Design of the Verbiest trial: cost-effectiveness of surgery versus prolonged conservative treatment in patients with lumbar stenosis

Background  

Degenerative changes of lumbar spine anatomy resulting in the encroachment of neural structures are often regarded progressive, ultimately necessitating decompressive surgery. However the natural course is not necessarily progressive and the efficacy of a variety of nonsurgical interventions has also been described. At present there is insufficient data to compare surgical and nonsurgical interventions in terms of their relative benefit and safety. Previous attempts failed to provide clear clinical recommendations or to distinguish subgroups that substantially benefit from a certain treatment strategy. We present the design of a randomized controlled trial on (cost-) effectiveness of surgical decompression versus prolonged conservative treatment in patients with neurogenic intermittent claudication caused by lumbar stenosis.     

Sexual risk behavior and pregnancy in detained adolescent females: a study in Dutch detention centers

Background  

The purpose of this study was to investigate the lifetime prevalence of teenage pregnancy in the histories of detained adolescent females and to examine the relationship between teenage pregnancy on the one hand and mental health and sexuality related characteristics on the other.     

Transport of diclofenac by breast cancer resistance protein (ABCG2) and stimulation of multidrug resistance protein 2 (ABCC2)-mediated drug transport by diclofenac and benzbromarone

Diclofenac is an important analgesic and anti-inflammatory drug, widely used for treatment of postoperative pain, rheumatoid arthritis, and chronic pain associated with cancer. Consequently, diclofenac is often used in combination regimens and undesirable drug-drug interactions may occur. Because many drug-drug interactions may occur at the level of drug transporting proteins, we studied interactions of diclofenac with apical ATP-binding cassette (ABC) multidrug efflux transporters. Using Madin-Darby canine kidney (MDCK)-II cells transfected with human P-glycoprotein (P-gp; MDR1/ABCB1), multidrug resistance protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) and murine Bcrp1, we found that diclofenac was efficiently transported by murine Bcrp1 and moderately by human BCRP but not by P-gp or MRP2. Furthermore, in Sf9-BCRP membrane vesicles diclofenac inhibited transport of methotrexate in a concentration-dependent manner. We next used MDCK-II-MRP2 cells to study interactions of diclofenac with MRP2-mediated drug transport. Diclofenac stimulated paclitaxel, docetaxel, and saquinavir transport at only 50 microM. We further found that the uricosuric drug benzbromarone stimulated MRP2 at an even lower concentration, having maximal stimulatory activity at only 2 microM. Diclofenac and benzbromarone stimulated MRP2-mediated transport of amphipathic lipophilic drugs at 10- and 250-fold lower concentrations, respectively, than reported for other MRP2 stimulators. Because these concentrations are readily achieved in patients, adverse drug-drug interactions may occur, for example, during cancer therapy, in which drug concentrations are often critical and stimulation of elimination via MRP2 may result in suboptimal chemotherapeutic drug concentrations. Moreover, stimulation of MRP2 activity in tumors may lead to increased efflux of chemotherapeutic drugs and thereby drug resistance.     

A novel diketopiperazine improves functional recovery given after the onset of 6-OHDA-induced motor deficit in rats

Background and purpose:

Cyclo-L-glycyl-L-2-allylproline (NNZ-2591), a modified diketopiperazine, is neuroprotective and improves long-term function after hypoxic-ischaemic brain injury in rats. The present studies were designed to examine both the neuroprotective and neurotrophic actions of NNZ-2591 on neurochemical and behavioural changes in a rat model of Parkinson''s disease.

Experimental approach:

To examine its protective effect, either NNZ-2591 (20 ng·day⁻¹) or saline was given intracerebroventricularly for 3 days starting 2 h after 6-hydroxydopamine (6-OHDA) induced unilateral striatal lesion. In a subsequent experiment either NNZ-2591 (0.2, 1 and 5 mg·day⁻¹, s.c.) or saline was administered daily for 14 days starting 2 weeks after the lesion. Behavioural and neurochemical outcomes were examined using the adjusting step test and immunohistochemical staining.

Key results:

Cyclo-L-glycyl-L-2-allylproline given 2 h after the lesion reduced the degree of motor deficit compared with the saline-treated group. Delayed treatment with NNZ-2591, initiated after the onset of motor deficit, significantly improved motor function from week 7 onwards compared with the saline-treated group. Neither treatment regime altered nigrostriatal dopamine depletion. NNZ-2591 significantly enhanced the expression of doublecortin-positive neuroblasts in the sub-ventricular zone.

Conclusions and implications:

These studies reveal that early treatment with NNZ-2591 protects against the motor deficit induced by 6-OHDA and that treatment initiated after the establishment of motor impairment significantly improves long-term motor function. These effects of NNZ-2591 on functional recovery were independent of dopamine depletion and also appeared not to be symptomatic as the improved motor function was long-lasting. NNZ-2591 has potential as a therapeutic agent for neurodegenerative disorders.     

Offense related characteristics and psychosexual development of juvenile sex offenders

Objective:  

This article reports on offense related characteristics and the psychosexual development in subgroups of juvenile sex offenders as measured by the Global Assessment Instrument for Juvenile Sex Offenders (GAIJSO). The predictive validity of these characteristics for persistent (sexual) offensive behavior in subgroups of juvenile sex offenders was investigated.     

Critical appraisal of the revised Ghent criteria for diagnosis of Marfan syndrome

Radonic T, de Witte P, Groenink M, de Bruin‐Bon RACM, Timmermans J, Scholte AJH, van den Berg MP, Baars MJH, van Tintelen JP, Kempers M, Zwinderman AH, Mulder BJM. Critical appraisal of the revised Ghent criteria for diagnosis of Marfan syndrome. Marfan syndrome (MFS) is a connective tissue disorder with major features in cardiovascular, ocular and skeletal systems. Recently, diagnostic criteria were revised where more weight was given to the aortic root dilatation. We applied the revised Marfan nosology in an established adult Marfan population to define practical repercussions of novel criteria for clinical practice and individual patients. Out of 180 MFS patients, in 91% (n = 164) the diagnosis of MFS remained. Out of 16 patients with rejected diagnosis, four patients were diagnosed as MASS (myopia, mitral valve prolapse, borderline non‐progressive aortic root dilatation, skeletal findings and striae) phenotype, three as ectopia lentis syndrome and in nine patients no alternative diagnosis was established. In 13 patients, the diagnosis was rejected because the Z‐score of the aortic root was <2, although the aortic diameter was larger than 40 mm in six of them. In three other patients, the diagnosis of MFS was rejected because dural ectasia was given less weight in the revised nosology. Following the revised Marfan nosology, the diagnosis of MFS was rejected in 9% of patients, mostly because of the absence of aortic root dilatation defined as Z‐score ≥2. Currently used Z‐scores seem to underestimate aortic root dilatation, especially in patients with large body surface area (BSA). We recommend re‐evaluation of criteria for aortic root involvement in adult patients with a suspected diagnosis of MFS.     

Human fibrinogen polymorphic site analysis by restriction endonuclease digestion and allele-specific polymerase chain reaction amplification: identification of polymorphisms at positions A alpha 312 and B beta 448

In the fibrinogen molecule, a total of seven sites have been tentatively identified as polymorphic; however, disagreements about these sites have been observed among the various protein and DNA sequence data published. To allow examination of the potential polymorphic sites at the DNA level, human genomic DNA samples were prepared from 110 unrelated, healthy individuals. Either allele- specific polymerase chain reaction (ASPCR) amplification or PCR amplification followed by restriction endonuclease digestion was used to detect the presence of possible polymorphisms. Two polymorphic sites were confirmed, one at A alpha 312 (Thr/Ala) by RsaI restriction analysis, and a second at B beta 448 (Arg/Lys) by MnlI restriction analysis. Mendelian inheritance of both polymorphisms was demonstrated and allele frequencies were estimated as 0.76/0.24 and 0.85/0.15 for the A alpha 312 and B beta 448 sites, respectively. The sites at A alpha 47, A alpha 296, B beta 162, B beta 296, and gamma 88 showed no evidence of variation in any of our samples. The amino acid polymorphisms at A alpha 312 and B beta 448 reflect conservative residue changes with unknown effects on fibrinogen structure or function. An additional, previously unrecognized DNA sequence variant was detected in a single individual in the second intron of the A alpha chain using HinfI restriction analysis.     

Factor XI antigen and activity in human platelets

Washed platelets, contaminated with less than 0.20% plasma factor XI, were examined for the presence of factor XI antigen and activity. These platelets contained a factor-XI-like coagulant activity (0.67 +/- 0.11 U/10(11) platelets) that remained constant after successive washes. By means of indirect immunofluorescence, a monospecific antibody to factor XI showed specific staining of both normal platelets and platelets from patients deficient in plasma factor XI. Radiolabeled Triton extracts of washed platelets and labeled purified factor XI solutions were analyzed for factor XI antigen by Staph A immunoprecipitation analysis using antibody to purified plasma factor XI followed by SDS gel electrophoresis. On unreduced gels, the platelet material ran as a single band having an apparent molecular weight of 220,000 daltons, whereas purified plasma factor XI gave a single band at 160,000 daltons. On reduced gels, the platelet material analyzed as a single band at 52,000 daltons, whereas purified factor XI gave a single band of 80,000 daltons. Analysis of a partially purified factor XI preparation from platelets by immunoelectrophoresis revealed that the platelet preparation displayed a slightly lower cathodal electrophoretic mobility at pH 8.6 than did plasma factor XI and yet appeared to possess complete antigenic identity with plasma factor XI. These results indicate that platelets possess a form of factor XI that exists as a disulfide-linked 52,000-dalton tetramer in contrast to the plasma form that circulates as a 80,000-dalton disulfide-linked dimer.