Glibenclamide—10-h Treatment Window in a Clinically Relevant Model of Stroke

Glibenclamide improves outcomes in rat models of stroke, with treatment as late as 6 h after onset of ischemia shown to be beneficial. Because the molecular target of glibenclamide, the sulfonylurea receptor 1 (Sur1)-regulated NCCa-ATP channel, is upregulated de novo by a complex transcriptional mechanism, and the principal pathophysiological target, brain swelling, requires hours to develop, we hypothesized that the treatment window would exceed 6 h. We studied a clinically relevant rat model of stroke in which middle cerebral artery occlusion (75% < reduction in LDF signal ≤90%) was produced using an intra-arterial occluder. Recanalization was obtained 4.5 h later by removing the occluder. At that time, we administered recombinant tissue plasminogen activator (rtPA; 0.9 mg/kg IV over 30 min). Immunolabeling showed modest expression of Sur1 5 h after onset of ischemia, with expression increasing 7- to 11-fold (P < 0.01) by 24 h. Rats were administered either vehicle or glibenclamide (10 μg/kg IP loading dose plus 200 ng/h by constant subcutaneous infusion) beginning 4.5 or 10 h after onset of ischemia. In rats treated at 4.5 or 10 h, glibenclamide significantly reduced hemispheric swelling at 24 h from (mean ± SEM) 14.7 ± 1.5% to 8.1 ± 1.6% or 8.8 ± 1.1% (both P < 0.01), respectively, and significantly reduced 48-h mortality from 53% to 17% or 12% (both P < 0.01), and improved Garcia scores at 48 h from 3.8 ± 0.62 to 7.6 ± 0.70 or 8.4 ± 0.74 (both P < 0.01). We conclude that, in a clinically relevant model of stroke, the treatment window for glibenclamide extends to 10 h after onset of ischemia

The Nordic Arthroplasty Register Association: A unique collaboration between 3 national hip arthroplasty registries with 280,201 THRs

Background and purpose The possibility of comparing results and of pooling the data has been limited for the Nordic arthroplasty registries, because of different registration systems and questionnaires. We have established a common Nordic database, in order to compare demographics and the results of total hip replacement surgery between countries. In addition, we plan to study results in patient groups in which the numbers are too small to be studied in the individual countries

Inferior outcome after hip resurfacing arthroplasty than after conventional arthroplasty: Evidence from the Nordic Arthroplasty Register Association (NARA) database, 1995 to 2007

Today, total hip arthroplasty (THA) is one of the safest and most efficient surgical treatments. New materials, surgical techniques and design concepts intended to improve THA have not always been successful. Thorough preclinical and early clinical investigations can detect some aspects of under-performing, while continuing surveillance is recommended to detect and analyze reasons for any later appearing flaws. In this thesis, several ways to monitor and assess THA performance are explored and carried out, using survival analysis in registry studies, radiostereometry (RSA), radiology and clinical outcome. In Paper I, a study using the Nordic Arthroplasty Register Association (NARA) registry shows that HRA had an almost 3-fold increased early non-septic revision risk and that risk factors were found to be female sex, certain HRA designs and units having performed few HRA procedures. Papers II and III contain comparisons of highly cross-linked polyethylene (XLPE) and conventional polyethylene (PE). XLPE had a considerably lower wear rate up to 10 years but showed no obvious improvements regarding implant fixation, BMD or clinical outcome. In the NARA registry, in 2 of 4 studied cup designs the XLPE version had a lower risk of revision for aseptic loosening compared to the PE version. Paper IV describes that stem subsidence and retrotorsion measured with RSA at 2 years predicted later aseptic stem failure in an unfavorably altered, previously well-functioning cemented femoral stem. In Paper V and VI, a novel approach to measure articulation wear with RSA in radiodense hip arthroplasty articulations was presented and evaluated. Subsequently, a comparison between ceramic-on-ceramic (COC) and metal-on-conventional PE uncemented THA displayed a considerably lower wear rate, smaller periacetabular bone lesions and a relatively high squeaking rate, the latter with unknown long-term consequences, in the COC hips. Implant fixation, heterotopic ossification and clinical outcome did not differ between articulation types. In conclusion, it was confirmed that implant surveillance can be done with RSA, also in radiodense THA. Early migration predicts later aseptic implant failure. Prolonged surveillance can confirm long-term material and design performance, verify or contradict anticipated advantages as well as detect unanticipated long-term complications

A Minimal Threshold of c-di-GMP Is Essential for Fruiting Body Formation and Sporulation in Myxococcus xanthus

Generally, the second messenger bis-(3’-5’)-cyclic dimeric GMP (c-di-GMP) regulates the switch between motile and sessile lifestyles in bacteria. Here, we show that c-di-GMP is an essential regulator of multicellular development in the social bacterium Myxococcus xanthus. In response to starvation, M. xanthus initiates a developmental program that culminates in formation of spore-filled fruiting bodies. We show that c-di-GMP accumulates at elevated levels during development and that this increase is essential for completion of development whereas excess c-di-GMP does not interfere with development. MXAN3735 (renamed DmxB) is identified as a diguanylate cyclase that only functions during development and is responsible for this increased c-di-GMP accumulation. DmxB synthesis is induced in response to starvation, thereby restricting DmxB activity to development. DmxB is essential for development and functions downstream of the Dif chemosensory system to stimulate exopolysaccharide accumulation by inducing transcription of a subset of the genes encoding proteins involved in exopolysaccharide synthesis. The developmental defects in the dmxB mutant are non-cell autonomous and rescued by co-development with a strain proficient in exopolysaccharide synthesis, suggesting reduced exopolysaccharide accumulation as the causative defect in this mutant. The NtrC-like transcriptional regulator EpsI/Nla24, which is required for exopolysaccharide accumulation, is identified as a c-diGMP receptor, and thus a putative target for DmxB generated c-di-GMP. Because DmxB can be—at least partially—functionally replaced by a heterologous diguanylate cyclase, these results altogether suggest a model in which a minimum threshold level of c-di-GMP is essential for the successful completion of multicellular development in M. xanthus

Quality of Data Entry Using Single Entry, Double Entry and Automated Forms Processing–An Example Based on a Study of Patient-Reported Outcomes

Background: The clinical and scientific usage of patient-reported outcome measures is increasing in the health services. Often paper forms are used. Manual double entry of data is defined as the definitive gold standard for transferring data to an electronic format, but the process is laborious. Automated forms processing may be an alternative, but further validation is warranted. Methods: 200 patients were randomly selected from a cohort of 5777 patients who had previously answered two different questionnaires. The questionnaires were scanned using an automated forms processing technique, as well as processed by single and double manual data entry, using the EpiData Entry data entry program. The main outcome measure was the proportion of correctly entered numbers at question, form and study level. Results: Manual double-key data entry (error proportion per 1000 fields = 0.046 (95 % CI: 0.001–0.258)) performed better than single-key data entry (error proportion per 1000 fields = 0.370 (95 % CI: 0.160–0.729), (p = 0.020)). There was no statistical difference between Optical Mark Recognition (error proportion per 1000 fields = 0.046 (95 % CI: 0.001–0.258)) and double-key data entry (p = 1.000). With the Intelligent Character Recognition method, there was no statistical difference compared to single-key data entry (error proportion per 1000 fields = 6.734 (95 % CI: 0.817–24.113), (p = 0.656)), as well as double-key data entry (error proportion per 1000 fields = 3.367 (95 % CI: 0.085–18.616)), (p = 0.319))

Failure of dual radius hydroxyapatite-coated acetabular cups

<p>Abstract</p> <p>Introduction</p> <p>Many kind of hydroxyapatite-coated cups were used, with favorable results in short term studies; it was supposed that its use could improve osteointegration of the cup, enhancing thus stability and survivorship. The purpose of this study is to analyze the long term behavior of the hemispheric HA coated, Dual Radius Osteonics cup and to discuss the way of failure through the exam of the revised components and of both periacetabular and osteolysis tissue.</p> <p>Materials and Methods</p> <p>Between 1994 and 1997, at the Department of Orthopedic Sciences of the Insubria University, using the posterolateral approach, were implanted 276 Dual Radius Osteonics^®in 256 patients, with mean age of 63 years.</p> <p>Results</p> <p>At a mean follow-up of 10 years (range 8–12 years), 183 cups in 165 patients, were available for clinical and radiographical evaluation. 22 Cups among the 183 were revised (11%). The cause of revision was aseptic loosening in 17 cases, septic loosening in one case, periprosthetic fracture in another case, osteolysis and polyethylene wear in two cases and, finally, recurrent dislocations in the last one. In the remaining patients, mean HHS increased from a preoperative value of 50,15 to a postoperative value of 92,69. The mean polyethylene wear was 1,25 mm (min. 0,08, max. 3,9 mm), with a mean annual wear of 0,17 mm. The mean acetabular migration on the two axis was 1,6 mm and 1,8 mm. Peri-acetabular osteolysis were recorded in 89% of the implants (163 cases). The cumulative survivorship (revision as endpoint) at the time was 88,9%.</p> <p>Conclusion</p> <p>Our study confirms the bad behavior of this type of cup probably related to the design, to the method of HA fixation. The observations carried out on the revised cup confirm these hypotheses but did not clarify if the third body wear could be a further problem. Another interesting aspect is the high incidence of osteolysis, which are often asymptomatic becoming a problem for the surgeon as the patient refuses the possibility of a revision.</p

Association between overweight, obesity and self-perceived job insecurity in German employees

<p>Abstract</p> <p>Background</p> <p>Recent studies have shown an association between job insecurity and morbidity as well as mortality, however until now, knowledge about a potential association between job insecurity and overweight or obesity has been lacking.</p> <p>Methods</p> <p>In order to identify a possible association between job insecurity and overweight or obesity, we analysed data from the German Socioeconomic Panel (GSOEP) 2004/2005, a longitudinal study of private households in Germany. In this representative cohort of the German adult population, living and working conditions were observed. Data on Body Mass Index (BMI) and self-perceived probability of job loss within the next 2 years were available for 10,747 adults either employed or attending training programs.</p> <p>Results</p> <p>We identified 5,216 (49%) individuals as being overweight (BMI > 25 kg/m²) and 1,358(13%) individuals as being obese (BMI > 30 kg/m²). A total of 5,941 (55%) participants reported having concerns regarding job insecurity. In the multivariate analysis - after adjustment for relevant confounders - a statistically significant association between obesity and job insecurity (100% probability for losing the job in the following two years) could be observed with an adjusted odds ratio of 2.55 (95% confidence interval: 1.09-5.96).</p> <p>Conclusions</p> <p>Because of these results, we were able to conclude that overweight and obese persons perceive job insecurity more often than their normal weight counterparts in Germany and that the concurrence of obesity and job insecurity might lead employees into a vicious cycle. Further research with an emphasis on the occupational setting might be necessary in order to establish useful preventive programmes at the workplace.</p