained challenges and subject of debate in the literature. Currently developed biodegradable materials, including rare earth-containing magnesium alloys are promising candidates for application as temporary implant materials. The Mg 2 % wt Nd alloy (MgNd2) was used to design a nasal stent that fit the porcine anatomy. In the current study, we evaluate biocompatibility, biodegradation and functionality of a frontal sinus stent in 16 minipigs over 6 months. Intraoperative endoscopy revealed free stent lumen in all cases. Blood examination and clinical examinations indicated no systematic or local inflammation signs. The histopathology and elements analysis showed a very good biocompatibility. The µ-computed tomography-based volumetric analysis showed substantial stent degradation within 6 months. Our MgNd2 based stent appears to be a promising, solid basis for the development of a frontal sinus stent for clinical use.

MgNd2 alloy in contact with nasal mucosa: an in vivo and in vitro approach.

Biodegradable and biocompatible magnesium alloys appear to be very promising not only for temporary clinical application but also for developing deformable and degradable medical implants. This study analyzes the in vivo degradation behavior and the impact on the paranasal sinuses of the highly ductile Mg-2 wt%Nd alloy (MgNd2) in order to provide a basis for a satisfying stent system for the therapy of a chronic sinusitis. Moreover, in vitro tests were carried out on primary porcine nasal epithelial cells (PNEC). For the in vivo tests, cylindrical MgNd2 specimens were implanted into the sinus' mucosa of minipigs. During and after a total period of 180 days the long-term biodegradation and biocompatibility properties after direct contact with the physiological tissue were analyzed. Biodegradation was investigated by measuring the mass and volume losses of the MgNd2 specimens as well as by performing element analyses to obtain information about the degradation layer. The influence on the surrounding tissue of paranasal sinuses was evaluated by endoscopic and histopathological examinations of the mucosa. Here, only a locally unspecific chronic infection was found. The degradation rate showed a maximum after 45 days postsurgery and was determined to decrease subsequently. In vitro experiments using PNEC showed adequate biocompatibility of MgNd2. This study demonstrates a good in vivo biocompatibility for MgNd2 in the system of paranasal sinuses and underlines the promising properties of alloy MgNd2 for biodegradable nasal stent applications.

Clenbuterol - regional food contamination a possible source for inadvertent doping in sports.

The misuse of the sympathomimetic and anabolic agent clenbuterol has been frequently reported in professional sport and in the livestock industry. In 2010, a team of athletes returned from competition in China and regular doping control samples were taken within the next two days. All urine samples contained low amounts (pg/ml) of clenbuterol, drawing the attention to a well-known problem: the possibility of an unintended clenbuterol intake with food. A warning that Chinese meat is possibly contaminated with prohibited substances according to international anti-doping regulations was also given by Chinese officials just before the Bejing Olympic Games in 2008. To investigate if clenbuterol can be found in human urine, a study was initiated comprising 28 volunteers collecting urine samples after their return from China. For the quantification of clenbuterol at a low pg/ml level, a very sensitive and specific isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed using liquid/liquid re-extraction for clean-up with a limit of detection and quantification of 1 and 3 pg/ml, respectively. The method was validated demonstrating good precision (intra-day: 2.9-5.5 %; inter-day: 5.1-8.8%), accuracy (89.5-102.5%) and mean recovery (81.4%). Clenbuterol was detectable in 22 (79%) of the analyzed samples, indicating a general food contamination problem despite an official clenbuterol prohibition in China for livestock.

Treating menopausal symptoms with a complex remedy or placebo: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of a complex remedy compared with placebo to treat menopausal symptoms. METHODS: A total of 102 peri- and postmenopausal women requiring treatment for menopausal symptoms were randomized to receive a complex anthroposophic remedy prepared in the homeopathic manner (Apis regina tota GL D4, Argentum metallicum D5, Ovaria bovis GL D4), 3 × 10 globuli daily (2 × 12 weeks) and placebo (12 weeks) in different orders of remedy (R) and placebo (P) (1: R/R/P, 2: P/R/R, 3: R/P/R). The primary endpoint was change in climacteric symptoms assessed by the Menopause Rating Scale II (MRS II) after 12 weeks. Secondary endpoints were changes of symptoms and safety throughout the study. RESULTS: Reduction of symptoms after 12 weeks did not differ between remedy and placebo (total score MRS II: -1.4, 95% confidence interval (CI) -2.8 to 0 vs. -2.3, 95% CI -4.4 to -0.3, p = 0.441) and had no clinical relevance (defined as reduction in MRS II ≥ -3.5). Comparison of secondary outcomes at 12 weeks between remedy and placebo or between groups after the 2nd or 3rd period compared to previous periods did not differ. Treatment with remedy for 24 consecutive weeks did not reach clinical relevance either. However, total reduction of symptoms after three periods in Group 1 (R/R/P) (-5.0, 95% CI -7.5 to -2.5) and Group 2 (P/R/R) (-5.9, 95% CI -8.7 to -3.1) reached clinical relevance whereas almost no decrease of symptoms after three periods was seen in Group 3 (R/P/R) (-0.5, 95% CI -2.9 to 1.9). CONCLUSIONS: Treatment with the complex remedy for 12 or 24 weeks did not result in clinically significant improvement of menopausal symptoms.

[Pre- and post-treatment in inpatient psychosomatic rehabilitation]. / Die Vor- und Nachbehandlung in der stationären psychosomatischen Rehabilitation.

Patients who are referred to psychosomatic inpatient rehabilitation are mostly suffering from long-term illnesses. Therefore, it is necessary to take pre- and post-treatment into account. Epidemiological questions are frequency and type of pre- and post-treatment and their relation to course and outcome of rehabilitation. Pre-treatment, recommendations for follow-up treatment, and course of treatment in 1284 patients of the department of behaviour therapy and psychosomatics of the rehabilitation centre Seehof were assessed. Before admission, 75.4 % of patients had been in psychiatric treatment, and 31.3 % had received psychotherapy. The inpatient stay was significantly longer in patients with psychiatric pre-treatment and those with a combination of psychiatric treatment and psychotherapy. These patients were more often unemployed and showing an insufficient social network. Pre-treatment was unrelated to changes in the SCL-90-R, to physician ratings of therapeutic outcome or the ability to work at the end of rehabilitation. Patients pre-treated by a general practitioner, psychiatrist or psychotherapist returned to that therapeutic setting after rehabilitation. Patients only treated by general practitioners were referred to specialist treatment. These data show the need to integrate inpatient rehabilitation in long-term pre- and post-treatment. One effect of inpatient rehabilitation is to optimize treatment. This requires good communication across different areas of health care.

Frequency and predictors of osteoporotic fractures after cardiac or liver transplantation: a follow-up study.

BACKGROUND: Osteoporosis and related fractures are a major complication after organ transplantation. The aim of this study was to find out the frequency and predictors of osteoporotic fractures after cardiac or liver transplantation. METHODS: 235 consecutive patients who had a cardiac transplant (n=105; 88 men, 17 women) or a liver transplant (130; 75 men, 55 women) were followed. Vertebral fractures were assessed by a standardised analysis of spinal radiographs before and annually after transplantation. Clinical and non-vertebral fracture data were noted from hospital records. FINDINGS: In the first and second years after transplantation, the proportion of patients (Kaplan-Meier estimates) who had at least one vertebral fracture was slightly higher in the cardiac group (first year 21%, second year 27%) than in the liver group (first year 14%, second year 21%). In the third and fourth years, one third of patients from both groups had had one or more vertebral fractures. Non-vertebral fractures occurred in nine patients (7%) after liver transplantation and avascular necrosis of the hip head in three patients (3%) after cardiac transplantation. In both groups, no dose-dependent effect of immunosuppressive therapy on fracture development could be identified. Independent predictors assessed by multivariate analysis were age (hazard ratio [95% CI] increase of 5 years, 1.71 [1.1-2.7]) and lumbar bone-mineral density (decrease of 1 SD t score, 1.97 [1.2-3.2]) in cardiac transplantation patients, and vertebral fractures before transplantation (6.07 [1.7-21.7]) in the liver group. INTERPRETATION: The high frequency of osteoporotic fractures in the 2 years after transplantation and the limitations of reliable fracture-risk predictions, show the need to investigate preventive therapies.

Autochthonous cutaneous larva migrans in Germany.

Cutaneous larva migrans syndrome is extremely rare in Germany. However, three cases of this syndrome were diagnosed in patients from Berlin, Germany, in the summer of 1994. Exposure to the infective agent in endemic areas and close contact with animals were excluded. It is assumed that the extreme temperatures in summer 1994 favoured the conditions of infection.

Somatostatin modulation of adenosine receptor coupled G-protein subunits in the caudate nucleus of the rat.

5'-(N-ethylcarboxamido)-adenosine (NECA) and N-[(R)-(phenylisopropyl)]-adenosine (PIA) were incubated in an adenylate cyclase assay of a particulate fraction of caudate-putamen tissue of the rat in order to examine the effect of somatostatin on adenosine receptors coupled adenylate cyclase subunits in vitro. Somatostatin was able to inhibit the enhancement of cyclic AMP formation induced by NECA in the presence of the hydrolysable guanine nucleotide guanosine-triphosphate. The adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine as well as the somatostatin receptor antagonist cyclo (7-aminoheptanoyl-Phe-D-Trp-Lys-O-benzyl-Thr) did not influence somatostatin induced inhibition of NECA-activated adenylate cyclase. Somatostatin did not modulate the effect mediated by the A-1 adenosine receptor agonist PIA. Both pertussis toxin and cholera toxin activated striatal adenylate cyclase acting on the guanine nucleotide regulatory subunit of the enzyme. The stimulation induced by pertussis toxin was antagonized by somatostatin, while in presence of cholera toxin somatostatin enhanced cyclic AMP formation. These results suggest that somatostatin acts through a stimulatory as well as an inhibitory guanine nucleotide regulatory protein subtype to affect probably postsynaptic A-2 adenosine receptor coupled adenylate cyclase activity.

Use of tocolytic drugs to reverse oxytocin-induced uterine hypertonus and fetal distress.

The use of oxytocin in labor has the inherent danger of producing uterine hyperstimulation with resultant fetal distress. When produced by gradual titration of intravenous oxytocin, discontinuation of the medication is usually sufficient to reverse the process. However, the rapid administration of a large intravenous dose of oxytocin, as occurred in this patient, may result in hypertonic uterine contractions and fetal distress unresponsive to traditional measures. The rationale for using a tocolytic drug to reverse the uterine hypertonus, produce intrauterine fetal resuscitation, and prevent cesarean section is discussed in this report.